AU2017200704B2 - Modulation of chemosensory receptors and ligands associated therewith - Google Patents

Abstract

The present invention includes methods for identifying modifiers of chemosensory receptors and their ligands, e.g., by determining whether a test entity is suitable to interact with one or more interacting sites within the Venus flytrap domains of the chemosensory receptors, and modifiers 5 capable of modulating chemosensory receptors and their ligands. The present invention also includes modifiers of chemosensory receptors and their ligands having Formula (1), its subgenus, and specific compounds. Furthermore, the present invention includes ingestible compositions comprising the modifiers of chemosensory receptors and their ligands and methods of using the modifiers of chemosensory receptors and their ligands to enhance the 0 sweet taste of an ingestible composition or treat a condition associated with a chemosensory receptor. In addition, the present invention include processes for preparing the modifiers of chemosensory receptors and their ligands.

Description

MODULATION OF CHEMOSENSORY RECEPTORS .4ND

LIGANDS ASSOCI ATED THEREWITH

C ROSS-REFEREM'E TO RELATED APPLICATIONS

This application claims priority to U.S. Patent Application Serial No. 11 760.592= tmirtled et’Cketnoscn-un Receptors ,md I -gattd' As'-xcmtcd fbcicxxnl/\ fifed

S. 200”; I S. Patent Application Ncthil No. = ! 8.-6.67-1, entitled Al-.-ditiaVeu cto 'ki.tna-cr--ury Receptor-' and I igands V-ociatcd I hetc^rilf'. filed August 8, 2007. and I S. Patent \ppiic:ition Settal N-. «-1 02T410. ent-’ded' Modubtt.on uft bent scr.sm'x Revcot. ts ,md 1 tgands \-soc:med Ί nct-.-w nb' filed hd-unux x. 2008 Πκ cento it of file·. nppl.cOn -r.s xte herein incorporated by reference in their ettnten tot all purposes.

BACKGROUND OF THE INVENTION

The taste sxslctn tm-u.k- -m-> -? y tniotniatton .-.boot the v.bcnrci.1 -.(-mpeotiun i-f th. >.\:crn.ii 'xodd. Taste uattsducnor is otu --1 '.be most scphistiva'.^ to nts ><' Λλ'μΙ i juu.’ec \tia? tn - ural bunak o* taste .s tbit > _ t<*ut ’ tv a tneai s iij.di'ie, ffetn sotjpic tnct»./-) .us to tL· nte.n e-trnp v\ >-f sericbtaica Scns-.itiens ..u'socxated unfit uau atv «bought «>' tnwh c chsOuei signaling pathways mediated by receptors. / i., meubutroptc i tenet'<u'iv'cecpti s (ALsX'fecb ex > v-sNOe etv| to»s,'Xpert -.xne^dv CvPae.ehcmtvu -06085 chest u-fc ws..'..Per y, uepolattznsg ι-t g-rer tie or action po.vntt'J, xs t^b u KXxed to trigger the sensation. This -event is believed^ to trigger the release of neurotransmitters at gustatory a fie tent neuron synapses, thereby initiating signaling along neuronal pathways that mediate taste perception.

As such, taste receptors specifically recognize molecules that elicit specific taste sensation. These molecules are also referred to herein as ‘Τ8>ωηί<’ Many taste receptcrs belong to the 7-trammembrane receptor superfamily, which are: also known as G protein-coupled receptors (GPCRs). Other tastes arc believed to be hiediated by channel proteins. G protem--.copied -cccptot^ comr-*1 mmy phy siologival fiawtm:w such as endocrine fenetion, ρ\·-·> fine fimetom heart rate, hpolyrfs c>ssu._thsdr,sc -netaboli.-m .eul t?ansm-.-mbmue signaling.

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2017200704 02 Feb 2017

For example, foimlx C of G-pr<>tein coupled receptors (GFCRs) fetor humans comprises eight meRm<_fn\-pie giuunnaw tmGhi(l -k'd receptors, two:heterodimeric

WiM-e aeidfBi u t \B.\tBd u\. pirn-» a i ,d< lari-xenxire, 'veeptos it aRi {?< e urL; (Tl R) receptors, a promiscuous l.-alpba~ainino acid receptor (GPRC6A). and five orphan weeptors. The fomilv C GPt 'Rs an characterized by a large animm-teimiuul Joinani. Ahich binds the endogenous: ortho^teric agonists. Additionally, allosteric modulators which bind to the seven. transmefehtaiw donum- of the receptors hate .<lso been reported.

in gencud. upon hgand binding to a uPCR. toe iccepto' pu'Miinabb uudcigecs a coiUbrinational eluiitgc leading to uefeafeu of a Gprotein. G piotcms are cotnpitscd of thwc subunits: a guanyl nucleeiidc binding «-subunit, a β-subunit, and a γ-snbnnit, G proteins cycle between two terms, depending on whether GDP or GTP is bound to the «-subunit. When GDP is Pound. Uic i > protein exnb as a hctctoti nnc* the to_:-. complex V< hen 1ITP is bound, the u st aurm dissociates fiom the Ite’ci* nimei, ic-w ng a G e> mplex ^\beti a o,,,. complex operatively associates with an activated G^: protein-coupled receptor in a cell membrane, the rate of exchange of GT P for bound GDP is increased and the rate of dissociation of the bound G* subunit from the G^ complex increases. The free Ga Subunit and Gy? complex are thus capable of transmitti ng asighal to downstream elements of a variety of signal transduetion pathways. These: events form the basis for a multiplicity of different cell signaling phenomena, including for example the signaling phenomena that, are identified as neurological sensory perceptions such as taste aim m -nell,

Mammals are believed to have five basic taste modalities: sweet, bitter, scan salty, and umami (the taste of monosodium glutamate). Numerous pin sioiogical studies in animals have shown that taste receptor eelk may selectively respond to different chemical stimuli, in mammal.», taste receptor colls me m-wmbled into tame bud-' ihat inv fouribuied iat»· different papillae in the tongue epithelium Circunn-illatg papillae, found at the very back of the tongue, contain hundreds to thousands of taste buds. By et.-mra-'t. foliate papillae, localized to the posterior lateral edge of the tongue, contain dozens to hundreds of taste: buds. Further, fiiilgiform papillae, located at die front of the tongue, contain only a single or a few taste buds.

.uh 1.--JC hn-l J,pi iiduig mi tew sp, , omwn-» efi-l >0 eellx, melu-lmg precursor cells, support cells, and taste receptor eells. Receptor eolls are innervated m their base by afferent nerv·,.- endings that inmr-mU information to la·..- taste ccntem of dm umes Through

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2017200704 02 Feb 2017 synapses nt the bianj sicm ,nid thalamus Elueutomg the meek:;nMix oj taste ceil ^igtialmg and humnattorn procx'ssmg h miportartt to undcrsutrtding the iunciion. regulation. and perccpbon of the sense of taste, fhe gustaterx sx'-toB: has been seketed dot nig evolution t·., detoet mmitixe and beneficial comp<umds as veil as haijuful m toxic substances, < kitside the t.-ngne, express;-?» of tUt-J''”' th bee 11> xa »zcd to u wnc aed p t κιοηκ. cells. *- ^c?tjj.t,j ,' t'-fc set·! 'g »<.? 'an ή, max a ', cxtM n the j-aOio nt»', mol i* fij i tci I sp _{Css n} e: msv cccg.o ' hss also b-ecn i- -und in tbc Imuig of sumach and jntcsiine, Oggcstmg that taste ·οοορτοί< n-ax plax a :<';·.· m Bb-leenlai sensing -f thmapeuue entities and mxnis

Complete or partial sequences of numerous tonran and other eukaryotic ebetnoscns-aix receptors ai·, eunenilx l.-tcrni· Wtthin the tot smend xx-ois, a number,fgroups including the pwseiir assignee Ncnomx x, inc, totx : icpoUcd tbc idcniificatinn and cloning of gem-s from txx,· GPCR ;.xrnihos that are imohed in taste modt-toton and luxe ••brained experiment;» results related to the understanding of tato biology fhcse m-toto inda.?,:·. that vies sn ot a ό <nrm-> aeijtastt' ah, iclcned is umoms ,<v u icd m act xaiion ft >>'o upes-d ap-.-di!·. tecopi'Hs located d tbc<mfa,.o ·>Γι.;·η·. re-.'opt, j cel s tJRCs) ·>η the t-ngno < <. , i .’Rs ano i I Rs h <, emto'ep hekex cd ‘tor ,n least ?o to 5 '< g.oes er,.ode iurxtio'tal x\ent, js 11 'Rs) for bitter tilting sutotaoees in human and mdem -'espeetH Jy.

β\ e--jur;jst are only 3 ffRs, ΓΙR I, I JR ' .ord 11 R3, nbieh me involved in umami and sxveet taste. SWcto.Hto th» fl R and Γ./R reeopnns p-»ssos$ rhe bali-oark >>f G > ο n . > ,, e, o_t',rs{y.pt _r, n omu i e Jem .ne 'ark, d οχ -, n. I exfracelluhr and intracellular amino- and cartoxyMermini respectively.

T2.Rs have been cloned fem different nxammals ineluding rafemiee and humans, f'Rs comprto' >i ooxel family ·.»' him-un and ·-.id-'ni G piotoirt-couplod ’eceprop'· tk-ir .tr,.exprc'iscd in subsets ,·ί taste receptor eeiN of th? tongue and palate epithelia Those teste i'cceptojs ._ifK> organised in ehn-rors in Jas;·,- c· to ami ;n·, gen· ti·. abx lifted Jo I,. that tolnera'c bitter tasie. The fet. that T2Rs modulate bitter taste has beenxlemonsirated in cell-based assays. For example, mT2R-5, HT2R-4 and mT2R~8 have been shown to be activated by bitter molecules in to vitro giaskhicm insaxs. pro', ixiiug cxpei emcmai pr-j,?· thm T2Rs function as bitter taste η cortot. Sec also T2Rs 'disclosed iu U.S. Patent No. 7 ju'.toO.

2017200704 25 Jun 2019a ⁿ*lAUPR

T1R family members in general include T1R1, T1R2, and TIR3, e.g., rTlR3, mT!R3, hTlR3, rTlR2, mTlR2, hTlR2, and rTIRl, mTIRl and hTIRl. It is known that the three T1R gene members T1R1, T1R2 and T1R3 form functional heterodimers that specifically recognize sweeteners and amino acids. It is generally believed that T1R2/T1R3 combination recognizes natural and artificial sweeteners while the T1R1/T1R3 combination recognizes several L-amino acids and monosodium glutamate (MSG), respectively. For example, co-cxprcssion of T1R1 and TIR3 in recombinant host cells results in a hctcro-oligomcric taste receptor that responds to umami taste stimuli. Umami taste stimuli include by way of example monosodium glutamate and other molecules that elicit a “savory” taste sensation. By contrast, co-expression of T1R2 and T1R3 in recombinant host cells results in a hetero-oligomeric sweet taste receptor that responds to both naturally occurring and artificial sweeteners.

There is a need in the art to develop various ways of identifying compounds or other entities suitable for modifying receptors and their ligands associated with chcmoscnsory or chcmoscnsory related sensation or reaction. In addition, there is a need in the art for compounds or other entities with such characteristics.

It is an object of the present invention to provide compounds and methods which meet the above identified need. It is a further or alternative object of the present invention to at least provide the public with a useful choice.

BRIEF SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery that an extra-cellular domain, e.g., the Venus flytrap domain of a chcmoscnsory receptor, especially one or more interacting sites within the Venus flytrap domain, is a suitable target for compounds or other entities to modulate the chcmoscnsory receptor and/or its ligands. Accordingly, the present invention provides screening methods for identifying modifiers of chemosensory receptors and their ligands as well as modifiers capable of modulating chemosensory receptors and their ligands.

In one embodiment, the present invention provides a method of screening for a candidate of a chcmoscnsory receptor ligand modifier. The method comprises determining whether a test entity is suitable to interact with a chcmoscnsory receptor via an interacting site within the Venus flytrap domain of the chemosensory receptor.

In another embodiment, the present invention provides a method of screening for a candidate of a chcmoscnsory receptor ligand modifier. The method comprises determining whether a test entity is suitable to interact with a chcmoscnsory receptor via a first interacting

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2017200704 02 Feb 2017 sito 'odbin rise Venns fix trapd-emameftin.· cbcniosenserv icccpt.n. Mierem tht first interacting -ne is iiknttfied m fight -efa sccv'nvi mle; auUng she identified based ou ike toesaction Muxecu a chcninsenseix tevepbu hamfi and fine J'enm'C'isojv 'Cuepu·!.

bi set axmtl;Ci embodmicnt. ibe present invention ptox n.k - a njcilmd of setceiling Im a s.andfd;ik' of a chemx>seusOfs icceptor middle;, I'hc mods-d c<mipp determining vj-eih?: n test •roiin L suitable t·· mb.-iact Aim a chcnu-sc isorx evoptrn c c a i mktxctni^ s.k 'x .thm th·. \ onus lb nap d-mam of the ch·. mos.n-· n tec.-pica. uh..etn rhe . it..3ctw<> _?1t. includes .m mleuctjog ro^dne selected Item -he stoiip e- -nstsimg of N s 43. 8144.Ι|(Γ, 84;;, Si 4k 81 <·5 3 MO, i >U2. ΡΙΓ, KM. Rjsj, I13M. E.h'>2. pp~j-\ MM. 11 84, Γ3>, E3<k. v3X4. VM. 1325.130P. D3M, E582, m™, M. \_on, \ ,w. >eM, Γ242, MM (.)328, and Mtrn M i I R2 and a ..ombmation fbcicni Abcfc u a \>t a mp· .nmable b .nt.:acr a ill; rhe . ne-actmg s,i. of the ehcmoxs.B’On iceepnu n- mdivai-xc· i a cenduhne of a ckemo'-'.-rM-p', tccepk'i nveibf.C!

In yet another embodiment, the presoni invention provides a method of modulating the οοηχην of a ehemoaemb-.ry receptor ligand. The method comprises contacting a chemosCB-s>r\ receptor ligand modiikr o hit a cel; -.onraming i 1R.? Venus dv imp dotn n'n ; i ,be presence of a ehemosensory receptor ligand., wherein the chemosensory receptor ligand moo lie interacts : with an mteraeftng si te of the ehemosenc-oi'v reeop'· st.

In still another embodiment, the present invention provides a ehemosensory tecopmr hguntl modifier, wherein m dto presence of a ehemosenson. roecpior ligand;it interacts X',ith HR2 Venus ilyn.ip do*n co ' «>t at least tine· mto’m I mg residue^ select,-d Rom the group consisting of ΚΙ Ιλ 8144 11 ¢.7, $ 10, 8144, S165, YT03, D14.2, P277. KM R383, 0307, Γ 302, D2?\ Plt'5, TJ iS k Γ326. Γ302. V381, A305,T32§, 1306, £382,1279, IM, V66. V3fi9, S3O3, I.'. 12 t 103, ¢^328, and MoS o^f I 1K2

In sfili aroiib r embodiment, me present invention, provides a chemosensory ;e>optor dgmd momfior havm; a structure m I'-u-rruia td>

A s or a tautomer, sidt, solvate, and/or ester thereof, wherein:

¢1 -forms a single bond with cither D or E and a double bond vvi& the other of D or B;

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R* is bx dregen, alky k uibxiituted Jky k arx L siihndau.d ωχ 1, urxLi'kx L '•ubstnuted a LAG jv.xl xulvnuKU an I heknesdL· . ·» i Mit.iteu beuieaNy k h>..e'<»aix L substituted hetcroaryi. heleroarylaikyk substituted heteroarylalkyi, -CN. AOs -OR.’. -S(Oj,_;R. \ -NR R'. -CONR R\ -CO_?R . ART ORA AR\XARV. NR CSNR A '. AR\1 NHAR'V, •SOARV. -NrAaR , \rS< > AF. ' R , -BtOR’ltt iR A PVO(OR\OPb or IM q-R ){ΟΚΑ

R’ is hydrogen, aikyl. substituted aikyk aryl. substituted aryl aryiulkyl, substituted my lalkyl, acy k substituted acy], hc-ei'Akyl- substituted lietoioaikyl, he?;u'>ary L '-nhstituied hctcioary L hcfcroaiy Glkyk substituted hotel oarx ialky k -ON. -N<)., -OPA 8(01,,R'\ -NR'-Rk -CONR'Rk -<O.-R'\ -NRAoJA -NRAiONIVIV, -NRASNAr \ -NR.A( NilAlAlA, SOAR RA AR SO R . NR SORmOR'. -BlOR HORA P(O)(OPA(QRA or ?(())( iAhORA <: ubernatsxeh, 1A and R\ Mgcihei xvuh the >(&> to xthieh they are bonded, form an aryl, substituted 3:y k iie:Ci<’an L siAsufuicd heu-ioaryk ex cfo-iiky L substituted cyeloalkyk cy v.iohoi'.'iwfskyi ot sanguined ex ei>len-.iiky i ring \\herein ih·..- ring is ηρϊΐοιχΗΙχ tused R> another ary k sabs·a-bed <iry I hennaerA sabs-nuk'd iv.-ten-.u-y I. eseloalks k sabstuuR'd cydoaikyi. cyeloheteroalkyl or sttb-stitmed cycluhetcroaikyi ring;

th te psox se tdR are R aie tot bo’n !r> di> iut,

A is hydrogen, ,JkyI substituted alkyk ,uy^:,sabsifttred aiyl -ay ialkyk substituted arydalkyl. aeyl substituted acyl, hetcroalky L substituted hetcre»ylkyk he ternary k substituted r'eRwaryi, n-teic^ xkdkxl, si'bxhuge''beie'Sijry'allxl ha >, -C\ AO -t»R' Ai<0'AA ak'corA ahoiA ar'rAaor' -aar 'rA -<'x\r*' ar\\\r ’ akVo\r'¹r , -NR TSNiArA ARA(A)IH)NR^rA^h, -BfORJAOK A ~Ρ(Ο)(ΟΒΑ(ΟΚ^η) or -P(Oh R^l%ORⁿ);

B is- A~ or ~Cf R? 1-;

R^Ji is 'hydrogen aikxl siii'str uted .Ayl, a~yl, subsb'utod '07' ary * syl subAii-i>. J ary kftsy I, aes L subsuiiitod aex I Iwre. dl y' suAiit j\-u beteroa \χ I beU'-narJ substituted beUToaryk heierost s'i'jikxl, subonnird hevroaiy Olky .. AR‘'R \ -OR '. -SiOhR¹³, ~CQAⁿ or -CQNR^! AA

G is -Ο- or -S(Q A;

provided that, when G is -.S(Q)r> th® C forms a single bond with E;

olien tlic h><nd between Γ> and <1 is 1 single bond, then D is hydiogen. alkx L subafituted aikyL aryl, substituted uty I aiykdkyk substituted utxlalkx I. aex k suhstitutedaevk

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2017200704 02 Feb 2017 hale. ;x tcroatkyl, mbsimtted hcter>>alk\k hcteu-a· > k ,'UbstiruteJ heteP.-atx L hcteroas5 lalkx ί subdued hetcroaryhlkyk -OR^;k ^H-OR¹⁵, -SiO)_;;R ‘, -NR^lV -MbXIlR'k 4 t »-R’ \ -CONR^!5R⁵⁶ when χί tbnns double boud xx ilk Fk then Π >s O. S, X-<?R^!'<q X-XHR'';

ii js ί» 'X hen G U SlOt . and u is ’ Vi her (j ·,- <',

Eis -XR ·. X· or -CyR V·;

pioxtded that E XR* onb, xxhs'ij G knots a s?ngk' h<-nxi xx ith E;

R^f xh'.Jioce' akxl Mikojid. kxl a si xubxteuted s.. e'-vlabcvt sub-hunted :nx k?ifx k acsi, substituted aes], hctets-tilkx L sub-muited lteteiou?hx L heteruarxl, '-ubsb’.iHvJ Itetetoaixl ncrcfOsttskrikxl. sul>nn?tcd heteu-arx lalkx? oi -CO R' .

R^ls is hydrogen, j'ib I, .substituted a\xk ux L --uRm ruled s?? j , .nx k? kx k substituted arylulkyk ;.icyb substituted ucyi, hctcroalkyi, substituted hcteroalkyk hetetoaryj, subsi.iii.ii.ed heteroaryk he te so ary h? iky I, suKhOiicd bote· oatx bilk) i. -XR R ' -CX -OR ' -S(O)_fR/^i;.. -CO<^! or -CONR^R?’;

& b. c, d, 0 s?nd fare independently 0. I or 2; and

R^:. Rb R\ H\ F\ R\ R\ κΛ kⁿ R^;\ R R^!\ R^!’. R'\ Κ^Λ\ and R ' are independently hydrogen, .dkxt substituted alkyt an k subsuuned an k nrykdkx k substituted i?rxkdkyl ;.svyi sitesdteted -teyl: hoteioalkyh substituted heterojikxk hetero·?ryi, {substituted heterOstrxi, h>..ten'ar\ bdkxl o? substituted bcteri>arxb?lkx I: or nhcmat!\elx, R ' and R R ‘ ,?nd R , R aniR.R and K\ R ano R⁵ , R^>( arc Rⁿ, K ereR'¹ R ,^d R ‘ ,fR anted .tegefii a uh ti>e ,U'>n·?-' to χΟη,Ο hu-\ as·, horded R-nu a eyeh>iu'{e?>M':kxI or subciiteted ex·, frbeteroalsyl ring.

.In one- embodiment of Fomtula (I)* the compound of the present invention has structural. FOi'rnola ill):

A wherein:

) fours . s>_A'g[c bojd y, n ; Ά <?t / cud a double bond ?· tt 1 the elite* of x\ ο, Z. xx ts -C(R S'. -S-, -X·, -X^R ;-,>?

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Y κ -< '{R ‘“j- ο,' -X-;

R \R' )-, -S-. -X^:-, -N(R-^X)., o··

R ⁴1'· b\dsogen. alks L substituted alks i, arsL sub-foraYd ani. aty bilks I subsriuittu ayHtdkO. aeO. sulMnuicd ain I her-aioalks k nubsUtutcd hektutdk>k kek''<uas ·, '^-instituted hetero.asi, heieo-mskuk) L <uhMiUOeu beu-twusUll.\ L ( X, OR'. '•e b<,R \ -NIRR/’, M>XR 'R,-U<> R\ R'< .BiOR-’ HOR’”'}. ·Ρ{0χ·0Ρ ’ HOR^l)>r

1Ή»){i< ‘kck'

R ¹ :s I><j;open. ,iik\L s-fostnmrd allsL aQ k >ans<imtec. jnl. -i’\ Salks·, >at»sufu:cd aryhdksj. acyl, substituted acyl, hvtcioalkyl. substituted hetotoOkyl. bete-van L substituted neu-rvorsL hrtuea: ·. kdkU sdb-ruuttd I’.cksoai suilkH, halo. ( X, V)>, OR' . ·>(* bf,R' •0<UR ^!. YR ^}R' M'OXR df ,-UO,.R'\ SO.X’R d< \ -YR'^lSOR’ . Bif iR^!ROR' ).

• Pl Oh OR M OR* }>··: PiOhR hfOlV\

H is b\d'h?..'n. alksi, sdbstbtned alkyl, uni. subsuttded aryl, arylalkyi. subsutimi ary hH:\I. aeJ. substituted acyl, bctcroalksi, ^ubstburod heteroaikyl. hetcroaryi, substituted hercroarsi, heten'-v.-yjaikyi, suhslttuts'd bcter-iardail.y! ba ·>,-C\ -XO . OR -Sip),R -OCUR,-XK''R^!> -( i ‘XR^R’' Λ OR a O_?P ',-SONR R ' -XR ’iOR”. •ΒίΟΡ/'Χί’Κ’·⁵}. PWb(ORM'>R u>r ·Ρ<,Ο>{Κ”ίΠ JR 'Ί er aiUrnauscR R'⁵ and R'¹’ er k^;i' and 1U' together with the atoms to which they are bonded Rum a eycloa&y.i substitutedeyeloalkyt eyetoheieroalkyior subsiuwed cyesoh» ten 'dkyl ring· g, b and i are independently G or 1;

R*' and are independently hydrogen, alkyl, substituted alkyl, aryl., substituted aryl, arylalkyl, substituted aryialkyl, acyl, substituted acyl, heterualkyl, substituted heteroalkyl, heteroaryi, substituted he tern aryl, beteroarylaikyl or substituted heteroaryhukyk and

R‘ k ’ R' R' K and R ⁴ cm sreefx Ye U s Indioge' a -λI, -nhsl Heed Hks arU sub't J’t> J a\ .'..,ί.'.Ι sub-t on J >a\k ,κΗ, <ks ^ib'.m iks· <r·> h 'en >JkU xOmu n c hclerualkyl, heteroaryi, substituted heteroaryl, betcroarylalkyl or substituted hetemaryialkyk or akerna-isds R' ' and R R'^! and R' <>r R and R'^f taguther ssilh the ;unm- to sshicn ihes ate bonded form a eycloheteroalliyl or substituted eycloheieroalkyl ring: and

U!lh -be fi'sk'O>n? pnnRcs (a) svhen W is -O- or ~S~ or -NR.^, then Z i\ CfR^ ) m -N-; and (b) when.Z is -O- or-S- or -NR^S, then W is -('(R'Qnr -N-.

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In one cuiBeduneu* oil mmnk; <b. the c-,snpom»d mine pr-j'-cni inxenhen has structural Formula (III):

(ili) svbcrem:

Η -GR' )- or »hi<

I is -GR }or->F:

J is -GR' )- ,--r -N~;

K is -GR )- ur -N-;

RR l-ydiogen, alkyl suixuiuned alky i. aryk substituted aryl. anlaikyi, substirited asy talks k acyl Mjbouuk'd acy 1 h Jo hcteroalkyk subsiu-ited Fi-term dky I neictoary; .’.uosiimted iieteioaryi. nets roar,talk'd suixmteudhe^feroars talks t. -CN. -N(N, -OR -SfC>)tR ' -Of OR ' -NR 'R\-CO\R R -(OP -SONR'R⁴ -\P NO P? -BidR >oR », -P((»){« )R''\OR ¹ Ci -pfyu^;i 'hOR Ύ

R·.’< hydros o, alk^i, ,-^0-411-10,1 alkyl, an I sjUsihaG: msI, ary tally. s₅r)siitu;ed a,xtall y s<vl m'Orole l ,ή! bob bevroally \'il’<nm d-^0000,-Iks , ide; -y νίκίΆΊ: heteroarsk ta-lere-aryk'slkyh <ί·ΚχίΐΗΗοΟ hm-zn>ar\ Ldl.y'·. -CN. -NO_;>, -OR'^!i. -S(O);,R^+!. -OCORfy -Nk ^fR^h' OCR R^k J D'R'\-SU \R‘ R’\-\R' SO'R^r -B(OR'’kOR''> -taU}(OR ' ?iOR% Ο -PiO)(k⁴ⁱ)(OR ^:U;

R Kdrogen aH,\ L substituted alk',a;sI. subsrimod ar, L anlalky I. submmod asy talkskat'sl, Mib^nnireJ .u \l. halo, k-ien-alkyl. substHured ;idcm:dkU. hefetoanI. 'mb'duuOd ,ιΚ'<ι<«\ belts.'.. \ tai', L M,bmk',i.d he\ ,ο,υ CJkd. -t N -NO -< ’R¹ -RtU'R⁴ -Οί «»R⁴ -NR’ R’·. -OONR^,’R^,i. -( O:P.'· , -SO?\R^4,R⁴⁴ -NiC SO?R”. -GOR⁴>OR A -P(O)(0R⁴³)(OR⁴⁴) or -P(O){R^! KOR'\

R a- l:\sl·:''(θα:, alkyl. subsUmOJ alkyl. :in^-l. -.uiMhuied myk ar, lalkA L suUMikned arylalkyk aeyk .substituted acykhalo, heteroalkyl. substituted hoicroalkyi, Iwteroaryl, substituted ’el· toan 'Klei, « \ kuk<.i, mhstJUee i, k <>ar, alta ~i \ -N<»' -OR* -mO) P,’ -O('0P, -NR^lC , -CON?/ R'‘, -G >R⁴\ -G..GC \ -SO AR⁴ -R⁴ⁱ\ -NiC^?S(» 4 ”, -B(Ort«>R^-i'). -F{O)(OR⁴''}(OR⁴‘') or -PtQXR^XOR.·’): or alternatively R’ andR”¹ or R. '' and R' ·' taken tegcPies onh 1’ne anno t<- v. nah Ο,.-, uu b<.rukJ, fr-u a on oaky I, aubstduted inetataks',.

2017200704 25 Jun 2019= ^n/;lAUPR cyclohctcroalkyl, or substituted cyclohctcroalkyl ring;

j, k, 1 and m arc independently 0, 1 or 2; and

R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³, R⁴⁴, R⁴⁵, and R⁴⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, hctcroaryl, substituted hcteroaryl, hcteroarylalkyl or substituted heteroarylalkyl or alternatively R³⁹ and R⁴⁰, R⁴¹ and R⁴², R⁴³ and R⁴⁴ or R⁴⁵ and R⁴⁶ together with the atoms to which they arc bonded form a cyclohctcroalkyl or substituted cyclohctcroalkyl ring;

with the proviso that at most, two of H, 1, J and K arc -N-.

In one embodiment, the present invention provides an ingcstiblc composition comprising a chcmoscnsory receptor ligand modifier, wherein in the presence of a chcmoscnsory receptor ligand it interacts with T1R2 Venus flytrap domain via at least three interacting residues selected from the group consisting of N143, SI44,1167, S40, S144, SI65, Y103, DI42, P277, K65, R383, D307, E302, D278, Pl85, T184, T326, E302, V384, A305,1325, 1306, E382,1279, 167, V66, V309, S303, T242, Fl 03, Q328, and S168 of a human T1R2. In one embodiment, the chcmoscnsory receptor ligand modifier is a compound having structural Formula (I), (II), or (III), or a tautomer, salt, solvate, and/or ester thereof. In another embodiment, the ingcstiblc composition further comprises one or more sweeteners.

In one embodiment, the present invention provides a method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a chemosensory receptor ligand modifier to form a modified ingestible composition. In one embodiment, the chemosensory receptor ligand modifier is a compound having structural Formula (I), (II), or (III), or a tautomer, salt, solvate, and/or ester thereof.

In one embodiment, the present invention provides a method of treating a condition associated with a chemosensory receptor comprising administering to a subject in need of such treatment an effective amount of an entity selected from the group consisting of a chemosensory receptor modifier, chemosensory receptor ligand modifier, and a combination thereof, wherein the entity interacts with an interacting site of the chemosensory receptor. In one embodiment, the chemosensory receptor ligand modifier is a compound having structural Formula (I), (II), or (III), or a tautomer, salt, solvate, and/or ester thereof.

[FOLLOWED BY PAGE 10A] ^n/;lAUPR

2017200704 25 Jun 2019=

In one embodiment, the present invention provides a method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (lib):

_R17

(lib) or a tautomer or salt thereof, wherein:

W is -C(R²⁴)- or -N-;

Y is -C(R²⁶)-;

Z is -S-, or -O-;

A is -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁹ and R¹⁰, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl;

R²⁴ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, -CN, or -NO₂; and

R²⁶ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, -CN, -OR³¹, -OCOR³¹, -NR³¹R³², -CONR³¹R³² or -CO2R³¹, wherein R³¹ and R³² are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R³¹ and R³², together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring; wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted heteroarylalkyl, and substituted

10A [FOLLOWED BY PAGE 10B]

2017200704 25 Jun 2019= ^n/;lAUPR cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of-R^a, halo, =0 , -OR^b,

-SR^b, -S, -NR^CR^C, =NR^b, =N-OR^b, trihalomethyl, -CF3, -CN, -NO2 , -S(O)2R^b, -S(O)2NR^b, -S(O)2OR^b, -OS(O)2R^b, -OS(O)₂OR^b, -P(O)(OR^b)(OR^b), -C(O)R^b, -C(NR^b)R^b, -C(O)OR^b, -C(O)NR^CR^C, -C(NR^b)NR^cR^c, -OC(O)R^b, -OC(O)OR^b, -NR^bC(O)R^b, -NR^bC(O)OR^b, -NR^bC(O)NR^cR^c, -NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7membered cycloheteroalkyl.

In one embodiment, the present invention provides a method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (lie):

or a tautomer or salt thereof, wherein:

W is -S-, or -O-;

Y is -C(R²⁶)-;

Z is -C(R²⁷)- or -N-;

A is -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁹ and R¹⁰, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and

R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl;

10B [FOLLOWED BY PAGE 10C]

2017200704 25 Jun 2019= ^n/;lAUPR

R²⁷ is hydrogen, alkyl, substituted alkyl, substituted acyl, substituted heteroalkyl, -CN, -NO2, -OR³³, or -NR³³R³⁴; and

R²⁶ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, -CN, -NO2, -OR³¹, -NR³¹R³², -CONR³¹R³² or -CO2R³¹, or alternatively, R²⁶ and R²⁷ together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring, wherein R³¹, R³², R³³, and R³⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R³¹ and R³², together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted heteroarylalkyl, and substituted cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of -R^a, halo, =0 , -OR^b,

-SR^b, -S, -NR^CR^C, =NR^b, =N-0R^b, trihalomethyl, -CF3, -CN, -NO2 , -S(O)2R^b, -S(O)2NR^b, -S(O)2OR^b, -OS(O)2R^b, -OS(O)₂OR^b, -P(O)(OR^b)(OR^b), -C(O)R^b, -C(NR^b)R^b, -C(O)OR^b, -C(O)NR^CR^C, -C(NR^b)NR^cR^c, -OC(O)R^b, -OC(O)OR^b, -NR^bC(O)R^b, -NR^bC(O)OR^b, -NR^bC(0)NR^cR^c, -NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7membered cycloheteroalkyl.

In one embodiment, the present invention provides a method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (He): 10C [FOLLOWED BY PAGE 10D]

1AUPR

or a tautomer or salt thereof, wherein:

G forms a single bond with E and a double bond with D;

A is -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁹ and R¹⁰, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

B is -N-;

E is -NR¹⁷-;

G=D is C=S·

Wis -S-, -O-;

Y is -C(R²⁶)-;

Z is -C(R²⁷)-;

R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl; and

R²⁶ and R²⁷ are independently hydrogen, alkanyl, substituted alkanyl, alkoxy; or alternatively, R²⁶ and R²⁷ together with the atom(s) to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted heteroarylalkyl, and substituted cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of -R^a, halo, =0 , -0R^b,

-SR^b, -S, -NR^CR^C, =NR^b, =N-0R^b, trihalomethyl, -CF3, -CN, -N02 , -S(O)2R^b, -S(0)2NR^b, -S(O)2OR^b, -OS(O)2R^b, -OS(O)₂OR^b, -P(0)(0R^b)(0R^b), -C(0)R^b, -C(NR^b)R^b, -C(0)0R^b, -C(O)NR^CR^C, -C(NR^b)NR^cR^c, -0C(0)R^b, -0C(0)0R^b,

10D [FOLLOWED BY PAGE 10E] ^n/;lAUPR

2017200704 25 Jun 2019=

-NR^bC(O)R^b, -NR^bC(O)OR^b, -NR^bC(O)NR^cR^c, -NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7membered cycloheteroalkyl.

In one embodiment, the present invention provides a method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound selected from the group consisting of:

or combinations thereof, or a tautomer or salt of the foregoing.

In one embodiment, the present invention provides a method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (Illb):

[FOLLOWED BY PAGE 10F]

10E ^n/;lAUPR

2017200704 25 Jun 2019=

R¹⁷

A (Π I b).

or a tautomer or salt thereof, wherein:

A is -NH₂;

R¹⁷ is hydrogen, alkyl, or substituted alkyl;

H is -CH-;

I is -CH-;

J is -CH-; and

K is -C(R³⁸)-, where R³⁸ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, CN, -NO2, -OR⁴⁵, -OCOR⁴⁵, -NR⁴⁵R⁴⁶,-CONR⁴⁵R⁴⁶, -COR⁴⁵, or -CO2R⁴⁵, wherein R⁴⁵ and R⁴⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁴⁵ and R⁴⁶, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted heteroarylalkyl, and substituted cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of -R^a, halo, =0 , -OR^b, -SR^b, -S, -NR^CR^C, =NR^b, =N-0R^b, trihalomethyl, -CF3, -CN, -NO2 , -S(O)2R^b, -S(O)2NR^b, -S(O)2OR^b, -OS(O)2R^b, -OS(O)₂OR^b, -P(O)(OR^b)(OR^b), -C(O)R^b, -C(NR^b)R^b, -C(O)OR^b, -C(O)NR^CR^C, -C(NR^b)NR^cR^c, -OC(O)R^b, -OC(O)OR^b, -NR^bC(O)R^b, -NR^bC(O)OR^b, -NR^bC(O)NR^cR^c, -NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is

10F [FOLLOWED BY PAGE 10G]

2017200704 25 Jun 2019 independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7membered cycloheteroalkyl.

BRIEF DE SCRIPTON OF THE FIGURES

Figure 1 contains exemplary human T1R1 polymorphic variations.

[FOLLOWED BY PAGE 11]

10G

WO 29(18/154221

2017200704 02 Feb 2017

Figure 2 emmdns exemplars human 1IR2 ρ-,Α mmphic mnatious

Figure 3 shows rhe dendograms lor the sequence alignments ol’TI R I. Figure 4 shows die dcud>>gmmx un rhe sequence augsnncnls of Π R2.

I p<su' '* duns- eveiupkus mteiaeinm space' for siicraL'C and one <»fthe compound ol the pu'em msentmu. Pi-atcm ;s jvpiC'cntcd as a nbbon diagram.

³ igiue u shew^ _vscnq’Ljj\ :mcmcuug 'paces ,:rd esidcc·» fin suem-oe and on·. <d the comp<<n Us <q thc/U'.i. msent oa, Ikotont ss jcpu'.rted as 4 rthn» 1 dum-am

I tguu, ”* show» exemplars mreruetrng 'paces and sestdues associated cvith the l-mg·.· w'gsou for sacu; lose and one of the compound^ of ?bc mesem rm euw-n ³ igu^fc h shem,' ,scmplai\ pwwd :_Utc aumg hh! ices _taj internet, tg u'?uues proximal to the binge region f- ? 'tu-wc and 'luraloxc fgme^-i sherw.- i.xeniptof\ oncmeung 'faces je-J csiducs assocuncu w sth uic b>l···^ for sucudose and one m the ewmmmnds > the present {mention.

figure lb shows exemplars interne¹ ing -ηχιεοχ :md residues associated \sith an intemcring sire for sucrafose and one of the cosnpe-cnds of the present invention.

t -gore 11 shows exemplary rest If V mapping studies using human-rat chimeric receptors.

Figure 12 shows results for exemplars mutagenesis results.

DETAILED DESCRIPTION OF THE INVENTION

Prior to spedfically describing the invention, the following definitions are provided.

The term “TH? lumtlv includes polymu^hie variants, alleles, mutants, and homologs i.h.jt'11 > has ·,.- about 30-10“«. annm.: add .'cqucnc·..· ab, mux, mor,' -'pec it kalis almm 10. .50.60, 7th 75, rfo, 85, 90, 95, 96.. 97. 0* _Ci 00'», _an- _n>, _A-ij sequem 0 idemirs to the TI Rs knosen or disclosed, e.g,, in patent app'n at on I 7 nd \o Η) I Ό 5-3 og.g _on }_[inc \\ 266.:, S. {i 0 \o 09 790/,2° fikd ,w \pt 1 2001 and Γ >^{'ai \e 10 035,0+^ Fled on kma'c's '» 2002, over a, window of about 25 amino acids, optimally 50-100 amino acids; (2) specifieady hind to asstih'fdic'. mimd ag nn-r .m immunogen vomprtMng au ammo amd -sequence scleided fr»>m rite gte-up {.on-si-sting -.0 the TIR set puma's IRek-i.·,! mfia. and couscn’.ativeiy modified van n’stlm<. «''«Iqsx’k<i s h,h du . p> u a m/c 1,0 n ,»st about 100 opt’ona'bc v n-aM

WO 21W1S4221

2017200704 02 Feb 2017 about 500-1000 nucleotides) under stringent hybridization conditions to a sequence selected from the ur>>up v<msist.'ia ο·'ΐΙ:θ 1 IR F>\ \ sequent enclosed imm and e>msefx mxeh modeled >. miauls ikuvi. {-1} c^mpii-c a seeuciKc at least about Jffio mkutai to an emmo auid '•-quenec selected bom the croup consisting of the I i R imino amd -e.jucisces di-cto^d na'ra <u (5i aio amplified bx p= smew ?li,n sncvdkahx hxbmtoe under so mgent Inhudtoation >.oudii>'>ns io the d-.--<.ubcd 11R sequences in pitincdm', these '' 11« include taste receptor uPCRs lefctred io ?*> bl I Ri. ΚΓ i Rd. hT I R3. rTί R ί. fl IR2, flI R3. nil' IRI, m ΓIR2. and ml IR '· lux me the mu le-e :-cid sequences and amino acid sequences kamxn <n disclosed. ν.χ>. m I ho. Senal N>·. 10 ΐ 74,)0 filed on June de, dO*'lj. I S Sena] Ao. 04 ‘“«.to hied os \pnl ^A, dOOl md F.S «mil \e 10 035.045 filed -m krnmuy 3, dOild. and xa= Sums, alkies, mmants. mihologs and dinners iheivof which speed leal h bind amim respond to sweet, umami. er any oilier cliemoscmsory related bganjs including actixsb.-r.s. mhihroi- and enhancer^ Ak-> I 1 Rs m-Jude taste receptor GFURs expressed in haniurs or other mammals, e.g.. cd Is associated with taste and/or part of gis,n *estau sss’er ικ udirg \«beu unx >m to m», - Hug .s sm na n ir, no h’ al and large) colon, sis c?, biliary iract. pamreas. gallbiaddei. on . -\R-> HR pels peptides include chimeric sequences derived from portions of« particuL: I ll< poA peptide such as Ti Rl, T1R2 or T1R3 of different species or by combining portions *' d if fer ?:v. Π Rs wherein such chimeric T1R sequences are combined io produce a functional sweet, or umami t.n to n. cept> >r For example chinienc Ti Rs may comprise lite extraedlular rsgimiufone flP.i ·.·., I IRl orTlRl and the transmembrane region of another TIR. ehher Π R t or T1R2.

Tupofogically, certain chemosensory (Mlb base an *'X~ierntin8.I domain;” “extraeehular domains,” a 'hransmembrane domain’' compn^ng sex on i ratismembwte regions, and co '> spmidiug c' u mbsru» .md ex’r.a e ‘utn loons, ''cyhmkismie ? eg ions, and a '‘C-iermind , egio;' {see, u e th· no « . «</ « - I«1 C 4«)oy R_Uek<'/ m. t \.’' «< < > (1991 j). These vgiens can he snuc'm . h 'dent»rie-l usmg radwds imone m those .«Γ<kill m the art, such as sequejicr .mdysis pmgfam'i that slewiis hxiir<'ph-ihic .md mdropbibi domains pw >, _t . Stnei. fhochensstiv. (3rd cd 1 «to, sec also „5 \ of.< rerdxr ol'bitomet based '-eqncnec anxlx-5pmgiama such <s these Rmml at Jet m-gen l>em intv edni Irese regions are usefiil io; making i himt re proteins and hu ;=< r:U<> <i-;<w s m ike imemion. c.m, ligand hmdme assays

WO 20118/154221

2017200704 02 Feb 2017 ”1'>iracclhdai ammons'' therefore refers Li the d-,-mam,' -.4'chcinoseu-mx reccptoix, e-g . TlR p<>h peptides dun pionode uem the cellular ntsmbtane and uic exposed r·: the extracellular face of the cel L Such regions would include the “N-ienninal domain’’ that is exposed to the cstracrifob: hs^c cP the cell a- v,dl as the cxhaeribdji lo-.p- ot'llix nammcnihum·..' d<»ni.nn that arc cxposcxl to ?be extracflluiar face of the cell, be., the extracellular loops betx^een h;;mmcinhmiic :egions 2 and 3, u ansmcmbranc rcgj>-ns 4 and 5, and

- ,tn\'nh iu ^10 >' c t id ~ h, \ k<mn dd i ,<n st. , n hc\ kun wh an ^xteids io a icgior d?'. tn du- sk ' of rhe tiansmcmhmiie legion HiCsc extrac-.-Uuinr meimk ,uc useful |<.i .’/? ru··’.,· η^· id bind, tg o' iys. botii sdubic and solid phase hi addmon. mmsmembmue regions, described bekm. caa also be involved in ligand binding, either in combination with the extraedfehr region or done, and are therefore also useful for;« vitr.> ligand hu-ding s

Tkin.-nieinbranc doinahid ulnch ioinpnscs the seven irun»mvmbta-K iegiorsd' refers to the domains of ohemosensciry receptors, e.g . TIR polypeptides thru fo u uhin the plasma membrane, and may also include the corresponding cytoplasmic (iniracdid an and e.xtracclkilm' i-> >ps. altw· referred n- as mmsmembrane '’rngions.' ffe sc^en transmembrane regions and extracellular and cytoplasmic loops can be identified using standard methods, as described in Kyie ez <.?/..·/ Ifo/, 157:105-32 (1982)), or in Stryer, ^,<( x epl i⁴ itv J mam' e e s to h < <> r> uis o -he r* *ό uo ' x\ept‘ s <. „ TIR proteins that Eke tbo inside > f the celt e.g , tire Cgernrin.al do mam” and the intracellular loops of the transmcsnhrcme domain, the intracel.h.ilar loops between transmembrane' regions I add' 2, iraiisnternbrane regions 3 and 4, and' transmembrane regions 5' and. (4 “C-termihal domain” refers' te foe region font spans from foe end of foe Igst transmembrane region to the C-t.-mimiis m, tiie pro-e:n, .mJ vJuch is mu-na’ls -ee red xsObir the c^ mp .ism

Ph,· n. nu “ 'm.innnernbmne roc.'p’of mo.ms a p, x p., pn-L» helo>-ging to ,i snpcrfomih of transmembrane proteins that, have seven regions thai sp<m t he plasma membrane sexen limes (thu-x the seven regions are called ^transmembrane” or ΊΜ“ domains TM I to TM. νπ·.

The phrase ^fboctfonal effects” or foctivity’lfo. the context of the disclosed assays Im testing compminds that incduial,: a chtmoscnsm'x iccspto?. coy, enhance TIR i.tmil) meniho; mediated signal transduction such ns sweet or umumi receptor functional crrccts or activity mdudes the deternsinaiion. of any parameter that is indirectly ar .directly under tire i.ufiuence of:

WO 20(18/154221

2017200704 02 Feb 2017 fee particular chenm-ensorx m-.,epU>r. <' mnUmnal phxsical and ehc'-mcai effects. h nndudes. onhout any iumtaUon. Lgaud bmdmi,', changes m h-π lltix. mcmbmne poten-'ial, c.irrei't tlen, ’ufxeMHiO'j, % ΐ piotem beidatg, GP* 'R pho-ρί.»-s\ feu.-ii oi depk-sphe: -Gtion. signal n ju-dacnoin reccptor-ligand nitenictions, second messenger concctmations fe.g.. cAMP. cG.MP, 11'3. or mtracdlubr t ;.r >. to <'/;<., m m>>. and <-x i w<> and also includes orhe» pbx-i->logic effects such mcrcuscs oi decreases oi neurotransmitter or hormone -elcase.

Ihc term down mumm the fi.iih.ti--md effect ’ ,·; reec-p-or actix ay^-' means assays foi a eomp> und that mutases <’= d^cato- a p.mmutet tn-it j- mdi c>.ib. os u uefix a idci tne imluenec oi a uientoscnsury receptor. .\y.. tuactiom-i, pln.-Ral and cbenneaj etlects. Mich functional effects can be measured by any means known to those skilled in the art. changes .'isp.ri p,e s'at.Ktcti< es( ? thi ?.-.cnee, ./o- Guu: tc'nctix. nJ.-'»,hx Ji >Jxn .me u- g.. shapci, el-ionuiographsv. or solubthts p-opcriws, pa-el- clamping, vol rage -sensitix e dyes, nboie ceil currents. radsm-x-iup-.. efflux, mduemle markers, ooesic chemo-sens-arx receptot ..g , I iH gene-.'Xpressi--n* tissue culture-eb chemo-.u-'ors rceeptot. < χ.,T1.R expression; transcriptional activation of chemosensory receptor, e.g<, T1R genes* ligand binding assays; xidtage. memnranc p-nemial and ^ondULt;m-..c changes: ion Hus assays;... Ranges in imraedk-lar set--nd messcngcis ,-ueh as eAMP eGMP and inos-t. ^: *ophosp'tate it Pan c t-mges m immcellubif calcium levels; m'urotmnsmittcr release, and the like.

’’Ininhitors,'' ''uctiv:*iors.” and '‘'modifiers of chemosieiisrirx' receptor <·>£., TIR pi oto is are used interchangeably R> refer io inhibitory, m.rn anng, or modulating moicettlos id mined using m xito and /n v/vo assays for chemosensory signal transduction, e.g., ligands, agonists, antagonists, and their homologs and nmuetic$< Inhibitor.- are compormds that, e.g·., hmd S) parn'.dly e-nouJly htock simmlatmn, de-'roasc, prevent, do'jy .leiixwtion. Inactivate, des-rnsiii.'c ordmxn reg-Au-. las-e ransduem.m, < , antagonists. Avth aiprs are compounds

Out . g bmd to stimuM.n.. mcr-.-as·. open acuvafe facilitate, enhance activation, sensitize, or up tegniate elierne-'-.-m-my <:<na; transJurtmn e , agonists. Modifiers include compounds that, e.g., alter, directly &r indirectly, fixe activity of a receptor or the inferaciirm of a receptor with its ligands, e.g., receptor ligands and optionally bind to or interact with actryators or inhibitors; G Proteins; Linases (<'g,, homologs of ria-d-ipsm l.mase and Ktu adtenermc receptor km.^es thai ate inxofeed in deactisanon ami dcsensitizm-on -d a receptor»; nud ane-tom*, xxhkh ah-i deactivate and descnsit;.7c receptors. Modifiers mGude genolicails modified versions or

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P:CTtoS2(lW065658

2017200704 02 Feb 2017 <.hcni<xsenxotx iecepims, x g . tlR/amto nscmbe's <. c . χχ tt-t alteiCxi ax'ttx to., <is λ ell ax nahmdb, oceannig and sxndictfc brands, ;ιη·ί:ρ>>:ο·-ΐ·-. ag<>m?>K smad chemwal mto-edu. and rhe hke The lum chem<'senxurx jeccptof kyatal modifier' as used huem iadudex < 'tot '.>s,ijw<i' x u<xph> bgarC ·, n, mu l Ή’..'m.-un >ux „.).: t. .h - ⁱxt,.i’* *' hmsiauom s'xcci hgandx ptgutjte, 01 .ijnaeorixtsk utna in tea tdx u ^nd aemg-mMu. •mevt c-maneem and umams enhaneem and sxxcvt taste or untatrn taste ml·:bums ''FnhutKCf hereto rckr< to a xompcmml that modulates tinotcascx) the muwtoort of a pauicubr Ktecpt»··. p-ete-rablx the chcttRVteUsOJx, · .y·. IIIC Π Rd mceptm ot I IR.I T?R3 meept··? but χΟικϊ; h> tisclf does am result m suhstattttai .urttsatrnn of lite pat nculur receptot Herein such enhancers-will enhance the -activation of achemoserisory receptor by its ligand, ixptcadx the enhe.axei' xsdl be speufle b· a pm-tc'dla ligand, ' e. it ?ul not enhance tuc actixattoi'to a vhcnb-sonsorx revcpt»·’ :>x chunoxens. »χ jga.sd· <>thu than the p.iii>cuutt xtounoxen-mry tkand or ligands closely rdatcxl thereto.

''Putetit x* x'nhun-.er' hotem reteuUo a v.mnpotrml idemib·.J < χ. <<' -.<'<'?< or nto. as a potential enhancer using assays which are described herein but which enhancer activity has not yet been confirmed zn vz'wz, e.g<, in suhable We tests.

The terms ''polypepfide, “peptide'’ and “protein’’ arc used interchangeably here tn to refer to a polymer of amine acid, residues.. The terms apply to amine acid polymers in which one or more amino acid residue is an artificial Ghenuc.J mimetic of a xmrresprmdmg naturally occitH Ing amino acid,; as well as to naturally pcctpnng amtrw acid polymers and mm-naturally occurring amino add polymer.

The “cxtra-cdlular domain” and ehemosensory receptor, u.g._s HR receptor wgiom- or comps>x:fis'-xx A’sx'toxxi hereto dsxx mdm\>' snalogx,’ ot “conx. rxatixe x o* ams' ar-o 'm moucx ' t’'pepn'uoixxitrel > χ b Χχ it x xRuci'.m - ar·' acti\x, xuK'iant <d x x'cftx’soonxi to toe ex.-mpl'·,') xcquomvx 1 bus. 'ho vims 'coxxutxatixexutt.mt \>t “analog’ or ''mimetic” refer to a polx peptide xxhich has s m->dtoe·’ ,um m a» al χχ' pte s e xuch that the change(s) do not xtto-tant;alb ah.·: rhe ptox ixmidc-ulhc x'enx.'rs-toxx' xutta-if'·} torm imo and or ueRs Ox. ax defined here to. These include cemservativdy modified variations of an ammo acid sequence, t.e,, amm< > aeixl subuiintion^ additions or deletions of those residues that are not critical tor uV'i.OUx i - out, .h't x’lldH'tr'.xiu-wfi'iT.'fL’M'nauq xt’.lo ’‘I- 'to-h /

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2017200704 02 Feb 2017 acidic. basic pcsinrcly ot negalwds Cmuged. polai m ι,> ·!.-ρ<Ί.·ι. <.>< ;sich I lai the wibs{,tmimis of men critkal amino .u. ids decs n> >l substamially ahes nritcuisc and <« density.

More partioulady, “conserva lively modified variants” applies to both amino acid and imdeie acid sequences. Vtιth respecl m pa> ticular nucleic aud 'Cinicnues, conservatively modified xa?i.unts icfcrs to tho-w nucleic acids which encode identical oi cswimaily identical amino acid sequences, ur where the nucleic acid does imt encode au amino acid sequence, to e«scntiaUy identical sequences. Because of the degeneracy of the genetic code, a large number of iancfionailv sdcmieal nucleic acids encode any given protein.

F>ί instance, the codons (ί< 'Λ. th '* \ xJCG and i <1 ali eiuodc (he ιπηιη*· acul al:.miiic. 1110-, ci ·?χ cty p-.-ttioa where an alanine is specified, by a codon, the codon can be .ilicrcd t·' any of die c -iiw-pondiiig codons desei-la-C will· ut aitci ,su tr.c encoJvd pUyp.punc

Such iiuide:c acid saicnb-ns u··, -ncm <. aiijimn,-/' wIndi aw one specie-» of consersatiseb, nt>>Jsfk\.l sari.nions Ificry nucleic acid sequen-.e neroni which imcodes a polypeptide also desenixs eseiy possible .-dem ', a? i.iti<'j· of die nucleic acid. One of skill svi.ll recognize tlrd each codon in ,i nucleic acid (except Al G, wh:Lh ;s ordinarily -he only codon mr methionine, md I OU, 'ankh 0 ordinal ily die only codon n-r tryptophan i can be modified m s ·. fid a tuner ion, 11R iden0e,fi molecule \cc-'id'ngly, c-uh silent x atianoi' < l a nudc'C ,>eid which encodes n polypeptide is implicit in each described sequence.

Gmsei-vtaive subsi.iim.ioc table- p»os iding iciicfiomd.ly similar amino acids are well known in the art. For example, one cxentphny guide! ine io select conservative substitutions incl tides (original residue followed by exemplary substitution): aia/gly or ser; arg Is st asn gin or his; asp/glu; cys/ser; ghifiisn: gly/a$p; gls al;i or pro; his/asn or gin; ile/leu or val; leu do or s al; lys arg or gin os ghs: met 'leu or ivr or ile; phe/mei or leu or tyr; ser/ihr; ihr/ser; trp ly r, tyr trp or phe: val ile or leu. An ahematis c exemplary guideline uses thedhllowing six groups, each confainmg amino acids ihal are con-,·, native substitutions foi »n< anciK'i' I > X'.minc (A). Srnne (S), Threonine ΗΊ: 2) Aspartic acid (DI. Glutamic aciil (I }; D Aspa’-a^’w* (\l Glutamine (Q); 4) Arginine (R)_? Lysine (I); 5) Isoleneihe Ojs Lmmme (L), bfethionine (M), Valine (Vi; and 6) Phenylakaunc {I'), Fy-nMne (Yh Tr\plopban tWV. per ίϊμ>, _t’g_. Coughmn. Ptoleinw A . H Freeman .md ( ompany s rfiAt p Schultz and Schemes, Principles nl Puwem Sinsetarc.

Spi :tiyi.r-Verlag (I⁰'⁰)} < hie of skill m ii a- .erl w ill appreciate that the ohm «..‘-identified subs din lions are not l he only possible conservative substitutions. For example, for some

WO 2iWln4221

2017200704 02 Feb 2017 pmposes, one may rcgarxl .ill ehaygvil ammo amds a- e.wsmxmoe subst ituti<»ns fin each odivr x\ h.'thv they ate posit-'. c or ucgativ e in -additf<’u. iit-.liv ideal suh^rimriotw, deletions or ailJiumis that alter, add or delete xt single amino acid or a small percentage of amino acids in an encoded ^cxinenee can als>> be convulered '’coHserxatix eh modified v miari.ws.'’

The team'; 'numeric” and ''pewmemimetn.” refet to a syutheric chemical eontpo-anxl that has subsmntialiy the same siuicmrai and <n funcm-md charactenstics of the '< h ps/Mes e.sxUas 'Ju m I mas' <> no teesn how's st'' > 11 < K2 m I<K <'h» i nn'et _v can be c .te cumcR c>-mposed of synthetic. mm.natural analogs of amino acids, οι may Oc a dmnei c mokxule of pattly nutuial peptide .mum- ac»d*- and p.atb ro.i-aoumd au.ri<igs <4 am n-> acids The mimetic can also incorporate .any amount of natural amino acid conservative substitutions .-.- long as such siihsthuticms also vic rmt substantially al-ci the mnuctie’s structure and >·: acrix m.,

As a uh noKpephxk's ->f tits' invention v. hieh are e->nsert.irivx' variants, routme cxpcrimeniauoi': vwll dcteimme whether a mimetic is w bhm the se-»pe ot the invention. ? e. that Its structure and/or fbnctioii is not substantially altered. Polypeptide mimetic compositions can contain my C'-nWimmou of n.-n-nminal oruemrd uomponems ohieh arctvpiealh from three structural groups: a) residue linkage groups other than the natural amide bond (’’peptide bond”) linkages; b) non·’natural residues in place of nmumlly .<eurring amino acid residues, or cl residues which, induce econdmy unurural niimioy <'.. to induce or stahdL·? a secondary m it. e a be . io v g. nme ur, s I., s <?* r pea bobs xrn u ”'iatu i >iduel’’-i A polypeptide can be characterized as it mimetic when all or some of its residues are joined by cbx'mird means other than natural peptide bonds. Individual peptidomimetm K'sidiies can be mrned by poptide bonds, other chemical bonds _Ksr coupling means, such as eg, ghtiaraldehvde. \-hvxko\vsuccinimide eswr^ h:fmi,.tie.n;J malemmk-s, N.h^!-d:evekbe\skatboxii-muk’ IIXX'l or N.N-dii'-Opropyk-arbodiimide (DIC), Ltnk<*\’ <wou|^w that can be an alternative to the Traditional imide bond (f cptid·, bond”) linkages * τ \<de, Rgy, ketomethylene (e. ·?,, -C(O)-CHsfot-¹ u n-MI-?, amm<uu.;ih\l'.u..' -('I I a,\l IV-, x'thv iene, <>klm -< Η ί II-, ·Α'ηοι -ί Ή Ο-, ini^ethei Ahl S- iet'az.'k (t Nj thia'ok wt.oar.'.k. Jimaomk <u t Res t w.. _t t S iato’. C .> n'^jx and Biochemist! x <'f Xmine AciJ-. Pepndcs and Pr<'terns. Vo! ~. 2M-.557. Matcdl IXkkct, Peptide Backbone Xfi'di-le.itions. \Y i 19831 i. Λ poly peptnk i.an also be eliaraeierizcd as a

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2017200704 02 Feb 2017 mimetic bx ceitgiiumg Ji or some u·.-ii-kaliiral sesidue.' in place ofiiatuiallx <<<_LuiUi’g amnm acui mutoics non-mitiir.d residues are web dc.'C’ibu-d m Hie scientifk and ptoem htombnv ' Xlky Ihx asp.ut<0 another feistm.ent. iclbis u· a saltaatod <u unsaiutatod. branched, stmight-cltam >,r eycbc mmiovakm hy Jr>>carbou otoe-J derived by the rcinoxal of one hydrogen atom from a snigk curbrm atom ,f a parent alkane, to cue or alkvn·?. I he xnt. J ' includes a,el >?k J '»s defined amen b Je*x bmcak kx „ mi-w m> mde but are not bnoiied to, mcihyl, ethyls such as or han x I. erhenx I. ethynyi; propyls such as p.oo.m >-\l. piopan-2-χΙ. >.χο1<’ρίορΰη·1 >1, i η p I e>i . ' , p op . mix' ;\v_sk ,·' 1 xl tall? 1 h cxeh’pfop· I -cm I -y I, cy cloprop· J-en-i -y i. ptop- i -y n-l-\ L prop-2-χη- l-x I, <·<’<.. bitty h <u>.-h as hman· t yl, bumu-2-x L d-tnerhyl-propan· i \ L 2-metbx l-propan c-yl. cyclobiituu· I yl, mu I η» I-yl. but I -cn-c·>I. d-iucuiyI pi<w I cu 1 yl, Irnttoen- x'.. bui-ben dy·. buta-lm-dicml-xl. nata-IJ-dtuu-d-yk ctonl-to-1 on·: xt eyvlobut-l enoy , cydobito-l, tolien-l-yi, hto-l-xml-yl. bur-i-y m3-x i. bur-ky n-i-yl · a , and the like, fhe term “alky Γ is specifically intended to mehtde groups h.ix mg any degree m level ol ·' ttuixmon. < o groups having exclusively single carbon-earbmi bonds, groups haying one or more 'double caih, n-enbon bonds, , -nps luxmg ,-nc ot mote tunic carbarns croon h >nds .» c. gtomw navtm; mixtures of single, double and triple: carbon-carbon bonds. Where a specific level ofsaturafion is intended, the expressions tolkapyl,’’ “alkenyl,” and “alkynyU used. In some: embodiments, it, sx L’ov'> > ec'n'-Kcs nr l\'2fiur(x ' <m m-s o' -s' > oiks t in toot 'itoJ’f'i ’s <m alks. gtonp,i>npt ses I <>m h> fid , eibon ootrs ,-( , ikslj tosh! mbe BOodtments an all x t \ i -np eompr^es fix >m = to <> e.v u. >» _tm^ {f , -(k all x 11 If u n· itod that v Κ·.->' an a' -λ I group is further connected to another atom, it becomes an “alkylene” group, In other words, the term '‘alkylene” refers to adiva'-eni alkyl, for example, »C'H;CH.i isan . tny I, vxb>l·, -CHOI,- to an ethylene. That is, ''Alkylene,” by itsuifor as part of another substituent, tcx t*> a '-mmued or unsaiumted, t'um'hC'i, sttaigh·-chain ,'·? cyclic dixto rt hydn ^atbon radical eemed by the removal, of two hydrogen atoms from a single carbon atom or two toiler· m ·. .roon monwo parent alkane, alkene or alkyne. The term “alkylene’' includes “cydoalkylene” as defined: hereinbelow. The term “alkylene” is specifically intended to include groups having any degree or level, of Stotmithm, i g; oups has big exclusively single carbon-carbon bonrls, groups having one or more double cat ben-carbon bond, m-rnps h.oing one or more triple e.trbou-carbon bonds and groups box mg mixluws of single, double and triple earoomcarbon bonds. \\ here a specific

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ΙούΙ m -JuuDeii ;s mkmde·!. the c-spressiou.' 'alkans kmc.' LilLunsleiiu,” and folks us k'ne yc u-oJ hi ciimodimcttK an a Ik s kmc group coinpiiscx bom I k· 20 catbon atoms (CrC <· «dkskiic). In ethei cmbodmu-nis, an idkslctsc camptt.'C.' frmn < to 10 eari»<m al<mtA s<.’i-< ho dks kmc;·. b- suit other emPodnncnts. an elks lune group eon:|« j >c« from I to b carbon atoms (I i ('<· a Iky lend.

' Alkmo L ' in ilseh'os a- patt of an->thcj ^ibsiituuit ek·;·· io a sa'ui: icd nmih.hcd. stiasght ehanj os >.yehe -dksl mdiCal du'oc.l by 'hu icmcsal et'-r.c by Jiogcn .mun f.Oiii j suiglu ujibo:! item ·43 paient alkarc foe kum ' ilfoms. mcliaics' ,.y cloakjuy I as deheed h·. icnibJoss. Is pual alkmy 1 gumps -iidudc. imt .no -lot bmited b . meriam i. umms^s, ;>:opan\'-s sue:'.o-piepa i I si,poem ? ' 1 (tsopfops fi. enkpiopan yh-k , ot \my X such a·huum· l-yk butun 2 si {se.’-lmtyl>. g-mcdis I-propan· i-y I {i^buiyin 2-rncthyi propan-2-yl s₍' biitsh, vych hiii.;:!· 1 yk · <\·.. and ihehke.

*' Xlkon> I' by srseif,._} p_4!t .q another <ubsihuenk refers m an unsarui\ited branched, straight-chain or cyclic alky I oidtcaJ has mg ai least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The term alkenyl includes foyek>alkenyr us defined hereinbelow. The group may bo in either the ₍'?s or conformation ahm.it the double bondt/). typical alkenyl groups include, hut are no? limited teg ethenyk propenyfe such as .prop-1 .-en- l-yk prop--l-eu-2--yL prop-S-cn-i-yl (allyl), prop~2~en~2~sT cydoprop- l>en-l~y.l; eyeloprop-2-on~ I ~yl; bmenyls such, as but.d -cn~l ~yl, but-l-en~2~yl, 2-methyl-proj>l~en-l-yI, but-S-en-l-y I htit-2-cn' I -yk biti-2~en-2~yl, buta-d ,3~dien-l-yl, buta-I.3-'dien~2~yh cydoWt-1 -en-1 -yk cycBbirt-l -en.-3-yl, cyetobuta~l.,3-dien~i-y 1 fo ' a (id the like.

TAlk.y oy 1 hs -isolf or m· par· ofanmbo: substituent refers m an un-aiuniied branched, stmight-elimn ,<r eyefie alky i radical has iug ai IcasT one cai'brm-ca?bon triple bond Peris cd by the remm.d ·.; one hv'lngen .num from a single carbon atom of a pnivnr alkyne. Ty pi cal alkyny I gronp- snelud» but aie not limited to, ethynyl; .-propynyls sach as pn^vl.-ym-l-yl, uorOsti- < k \ ,sns'’tu . as p.ii-'.-'H-l-sl, hie- -\i-^{-\ i I ul—sn-< k a id the like.

' X Lew b\ itsidl or as part -d anodur sub-miiient. relets to a tadmal of ike formula -O-R . sshe.e R ' ' alkyl or substimtod alkvl as defined herein.

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2017200704 02 Feb 2017

Aesf' by itself or a- part of ms-tbcr -ahst ihscnt relets tf- a radical < '{< BR where R ' is hydrogen, alksl. sub minted alkx I apxk subst puk'd .a n\ laXy I. subst Puled mx kdkx L hcicroalksd. sab-titaxed hrlom '·.»; heteroaty hdksl or sub-minted helottuirylalkyl as dcimcd herein. Rcpre-crtlafis e examp es nwlade. bat aw n,n limited t<» formyl, acetyl, cyelohcxslearhony I. extiohexshacihy ieaih» u 1, I'-enzoxI. hettzxIcarbeny s and tne bkv

Aryl’ by irsdfor as par? »;-t another substiment, refers to a rnonoxaknt aromatic hydrocarbon group deified by the re-uox:d of one hydrogen utota fr-m ;.t single carbon atom of a. i>ateiit au-matte uug sx.»tem. as defined hvtent. typical aryl giottgs inc tuk. but :-ie not annted ?o, gi· -tips derived from uccautbrx tone, acettaphihy leno, acepbenanthis tone, anthracene, azulene, benzene, chrysene, coronene, fluorwhene, fincrene, hexaeene, hex.aphe.ee, hexalene, on mda^ne, χ inda<.cnc mdmw. mdenc. naphtha-ene octac,.sc. ectopbene. >«Uaknc. ovalene. penta· 2,4-dtene. penhteoae, pemadenc. pentapbene, pcryiene, pheualenv. pnenanthiene, ptee-ne, pteiadeuc. pyrene psi-mtbreno, nrbicene, tripbonyhTu.-. <rmnpritbaleite ,mu sh-..- like hi some embodiments, an aryl grrmp comprises from ^f> to .‘fit Ctohon amm- tl'h-l'w aryl». In other embodiment- ,nx ary I group ».ompusos from p n> I' -.argon moms (G ,-Ci my I) hi st ill tthet emb-dimonts. an atyl gump ee-mpH-te* from <> to 15 ee-non as>>m< ίί.>1anl?.

\ty lalky I. by iiselt or m- p.m of an».-?het sub-titnent. ietem to an any ebv alky I group in. which vne of the hydrogen atoms: bonded to a carbon atom., typically a terminafor _:s/X carbon atom., is replaced \x ith an aryl grotip as. as defined.herein. Typical arylah-.y 1 gr-'mp.s. mchbL·. bm are n-n limited to, benzy' -pheny loth j^-1-I -y 1 ^s-pli'nyletho>-i-yb raphd-y Imetby ^! ?-maphihylote.m~l-y 1, .l-naphthsk then-:-sp n-mlvhobon/yi, ,7-n.jphtbepheny Iwhan-l-yl end the like. Where specific alkyl mrneties are intended, the nomenclature mylalkanyl. aiylalkenyl. iilo an alks. ts used I . so ne emhv worn- . 1 ms'¹ id x' j-e,p ». i( -s. ,) . \ la -λ I t ; the alkanyl, alkrnp 1 ,-r alky ns 1 m,.,tets of the arxtalks I group s ft ) <- kyl an-1 the ats m<\., sy is (Cfi-Cyjj an I In cab-r embodiments, map, kdks noun is μ R-i's ) ars J\d < y the. jRansl. alkenyl nr alky,ny I moi-.-ly -d the ars Inkyl group is (s' -s\^! alky 1 an-l tne myl rmi- b i- ({ ..u }4 aryl. In. still other embodimenis, an arylalkyl group k (Cg-C_is) arylalkyd, eg., the alkanyl. alks'isl es alks si mo.stx ·> the mGa kd moia> i-<.C -C i .»lksi an I the anl moub e p ₍ l aryl.

'CvdoalKvl, by itsck or as part of another sub-huteur, relets to a sataiated or unsalnrated cyclic alkyl .radical, as defined hereim Simi.lariy, f \ do'Jkx len-., bx itself or as

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P:CWS2(H)8/065058

2017200704 02 Feb 2017 part >-f anoihor sub-iitucut, refers h>'-auuwed >ί unsaturated ex dur aluxlcue raroetd. as defined herein. Where 3 specific level of saturation is intended., the nomenclature Aydodkariyd''.

exck'idkeux C οι ' i'xeh>alkxox 1 is used. l\meal ^xek-alk.', croup- irchidc. I lit ate u. t homed ro. gjoup de> fx cd h<ui: eyciupiopune. exdohuumc, cyefopcnwiie, esckdicxane. and the tike. In some end·· -danenk. the cydodkyl m can comprises fu-ui 3 to ID ung moms (CvCi·, cydwdkyli h> othci embodiment, rise vxch-alkx ΐ gimp comprises from 3 to ? nng mures (Ci-C- cycioalkyb. t h·. erjo.dkx I may 1-. turthci subitum.d by om. ? mote hot·.:wt<’ ns incbid .ig, lair ma hmr.-u 10, \, P. O, 8. and bi. which much re rhe carbon atoms d die eych'Jikyl \ w monoxtuem or astihix idem bond.

' HeterodkyI/'' Hcteromkrroy 13'' Hercfo-ukcnxi and Hctercalkynyi.' by

-1 r sets e< 0 i. ms t >t otl x \ 1 ouxi t> <' < t >.. vx I ,dk s ix I elk λ i 'di' x .x I m < ->_s iexpccnxch, as win'en oue >? mote of Hi·..- carbon atoms (and optimally ;mx associo'.cd hydrogen atoms), are each, hxdcpoHdcnfiy of one another replaced wuh the same or dd'forem heroroatoms or hcfcromomic groups, Sirniiariy. 'Tlci'..roalkylene ' Hetere-idkany term. ''Heicroatkenyiene and “Heteroalkynyleue?' by themselves or as part of-other substituents, refer to alkylene, alkanylone, dkenykmc and alkyuycncl groups, respectively, in which one or more of the carbon atoms (and opii-'u,dh any ^soemied hydrogen monish mocaA, iudepcndcmly of-no tmo'hei, replaced with the sanie or different heteroaronis or heteroatoxnic groups. Typical heteroatotps or heroroatoniic groups which can >> p\u e the .'mbrm 'doms i _u hide, bin are not limited to, -O-, -S-, - ~v~ ·\Η- -mi β- -Άη - -S(t nM!-, Α(Ο > \Η· ,’d'b-b<e mj . mib na <om loci of

The heteroatomx or heteromomie groups may be placed at any interior position of the alkyl, alkenyl or alky ay I group' I ypi> al Ixetenatomic gi'-npx whieix can be included tn dune group inelude,. bm are not limited to, -0-, -8-, -O-O-, -S-S-, -Ο-S-, -NR^R*'-,

-N-N-NR'“’R ^j’\ -Pk^>K- -PtOp-, -Pi JR'*-. -O-PfOV, -SO-, -SO;-. -SnR^j:OV^<::;- and foe like, whore R‘^>!, R 'h R' , R ^u R R' , P' ^! and R‘’”' are independently hydrogen., alkyl, substituted alkyl, aryl, xubstiUrigd aryl, arylalkyl, substituted aryhdkyl, cycloalkyl, substituted ex c o,sAx 1,1 xch' sJexi.. i.x I Mm-oum-J ex-Jc'neu roalkx 1 houroalk J sifoguiircd luteim.-kx L heteroaryl·, subsutiited heteroaryl, heteroarylalkyl or sifestiwed heteroarylalkyl·.

Oxd'ihc-eumlLxl,m 'lk.-icn>cxcb’k'’hy uselfo? a< p,us ot'niiothcf -mbstguent. vfeis U' a atmated m im^.Oinmcd cyclic alkx 1 rad-e d in wInch rnw or mow eurh.sn m-mf? (and optionally any associmod hydrogen mums) are independently rcpl'ared χχί-h Pie same or different

WO 20(18/154221

2017200704 02 Feb 2017 lick'wijouL SinnUri\, Xλ cfohmcr,>;dk; leno, ly hxclf or as pari of caaabcr .xubxtmkiit. Evicts (<» a saktrated os unsmniaicd excite alkx tore kunal se uludi arc οι m>'K ,atl οι» Ootnx K.nd (•ptiCEXllk <EUX US'·» >uKttov k) <fo WC?ί atom' ; U1C .ndcpcudei'dx ί Cpl.-CCil A uh tl)C -aiito ·, t ddkuiji hctoiOxWan, I he t'><ioheici03ik>l Enas be tuuhcf '.nbsuEuk'd bx otic o- mem bdcioato.ms mvludtuij. n:>: not limited to. N, P. O. S, and ''•i. xxlncn attach to tip. carbon atoms J the co -,> irtci J.kx'. si,- .nonoxaka’ t r\dnx,· -.tn ,n.md 1 ymcl ho'ouau ns- to t./k-x. kic carbon 4tctn<<> tikltklc out cue not fruited to V P. Ch S, Rt, 11- W he e .-. 'p .ce I c ex cl <>f .όπκογε-ίι ex tnk'ikk-d, the roEncnckninc' _vx cfrhekm'-dkanxF' or''eye to! Met-mkcnxl' :s used, 1 xmcal cyekhctotcalks: gr<»upx nkluJc not .,·< not li-utied m. suoupx dct-s.c t.n it epoxides. a^-nr.·'. flummox, :miJar<-hduk'. morpholine. ptpx-raem,?, piperidine. pxmzolidm·.'. pyrrolid<me, qumtufodm:. and the like. In sonic cnth-Jmicn?-. rhe oUohcmroJkx I g:<mp compitscs h<-m 3 o 10 nog atom.' <3- in niembemd cxcbohciet-nlkx It In othej uEnnodEmcEUs. flie cxc^!ool\'l group Cvinpn-·.' mm ? to ’< ring aronix to-” oerok.Ecd excIvhe-oroJbA B A ..xch'lietero.nlks, nenp xia> ;>e .Obxitnitod at a lx ter,-a; on- for ·,χ.ιηιρ1ο a nikogen atom. Xx:tb .t tf Jkx I group As specific examples. N-mctiiyl-irnidazoliilinyk N-methyl-morpbolins k N-ntctb> l-pipcra/rts I l-ptpuidtm I, kpst.tooiidiusI and N-E-neihyl-pyriOhdinsI a··.- ;:-_l..lude,j v rfim the .definition of '“cycloheteroalks k 3 ex dohoteroalkyi group may be attached to the remainder of the molecule w a ring carbon mem or a ring hcteres&tom, 'X oiw>imd<' rulers i,· compmuids encompassed, by strueftiral fbnnulae disclosod herein we nc u l> - ar% 'pecrik compounds Within those formulae whose structure is disclosed, herein; Compounds may be identified: either by their chemical straeture and/or ehemical name. When the ehOTical structure and. chemical name conflict, the chemical structure is deicrm.inative of the identity of the comp, mud. The «οηηνηη,ΐχ >k «ibod herein may eontam one or more ehiml centers and/or double bonds add th> wforc, mas e\M as xterootsomxrx,. such as double-^,>nd txon>ei' < < · gemm it ts<> η/·'Ά, en.m<icre s-< or d a-Jc-e·tmorx 3ee,'r,'ingls, flic chemical structures depicted berem encompax-· JI poxUbk’ cnantiomers_:and Je'eoisomers e the ilhsstraied compounds including the stereoisomerically pure form. (e.g., geon'ck m Jly pure, enantiomerieally pure or dlastereomerieally pure) and enantiomeric and sie.u'o. wmeric rnixiures. Enantiomeric and: stereoisomeric mixtures can be resolved into their component enantfomers or stereoisomers using separation techniques or chiral synthesis techniques well kuoxyn to the xl'flkd atixan 'he fompec'wx max· al«'>vx^-s;·»r ·_Λ-ν·_;·_κο ₅-_nr--_n-cjH < >fr,· uri idm * ι.\ i >1

WO 21W1S4221 .FCT/l.sS2SWOOiS)

2017200704 02 Feb 2017 h>nif, the k-'to Fenn ami mixtures dicieef Vev.nbugl·. die chemical .'iruclmcs dep'eted heitm e>ic»aupas- ml pas-able uintorncrtc ionr* of the illustrated compounds. The compounds described also include isotopieally labeled compounds where one.or more atoms have an atomic ma-s diffeiem from the ;mimk nuiss eonxemloualh toimd m nature Examples of Kumpe- -hat max he mc’-q'-'-mtcd im>- the compounds <4 the inxemiou mcluJc. nu? me noi limited ι>·. *-1. Ή, ^l\\ “C, 'to, O <'<. Gmipuunds max exist maa,xu.l\a\q to mses wel as^hmcefoims, m-.ludmg bxduiied loims aud \-o'.:dc» lu gc-ieiul. c> lupeund» imu K l>d atod. s<>|xat.d tv \ ,-ssdcs. i 'citam vompemtos mux cx« m .nuBiple c i Imc or amorphous itoms la -.ιχ'.,ιΐ, nil physical forms aic eqmxak-ut fin the uses comemplatcd herem and arc imended to be xutlmi ?ic s».opv s i 'c picscm . ixcnn.cn *· minei, r. m<wfi: bo und.mtocd, xxher. part al stnieiaiCs ef fit. >.ompoumls me il u-aimcd, tuat brackets md ca\ Ba. p mt > t attac i n.rr of toe paipal structure to the rest of the molecule. 1 lie term imitomcs ” as used herein refer» to s«<mu-s mat change into one another with great ease so that they can exist together in equilibrium, nor example, the following compounds A and B arc tautomers c-f each other:

(A) R 'Hah·.'’ bx ssdf,ax part <4 arothei snUt'mcn* icfi.te to u 'adieu -Γ. -Cl. -B; <*' «icteto&ryl,⁵’ by itself or as part of another subsiituenfi refers to a monovalent hcUToaiematic tadical dctixcd bx the icmoxal at >-uc Indfogen ato'U ueri a ung c mem otto p;tr-.-m heter-'aromatic rmg system», as d;.-fmed hecem. lypu-al hetcroarx I gr-mip» include, but are not limited to. groups derived from acridine, β-carboline. chrormwte, chromone, cinnolinc, feran, imidazole, indazole, indole, indoline, indolizfee, isobonzoferan, isochromone, isoindole, isoind-oline, isdqiiinoling, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridihe, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrane, pyrazole, pyridnzine, pyridine, pyrimidine, px rrole, p\ n> dizine, quinazoline, quinoline, qninoiizine, quinoxaline, tctrazole, thiadlazole, thiazole, thiophene, triazoie, xanthone, and the like. In some embodiments, the heterouryl group comprises from 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiment-' the hcieroaryl group comprises from 5 lo 10 ring

WO 20(18/154221 .FCWS2(H)8/065050

2017200704 02 Feb 2017 atoms (5-10 memhcicd ki.k<'Urx i) Fxcmplan hckreaty) groups include tbow dc'-ncd h”m Iman i!ik'pl:>'i»e p'-nokx b>.'it/x'ihi>'p^:K'ik. ben. <4m.m, b-ijzmm'd.'»· c. md”L·. pxiidcie, pym/okx mmwhnc. ’tmd..tzole >>xa/ek'« ki.-xa/ole anti pvrazine.

'‘HctcroarylalkyΓ ip itself or as part of anothet -ubslttucm icfcts -e an a<. chc ;dl\I gi--up tn winch one of the hydrogen atoms bonded 'o a easls-n a?, m, -xpicalh a tcimmal m y’ >.erbon atom. is replaced v-ith a hetvroaryl group. X\ here specific alkyl mmelics are intended, 'η. r.<· u.:ach,tiiich<_ic’,».a\ i.’ hoax'., hckioa y Lkcnyl and <> huei >. <yla sxuxί > used In seme caiiw-dnnonts, the heteroakdalkxl croup is a ¢,-21 member». J nck-o-ax iolky 1, e.g . the alknnx h alkenyl or alkynyl moiety of the helerourylaikyl is (C'i-C$) alkyl and the heteroaryl moiety is a 2 lo no id'-Acd lu'cnxt x I I' .cbet .n.nodaucnts the ^bet ,ο,ιηΙ,ιΓ ». v ,ι ο B u..nbcKd heteroary Ulxyl, kg... the alkanyi, alkenyl, or alkynyl moiety is (C rC?) alkyl and the heteroaryl mouP s a ρ··’·0 membered heiermmx I

1‘arcm V->m,’.uc Ring >\<fi.ni refers -o ,m unsaturated -..relic ·ί polycyclic ting system bur mg a '..oniiigan..J a cieciron system Specίiieaily induded v iihin rhe dellm-mn of p-arcm aromatic ring system'' arc based ring system·* in 'xbich one er mme of the ring arc aromatic und one or more ».d the rings arc saturated or unvatm ated, such as, fur example, finpreud indane,indene,phenalene, um. Typical parent aionmtsering systems include, but are not limited rit, aecuuthiyleiu, accuaphthxkmc. acephenamkrylene·,-aUthfoeene. atndene, benzene, diksenc, veo-usme. Γ.η<η..ι/0^ηο. Ih.> cik. hevsuene, hexuohenc, hcxuldx, u'-na'.ucdic, ',-mdoscnc, md,me. mdciu. oapbt udene, «‘cRk^oe, ee^fapbenc. ><iakre owdere pcuta-2.4 dune, pentaeene, penudene, pentaphene, pcryle-ie, pfamakme. phenamfwne, pinene, pfeitidenu, pyrene, pynmthrene, rubicene, triphenyteue, trinaphthalene and the like·,

Pukm I Idem-o-maue Rmg Sxswm tele’s to a p .'cut moinarie urg system in uhteh one or more earhon amnk icmd optionally uny assoernkJ hydo gen atoms} are each independently replaced with ihc same or different heteroatom.- Typical heteroatoms tp replace the carbon atoms include, but are not limited to, N, P, O, S, Si, e/e. Specifically included within 'the definition of “parent hctercaromatic ring sy stchi” are fused ring systems in. which one or more of the rings are aromatic and one or m a r of the rings are sati.ir.itcd or unsaturated, such ;.ts.. for example, 'bensodioxan, bcnzofltran, chrc-mane, chromene, indoku indob tie, xanthene, etc. Typical parent 'heteroaromatic ring systems include, but are not limited to, arsindole. cMwolc, p-emb c-m-manc, cbu-menc cirrohi'e, furar, nr -Ij/nL·, mJ.’/· de ircol· , idol ί. ,

WO 20(18/154221 .PCT/l.lS2(lW065050

2017200704 02 Feb 2017 indo!(zine, isubcnzo furan. isocnromcnc. isoindole. isomdolinc, isoqumolmc, iscahiurote, isoxazolo, naphth) ndine, oxadiazolc, oxazole, peamidinc, phcrtanihridme. pbcnantlu. me, pheno/nm, phlhaluy'iiR'. ptendme, ptnme. pyau, pym/mt, pxrazok, pxnda/hic. pxudeR. pyrinbdme. pyrole. py'<Jfrn:c, qiamizoiinc, qutodtoc, quirtoiizmc, quino.xaline, tcuazoie, Wi-aducolc. thuuolc. thiophene. nia?·· e, xanthene and the Hke.

Paticnf' include.·' humans. The terms “human and. patient” are used iutcrcliungcanh· hesein.

'•Phurmacvutio'il) acceptable'’ refers to being suitable for use in contact ufth the of humans ;md ainm-i^ v, about undue- tosieitx. irnummi. nlleigic ιοχρ-'ηι.Ό. and the bke, commensurate xxnh a leasonulde benefitfisk ratio, and effective for their intended use within the scope ofsound medical judgment.

' Piexnig orprexcr.'ior .tors* a .edue'O , w ι si < t ny nmg -t dise.ue ei disorder R,_t caii'dcg at least on·., to the clinical sx mpt>>nw of sh·..- disease not to· develop in a patient tb.u max be expos·-.J u> or predisposed to the disease but dues not vet experience or display symptoms of the disease;.

“P: electing group’’ rd'eix n> a grouping of momsthat wrh.-n aua-.bed to a reacts·, lunctional gtoup in a mok-culv nia‘'ks. tedueuaor prevents reactivity of the functional group. Examples ol protecting groups can h·.- found in Green e( u/.<₅ “Protective Groups in Organic ite'n'x’h' iUfo' ?^U>J 'Nil m>l ikiN>n <* >><' '( empen bu< i >< Sxnd'eU Gtg.m > Me^,rbo_W'\Kc.s Ι~\ (hv'o \\ lx m.l S> ns > i-l*V> ReptCxcnkW' e . nm· g toeu eg gtonpx m* hide, bu? are not limited k\ ibmyl.acetxl irlfluoroax'crx 1, bens.y'·. ben/x'lexycctbon'l t'X.Hzi,ter-tebutoxycarbonyl (“Boe”), trimethylsilyl (“TMS”), S-trimethylsilykethsnesulfbnyl i 'si ‘ I H\l. x'».>xm . e>'tnix gu I px mk o' ό irk m h.e end n ’*xh <. > fin ' I ! TMC? ) mi dln.'ixv,aibonx ) .rd h If-e R _t>'e.xeiiLsL\ehxuroxx pnmrtmg groups mclude but are m>- h'maeO: -o tnaxo v.her·.- ih·. hyimxx go-np eiiher acylated or alkylated such ax benzyl, and triivl eihers a$ well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl, ethers.

“Saccharide ring” is also tawa as sugar ring and includes monosacchride, dtsacchaudc. and poh.eaa'hariiL· nog Fuvlemblx fne -.itch aide jng is a 'noiK'-ewbarri-le >.ny Examples ol ueh:md,.s memde glucose Idcxhoxm, fiuemse. g'daeto^·.. wioxc and lihoxe By denvauve ofsaechandt nng, n is meant the non-uamral or attiticial saccharide rmg

WO 20118/154221

P:CWS2(H)8/065050

2017200704 02 Feb 2017 xfiuaem the sleuoehemisU- (.enter- .uc pas o.-ab. o: c. trpfe'c'.y different 1'«»ii t mse . ''i-κ naturaf .utcchai kk ring ' Xalt’ ufeis η - a salt of .t co)Up>-ui.d '.shici. pos..exs^s l κ deseed phaniiaeokR’tcal ack* nv m the patent compound Sadi sj'u irdudc {I) tied add'm-n -ails. !<:: med with inorganic acids sud· a- hydrochloric acsd, ΙινΤπ^οηηο acid, sulimr. amd. nmic <K(d. ph-'.-phoiie aud. and the like, <> foimcd w sth >· game acids -adi as aec'ic acid, pi> p-oinc acid, hexanoic acid, <ycl>:-nemanepi>-mume acid, gixeoltv acfe. pyrmte acid, ukuc -kJ. makmic acai, siicc tntc acid. malic acid, -n.de w acid. fian-n »c acid, tai lane acid, cm sc tie id, bcii/oic acid, 5-(4-hydroxy benzoyh bcnz--ic acid, vinnanne acsd, mandate acJ, motl-a-ic-ulfotsic acid, ethancsulfbuic acid, 1,2-et:hane~disulfbnic acid, S-hydroxyethaaesulfonic acid, bcnaencsuifomc aetd. d-chloi-’Kiicciiemk'-toC acid, .' -lap-iin-ak'ise-idfo.nc ac J, 4 toluene wdf-nne acid, cm-iphm.-uln-me acid. 4-nicih\lOii.xel>-|2.2 di -(’Ct-2-enc-1 -ca-boxx Re acid. glue*-l-eph>:iic acid, 5-phenslpr-tpiomc acid, rinn.iby bi-.:ette acid tertiary hutxkteciie ueid. lauryl sulk-tie a-,.id. giueonk acid, gkifamk a-..id hydroxy mipbtl-e-l·. acid salfexb·.. neiri stearic aetd. mticouie acid, and the bk>... or _v'l χ-ths formed wm.n .m audio pioton pm-.m in the px-vni tempojad ni replaced by a metal ion. _t an alkali metal ion. an alkaline earth Ion. or an akiminum ion; or eo-'idmatcs χμΗι _3;! oig.-.r.ie hose such as cthanoki'rth'c. diethanolamine, nieth.me'..m'me N-methylgiucamine and the like.

‘'Soixarc*' means a compound formed by solvation (rhe eombin.itmn of solvent molecules with mdeeaies or ioiw of the sohtte}, or an: aggregate that consists s.<f a solute ion or molecule, i e.. .1 compound of the present inxenlkm, with one or more solvent molecules. When water is the solvent the corresponding solvate: is ^ikhydrate”.

'fx-Aido' aNs» know si as ..'nine oxn'e oi , mre-Voxide. mean- 1 c-tmpound tho derives from a compound of the present nivcrtrion via oxid.aion of an timine group oftbe compound of the pn-x-m mxenk-m. An i\-i>\ido typically commos ire fimctional group R A -O i-c-mrtimes -x ritten R \ ~>' i or R>\- -AJ1.

^Substituted,” when used to modify a specified grcuip or radical, means that one or more hydrogen atoms of the specified group or radical aro each, independently of rme another, replaced with the same or different sabstitucnt(s). Substiiaerit groups useful for substiluting situated carbon atoms m fne sx» iu.'d ,'t-*tip o^!' tadn al inc tide hut ,ue isol 'trifled to -R‘, hale.

m-OR’-SR^-x, X -\R R\ \R \o fR' r ,bal mn d'S., <Ί -\-ίλ\.-8(\

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2017200704 02 Feb 2017

-Xtt.-XO'. X-,-Nv-xo -xt'BAR’ -8|()1,1> Ν'>)ΟΚ>ί$(()Ηΐ’, -O$(()hOR“, -ΡίΟΚθ'λχ -KOh;OR^:')(O k -P(0)(OR^!'}(GR¹'». -C(())R'\ -CtS)R”, -CiNR^l')R^b. -C<0> ί. ·( ΙΙΨ »R. Ί tSh A. -t tOAR’ R\ -CAR* )NR’R', -(X (O)P^!. -( X (S)P'. -(X ((ft; >. -< >('(()IOR ’. -(X Mk. -XR^!(’(O)R’ AR’C<MR\ -\RV<O)<>. Ap t'((W '. ••NR^hCiSK)R\ -NR^bC(O)NR'R\ -NR^bC{NR^f,)Rⁱ’ and -NR^bC(NR^h)iXiR^l'R'. where R^d is selected from the group consisting of alkyl, cycioaikyl hcteroalkyl, cycloheteroalkyl aryl, arylmkyb heter caryl and hetcruaryhtlkyl; each R^b is independently hydrogen nr R; and each R.^e is sndC:K^;jd’U:l· R <u ab.t.jat vdw *h; ‘vo PX run be:a\ert togetherwttn 'he utiogen .tom :o which they a;<. bonded f--im a4·. ?·, h· <»; membemd cycloheteroakyl which may opimiully •nciude i:<-m : n> 4 Mthe same ot JdTctc.r .-.umtsma nerciOsUmt^ sJcuol Horn the ri mp consisting of Ο. N and S. As spemtk example-. XR'R w meant to include Nil . Nil alkyl. X p\;:<'hdmxl and X mxnhobay I A -m- mu spcuf.c Cvtmp.e, a sui'sntatvd alky, is mearn to include -alkykne-O-alkyl -alkylene-hoic-vary i -alky ione-,.y cl'-hctcrmtlky i. -aikyk'ne-C(C<;0R^:l·, -alky kne-C(O)NR^bR^b. ami -CHrCH-C(O>i Ή;. I he one or more substituent groups, taken mywmer w uh rhe atoms to which they me bottded. may form ;; img mclujmg clo.dkyI and eyclohetcroalkyL

Simtlatly. stdxmtucnt groups asetnl foi sub'-mmii'g unsaturated e-tik-'i au-ms in th.' specified g’oup or t ttdiea I include, but ate. «Ό I mited io R'_ h-tio. . vlV’. xR \ S , -XP'-R’ ir:halom>,.ihy I -CF .-IA -OCX -St X,-Au,-NO',-X^,-SO 5Ά'\-bFJpO . -S(Ol'UR'\ -Oo(0\R^;'. -oStOK). -OSfOpGR*'..-ΡίΟΗΟ i , -PiF'hOR^M 1, -PF MtOR 'XOR;. ~C(CHR^h. -C{$)R^b. -ClNR^R*, -C(O)O\ -CiOjOR^, -CfSjORfr -CiO)NR^£R£ -CfW'dNR'Rh -OCtC)K\-OCfMl>' .-ίΚ'.ιψ} -OC<0VR^f' 4XM)k^b ~\r‘7'<O'>R¹' -Xfi'AMR' ~NR^ilCtG)O -XR^bCiO)OR^b. -NlAXSjOR’⁵, -NRfc(0)NR^cR£ -NR^'fNR>R^b and •AR'ONR'hXR' R'\ vs here R'\ R' and R' are as previously defined.

Substituent group* lawful n.-r wihstoulmg nm.-rwn ah>ms in howmalky I and cycbthctcn«alkyl groups include, but.are net limited h> -R'\ <)'. -OR' -SR'f -S . -NR^CR^C _; idbalomethyl -CF:g -CN_; -NO, -N( π, -S(O)a), -S(Ofr( (R^h, -OS(O);R^b. -l ^sS(O)J),

-08(1 >pOP.·. -P(OM'). -FnOKOPf HO I -PiGRt >R ’k\)R^l R ~t (< uR^e X\x)p -A\k ’)R^!, -t <t >h)R\ ~i iS)()R\ ~i o (AR R' -C(XP. )XR^CR\ -Gt tO)R \ -Gt t>)R-Οι tOu)k\ -GCtSOR. AR\YO}R^h. AR^!'C(.S)R^b. -NRVlOiOR’'. -XR\ iSiOR¹'. AR^bC(O)NR?'R* -NR’ CCXR^R’ and -NR ^>f '(XR^KjNR'‘R^-, v,hs.m R'\ R^!' and Pd .m: a- prccionsiy defined

WO 2lWl54 221

2017200704 02 Feb 2017

Snboilueni grrnip- from the above kxlx asehd tbi sutWHutlog mhcr specified groups or atoms will be apparcm to fliesc of skill in the _:rt.

I he siik-utea'il - uw,l t<> -ubsunae a -p>.c.h,d g'oup uan K fn-fo,.: m bstin.ted. ypscmh with one >>r nrnie oftbe -mue >>r du;e>ent ;n<»nps sekeicd tf,mi -he vam-ns immps specified above rrcannv»' οι' ticafnienf' <q <nr- ekx-ase <h.s<>idvi icfciA j_u some emb<·«.; men:,. \> ,-rach io'.mg the disease or discide= i: c,. arro-tsae -i <educ the de- efopir.ent <d the di-.axe or at least one >·! the ebm'cal ,-y mpt-mis iheicot). In - thcr cmbodonents' nc,’^fuig' or ’hrcat.nwmf' ;ex·!- i<< amchwafine m least one physical paraniciei. which neo. not :»e dwcermbk- hy the paouu hi -et ctltci cnfoodmK’nn-, ' tie-itrng' o:' trc.ihnem' wfei- m rabmm vg the disuse m oi.-ofdcu cither phy-icahy. ic.g.. sm.hiii?.;nw-n of a discernible sympionu. physiologically, (e g , stabihcauon ·Ί a pfo,si>.al paiansetci) 01 I*r:> in ymbei smbodi turts,-'beating''«», '’troarmcni refers p·. delaying ih>.. onset of the Jisea-l·.- or disord·.. r.

‘Therapeutically effective amount” means the amount of a-compound that, when administered to a patient for treating a disease, is sufficient, to effect so'ch treatment for the disease The “therapeutically effective amounf’ will vary depending on the compound, the disease and Us seeetuy sod the ago. ‘weigh?, _t ic. ofthc patient k> be treated.

“Vehicle” refers to a diluent adjuvant excipient or earner with which a compound is administered, fhz present invention is based, at. .least in -pari, on ths discovery (hat an extra-cellular domain, e.g,, the Venus flytrap domain of a chemosensory receptor, especially one or more: interacting sites within the Venus flytrap domain, is a suitable target for compounds or oih.· euPtics :-. modaluo'he chermsen-oty rviep'm arc a w- hgan-l- \e· em-ngly thep e-cni mvcn’ivm p-<w ί-Ιο⁴- -, ver ng n'cdws for Id· elds ng chemo-.- tso-rs -i-cepto'' m.,.Id\-fs > w .-Π cn/POscnvirs roc> plot 1'gar,' moJilu r- fo addition me present m- rm, n p>'>>\idcx Ci>mpou^!’<ls and , ompo-ih ηχ , aw,ib> > , t rumbife'! \i bo n, scrxor- ?e· epi, rx ·.-' w I ,-x , 'lerroxcnxivy receptor ligands.

According to one aspect of the present invention, it pro vides methods of screening for chemosensory receptor modifiers by determining whether a lest entity is suitable, to interact with a chernoscnsoiy reeephu '<>./ -me or more iuler.uaiug xites xs ilbin the cxtra-celluku domain of the chemosensory receptor, e.g., the Venns flxttap domain of the diemosensory receptor.

WO 20(18/154221

P:CT/l.sS2(H)8/065050

2017200704 02 Feb 2017 \cceribng i>_; swlkr a-pecl >Y ihc pi_v,>enl imcuti.m, u pros ides melimds of succiiing for chemosensor y receptor ligand imuliflei.' os Jetenuirnng whclhcr a u>l entny is iiiuibte to interact with a chemoscnsory receptor,, and . ptionally its iigami w one or more interacting, sites ctdhm the estni-ecHuL:i donnon. t.<;., the Venin flytrap domain <·! -he ehoiie<iis)i> ueeptor. optionally m the presence cfs ch-cmosciwniy receptor hgand

In ecneod, the cxim-ccHtikn dom.ms ol a chenioscnson rcccptoi refers t,· ike extra-eelb ,at .. ns ό , ..aa.es, | a vben»» sc'so’t e> epi i and n-ua te ? «Λ » c> a .icy d ^hfb’ tg domain and a cyMcme·ueh Lnkci domam, which c -imecis the ligand toiiidhig domain and die test of the protem In ( kt·-.' C GPt Rs, the ligand b.nding uoma u is generally letemcd to a.- a Venus flytrap domain, the structure of which has been elucidated, e.g., using.X-ray ciy.4ml>-go.tphy.

A Venns fix trap domain typically consists of too relate. vA rigid lobes e>ameetcd by three -ti'ands lotmmg a flexible hinge region. In rhe absence of ligand, the \ cam- fly η,ψ domain tenU to adopt. pen c· nloimmi. ns mih welMep anted lobes as nell a<. closed eonfermations with lobes closer togei her In one example, the Venus flytrap domain, includes a region from amino acid 36 to amino .idd of human ΓΙ R.I, amino acid 31 ro amino acid 507 of human T1R2, and/or amino acid 35 re .mime aeid 511 of human IIR3,

The Venus flytrap domain of the present invention includes any ligand binding domain or ligand interacting domain within the extm-cellular domain of a ehemosensory receptor. In one embodiment, the \ mrus flytrap domain, of the present invention includes any ligand binding domain of a member of the TIR family. I n another embodiment, the Venus flytrap domain of the present invention inefodes any exfra-cellfoar domain of a chcmgsensory et op. r wnh .i shocm-v , omprismg t«.f fohes connoeied by a 1 tinge r-zg-on in yot amuhx-r c.mbeminent, the Venus flytrap domain of die present imennon inchsles any doinain cime-gn'mlme to the structure and/or fuiwu.m of a region iiiJitdmg ammo acid 36 to amino acid ^li*’ of mwan I IR I, am.n, .xiu Ή te mn<> ac.fl *n) . I bu oar I' R ' aid,ram i<aujb\' ammo .;cid 511 ol miwan fi R⁴ In sufi anoihe cn.bodmicnl, foe Venus flxltap domain oftho present invention includes any ligand binding domain of T1R I,, TIR2, arid/or T1R3 as well as aus pe -, mmpb.e wevuioi al'i le n ma. .tier 'hew<e [ xemp ais’le.-out. ms „ p.>\m cpK,., '.dilations to? Ti Rl and IIR2 <u.· sbeo.i; m I mures tel

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2017200704 02 Feb 2017 .WeOtdiUg. to the picsvut mxecu·,·», a chciiioscmvix reccpmt ixm l·».· uity receptor assaulted xxitb vhtnn-ens<ax se»<ation or ehcmosensory ligand triggered signal transduction, e.g,, w taste receptors or taste related receptors expressed in taste bud. gaterointesttoal tract, etc. In <«k cmbmluneut, a dwmmsensorx teccpim is a receptor tisat belongs to the feaumiembranc :c-..cpi>·? Upvit,smiix <j: <3 protciu-coupicJ receptee- U iP(Rs). Inunorhci cmht'temcut, a ehcn'osensmy riccpror is a mccptm wny. hig out ^mial trausducoou iw <me or luorc u proteins, la yet another end-odnaenn a ,. ftmosonseiy iccvptm is a rcccpim mat beh«r.gs to flniiik ¹ I or class C of (jPCRs. to \o^A . »»h.\ embcdii'ieiii, a cbeni> sc woi\ c,.c u, i ,s 4 fcc.p’.m that uck'isgs 10 the flR bunds Li yet an--toe; c.nbedi-ik.rL a c icmv'-eiMuy uccptot is 0 icecpt->i of 1 IR L 11 Rd. 11 R3 or tben ©quo -dc-ic·; οι \ :un ic? et a cmuhrot <>11 tr.eucf 11 still n:<ch,.. ernbodintcrit. a ehom-'sctoorx iveept-'r is a hctcrodimcr of fl P.2 and 1IR3. or then equivalences or variances,

According to dv. present Imams-η. an inb..-i\ien’ng site w ithin the Venns flytrap domain of a chcraoscnsoiw receptor can be one or moi,. interacting residues- or a three dimensional interacting space or a combination thereof, hi one embodiment, the interacting site of the present invention is within the Venus flytrap domain m I I Rs. In another embodiment, the interacting site of the present invention is within the Venus flytrap domain of TI R3. In yet another embodiment, the interactingsitc of the present invention is within the Venns flytrap domain of both TI R.? and T1R3,

l..to.i:dly such an interacting sit© can be determined by any suitable means known or later discovered in the art.. For example, such interacting site can be detemiiued based on computer modeling, e.g,, using snftxvarc such as Homology or Modeller (by Aeeelrys Corpoimion) to construct shnv 4imensicm,il hmwdogy models of a chemos© nsory receptor Venus flytrap domain, < >,’ . i he I IR,' and ca fl R3 Venus flytrap domains based on crystal' structures of b mmogoiw V>. nm: flytrap domium;.

fee·' an A' i, ling-no can ,,too ' m u\l , / baser ? . V a\ cry stellography and die three di mensional stoic tu re of a ehemosemmry receptor determined thereftmi, eg, the T1R2, T1R3, or TI R2/T1R3 heterodimer. Alternatively, for example, such an interacting site can be determined based on molecular mechanical techniques, e,g„ normal mode aiiotos.s Ice? < use anon \ elm 1;^- Monte ata, are -u mm.i ,d e d\ names sircilauci' to explore motions and altermuix e cunfonnation^ of the Venns ilytrap domains, docking

WO SW1M221

2017200704 02 Feb 2017 simulations -o dock candidate receptor bgand- and uanduLite receptor ligand modifiers into these moduss or mto experimental-v delctn v,j,.e w κ totes ci ebcmoseteOi» weep: ns / f.Rl and TIR.2.

in addition, for example. s-di an inieraet'-ne site can be determined based on amumciu.tes. i .g , .Mk-jiKViCd mutagenesis o, a vombination >·?'oxo “= more st·.table nivuiods hnovsii oi lute: discox med.i.g., 'meth·.ids described herein.

I , < X exaip.i e. sue ' an be uimge s >.?' < > s p. * e . d nes„ ->is ieecpfof . <.c . I I Rd and >.an he derennm rd m the presence - · absv nee of fia. > fis-re pm t >4 me cbemosensury receptor, e.g.. TI Rd. In another example, stub an interacting site >.an he determined in the presence or absence of a chemosensory receptor modifier and/or chemosensory se-.eptm ligand modifier.

In onv embodiment:, the mu meting site χχ itmn the x onus flxrrao donx-.in of a citemosensory receptor includes vik or more interacting residues of th·..- Venus llytran iRmain of a i-bcmcscnsory receptor. According to id·., present imemi>m, th·., mreracimg residue of the Venus flytrap domain of a chemccensory receptor is a residueassociated.-with any direct or indirect interaction between, a ehernosenwry receptor and a chemosensory receptor modifier or a chemosensory receptor Iigandmodifier or both.

In one example, the: interacting residue >:·( rhe present inx ention includes any residue of a ehemosensory receptor associated with an intenietion bctxx ecn a ehemosensory receptor modifier and. a ehemosensory receptor. In at-oHmr example, the interacting residue of the present invention includes any residue of a chemosensory receptor associated with an interaction -between, a ehemosensory receptor ligand modifier: and a chemosensory receptor. In, yer .inrehei > x.unpie the m ieraeting residue of the present invention includes any residue of a chemo sensor x r.-eepto» .-χν.»:.··'a tod withan interaction between a chemcsensory receptor., a ehemosensmx rcc>. plot modifier and a chemusensory receptor 1 igand modifier

In -till another example, the iteeracimg residue of the present invention includes any residue of a chernoscuaory receptor associated: with an. interaction, between a chemosensory receptor and a sweet, flavor entity, tog. any .natural or synthesized sweet flavor compoimd mciuding \x iihom am iinmatsom non-cah>rie ox eel hex or compouiid-c s edm cd cab me sa cel flasof compound, n-m-target e done sxxect flavor compound^. <ί> . Exempiai » sxxeer thix or compounds include, without any hmitatiou, cyclamie: acid, mogrosidej. iagaiose, maltose,

WO 20118/154221

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2017200704 02 Feb 2017 galaclOc, mammse, sirere-i.·, fructose, lactose a-partame, ncolarnc and other aspartame 0010..0:)0-. saceburm. suei.do-e, ueesulfame K. glncost, urxthsm>L D-i>xplophan, glycine. imnnr>>:.soshiloL mailstoL lacutol. isomall, in diega'tch'd gh cose -xiup (ilGSi iydio^e»iated lasch hx dioly /ale t ΗΉI;, stex it'ide, s ehaudioside A and otl;>.- s w cet Ster<w-b,iud gly cosides, ithhniK, sorrehmc and other giumdme·based sxxcetciicr-, tagatvse, xyiitra, high fructose corn syu.ip. o.O.

I j std m'Oinei cxaiuolc j. > /Ci.u: i?_ esiduo of the pscsei? noentaui i 'chides any n.'-aiue -'d a chcni-'cOUsOfx icecnn-i as* v: ccd χχ<th an mtvractKW betxwen a chess-osensorx :<·„ορι>·ι and a sweet flax-1 entit -..-00,10001 In .-tdl anotkei coinp',e, the i.jieiacting residue of the present invention includes any residue of a chemosensory receptor associated with an interaction between a chemosensory receptor, a sweet flavor entity, and- a sweet flavor entity enhancer.

hrs ,ιπ.-Hxer instance. the in rem·.: ting residue of 7·.: present mw. inion is a rex-due within the Venus flytrap domain of a chemosensory receptor, wherein -any mutation of which c· mid result m .1 change of the .win ily of the eh/mosui-rory receptor or the inip.wt of,i chemosensory receptor ligand to the chemosensory receptor or both. For example, the iruetacung residue -,>f the pfe.ren: smentkui can include any residue wirhsn theVerms flytrap domain of a chemosensory receptor, wherein the mutation of which results in a detectable change, e.g,, qualitative or quantitative change ,.«i the aetix hy of the ».bosm-sensory recce' »r »r response to a chemosensory·' receptor modithr and or elxnxosens-ny receptor l-g.md mod’ll »

In yet another instance, the interacting residue of the present invention is a residue Wsdxin -be Verats Hx trap domain of a,, hemosos'isory' receptor that miemetsor fornw productive •,met,ie^rie-i'(s), _t g xan dcr 'A ahs nuti J >' byrexipn-d'ie <jI<> n, m /.mrc groups, byd'Ogen bi'iuls ' ing 'Uaekmg inn ructions, >« salt-budging decWstaiie interactions with, a chemosensory se> opt--r modit:>. r-,-r chemi>sen-Ory reeepna bganj m-idif-er e-rbreh.

In still ,u-ai tur msi.mx'e, th*, in·ensuing residue of the A'enns flytrap domain of 0 chemosensory..receptor can be any residue.constituting one or more interaciing stuielitral cemponents of the Venus flytrap d/mam, which me ;is·^ related, directly or mdircetix, xx ifn the mretdiuen ucbxceii a shem- «sensory receptor and a chcmosonson teecplor modi tier or a theiw^ensoix teieplm hgaini modifier or both. For example, tla Venus flytrap domain st; uemre 01 ,s dieniosensoix receptor generally includes two lobes joint by a binge region.

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2017200704 02 Feb 2017

Rendles e<«isiitutmu mlem^img spoelwal uomponent of'L· V emis Ihliap d. iuam e-.-.n be. e a ies.diie» eo:wtm.tiea the InUiX legion die oinci side .'''caJ' lol·... o: 'cmba- on s. eh sobc that are brought -into dose proximity during activation or confermational change of the Venus Ils nap domain including w idionl aux mmiaium wrw.mcs on the miicr smlaccs of rise kibes pointing townds tc.eu oihci or-.-n ihe bp» of div h-he”> xriicrc the i endues aie pai Halix c.xpv.wd io solvent but »tdl cl»-sc to iv'iducs on the opposite lobe. <w.

I; Kempkin. miciocuuj. icsidae» of div \ enus fix ?mp d.-mom of a cbembsensory receptor me aide any ou·.· »-s more tcsidues *4 I) \I4J. SI 44. and Ho of a hunun H.R2, 2j S40, Si 44. SlUX YHB, I) 14.f and P2'⁷ of a human I IR2. V, R«. R3HJ>307 b.to?. and D2~S of a human Γ1Ρ2. 4| idh?. P1S5 U Sd, f3>, H<X. \ .«4. \a\ 1325. 13«. Rhx3. P3O7. E3K2, 132«, 1279, |n7. V6b. V3«. p = 42. Sin.', x ip. S3«. ⁵ 242, f -ρΐ. f,»32\ and Sl« of a human 1 IR2. 5) XI43. Si44. 1167. k<>5, Rfx.t. 1)3«. L 302.1 >2«. 1'1x5. Ϊ IS4. 1326. P302. ¥334, \3O5, kfi’YHOu Dip· J s.\2 i2 wjb\Vm» X 3«, f'>I 42 61 <>5, 340 s>m« I'.bl. J 1« O3?.\ and Sias of a hum-m HR? and to XI«, | μ,” Κίό R3S3. D3tY' FSG? ΡΓ;χΡ;« 1!« 5 3..Ο. v «4. A305 13?' Ht»O D3iP\ P 3S2.I.?« p. \ X .W DM.?. Sl« >hl 3 '03 ΐ ?+?, ΐ {’?, Q3?S ,md Sl« of a human I IK?

i'xeiupkto miciaCi'Ug ttoid :<» of the \ cmis fbto.ip ό nu.n of a chcmo»en»otx receptor with respecticr a chemosensotx r-.-ceptoi avdifict mcludvono ot more ie»»ducs of 1) X.i.xS'H and PU><· of.ί ht’run Π Is? ?iS40_vS H.Sio )li'\|}ll? and P2 '' of a bum m ΓΙΚ2, >} 11(0' Plc'.x, Π5k F42O, i,to2 \3Sk Mt)-J3.:>. 130« IWJ «?, D2?.x I?'0 16 \<>o χ'ίθ-q ϊ/ΐ i?, Sih?, Sti\ >j303, 12 Κ Π03 Q3\\. mid Slbx o- a himcr. ΓΈ2, B XII < and I.n, ofa bi'r .an ΠΚ2 to S i0, S 6^s S'03 P i I *, <mj >'/ , la mman I 11' .and Ojlb»' PIS' I IS I 13?.U Vn'k U0' I Η' ί'4η\ R3s'3J)3p, I 2x,2 P.?7XJ?to 167.. V66, \ W pi.p.Rlo' «ί}, 330-, Hi? I'lO.kQVx ano S't.S of a human I IR?

I xompkvy mlerai::K rcMdmw of die X’omis riwi ap e.oniam of a chcm>>sen»orx receptor wish respect i-> a <wxeet ilaxor ewnv sin h as -an -osc ar.e srem.ose include one or mor© residues of S40, S144, YI03, D142, F277 of a human T1R2. Exemplary interactmg residues of the Venus fly trap domain of a chemosensory receptor with respect to a sweet flavor entity such as saccharin or acesulfame K include one or more residues of 05; R385, D307. E302, and D278 of a human ΓΙ R2

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Exemplary interacting residues of the Venus flytrap domain of a chcmoscnsory receptor with respect to a chcmosensorv receptor h’gand modifier. chcmoseri.sofy receptor ligand enhance include one >>r ηιοκ sex dees >.4' I > Ko5. R383, I *30', F3O2 awl D2~S of a hout.m 1 ;R2, 2)846.8144 >Η'.\ΥΙΟ3 1)142, and Γ2~7 <.f a Immau ΓΙ112, .md 3i II t'7. Pi'S, Π84, 1'326, E3O2, V3S4. Α30.Ϋ 1325. 1306. R3X3. D3O7, E382, D27s, (2~fo 167, Voo. V3‘K ί>'·42. SIt'5,840. ^v363. Γ2^2,1 103 CVa, and Rios > I a human fl Pi

In the context of the present invention. any reference ro u particular h-stcracting residue. • '.r;-, Nt43 ci a human 1'1 R2 rceepkn. includes all of its corresponding rcsioues. e.«., 11 any residue of a human or non-human ΓΙR2 that corresponds to the same position in any method of xcqucnc. alignm.m. 2) aux jcsimie ol a mt-uat' <» .ivu- human 1'1 R2 tli:r, voiicxpabk to th·, same position in any methrid of computer modeling in the: presence or absence of a ligand or ligand its fortes, m any residue ot a human nr non human I'l R2 tli.c voncxponds to tin fo actinal or functional r-.-lc >n the particular interacting osiduc. -1) any residue of a Itoman or ·ι· m-hnman H R? that w .i poiym· -iplu,. χ wjauor, alkle<- mmah-m ,w -fl the paito.ulm tesicme '^;iany residue of a Immim ι-r rum-huinan fl R2 thnr h a eons,.r\ aih c substimnon ->r ccmsctx ath elx modi la. J sasiam of th-, particular re-ddu,.. and <'o an;- torrexpimding resfoi·..- e-l a human ->r non-htnnun T1 R2 in its- modified form, e.g., artificial chemical mimetic of the particular interacting residue or uo-modified form, e.g,, naturally occurring: form.

In another em.bodum'in. the interacting .foe: within the Venns fix trap domam of a (mcr.'>'en-oi\ 5 tops » is - u e Ιιονηχΐ- \d me a, irg-p*Cx'b* i he \ c i b fixtr ip jam i’' a ' I nee o ce ί cd p--” sellx m fo,r. χ bx rcr ι· ring ic\ dues - r om- » nx e ir iFk^- > e interacting poin ts, lines or surfaces between a. chemosensory receptor and one or more eheiBoxensiin' receptor modifiers or chemonerwrs receptor h'gand modifiers or a cpiaBinatinp rhere-»k Accouling to the present invention, a rufola·,.- ondminy or Um ng a sjxxv includes any hie 'ax one ο ί ec '>a- \ »>i - jv uMdo~d<-m Jct- i\r ate pc-es- re I x>> thi ε’ι x can pment tally interact xx bh atoms of a uhemosensi>ry receptor ligand or cheinosensory receptor ligand modifier or both.

F or example, fixe interacting space of fixe present inven tion can be. an j· parti al or xx hole ^pace xxithm -he Vet ms fix fl ap domain that i- usually occupied by one or more chemosensorx tecepbn sne-diilerx or dummserxerx tcceptm ligand modifiers when they iiitcrtict xx ith a chemosensory receptor individually or together. In one example,, the interacting space of

WO 20(18/154221 .FCWS2(H)8/065050

2017200704 02 Feb 2017 foe iux cnu>m is a space vx i(hiu the VcPti' Uy trap domain n.'Uall\ ><cupiC’l bx a chemos., ικο'χ uecptoi m.-daflci ·\ο , s>> ^ei f.ax m cutio ht aimhci ex. mpk, the mtciactmu space <4 the present invention i> a .'pace xvifliip the Venns flxtrap d'mam u<-milly occupied by a chcmox>.-i^<«y receptor Egand modifier,; g., sweet fbvor enhance’m the presence of a ehetnosens·-iy receptor hgand hi yet ,m--thcr ©xampk·. the mtviacimg space »4 the pu>em invention u-j sp,-.se vnthm the Venus Ex trap domain UHcrib occupied ip a chena xch.xop, ’Cecpb-i mode »i. e g . swca fl.-v* ..may and s chc ’VsCi’sch icecp' a ' uancm >J?f cn t e , sweet iia’-m csihty csmaiuct hi --rdi an· -mes example, me t Veiacting space > I ihcpmxtm ho cmι>-n is a specs vx iihm me Venus fly nap domain tuai is denned, shaped, or transformed imo based on an iniciuchou between a Jicmosvn'.oiy receptor and its ligand or its ligand modifier occurred partially or ciuitciy outside of the space.

Aec-'-Rlmg m ihe present invention, the Venus fly hup domain <d a ch cm. sensory receptor can be generally viewed >1* two lobes joined by a hinge region. Exemplary interacting space within -be ^s-’em.is fly Pap· domain of a dremosensory’ receptor mcm-l·..-'¹ any spa·,.© axsoeiafed a idt fixe binge region rhe nmei side of-me m ru > lobes the up »4 mw or !i\<> lobes or a combination thereof of :x chemexcBsmy rccepmr.

Exemplary interacting space within the Venus -lytrop domain of a ehcmoscnsory receptor \x ith respect to a ehemocensory receptor modifier includes any space w ithin the \ onus flytrap domain outlined or at least partially defined by the hinge rogmn. According to the presem mx codon, the xmge region usually comprises residues that are dose to the three strands connecting the two lobsS; In. sne example, th© hinge region comprises residues that are homologous: to residues observed coordinating agonists and antagonists in crystal structures of »me or mm>.. \ cnox ilynxxp d-mminx such ax d-J. m d-e mGluR rscepmr In another example, the hmge :'egi''-n of 11 k2 in-chub rcxiducx MB M4 1 ami Π67 ®f I 1R2,

Lxcmph: s imer.;ctmg x’fex iv uhm -he \ enus flytrap domain of j οη·,·η·χχχ?ηχ<>·'\’ receptor with tvxpcel t«» a ehemosettsory receph»’ hgand modifier include any space outlined ca at least partially defeedby ;th© inner side of one or two lobes -away from the hinge region,: as well as residues on the tips of the lobes that are brought into close proximity to residues cm the other lobe.

In yet another embodiment, the imcmeimg site nsthm the Venus flytrap domain of'a cheniosensory receptor is a: combmation of one or more mxeracting residues with an

WO 20(18/154221

2017200704 02 Feb 2017 nstewariniy. -pace of ibu dkm-wensmx secjpmr bm „-xamp-c. l κ ritaiacUne sue <-f a ehcsnuscU'··»- rceeplm can be mk:actmg usidiox ,.sscvuncJ v-<tb -;ne mteiac'mg sl'-iclmal component of a chemosensory receptor in combination with a three dimensional space adjacent, e e.. net less than I Angxbmu and n>a m>>rt than .-0 Angsltmns. m that mtaraeUng structural c- -inpoinjii Anmhc· c-amplc of the mieraetatg xuecu’a cbenioxenxer ivxzptot mchidc,m>. ae'n'g e,M,l< >.s av> uated w Mi ore iiuewet - lackra'. ccn.'^MKiP ?’ j -. u nnxetwvrv receptor in combination with u three -.dimensional space: apart from the intemermg struemrai component.

In general ?bc- sciecmm> methods pn-wded b- the present mxen?soi) c;m be curried >>ut by ;my suitable means known or lute; discovered, in one ombedhnent, rhe screening :-i<.ihods puw iced by the pieteiit mxtatu-n a=e earned our ?/ si.foo, iw 'N hruc screening” u-mg any -mtatae ».oinpuici moderate swtera or a.-.? specific or miu-nai design of u cmnpound using .my suitable compiler design -ystera la another enW.-dirnem, the screening net > > Is prm, idcd by the present invention are carried out w biological ass. ¢. s, <. e high thr-nighnut:screening of interactions between compounds and a chem-«sensory re-.epn-r or :N fragm-.iux, c q . goneiienlly modified chemosensory receptors or fragments thereof such as mutated Venus flytrap domai ns of chemosensow receptors., fin yet another embodiment, the screening methods provided by the present, invention are earned nni^!,-« a combination of biologic jiI .Hsay(s) and computer modeling and/or design. For exampl·', ihc screening .methods provided by ihx pu'sent invention can be a combination of high-throughput sew on mg of interactions between computer designed or pre-screened compounds and «nutated X'euus .flytrap domains of chemosensory receptors, hr a u’ example, ‘0,- se e- r ng moihm' pn>\iJo<l -sy the ptosor; Bweni on f->r chcm-isensoiy r-.-ccpi-a me-di:iers in- Judex detom-iining an inioiucring sb,- mme ,i km«wn cm.'moxciwmy rcc>. plot modifier, eg , <wrmlm,ifly -imilas n- a vboma.-enxory re».opu.r medioer of mlew.'-a and then determining wln-the- a test oamy h siiiiabJe to interact w ilh die chemoxi'n-'iy receptor w the interacting site so: determined.

In another example;, ihc screening method provided by the present invention for ehemoxcusoty receptor modifiers metades dcienninmg whether a text cnhlx Is Mutable m interact web chemascuscry receptor -.'<>/ a psedelesmnsed snleracing; site, <·.7 . an interacting site selected or -leterminod prior a> screening, including w uhoui any nnmaUon, selected or

3fi

WO 20(18/154221

P:CWS2(H)8/065050

2017200704 02 Feb 2017 «k'k'nijincd hasc«.l on ku.-wn chemnsen-urv seccptm moddk>- or de-srud ebamctcrLsUc- of a chcrnosensory receptor modi tiers.

I vi aa 'ihc’ vXantp e ( \ χίλιι'λ; an. .hoe »*'<<' ifod n the p’.'s^e. Lwent o.j for chemoses'sery receptof hg.;ud mod-ficro mctodcs dotes aiming a docking site tbs· a cbesnoscnsoix rcceptoj hgaud and .-ubscqucn?lv detcrnnumi* whc?hcr a test entity _:s suitable to intvuK't with -he chcmo.-eiisory leccptoi hetmd vZ.? au interacting site selected m bghi of the duckius ot the ehem- -i'Ciu-orv icccm.'i hg:md -\ecmdmj. m the present invention. docking p.oecs- e . s in Jude an- km v- n , i '.uci d - md med ·.*- I oi > a.mce. Λ - rom van tor - proccw m ohich th<. eeutot o?' nutss. oiicnteumi.-. and internal degrees ,.?' freed,m of a ruulecnie me modikvG to it? 'h..n n0 a p ed.-tcn'a.ncd -p tee m ., snort.n.d model I·' < m cvtmp.e, Gxkius can ·κ a p.oees- e me i include- uanskti tg one rototmg a ehe n-'.-ensoty iceeotor hgana iclati -, c t>- the chenio-cusmy icecpsoi suuctuial model, _t g , the \ 010.1.- tlvtsap doma-n of a clicinoscns.tr·,' icceptor model while ^hOubanoousiy .xdiummg micrn-J tomioual angle.- <>; the chent'>sensoty sei.cpt.tr KgimJ t·» -It it into the insoukting ί:ΐο of the chemo-eo-tts reecnioi \u example of a widely used docking program, is GO DE from Schroedinger, Inc.

In \\t anolhet example, th·., .sere-.ning method provided by the present invenhon for chemosensory receptor ligand modifiers ihelndes determining a docking site for a chemosenspry receptor ligand and subsequently determining an inuraelmg site using a knov.o modifier of the ehcmrwensory reecptor hgand and then determining whether o test enusy is suitable to interact with the chemosensury recept:or ligand via rhe mknictmg, site so determined.

I.-et tt s .er s_iJOip Jm’s *een 0 nie'bot poud'd^ ike pt -e s xenl.ti for chemosensory receptor ligand modifiers -includes deteminhig whether wtest entity is suitable to. interact, with a ebemosensory receptor vis a predetermined interacting site for chemoscnsory receptor ligand modifiers.

In -fils another example the screaming metl'md ρι·>\ shed by the present invention for ehemosi-msory receptor h'g.md moJ-il-.-rs mcltuks desi'm-ming Ahothei a tea entity is smtebte to interact with a ebemasenspry receptor by determining. < ,i;.. emictirretitly whether a cbemosensory receptor ligand and the test entity are su.hible t.« interact with the Chemosen.sary receptor in a predetermined interacting site of the chemosensory receptor or aft interacting site detenmned mmy known chem-.'^i^os > receptor hgand and s- mmkfi.-i ofmurest

WO 20(18/154221 .PCWS2(H)8/065058

2017200704 02 Feb 2017

In sldl another example, rhe scwcnmg method prox idcd bx du. pseseut imuition Io ch moxcrsotx fex-p’.es ic-a d mod lk> 'Klu< ex dcesnetmx’ 's-'ethi.: i k-Win hMiii.il h? to sutesacl with a ehemescitmix receptor rto .m mtciaetingsite, eithes prc-dcitrinuicdoi -urn as λz'd as whether a test cuntx is suitable to fotemei xs hb a ehcmosunxorY icccptor ligand, lu still anothci example. ?hc sc-eemng method provided hx (lie present inxciition fot chvtno'xtw··ιχ tcccpioi ny.nd moddk-ΐχ mcliRks detenu mrg whethe: a teto cnin r- xuiuthlc to interact '.x itli a ehemosensorx icceptor tor an interacting site, either pte-determined or not. as well as whethvt such miciach--n can χ-tahth'ze a coaiommtmma xenn-eh-sod or closed conf->rmatmi> v, irhm the Venn' ilynsp domain formed hx the totzraetton henuen a chcmo.w.n.wnx icccptm hganu and a ehcmosenscnx m-ccptor, e.g.. by Ibnnmg proteuctixe additional imet actions w Irhin the hinge region, lobe» of the Vcnu^ tlyntm domain, or ηρχ of the fk turn domain e.-fi xau de; Weak, Ritual of hyhophobiC atonw or atomic gi“Upx. hydrogen bonds, ring stacking interacF-ms or sah-bridging ekctn-staric miemedonx. <

In general, any suitable mean-· known or later Jiscoxered c.m be u^ed to Jeu-miinc whether a teat entity is suitable to interact with an interacting site of the present invention. For example, one could determine the suitability of a test entity based on whether pan or all of a test ent-ix fit» mto a paiticuku sp-wc emailed bx an mk-iacnng site, -'χ, whethe: a test enuix fits mto a particular space entailed by an intei acting site substantial ly the same xvay a/knoxvn ebemossnsury receptor modifier or»heme-sensory receptor ligand modifier does.

Alternatively one-ecmld dek'fo-ime the suitability of a test entity with respect to an interacting site based on: whether it forms interactions with ar hem· sensory receptor similar to the interactions formed by a known chemosenspry receptor nx· >>h For or chemosensnry receptor ligand modifier when, they interact with the interacting site.

In addition, one could dercmxinc the snitabilits of .1 test emin based on win (her h lo m» u Im u e mi oxionxo I c'mlerat i^ site - g xan»k 'k mix bu .u · I e In pl < n atoms or atomic groups, hydrogen bond-' π ng xlacking xwnicfions, or sab-bridging olectmxlanc intetaefions, ete. In. one· embodinient, one could determine the suitability of a- test entity being a chemosensory tecepior hgan.d modifier based on whether it forms productive iuteractfons wdh au interacting site w ithout forming vail der Weals overlapping with one or more atoms of a chemosenserx fccepsu or lux x'lu.-imwcnson uveptei ligand tg , m da cm.k'xi of me oi more

WO 20(18/154221 p€T/os2(mms<»5o

2017200704 02 Feb 2017 conformation- of die \ ones lb. tup Τ-ηΜιη ui hghioftiu· pos-ibL' Ikwbilm <4 the VctitK fly Imp domain.

Aceoiumg to the present noemj-.m. a tv't ei’ht' xu'.Jde to mtemU wflb one m more interacting site- w ithm the V-cmu fly trap domain of a chernoscrtsory receptor is indicative ota candidate fora ehemoⁱ<nsofy receptor nw-d-fie- orci.eine^:n<>5ry receptor Ugand inodtfivt. h> <cw cmh>-dmicm, a te-t entity -unabk to mtcjaet wifli one ot urn: mte e.i.',mg ·> tes wmmi flic \ cam· fly tiap .foimimnf ' IK2 >s mdicati\c <>f a candidate for a ⁵ '. R2 icc.p'.er n-odiflei or fl Ik receptor heand rnodifler. In anmhci cmh-diincnt, a ι·,·Ή entity 'much·..· n> interact w ah one oi mor·.; htfcf ae-mg u-cs wiflifo the Venus flytrap doinam of fl R2 is iijdicutoe ofa candidate for a I :R icccpfla iib-di.'ict m I IK i<.cepn>. hcand irodifiei. to ye:. i'otbci cmu<idm'cni. a te a cunts suitable to interact with one or more interacting sites within the Venns fly trap domain ofTIR2 is indicate ·.. <0 a candidate foi a fCv.ptOi nwdifiCi Of wccofln horn'd lt> dd'ici to; a i'CCvptOi of GPCR niperfamily. In still another embodiment, a test entity suitable to internet with one or note 'ntesaotior· su.,s Witlur foe x era·· fly turn dem..mi cl a •.bcmeserson ic-.on;m w n-bcame of a. candidate for a receptor modifier or receptor ligand modifier of a receptor that corresponds o the <.hem,-sensory re>..opior or belong·* to the same family o? '..lass as of the chemO'-mw-ry receptor.

According to die present invention, a test entity suitable to interact; with one or more trUcracring sites within the Venus flytrap domain of a chemossusory receptor s ndixative of a candidate fora du'moscnxory receptor modifier or cbemosensory receptor ligand mod her, to on. embodiment a test entity Mfoabte to ime’set with -m·. e·? more interacting siu-' wirbin rhe Venus flytrap domain of T1R2 is indicative ofa candidate for a TIK2 receptor modifier or TIR2 receptor ligand modifier,

In one example, a test entity suitable to interact with, one or more interacting sites confamme one or mure interacting residues of K65. D.lffo, 1.,2.79, D3i)7. Rns.V and V3s l >>f human 1 IR2 Is indicative ofa candidate for a Tl R2 receptor llgaml enhancer.

In another example, a test entity suitable to intenter w ith mis or more interactfog sites containing one or more interacting residues of S40, S I44, ¥103, D142, and P277 oflmmun Ί IR2 is ntdicame ofa candidate for a Π R2 receptor ligand enbajunr with respect m wurase or stseialosc or any hgand wth <i siniGure similar to sucrose or st-endosc or any ligand interacting

WO 2iWia4221 .PCWS2UW00150

2017200704 02 Feb 2017 with I I kJ tn a way oimiar s·· that <4 sncr-.-^c er saeudo'-c, e.g.. > o ore er nu-w interacting '-p.-tees.md et tea.lii>- U'-cd m -lur.'scei sacra-θ'-.-.

In the coiitcxl of the present appheatiou, any reference to a modil'.ci. i g enhaiteci <> inhume: <4 a ΠΡ.2 rcucpl·-' oi 1 IR2 icccptof ligand wclu.k·'- a mocilfc: ioj uw TIR receptor. any receptor of GFf'R super-family. or any ·ecopn-r corresponding to TIR2 receptor. e.g.. any receptor wuh a writetme, function, or expression pamua overlapping or similar to that of TIR2. In the present invention, a test entity can be any compound or molecule, < g . '=(> compound - r cntiu that poiemiadv se'.dd <v a >- uue ' i a d.-med J cm· scesory icvcpt--i niodihci >-i chemwseusOiv u-ecptei l>amt medifiei h ; cx.mj.de. a tee ciuity can twu member of a combinatorial· library, a. member of a natural compound library, a “specifically designed ' compound rh.ii w designed based -.m va- j->us Jc-nable femurns m mt <>:ulcs

In gcncwtl. a ehem-'sensoix wuc-w-? medium >·’ hg:ind me link's am Ci-mp»midoi corny capable of interacting w hh. < g. binding io a chcmesonsor. reccpte-r or m.-dt-brmg rhe *i-'U>..hne or lunct-on >>f a chcnv>scnsory recepf-n, eg , activate, deacr-varc. mci-.asc ot -lecie.ise the signal transduction activity of a chemoscuscry receptor, especially w G-protem signal transduction pathway.

In one embodiment, u chemoscasory receptor modifier or ligand is a compound or entity with sweet flavor including without any limitation anv natural or synthesized sweet Savor compound, non-caloric sweet flavor compound, reduced caloric sweet finer compounds, son-target-ealorie· sweet flavor compounds, < < . Tvempbry --'v.eei ilavorsempoimd'· include, wiih-.mt .my limiumon cy Jamie ajd, mog-vsJ-.·. Ligixtow. m.ihosr. galactose, mummw, sucrose, fructose. lactose, aspartame, neotamc and other aspartame derivatives, saccharin, sucralow, «teesuli.um' K, glu ό-.-, eiyt > mf IMrypiephan, gly>.me, mj<”m'uv, sc.'oitol. m>iliit<>l. iac-iiJ. woman hx d. i.wanc·- c glu. ov syrup JIGS), hy dmgvm':· J st.ii -. R hy d'olw'ate (I I SIB, stm U'Suf., roham' os. I - A , id oil'd» svse·. i 8te-y;</-bik'.'d ply >.<>' d-. \ .j'.mmie -.‘.’’cianu’ anc oibci guamdinv-bascJ bivi’cieners, wgatevu xy hi·d, high fructose corn syrup:, trie.

In another emhodimem, a: chemosensory recepior modifier or ligand (used uilc'd cave·., ih . du v.escrt ο A i- .' i owp. .* w u er ax K.'txJ'h >, a. rvaluw ehcmoscii*<rry receptor, i.,g , ac-wanin', the G-pioic-n signal trau-dneti.-n paihivay ds.-OCimcd Vrth thi- chi-mcsensorv .cc. picj !u set ante u-r einbodmui' a i heri<tensor, rct.'pim m.'c.fii-t or ligand is a cotiipnimd or entity capable of hWldng or decreasing the activation of a

WO 20118/154221

2017200704 02 Feb 2017 chenuxseiisorx iccepuu. hi si di ;motbex enihodnuenL a cheinoretj· y rcccptot mvd'.fic' 01 ligand is a compound <»j cnutx repablc m modulating flu.· activity of a chcrooscrisory receptor and inducing a thcrapeuheJK dcsirtibk' !νΛί!··!ι οι signal mmsducts<u. in still another embodiment, u chcmoxcnsory receptor modifier or hgand is u ehemosensory receptor ligand modi hoi.

Accoifimg t>· me present mxcurion. a chom·-..ei-soty ireepn-i iigaud nbu-fim includes any compound orcamrx capable of mka reimg et m-'idiiioore the .uu' ty <4 a chctuo.teit.'Oty Hzecptoi nmdifici et tre .tote nx <4 a Jji.nmscn.sotx serepU fo to·.. presence <>t\t ebetnoseHsoty rcceptoj modifies. In --1-0 embodiment, a ebenu-sensoix = crept--i Itgaad nic-mfici is an enhancer of-a chenwsensory receptor modifier. In another .embodiment, a chcmosenxory receptor ligand modifier is an antagonist of a chentvseasory receptor modifier, la x ci anothei caib>-diment. a dieinos»n--r icreptoi re.wd mou.fi·;; s.-ren e.ihuncci of a chcinosre-my receptor modifier wit.hum. having substantial activity of the ehemosensury reeepto? modifier fix still another embodiment, a cbomosensory receptor ligand modificr is an onhancei ->t a sneer flax cred rempound nuh.uu h.u mg sithst.mii.il sneer ttoxor by nselt .re . .i< nidged by -inimak i> no a 1·. t -. 1 as π 1 ι n - mol 4 r ust 11 1 < h> i n m 11» ι-t: \ i < > ».x . es cumniotily knox^i m the nekl. In sttfi yet another emh-.remem, a ehemoseasury receptor l-g.ind modifier is an enhanoer or inhibitor of a chemosensory receptor .modifierand-capable of inducing a desirable therapeutic reaction or signal traiw'ibictic-n

According to another aspect ni the present invention, it prex-des eben-i'.sonsorx receptor ligand modifiers. In one embodiment, it provides chemosensory receptor ligand modifiers identified by the screen methods of the present invenfion. In another embodiment, it pro vides chemosensory receptor ligand modifiers: capable of interacting xvith a chemosensory ecep-or r7? an imcrae-mg suem the present mseunon In ye: .mothm embodiment. ·} proxides ch-.-mos-. ns-'-ry rowp-or hgand modifi-. r- capable of mter.u -ing xx ah a ch.-mosen-v-rs receptor χνμ o:X>. >-r mote interacting resblii»'' of th-, ch- mosensmy teeopto? In s-tU am-ibet emhodin'ont if provides: chemfjsensory receptor ligand mtjdifi ers re pa bl c of in teraefin.g with: a: chemosensory receptor via an inicracting space within the Vemts flytrap domain that Is outlined, defined, or shaped pis't-ailx m entirely by atonac-ting residues of the ehsuroxeiw·my receptor. In still yer. anothe? entiiodimeni. it pr-n ides ehernosenrery· receptor heancl modifiers excluding, o.,g., natural or synthesized sweet euliancets knewnprior tn the presentuwxtnfioa.

WO 20(18/154221

P:CT/l.sS2(H)8/065050

2017200704 02 Feb 2017

In the «.outeO ef ‘be pwseul ΐϋ\.e ©f .nKmcnng wrb ' <·' 'wemUmg v, ith'’ inean.' that a eompounvi or «nokcuie binds to or forms one or more molecular vjt©wuu>'i;,. <- © . piedtictive iiUcraebi'»' otth ©noihei meteimle. <’ q , a chcnioxenxory mcepicr. ksemplais itwkxcL· miem©fio:>. _t .©.. preJuctr.e niter actions ht Jade van ,ki Waal·', baisai <·Γ hydrophobe ©Ληη- ot aiome gonips, hydiogen bonds. fine stacking itneruebo·).;, salt-bridging ck'CiK'si.ttic intt'iacnoiw, m a combination thereof.

-In one embodiment, the present invention pros ides chcna-sensory ’cceptm ligand noddkte capable ef inter uc'; nig w th ,. ch., nosin' my reccpror w'<? a group of interacting residues <·; a sp.»© within toe Venns Ihtnm deinmn that ' ©utlm.C. hapuJ. or defined, pai'ialiv o entirely by the group or any subgroup -'f ehcractiiig ; csidnes. ,:ptionaHy in ihe presence of a ch-.-moscnxmy receptor heund. _t e, 118-19,81 i-i. Slo5. 3'-(W D)4? Γ2 7“ of © htinrun ΓΙΡ2, ?) fj-5. Mfe 0.507, l.'i.k.ond 027? <g © human ΓΙΡ2, 3} Ho. Pls5. 1 I84. f.On E.VC, X 3s4. 3308.13 s ife- Ms* P.to'J .m/J}?' s I? e i(i\Xrn 3 ΙΚίΓ. -I? S W --.itoi, 1.242. ? 163, 032c·., and 316s or a human ΐ i R2, 4) b40, 81-1-1. S 1<W \ 014.? 1'2, K< ?

MS* IW b3fi2,andD.?>,tahnman fl R.?, 5} S-iO 81-1-1,80-- \ 103,01-1? Ife-Olo Pl85.. I 1X4, I 32.0. 1::311.., V3S--1. ,A30S, 1328 1*(Κ» R3h3. D3O7. 13382. 02 8, 12.79, R>7, v06. V309,8303. I .,'42, Π03.0328, and S168 of a human T1R2, -6) K65, R383, D307, E302, D278, Ho, Pls? I >x4_ 13.8-, F?0,', \'3$: 13.0 1306 b 3s,812^ I(<. 3m·. 3 3(0,01 W.

816,-,810 Siu.', f? ΐ 2, l· ΐ 03 Q Vs, anj Si6S e-l a human ΓΗ'?, fiolO 8 J i: Sh>5 3 103. 01-12. P2-7, Ki-- R3$3.1)307 b'30\ D278_: H67, PIX5. T184, T32.6, £:302. V38-L A305. 132-, 130b Γ382 1270 16, X bi-, 3 3{r>, 8 *0*. I ? 12, M 0 p Q3?s an-I Sb>8 ©f a human TI.R2, 8) V 17 χ,.Π, ©nd I i ma human HR? m Οι M I* sifi.^i Π wfi->x 3 JΙΓ. '»’ 1 ’ -¹'' (·,>'< Ms* 030' t te^!, O' s H6 0'8- Π81 Γ i ’<> I ft \ \ *m \ «o? BOf I 38? |? 0 to/, Vuo \30‘\ Sgp* I? I? riO.'.gO/s ,itm S't-S ofahunmn I IR2

In >inmiu r cmbodim·, m the presen' iiwenron pi ides ceemo'' nA-rs ivceptor ligand enhan, ors eapahk of inter-('imp with a dienr sensory wept, r m the: presence of a chemosimsory receptor ligand w one or more interacting residues of K.65, 0278,. 1.279, 0307, R383, V38-1 of a human T1R2.

In y et another embodiment, the piesem mvent-on pros s’ivn»e or sucralose i-nbanccm eap.iblc vf mte: aem-g u ;th a ehe-n,w.iKmy recepror m -h© p-exer-a- o- sucrose oi

WO 20(18/154221

P:CWS2(H)8/065050

2017200704 02 Feb 2017 suewito*·/ i*frz <·ϊκ· et nsoru iutcni^ling ic.siJtics >*f S40, x i 44. Y103. DI 42, P27~ A huimoi

T1R2.

In suit ai'elhci emb>'dnsicm. foe -ro/ntum provide* Aen.<oc'ixe>re iceeptes ligand uicddi/:*- capable of nsteraUing wsib a d.u-tnescr. ly rex/pi/i. opu. redly m the psecreiKC ? a chons·-.-cases y iccc-Voi ligand //.,- at cast I,2, 3, 4-, 5, (*. 7. s. 0, or ’.0 .nt.-racting residues ,-oLcreo 00/0 die group >4 N143 X4fi, 3144 > lob, YIO^;>. Di42, Pdf”'. KA. kgsg D3(>7,1 '.02. D2 to. HA ΓΙΑ, ΓΙΑ I 'A*. yyu2. \ 3>to, A-MS, (325,13<>h I ?A, re'⁵, h*, VA, Y30« S303, T 242. Π03, Q32S. and Si A of a husnars Ί 1R2.

In suil aooihci ojnh.-dhncnt, the pre-rent :nvenu<-n provides then ·<'sensory .receptor ligand modifiers capable of interacting with a chemosensory receptor to stabilize a con fori uai ton, reg., scire -dosed ot dosed conformation formed by the interaction between a chcnio.wn.-ofy iceeptor and a chcni..sensory reecpim Iraand.

in sfifi yet another enih*^!dnueni the pre-rent mwmiroi prox ide-* encmc-sen-rory receptor ligand modifiers, e.g. saccharin, saccharin analogues.acesuUaroe K. acesulfame K analogues, or any compound capable of interacting with a. chemosensory receptor w an interacting site that is similar to c-r overlaps with an interacting site used by saccharin or ,tce\iA tore lx in ore exantp e t re ptexe-n t-uennoti pi* vd«> eneiiio*-.-:»'** iy iceeptoi hgatid enhancers, reg., saccharin, saccharin analogues, accsnlfhote K, or acesulfame K analogues that interact with a chemosensory- receptor via an interacting site including one ^:of .more intoractitig rowiliex ef Kt -< R<x^J. I AV 1 3^!'Γ asm D2 s of ,1 biiiwin i R?

According to yet. another aspect of the present invention, it provides chetnoscnsory receptor modifiers. In pne embodiment, it provides chemosensory receptor modifiers identified by the screen methods of the present invention. In another embodiment, it provides chemosensoiy receptor modifiers capable of interacting ?* ifo .1 chemeiensbiy receptor νή.< an interacting site of the present invention. In yet anodier emb»>dimenf, it provides .chemosensory-receptor .ni*'*dt nets capable of interacting with a;. ivniososixory receptor via one or mme interacting re-idirex cd foe chem*.sensor* iei,eni*n hs stdl another enih-fdnnem. it pros ifo>. chemosensorjr reecpior modifiers capable of interacting with a chemosensory receptor vs? an. tnteraeting space wnhm rhe Venns llxtrap doinam ih 0 s* ,'Ulliia.d. defined, <*r shaped, pmlialb* *u i-nfin.fi. by hitosaidm·.' residues n the chemose-ises\ receptor, hi still xot another e-nbodinieiik

WO 20(18/154221

P:CT/l.sS2(H)8/065050

2017200704 02 Feb 2017 h >d·.·' dianoscust·!χ icceptoi m-.-ibfic’s usebidmg. ; mhurai <u \xnthcswed ήλΙ Paxor cnhib.> I Down ριiei a,> H:>. me.-eio im.cul.mi.

In one cwhodnEie-a, (he piKnemnut pie- .Jx'.- ubena •.-enso: - 'xuepu·! m-Udici' capable ef njiewwtmg uh a diemoxcnsmx κχ.-ριοι >,’<?.. ..‘'<'·ιρ of mtoiacl.ng i.<-'ddcx <a a vp.kc xxiflun foe Veraix 1 xtu- > d-.-mcm ilxu - o'.r.lin.u. 'hap.j. o> defmcd. pmtiahx <· enurelv ny the awwp i am 'OgKrnp i mdi'g e-uhi s, s e , ’ I 84Ω x,4~ 8’ χχ X 03 PU2, Pd”' of a hum m 11 R2, .6 Ku5, R3e3. D307. b 3M and IX. 8 of a human 1 I Rd 3) i P1X5. nx>.p p3> P3O2, x.yxp Λ3Ο5, 1325. l.W R3x3. D3fo'. E382. D27x. 1270. fo~. V(-6. VM 1.1142. Slofo 840. 8365, foal, MiK. Q328. ami SfoS ··! a human fl Rd, 4) 840, 8144. 8165. Yi03, DI42. P27*’. MM R3x3.D3M E302, ;md D2~8of;; hum;m IIR2. 5> $40. si 44. Sic?. V103. D142. P277. Ifo'k PIM. ¹ 184, f32n, 1’362. X 3X4, \3o5, 1325,1306. Rfok D.U7, E382, D278, 1279,167, V66, V309, 8303, 1'242, ΙΊ03, Q32X and $168 of a human TIR2. 6) K6\ b'38.> Dfo,’ I in? D3 ->, llfo 1>A\ I IM I3?o 130? XecRA.W l\'? |M»J R\?

7° fo” X66 X 30° D:.':.?, 31 n' 840. 8303 I..'4 2 H6.VQ3 2X awl >|6X of Jnim m RR? 7) $40. SI44, SI65. Y103, DI42. P277, K65. R383. D30?.. F302. D278. H6l\ PU?. THU.

P..?6 i Μ: X384, 13.25. I3O<>, I 352.1.:”° l<>7 \ 6n. X >0° 8363,1.212 I 161 Q32b. ami

SI 68 of a human T1R2, 8) Nl< Si 44, and. Π67 of n human T1R2, or 9) N143. $40,8144, 86'5 X 163.1642. 62. MM R3$3. D30? F.IO.?, D22S. lie . PI v.. 1'1x4 132a. F,si;2, x 3x4. ' O', 13\\ 130a l'3^s 12 ?9 1( Xnn, WiO x.fliS, Γ ’¹ ,1 101 8 r R Xle<'e>fa hrnnan

R '

In still another embodiment, foe present fowdtlim provides ehemoxenway 'cceptor modifiers: capable nf interacting with a chemoaensory receptor w at leasr I 2 3 4,5, 0, ’. S, 9. or 10 interacting residues selected <fo>m ilv group ufN613, 8 10 Si 14 $16^ ΧΊ03, D't? 1'’ 7, Ki Rix 4 Dfo? 1...9)..., D.'/x ( o/ FIX'* Γ84 , R₍. . ₅0^! x Is I A ><b 132' 1306. E382. 1279. 167, Vel), V36'R $363. Ϊ242,1 161, ^3?x and $h>8 e s mn'an 11 R2

According to Mill another aspect ef th·.'present ίπν·.ινΐιχη, it provides met hurls lor modulating a chemosensory mcepior and/or Its ligand:by modulaimg one or mom interacting sites of the chemosensory mcepfer. For example, one can modulate a chemosensory receptor by eoiifdehDi!, <?? ;'w</ er <w ι·«7ο, a cucm-'xenxorx recs-pto? modifier o? dicmasensorx mucpim ligand modifier or both, optionally excluding natural sweet tuivm: cntuv or sweet enhancers known prior to the present invention) with cells containing the ehemosensory recep tor, wherein.

WO 2lW154 221

2017200704 02 Feb 2017 the cbem<*sen\oix icccpun inedi'dcror eheiUo.-citsorx wi.cph.-r Itgund u capai*ie -.4' uirciactjtig w nh er largctmg one or more mtciacling «es of the vhens>-«*isorx wvcpl·.-*'

Ια <-;<, crols'd'ine'U, the ircth>-d ol roc.h. almc eheroo-enrofs uecptei -.nd ci « bgaud i> bx madtil.nnig one >-i ni<uc iiiioacting w-idiics o: mlefaetrig spaces <·> a uombn.al.<m thereof in another embodiment. rhe method of modulating ,i d-emow-nsws -cccptor and or to ligand !» by mt-aauing with one or moi. mtciactng u'ltbcs m me prose we <4 a vuem»-sensory receptor ligand. In yet another embodiment; the niethod of modulating a. chemosensory receptor ot it- l>g.md nivludc.- modulating the impact <4 a Jn.m<’senso:x ieccph* hgaiid on file chemosens--n receptor by imcractmg xxuh die chcmo'cn-s-is receptor e;u . nc<*· moic interacting, residues in the presence of the chemosensory receptor ligand.

I n yet another embodi ment, the method of modulating a chemosensory receptor and/or its hgand is 0' imciact-nj. with ’.he chemo-en.-orx ? rccptoi e,.; a group <4 mtei.x'tmj. residues or a space outlined, shaped, or defined, partially or entirely, by the group or subgroup of roleroe ting residues, .--piiomillx. in the presence of a eh-..mosens<>;y ree-..p-or ligand. e.e . 11 S-46 S144. 3I r.·'.. > I 03, I >142 F.”' of a mi mar. 11R2 2) Ri·' RfS) b.RF’ f ,-412 am; D.)7e ot a human Ti R2, 3) 1167. Pl85, 1'1x4, 13'26, E'30'2. V384, A3()5, 1325,1306, R383.1.)3(17,15352, 1)2>5,127**, I?'?, V66, \ 3C^}9,1)= 42, 3Α-5, MO. 3303. I 2-4.2, I 03, Q3_’x. and >I« of j human 11R2. 4) S4(). 314-4 Sie?. 1)142, P.'’' Ko.X R3S3, IWJ 302 and of a human HR?, 5)310 Si 1ijito > 0)3,1)1 I? P2’to, iI«<? H.V, list B2.6 I 30? VeM,-B05,

1^{4 !},\ I,'(Οι R «) I^s it?Λ. ί >χ ’ U? s I? Ό 16,< \ <><», \ )(»i S36 > ι I?, ’ ⁵ d? ip3?g ,$ί I >>I« ofahiiman HR mhos R«2 l\Xis;j 3O’J}?'\ 116, Rtgs π?Ί Γι ’nJ '««.«k

A30s J?-. Jp6 13-52 3 '6 162, \ oo 5 30° 1)1 12 Stop M0 S.W Γ’ to J IB Q3'^v’ Ή

S.6<s ofj human HR' ') 3 it; 5 ii.SIto \ 16*3,1)! 12 P'to' Riro (4-.5),1/36) F36? J\Iln’kPl.M DM I3?i., F30? \ RM A3O5 13?' 1«6 I «2 127-i 16 7, \ \ )0‘>, 32«

4? i rt) 3, Q3?S, ,md ,M*>5 of a hum:m I = k? s) Μ B M 14 and 116-a .- hum. n F'Ri’.ord'i MB ΜΠ si π v|_ny \ jp; dpi; 11 «« pifjj ){)\{)?'s H6' PBs ΠΜ

1326, E3O2, V354, A305,1325. 1306. F382,1279,167. Vor. V309, S303, T242, F103. Q328, and S165 of a human TIR2.

In yet another embodimen t the method of modulating a chemoseusory receptor and e, Us he,*re w bx niter a,: \ w th *hc ch.'r.-f'CHso.x nc.'p. u ' ,a one o' m a·. uiU i.k irg residues of N143, 5144, and 1167 of a human. Tl R2,

WO 20(18/154221

P:CWS2(H)8/0Oi58

2017200704 02 Feb 2017

In yet auotbex ernlmdimem. (he ntmhod >·('modtihitmg a cbcm<»senxorx tci-cpim ;md.or us hgtmd is by imeracmig w ith the ehcmoM/iKory ruccpter, eptionaily m rhe pic-crne ι-t a chumosenxorx tccepl-u kgaitd > n one or m<<w mteraclmg residue^ .a'Kcy. D27S, L2~4, Γ>3(Γ. R3K3, V384 of a human T1RX hi sub anoihci cmb>-dmmnt, fee mciimd of nb-duknmg a chcmo.wn.-Orx tcecpmt and, ©;· its hgand is by imernemsg a iili die chemosensory receptor, optionally in the presence of sucrose ! '-ih.rab^c cue os m<?=e mt-.iacnna tv*- du.^ of 8 Ό. S'.44, Y (o, f >14? Γ27 of j human TIR2,

In sub .rnmhei omh>-dnncnt, die rnetlmd oferJrauc_:ng ,» cuem.•sensor, iccepios and >·! sis hgand is m imcmctmg wuh -bo ehemoseusor ? .-ecptoi, ephona lx a 'he mcscr.cc >·! a chcmosensory receptor ligand via one or more interacting residues of K65, D27S, L279, 0307. R383. V384, S40, SI 44, YB3, DI42, P277 of a human T1R2.

In still another embodiment, the method of modulating a cbemosensory receptor and/or its ligand is by interacting with she chcnvxscnsory receptor, optionally in the presence of a chemoxCBviry receptor ligand u.< m Ica-n 1 ? ’ 4 5 b. t ?,°. >» Hr hiter.n.tmg rex-duex •wieeted fmm th». gnmp->f N143. $40. S144, $|p?. YIG3 Di 42.P.277. Kb5. 8383.1.)307.1.302 D278,:1167,PI85,1'184/1'3?«', ImO..’, x.fo p A3t)y, 1325. khfo,E382,1270,167, V66,V3(M S.0'3 I ..'475 I^; 03. fri32*S ,md Sb'-r of a human 11 R?_

In still another embodiment the method of modulating: a cbemosensory receptor

a.nd/or· its ligand is by mteraemie vx Uh -he ebersixeamry r,-ceptor, optionally in the presence of a ehemosenxory receptor ligand v/u at leart. L. 2.. 3.4. 5. 6, 7, 8, 9, or 10 m-erading residues selected from the group of N143. $40. Si44, $165, Y103, DU2_: P??”', K65, R383. D307, E302, Γ’ - Hn'Jbsx I \l I >2t 1 302 v \y>< B'- Ifop 1 B a ln/,5u \ «0* , $303.12.42, t· j 03, (4328.. and $168 of a human Tl R2.

According to tire present mv>..mi..n_v a nt·,-’bed c-l modukit tg j cm mox0Bx<>x receptor and/or its ligand includes modulating the activity, structure, lunch-m vxpr.Nst-m and or modification, of a chenwensory receptor as well as modulating., treating, or taking prpphydactie measure of a condition, e.g._s physiological or pathological condition., associated with a chempscnxory receptor.

In general, a physiological or pathological condmon associated with a cbemosensory receptor nicludes a condition associated wuu a taste, e-g. , sweet, umami, bitter,

WO 20(18/154221

P:CT/l.sS2(H)8/0OiS)

2017200704 02 Feb 2017 sew. -.illx <-r a uontbinahon thwe»'l 0· a c<»ndni,;n ,^.ακηαη. J w a’i '·,;, g<ts*i. mtcst'-iial m skin, metabolic disorders, functional gastrointestinal disc; dors, <·/<·.

1·κ>3Κ ν'ηΠ'-.'ΰ'ΐη-'Ζ. the teeth»>d ol du p'e-ent no „X)»'i eg modtJatrae ·. chemosensory receptor and er us hgam! includes modulating, increasing m .keteasing a sweet or nmaim t.-ist·.:· <?r a .-object's ieac?iom pbysi^logical or otherwise. to a sweetumami taste hi another embodiment, the method of the present inventmrt e.g,, modulating a chemosensory ic-.cpb ; and > i Us ic.-nd me tidm er. riiion: .« sw .at m ; nun, tae.- <; a ,-ubicei's scjcuou, physiological ·; otherwise. to a sweet dr umami taste.

In yet another embodiment. the method »d the prcsem imcn?ior. e g.. mmluluimg a chcnr-scr-seix icccm -j and >·* its I.ma:».. me w.k- m<»d.'l.r.ii.r. o.aurem and o. .v<iph-lacnc measure -'fa conditio·; associated wsth gaMrornte.-tmal system metading without any Imitation conditiofw as--v:.ited with esophagcji nu-iiith t< g , cueophaixnacal achalssu, £>l<ious hy stencils, achaia-ia dijitise esophageal spasm and related m»-i>>r disotders. ^e) erode; ma tm-oLin? the esophagus, <. n j. mflaranutory da-orders l.\c , g3<rroes>.>pivgeal reflux .md esophagitis, infectious esophagitis. _t n j, peptic ulcer, duodenal ulcer, gastric ulcer, gastrinoma, -uress ulcers and eri>sAis. drug-ax-a-ciaied citers md eiesier.s. gasttiu's, ·.-a'pb.ag..al earner, tumors of the stomach,, disorders ot absorption u ? , .few rprseu >«f spectre πι.ηκΛ- s ach as CiMbohydrate, proteim amino acid, M cholesfer-.-i and fa' soluh e vtamuw, watei .md sodium, calcium, iron, water-soh-lhie vitamins, eir.·;),. disorders of malabsorption, defects in mucosal fuHidixn ά .y inflammatory- or infiltrative diso’-l· r- b-.^chomfi a. or g·, i'etsc abromu-'ities, e;id-<> rme and nmumohe disorders, piotom-k^mc era·, ropathy, <.? t, autoimmune diseases ol the digestive tract (e.y., celiac disease,, Crohn’s disease, ulcerative colitis, em), irritable bowel syndrome, inflammatory bowel disease, complications- of inflammatory bow^;cl disease, extr Jnte-tmal iwamf. -amon- of mfkmunatc’y !’-iwel di-cx*,', dis·ad.-ra of ntestinal mi>riiity wi-cidar dimn-eu- i»f the hmwtme .mwvcual disorders ι>· e hemerrbo'ds, anal ;Γ(1οηη>ζίιψ· u. » a» fl ·. .me,':-, mmots of die smali iri, enne > anee; - of the anns derangements of x| m mliKs-H 'Hihfiil w \ κρ’ΐϋ'.Ί I ;. imulbXH ,n u „oss ;’ n c.inhosis. neoplasms of the liver, infiltrative and metabolic· diseases affecting the liver (ay., fatty liver, rove’s syndrome, diabetic glycogenosis, glyooga; storage disease, \\ ilson\ disease, hcineehromaiesixf. diseases el the gallbladder and bile hums, disorders ol the panera.^ (r-.y..

WO 20(18/154221 .FCT/lA2(W0OiS'(

2017200704 02 Feb 2017 paucieahlis. pancreatic exocrine insufficiency. pancreatic cancer. ete. ), endocrine turners of the gasuomie'-'linJ tract and pancreas, ate.

In still another embodiment, the method of the present invention, e.g., modulating, a ehem·,'<usen we enter and >>i it* fyauil mctoJes m<><.bilaucu Pcatmenl and oi pwphy laetu iueasme eenmnou u.-soetated wdh metal'·-he ummdcjx, appetite, ls-uy weight. food oi h>:mJ intake m a sul-jcu'»ica>.u>-n :o 6·>·6 o: huuto m-Ae, m max to -..incty <·’ a .-oop-ei's .vi.cpt o i ot a -late of sib.b mm η<» i mtar,. and icpokib r„ p e , pn tern en.igy n„.nuh it.on. physiology mipu-icmcms associated wdh pb-Xni-envigx nuhnii: ikon.. ), »-oenty, ‘wcomiap (•hscsib i< g . hvpothy ioidmni, Cushing's disease. msiiimb-ma. hypo'.ha .muc c -o.dcis. \ ), eating disorder- (uq., anorexia nervosa, bulimia, vitamin deficiency and excess, insulin metabonsm. aiabere- {tx eh < *uv Ih .1»' eon -wu* mis tl <* > κι at * atoioimahucs, iJniopmhv. dub·.-’κ nof-hu-parky. di.ilwt.c ncmopaeo, dmbcnc foot mecm, ere.x gjkose me':,’b,-lh'.ro, fat metabolism, hypoglycemia. bypcrglycermL·, i'ixp'.-rlipeproi'.-iiiemias. e>\

In ssill yei ,inmh>.r embodiment, the method ot'tbc *·..-<..m imcntfori, e g.. modulating a cheniosensory receptor and/or its ligand indudes modulation, treatment, and/or prophylaene measure of a e-mdhfon as^'<iau.d with fimcuonal gas'_:rmr_:i...-u-m.ii disorders. e.<,·.. in i i’s.n.cv'. < >.iit cu a pc h > o^ts d s > tdi im i i-ο p’a . ket 'd*. 'ts'i t s i.ijest r tabdominal dyspepsia, e.g., feeling of abdominal distemion. munta. Vs'mttmg. abdominal pain, anorexia, reflux of gastric acid, or abnormal b»»wd movement (emistipaiion, diarrhea and rhe like), optionally based on the retention nt cmUem- m gastrointestinal tract, especially m stomach In one example, functional gastrointestinal disorders include a condition without any organic disease of the gastrointestinal tract, but with one or more reproducible gastrointestinal symptoms that affect the qu-dity of life of a -'ubiect, e g., human,

Fsemplary functional gastrointestinal disorders include, without any limitati-.m, functional dyspepsia, gastroesophageal rothn condition, diabetic gastropantos redux esophagitis, postoperative ..gastrointestinal dysfunction and the like, nausea, vomiting, sickly feeling, heartbum, feeling of abdominal disten tion., heavy stomach, helehmg, chest writhing, chest pain, gastric discomfort, anorexia^ dysphagia, reflux of gastric acid, abdominal pain, e<msi:pati>m, d:arib,.\i, hie.jthk'Ssnesx, kelh;g ofsm<abcung,, tow mcent-ve or energy kv,l. phai\ ng.;al e.bst ruction, feeling of foreign substance, easy fatigability:, stiff neck, myotonia, m< >atl· dienes'· win. η» toth, thirst, efo.) tachypnea, burning sensation in. the gastricinlestlnal tract.

WO 20(18/154221 .FCWS2(H)8/065050

2017200704 02 Feb 2017 <„eki scustteou <u exttanmes, difficult’-. m ou-cemmfkm. {mpaticnce. sleep disorder, headache, general b'ahiisi.. palpmmem m-afir 'xcai anstefs. d..'0mcss, xctug.. k<·' il.w i cxvcs sweati-iy depression, ofc·.

In --fill yet ar»-thei cmKrnmu-nt. Uk* method <>1 the present rnvemion. e.g.. :iR>dulab:w ·! ehsmo'-cusor'- rceeptor ·ηια or in ugund mdudcs mmc.ismp or oronwtmg digested, ab*>-?p?5on, blood rmnrcrn kx cL .md or m>mutx <d ^tromk-mn.tl t.mct in a subject, i g , po-motion of g.-.M= w empty tnp u g . ekarance --fstomach c-Owmsk reduction of abdominal distcnnou m UK' curb p»-stp:.m-hal period, rmptvx uncut <9 ano:C\w. <n in general, such mom-mon »..m bea-Jnexedenhe: diuxtK or --../ mcw.-.smu the-cciomm <4 jj^itkr-ny corny, e.g., hormones, ete,

L; std \ .t aroma anti >' mo u, the moth - of th. > c.-em n>' eutm t. ,-. . modulmmga sh<.rt<wensoiy tc^pim j«C<’i tts ?<>a -d rrchuk- .noeasjeg <oe or more gasu-.'-i-oesdn. fu-wirrs, ia.-.muci _f o , to mptoxc rbe-pt* tn of Meet healthy stare of a sabjeot.

In still yet.-another 'emhxhmont the moih<O < >f rhe nr gsent invention, e,g„ modulating a . hi.mosen*r>iy rec-..pier and. or its fig.md mclode.- moduiating the .icrix ity of 11R (kg., TI R I, TIR2, or 11 i<3; exptcs-riug evils. < g fixer cell·- R g hepatocy t-z*. crtdmhcfial coils. Kupffer ceils, i-delkae evils, epithelial calk of bile duct ι-n.k heart ceils (e.g.. endothelial, cardiac, and smooth muscle cells, ek' g paurreatie cells fog alpha cell, beta edl, delta cJI, neu.Fosecret.ory PP cdl. DI cell, k cells in the nipple (e.g., ductal epithelial ceils. ✓&·.). stomach cells Mg., muccus cells, parietal cells, chief cells, G cells, P/Dlcellsl intestinal cells i_t V c' toeudoe m <. Is btU't cells .,<. ) sehxatx jamteel o< y S <o mice s < ¹ mucous cells, myoepithelial ceils, intercalated duct ceil, striated duct, cell, <w·.), L ceils (t.g.. expressing GLPJ, <-v·.). enterochromaffin cd Is leg., expressing serotemirtk ci'derochrumaffinalo>cd' u > cl - k .-xpC'sn'tLM ml 1/cel’s f-'elt t cel's . g cxovwmg om.itostat tk I ce k \ g cspt sir ’ rhole^' k imfitk'- t cels:, g e\’’i -^ippgas- t, mhbm w >okp. use.} P Dlul ' t. ox > es^ w ’hr. -r'« < hr M. Ik ( : oxp css u' p,.^, u me. S ceil- <-·.<;. expressing .tecrelin). In one example, the method of (he present invention includes incrcasmg the expresv-iou level of T.I R in T! R cxp-'c--smg cells. In another example., the method <-f rhe present insentjon imfmdes merea-mg the sce/ukm iesei -a TIR expressing ceils.

WO 20(18/154221

PCWS2(1W065058

2017200704 02 Feb 2017

In still x el -mother emlknifoieut. the iretiivd of the present invention .\r. nmduldtmg a uhcni<>xenxoix wvepuu ace m six ligand mehak·» modubitmu the οχρκ'χ<-Όΐι. secretion, and ci hrmtrnnal kxel of 1 IR espiessmg cclH axx<teiated wUh noiniere. peptide enzyme producing. hi one example, die method of the present foxcmfoii tnehidex mi-milaiiug Pie level ot glucose, e.g.. inhibitors ot a. chemosensory reccpior such as TIR2 can be used t>· deci case -glucose k-xcl ie.c . ghieuse .msoipimni m a sub:eu. in ,ιη«ν|ι·.-ι e sample, the method of the present invention includes modulating the level of mcretms, e.g.. agonist of u chemosensory receptor such as T.IR2 can be used io increase giucagons-h'ke peotide 1 iGLP-I) ami thus increase the production of instilin. in yet another example, the method of the present invention include^ modulating the expression, secretion, and/or activity level of hormones or peptides nroduceu ον I rRmspK-xi y cc k ot g^t >mre< '><> »re»'e p> >duvine> el - ί e < gai <'s tor 5H Γ receptors {c...e.. .•'Cu-tviiiii). mewunsh e, Gl l‘ : .md gluco >e· drpendc r msubiu kvpie polypeptide i GIP) j. gastim se>.rctm. pxp-m\ chole-.'V'nfvni'x any. kwe gmehn. lepton maleskiim.. k In <nli ,mmh..r examnk. the method of the present mvenfo>ri includes n>> hilat.m. the pathways .^soenned c nh .vemerex, pept de-' ..id m e ι/y roes »e> icted ey ί\ R expressing celts.

Exemplary chemosensory receptor liga-xd modifiers provided by the present unonnon and oi suitable io be used for methods of ths present invention include -compoundsof ^!-i,' te'.fowrig foimmao

I x i>n« c'nbod'm - s > me present invention, the chemosensory receptor ligand mndsf>or >x a ee-mp-mn-l hm mg a smi> unsi h\omu'a {Π τ I

A i· or a tautomer, salt, solvate, are ««r ester thereof whereins i fours : xinrk bond 'Λ id: ekh.'t P or Γ are a denha hare Xxph lilt’ el:u‘t ·η Γ? or F, R‘ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyi, substiiutod arylalkyi. acyl, substituted acyl, hctcroalkyk substituted hctcroaikj 1. hcteroaryl. substituted heteroan R hotcroarylalkyl, substitutedhetcroarylalkG. -CN. AO.. OR', -S(C\fR , A'R’R'b -«’> AR’Rk ·< 7 >J'<\ ΜΠ > >'Ri -AR C* ΑΠΤΑ XRX SAR’Rf -AR Ct AH sARR .

WO 20(18/154221

P:CT/l.sS2(H)8/065050

2017200704 02 Feb 2017

-su'\r‘r\-nr?so< ,.\r .-R{Or\gr^!i,-i^orr kgr^j)

P' ;s Pydmgeti. alkG sufotiti-tcd alkyl, aryL Sitbstiluted myk aryktlkyk suhstituted a··; la k'. , am I, •-abstuuied aey k hotel<>alk\l sid-shutted Itetenudkvk hetetoat G. substituted hciet<>m G. hetetea* Jalky I stibotintee l-cte*·* ttx elk'. , < Ύ.-X*» .-OR'.-SiOh-R ,-XR'R lOXR’iC <O>P. \R\o-p, XRttARR'. Xp''CS\p“p\ XR'i t YIB'sR'R . SO_?XR'R'\ -YR'SO R . -XR SO>NR⁶R^?,-B(ORdtOR⁶), -P(O)(OR’j(QR⁶). or-P(0)dVGQR⁶); <:; ahvfnatsxcb. K’ and R . togvihcr with the ;d<>ms to which they are bonded, form an rayl· -nlwt fluted my I, IteteK’Hp L '-Gwunaed betcroary L eydoalky I. '-tthsonned es eloalks k cycmhcrciealky > <»= sunsutu-ed eyemlMcu GkG tine wbetcm th. t ts. ynomdly tesed te another aryl substituted: aryl, heteroaryl, substituted, hetenwyl, cyeloalkyi, substituted cyeloafl.y I. eydehcteroalkyI ot .sub^iUtfod cycfobctctoa ky I t wah the ο*·¹⁵· ixo that R^l atsd R arc- tt-'t both hydrogen:

.-X is hydngen, alkyl, substituted alkyl, aryl, -uthst I rured aryl, aryidlsyl, -uthst fluted aryhflkyl. axyi. substituted acyl, beteroalkyI, substituted heteroalkyl. hcr.eroaryl, substituted heteroaryi, hcteroaryhlkyI, substituted heteruarylalkyl, bale, -CN, -NO?, OR.', -S(O}-R \ -\k'\ CP¹ ,.\HUR.’, -YR ’P^! , -YOP -CGYR ’b'^? ,-GO R -YR\\> R ' -\R.'COxr''K YR'tbYRV. YR'ct MP-YR’K BiOlf >,GR t PtsbttGG )(G>R’ i m rtOitR⁵'¹'.! Oik’S,

B ts -N- or -C(R'

R^!'· is hydrogen, alkyl substituted alkyl· aryl, substituted aryl, aryialkyl. substituted ledks I. acyl substituted acG he*er<\tlky 1 suUMituU'd heteroGkyk heienuryl suflsiiruvd heteraaFyl,.heteroarylalkyk subsiituigd heterearylalky.l, -N.R.^uR.'^l\ 'CN_i.~OR,’,-S(O)aR.^b, -CO.'R^r'or-GGNR^;!R^:l·

G is -C - >·γ -St0),-.

pro'· ;de-.l th,U a hen <1 G -'flOV. ?ho-ι t ? tor nu a single hood w ith E;

when the bond between D andG is a single bund, fhgu. D is hydrogen, alkyl, substituted alkx atO wSnodeu aixk atsialkG wbsflenee at\kill- \ ac\l -.trsiptitod am I bale heteroalkyl, substituted heteroalkyl· heteroaryl, substirated heteroaryk heteroarylaikyl, substitute JK'^fe'omG.flkG -OR b-YlbinG -Site} R .AR''!/ . -\| EMIR ' -t. O R ’ , m -CONR^i:R’\ when. G forms a double bond w ith D. then D is ^::-O, ^:::S , ^:::N-OR‘ . or “N-NHR’ :

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2017200704 02 Feb 2017 ni-OxGienG is -to¹ and nR i when G is -( :

Γί is -NR^r-.-N-<H -cm^!v.

pins :dcd i uii Γ I- AR - >'i x -xben G foiin- a -,mg e I and wr.h i .

R‘ :s hydrogen, alkyl., substituted alkyl, aryl, substituted aryl, arylalkyi, substituted arykdky I. acyl, substituted acyl, hvteroulkyl, substituted heteroalkyl, hetert>uryl. substituted hcKroaryl. hcteroasyblkyl. substituted heteroarylalkyi or -CG?R‘^:?:

R :-· bxdiu^n. alky e substituted alky ·. aiy I. suu»tu.it.g .«m.atxlalkx'.. substituted arJalkvL ..texI. siibsti-uted avyl, hcreroalks L rebsinuted ijctvroalkxl. kete:<siis\re xsinuicsl j-jeto-nsL h-oiei.rexkdfo L rehsutuied heteiuarylalky L -b-R *R' , GV -OR Sfl i»R ', <OR'\>i ioxr'r .

a. i\ c, d, e and fare Independently 0. I or 2. and

R ,R^{. R\R'.R’.R\R',R^!i,R , fedR'\R^!',R^l. R^{\ R '.andR.'’ ore indrexeiidv.r.ly hydrogen -dky I mhretoted alky L ary I sub-tirated ary i ary hilkyk subsriHired ary kdky I acx k substituted acyl, heteroalkyl, substituted heteroaikyL beteroaryl, sub-irirmed hetenaaryl. heteroaryialkyl or substituted heteruarylalkyi; or alternatively, R¹ and R*. R* and R R^;' and R .. r’ an-l R\ R'and P^5-, Rⁿ and Rⁿ, R¹ andR^i!.R' andRfonrR ’.mdR . logeiiur wiHUhe atoms to which they are bonded, form a eydoheteroalky] or substituted eyvlohctetoaikyl ring.

In one emboduneutof Fonnnki (I), R' and R’, together x\ sth the atoms to which they am bonded, form an aryl, substituted aryl, heteroaryl, subGilnted huorcuryl, cyefoalkyl substituted cycfoalkyl, eycfoheteroalkyi or substituted eydobuteroalky I ring where the ring is opii&iudiy fused te> another aryl, substituted ary I hJeroaryl, substituted beieroaryl.. eycloaikyi, substituted cyclo.alfcyi, eycfohetero.alkylfor suhst raked cydoheteroalkyl mg,

In one embsdimentaf f ormula (I), the chcmosensory receptor ligand modifier is a con-pmiiid hcixing u st-gc Hirai lornmki (bl.

f h y

A (11) wbcreirn fours . --ogle bead tx u : cjfire xt <u / uud a double bend $x u i the olhe- of xt ο. Z.

W is -('(RV-S-.A-. -MR Km

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2017200704 02 Feb 2017 ¥ k-C{R‘Vor-N-;

Z is -C(R'>. -S-, -N-, -N(R^>)-. or -Cte

R ⁴ R hxdrogen. alky to substituted alky k ,m I. substituted ary I, ©jy lalkvl. substituted tnykdk J. ami. sub-ntuscd I heteioalky h subsututed beteioatkyk iwte><uiiy ·, substituted itetero.ay L beiei· miy lalky l<>; '-uhstittitco heum>©ix bill y I OX.-XO .-OR , 8<OkR' , 'sR*'R’, •COXR 'R'\-CO R\ aO-XR’'P'’,\R'So Η'³. -Bl OR ^Λ|{ΟΚ’Ύ ·Ρ{θχ()Ρ’’ HOR^l”)>i hogR kC'R' b

R ¹ :s hydrogen. alkvL subteitete-d JIaL my k >uosmutei.: joI. my ialkyu >uOsittu;ed arylalky;, acyk substituted acyl hvtcroulkyl, substituted hetomtokyl. heteroury L substituted betervury 1. lKUiea:> lulkyl w stib'-timteu kete-n.nykdkyl ( X, XO>, OR' . ·>(* bf,R' . XR R , COXR ^!K \ CibR \ O( OR \-S()>XR^!,R^;>. -XR \O>R ', · B{OR%OR A. PlOhoRk'xOlf }. ·: PtOhR ^{M >k^; \

Η X byd-'igem alky to substituted alkyl, aryi. substituted. aryl, arylalkyi. substituted aryhikyl. ,uy I. substituted acyl. bct-croalkyi, substituted heteru.aikyi. he tore aryl., substituted heteroaryi, iteien-'u-y hlkyl or substituted beteo>.xry uilkyl -OX. -XO . -oR -Sipi.R -XRR'\ <OXi'R ,-COR” 4 o,p -O« op -ft ^!ARR’ -XR bt-'Βι,ΟΚ 'ίίΟΚ. ') -P(OXOR^?)(0R·⁴) or -P(O)(R· · XOR³⁴); or alternatively R²⁴ and R²⁶ or R^2S and R²⁷ together with the atoms to which they are bonded, form a cyeloalkyi, substituted ey cloalkyl, cyeloheisroalkyi or subst ituie»! cy ooh·., ten -a iky I ri ng:

g, h and i are independently G or 1;

R*' and are independently hydrogen, alkyl, substiluted alkyl, aryl, substituted aryl, mylalkyl, substituted arylalkyl, acyk substituted acyl, heteroa&yL substituted heieroalkyl, Iteieroaryt, substituted hetero ary I. heteroary laskyl »>r substituted heteroary blky k and

R‘ k ’ R' R' K ©nd R * e’e weq\ tee n \ In dims?' ©-λ 1,--KhsUute I Jks ©r\’ subo J’i> J subOf'i J \ k ,κχΙ, <us wlteu itoe <a. s h ten >ilkO w’Aiii'iu lu'tenxilkyk heteroaryt, substhuted heternary ; heteremy la;ky I o; suboiU-ted beteroary hdky I; or ahemafiselx R' ' and R ’* R'^! and R' . o; R ano R ’ uw,eflte? web the atoms m s-. iueh they are bonded form a cycloheteraalkyl or substituted eycfobeieroalkyl ring: and unh die h'slcwme puwlses (a) when W is -()- or -8- or -NR^2>, iheu Z is C(R* ) m -N-; and (b) when. Z is -O- or -S- nr -NR^S, then W is -C(R'^<)«ir -N-.

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2017200704 02 Feb 2017 or io Ο’ϋΚ',Ι'ΟΚΑ '1 l ·)·Π4χ 3 (II), foe . eUWOUlld e, the pfi'si Ot 13XCPlI,'ll ha, structural Formula (Ila):

A<

(Ila) with the following provisos:

ί,ι > when Vv re -Ο- <χ -S- i>r -NR' , foon Z re Ci R' i or-Y-:

(b) when Z. is -O- or or -NR A then W is -CdV^:) or -N-: and (e) when B is -N-, then A is not halo.

In one embodiment of Formula (Ila}, the compound of die nrcsent invention lias st: uen/'al I efiunlu 11R-s

R^1?

' (Hb?

'vhcrehi, \V is VIR)·'orY is -C(R ’Ά»γ·Ν< and Z is .-S-, A(k ^x)~ or.-0-,In <'Uk cnlx'd-nieto *n (Amida (lib), W re -C(R24i-. and Y re-C(R»In one ,uh'd:ns.u efo oiireU (Hbu V-< re -^f, (R Y re -i. (R ' R R ’ is hydrogen, alky I. sulre-ilntod alk-l .uol sub^-iiiicd uryl,. heteio,nky I, xiihstcnted beieroalkyl, ~( N,-NO'.-OR^m -S(Oi.R'’-~O«'()R'\~Nsi/’R ' -CONR^R’' ,*i -t O-R'and R' A hydrogen, alkyl, substituted alkyl, acyl, substituted acxl. heteroalkyl, <uihshtute>l hoieroalkyi, -CN, -NO_:>, -OR³\ -OCX)R^:’l -St0):.R’¹' -NR^?>lR'', 4 < tNR'/R? or -CO,R^U In a preferred embodiment, RA is hydrogen, -CTy. alkyl or substituted alkyl; and .R' is hydrogen, -CFj, alkyl or substituted alkyl.

Io u,e end ,'d'uicC e; I <umid? (II ji, W re C(R ’i . and Y re -((R . A re Iwdiogen, alky k -nhsutmed akyl, „re I. gavui.utee ay , ·< 'N, N^f W -S(( H-R', sR’R \

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-CC>\R R^k',-( O.-R’ <’i - xR‘( O'R R' ix hydsogen. okx L xulx-miiKd aikxkat AlkC. ot '-ul’U'UileJ a k:lk\ 1 R ⁴ i-· h Mi ©gen atkx . ’xutuod alkx . box k -> ibx.umod ac' k lute? .-alA I

substituted he\<xdkyl, -CM	-kO.x -C»R -,s(x'>\.R	-( H d >R ,	\R R	-CO\R'R \>r
> R \ .a id R i - hx di > -get	s, alkyk 'UbxtU’dcJ alkyl	, acyl, subst	UUted -Λ.'	I. hoOioalkyg
subxtimod hciCOulkyl. -CN.	M)>, -vR . PM s,R .	ocor5:.	NR ;R \	-CONR :R ?or

•CG_;R’^!, hi ©no oml--d:uK':U of Formula (Ilin. xV © -c\R V and Y a- ·( iR ’ >·, A i\ • \R''C0R^l \-MB H< \ AR ’R^! \-NOR '. < 'ONR P’ . ·Ο?>Κ'\ -NR'CO.R''. ·< >R“,

AR '< ύ >\R‘-‘R^l\ . NR'\ X.skhx'* ©i -NR’ C{ Mh\R' R^!\ R^s jx mdtoscn. alky I. substitutedalky k ary IJky I. or sub'-'timrcd aix lalky I. R ’ is hydu-gen, alkyk subsumed alkyl. .texI. subA-mcd acy I. hx'tetoaiky I. '-ulv-mmed hcciealky k -C\. -N< >·. OR' \ S(O>_t.R < ?COR \ AR V'. CtAR'K'* -·ι ·«'<> R ’ -md R' is hxdwgem alkyl, subxtimtod Ad. acyl, subsriuiicd .«.yl hotoroaiky k ^.il'-smutvd ben. walks k A A AC -Ob' \ -StCBjb' ’, -CCOR.^Λ AR ^!R' .-( c\R'^:R' oi-CO R'¹. Io a prefeiTod >.mbc>dimeBt λ ο- -OH AM . A|p, H , AiCIU AinikA'A'ik AslCtOK'M; AHCiOXVIL AHCtOAIl .-\|R\AW·;. •\HC(Xin\H -(A,-CH(‘H -CH ΑΠ . -ClCMIi.dk -I'll-ycil H-CC> ll.-COMC (.'OMR Hs or-CH \H( <O)CH<: R η»bydrogcm moby I. ohy L pr©pyi, .’s.' pwpyL?/ butyl. .><> butyl, sec htuy L ?-buty k phenyl -r booty L and R ¹ u- by dicgcn. -C f», n’Ctliy'k -.'thy L ptopyk ;><'>~propxl .-f-hutsk ’w-biuy I <.<x -fouy i ©i ‘-buiy I, and is liydr'ge-i, -Cl\ mrfoyl edp L p-'opyk < wpwpyk ;?-hu-y 1 ;v>~buis L w -hu-y I s>-' z-hniyl In a more pirfotrod embodiment.· A is AH- k x b\ Jiogo' o' mc'bxl R ‘nbxjiegen -{ 1 - nx-ibsl οι ,'bC m I R x\tl>© m -CFs, methyl orethyL

In xome omhAmoms ->f bmmu'a t HIM R' ix hsdn'-gen ky 1 © a» s kdky I Ιη·οί)ΐί emboJune: A of Fotmiua (Uhj R^>xn by dregim. methyl-irbon/sl In xome -p-.-cio'.' .'wbod’m/ms ©f J ©mm a (llhy 'he c.impouudx 'iaxo -Ί·.u-ti'mi formula selected from -bo g’'»up ci'-nx-x-ing A.

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or a tautomer. salt solvate, and or ester thereof In some pre:er eJ eniLoJimeuts. ..ah ₍.f tbexe compounds is hydrochloride or iritluoroacclarc sah hi one embodimem ofForrnula ι Ha) l-ie c<»'up. uu; of flu ;re-ciii mx _ a. n <t. hex structural Furmula ί He}:

w hemin. W is ·$·. -\{R ')·.<»:·<?·. Y A C{R ''>· Oi -X·. and / is C(K >· el -X-. h'> a preferred embodiment, Y b X\R ' )·, and Z h^; d'( R )-.

In one embodiment of Formula (Has Y is-S- -XiR i- or-O-; Y Is-CtRf^c}~ or -N-; Z. ix -CfR )- Γ -X-; K' is by drogen. alkyI, Mihsmuted alkyl, acyl. subxiimied acyl, hetem.iikx L xrih.fotuied hektoalkw. Μ. V),. OR, 8<Ο\Ε. OiOR“. xR“R'\ i (fX, P < ‘ x * * R a id R ‘ x s< iom dk- x. »s*h < c dl J . -^χ I ί’Κι m< J . < x I iietoioailiyl-'Uh.'t’tuK'-J hctoiOalkyi. k'R -MR -0R'^! -so';),R ^f'-i?( OR'¹ -XR 'R', MONR^?iR^a or -CO₃R· ί

L> <<>>e c-nb vl :m>‘ off oimfoa (Ifo), W b S XiR' * , οι Ο , Y's t iR) oi -N-; Z is -C(R^^;> or -N-; R²⁶ and R^2/ together with the atom to which they are bonded form a cyeloafe I. -nihxtmned cyclealks i, cy cl·dwlcnwll· xl m xubxiiiated ey*. lobeuroalky I ring b's i>-u embodim-mt m burmuia ίIla). \\ ix -XfR ^s)~. er-()-: Y ·χ -C'(R ’}- or

-X-; / :? -i.'fR'· }-or-Y-' λ ·χ ixydtogen, ,ιΙΚχΐ x-ilwiimu'd alkx I aryl xuhxtini-ed arvl -xr'\vr^! -yur\ -or '. -nrVoyr *'R^!!,-XP V8XR^i!'p” o?

-IM''< i XiRXR “R¹¹. -C\, -\O- -StOi.R'. -XR'R^:’. -Γ6'jfo<R’^;RM <D,k'\>r-NRVO;.R^W: and R^s is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl.

In one ootlx-lanem o^r'l ormrla (ll,i) Y b -$- -XiR' }- -ir-te-; \ s~('<R^c)-or x- Z χ-CfR i~ > ί - X- \ - xl y e alk' ^nximc- alk'I a< - xUMMulin , -X'R CX)R^f'.-XHOP.’,-X'OP.',-OR^c -XR.’COXP. ^<'R”,-X'R\ SX’R¹ R¹¹ <r

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-XR’Ci ^:::X1 hXR^:!'R^H. -fX, -XOs -S(O)t.R\ -NR⁹R^i!\ -XRXtOiR \ -CiO)XR <O.jR⁹ or -NR'CO.?? ; R' is hy du men, alkxk subsliuited alkx L an kilky k or snla-uuiicd my kdky k R ό 'od'<ao'i <dkd s.-bent »ke alkd. ..ex I snl -croud .oL beUioaNy 1 robstriOed lutco alk-', ~<’N -XOx-OR”. -S{O(R'\-C>eGR'\-NR”R^u -( iO|XR^!,R^ »·ι>.r” mid R n nydforx-a. all.x I s-d-»muu-d alky L acy I, -rolssutincd acy I, ucu'ioa.xy k sulM.'HteJ haici<-alkx XX, -xo , -OR’l-3(0ΜΓ\·*Μϋ)ίΓ\-Χκ^ϊ{Κ^ϊ'. C«iXR''^;R^,toi -CO P.'¹. or alienuitody R ¹ and R loecki-a '.x=d< υκ atoimj m xslucb r'-wx ai·. «rated -bom o _vxeh-alkyI. <il·auat.d CyCtoalR k ».xeh nefCKMky I >-i '-«Mitmcd CyCteheR'ieatoJ f. to hi a JtofC p;c'to>-<.d en'bodimrut. \ -s -XH\ R? is hydiogc r mcthvk etbx L propxk k>;-propx L e-buiyk zko-ht-ry L bm>l,< b.rto <u roJ R * .ax R’ jieioGc'ci R >tR aydiou '..Pnuix -rxsitu’e»’ alkanyl. alkoxy. e.ulx-\y lie ?cid. carboxy be a», ol utrude. or carboxylic acid estc-r; or akemaiivelyg R and R' mgc-ihci x\ =ib rhe .Honi« ?o -\h>d· ihey me bonded ?'··ηυ a cycloelky 1, »absiouted cyxioaihyl. Cyeloheleu>,xiky I oi .subshuiu-d cyda.hmero.PRyl ring

In $®ϊκ specific enilwdlroenis of Formula life?, the e-mtpound.s haxc stii.i-..iural lonnnii! sdeckd in m the gtoup sen$..x;ing oi

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or a tautomer, salt, sufoaic, and/or ester thereof In some.preferred embodiments, the salt of these compounds is hydrochloride or irifiuoroaoctate salt:.

WO 20(18/154221 .FCWS2(«)8/065050

2017200704 02 Feb 2017 hx om: embodiment ofFoinmia fIB *b, s. irooimd oi’fne present invention has strueturul Formula (lie):

A (lie) vvheMn, * I forms .: single bond a ilk I and a doable bend \v db I), B is -N-. Γ w -Xis’ -, D b \ , \-(>R ,>-r RAHR’' 33'is -S- A>R )- oj-ΟΆ'is-C(R ”b, and/Ά3 R )fo o-ix ends'd'aic'F <<· kmn.u a f IB flu cetrnoiiiki m the pu-->.m mvenu.-n has triicnii al I 'm multi Jlfi.

A (Ilf) wherein, (1 forms : double bond a ilk f. and a single bend a ilk f);

B i- A-,

I is -N-,

D κ -< »R ' AH-OR*'. -NH-NHR ' Afi >i,R^z' -σ AR 'R *

W is -S-. -Nf R, ' i- or -()-:

X'iS-GR ’)·, .md

Zis-'\R ).

Io <-'A, a al ewme'd e, I mn. Ja t ll>.) ci l Ilf), \ Ndiogcr. alb , - i wjtu.ei' alkv.aM.sMteiimMrnv .-<»!< \R .-<A, NR R' , OMR’R', C*)R’. NlV'COR¹ \ ARM >\kM>J\-XRV\NR⁵'R^;S or ΝΡ?<'{ NHAR’ r”, 3Iore pwMaely. R’ isnydieecu, alkyk subsiimted alkyl, arylaikyl, or sabstm-ted aiOJkyk R ' and R arc imlcpende-iily liydfogen, slksnyl, substituted alkenyl, alkoxy; or uliernMively, R^A‘ and R²' together with the_: atomls) to which they are bonded form a cycloalkyl, substituted cycloalkyl, cyclohcteroalkyl or substituted zyclohetctoaikyl ri·'^.

Iu some specific embodiments of Formula (lie) or (lit) the compound of the present mverstiesn has structural formula selected from the group consisting of

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2017200704 02 Feb 2017

or a tautomer, salt, solvate. are >- ester thereof. In some preferred embodiments, the salt of these compounds is hydrochloride or tritlooroacciato salt

In a embr-dimem of Formula (ll). the e·>mptmnd of the present invemmrt has structural Formula (lid):

qi?

A (Hd) with the following- provisos:

t A.bea \\ x-O-o -v <v AR the z w C(R t irA-, .ml (b) when Z is -O- or-S- or -NR⁸, then W is -CfR'') or -N-.

in a zmboJi m> nt of Ft » muia (ί Id >, W is -S-, AR' Ύ is -CR Ά / R .(.'^>< ;. · and \\ and Y : -rrw a smfoe And a to \ and / fern's , double bond h a e'nK\htei * ·> fAmu a Hid», \\ w-ClR >- ^χί κ -t R''-, / is -Ά AR

-O-; and W and Ύ forms a double bond and Y and Z forms a single bond;

In a embodiment ofFoimtila (Hd), W is -S-. AR' , -()-: ¥ Is -N~; Z is -C(R^;)-: and W and Y forms a single bond and Y and Z fottrs i double bond.

In a embodiment of Formula (l.l.di, W is - NR.A Y is -A-; and 7. is -( (R )-; and Y forms a single: bond with eachof W and .a double bond with 7..

In some embodiments of Formula (lid), A is hydrogen, alks I substimted alkyl.

awk -ebshnaed aw I -OR',-SR¹ -t A,-\R *R^!'.-r t AR’R* ’ - aR AR’fibR ¹

AK'< ΆΚ'’ρΛ XR'^}C\AR^s R ^s m AR C{ AlhAR^l'R* Ikew'alA.R r-IoAwui Mme

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2017200704 02 Feb 2017 pi >_<.·: ahh R ” and R aie mdepcndcmb. b-drogen alkem L subauutcd .: ban-I. frkoxx, carboxy He acid, taflwb·.. aesd ester: or idtcrnutn cly. R and R together w ith (he ai<«ut -i to whwh &ο aro bonded feur a cxdealkx <a -t ixjtated exckGkd <,ne

In some specific embodiments of Formula (lid), the compound of the present invention has structural formula selected from the group consisting of;

ο; a tauten A t. 'i.dt, sohatc. and ester thetco?'. hi sonu p? e; erred embodiments, the s:dt of these compounds is hydrochloride salt or irifliwoaeetate salt.

hi one embodimentof Formula i l), the chcmosensorv receptor ligaud modifier Is a compound having a structural Formula (III yu (fo) wltmem'

II k CtR ) Οι ·Ν·,

I is -C(K^;;'iOr ·Ν·.

J is ('{R ’ F or -N-;

K is ’C(R'^X)- or -N··;

R -I’XbO^'i' elk' Si hst tutxd - Ikv M- \L61iilJtl' It- if J SU>1J c awlalkyl, acyb substituted acyl, halo, hctoroalkyl substituted hetccoalkyl. heteroaryl, substituted·

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2017200704 02 Feb 2017 hcteroaryk betcroarylalkyi or substituicd hcteroaryudkyl, -CN, -NO.·;, -OR.*⁹, -S(O»jR^?1\ -NkV, -CONR’V\ -CO_?R7 -SO.AR^R·⁵¹·¹, -NR ⁱ⁹SO>R * -B(OR*^:>>R^il\ -hi toOR’feii »R A et -hi R \OR¹ '),

R ‘ re i:> d'ugcn. alkyl., substituted alkyl, aryk substituted aryl, arvkdkyb substituted aiylalky L oeyl, substituted ocy I hide. ho?-:-roolky I, substituted ucien tdky I. hetero.;!y k substituted betcrooiyb hctcroarylalkyl or substituted heteroaryialkyl, -CN, -NO·,., OR⁴', SfOkR/’k NK'^:iP \ < 'ONP'^!!R'k -COyR⁴¹, OCOR⁴⁵, -SO_?NR*^!R^{\ -NR^4,SO..R⁴\ ·ΒίΟΚ’’ι(ΟΗ⁴⁵). ΡίΟΙΟΡΑΟΙΟ hOiiR'hreA'’;,

R' re hydrogen, alky k substituted alky k ary I. substituted aiykasybilkyk sub .muted arylaikyl. ,t».y I. substituted acy I. hales, hetcnxdkx k substituted tictcroalkyk ucivruory L substituted het.efu.ii) k hctcroury l.dkyl or ^uhstituted hcteroaryialkyl ,-CN, -Ni)x -OR⁴'. SiOi-R ”'. NR'Afe ('(ΑΚ^ίζΚ^μ ( O*R^{‘, 0( « >R^{’, ΝΒ\Κ'^ζΚ¹’. NIC SO*R^{{, -B(OR^: ><< HC\ -lOpOH ')(«>RA _e:· -hi.H(R' XOR k ')’ obcrnatRely W and R.V, taAn s'gerthe·' wub she ate-m t· u Inch they .nc h-nded, l· >rm a ey chalky I, substituted cy efoJky I cyefoheC'roalkyl. or sub<tiiut>.J ey loheteroaiky I nog;

R is hydrogen, >dky i. substituted alky i. aryl, substituted arJ anialkyk .substituted ;ay lalky k aeyk substituted aey 1, halo, beteroalks k substituted hcien-albI heteto.iry k substituted heterouty 1 hereroatyl; kyI o: sub-til :*.d \’tet<*ny ulxyl, CN. NO - OR’', ·8(Ο)_;,Β, -NR R' ,-CONR' K -COR^r -«O k^is -tn'Ok^is -s,() \Rp %.\k No-R't -BORAtOR i, -Ry*.>V)k'')tOR lot -foOv.R⁵ ivOR^l<}'

j. k. I and m are independently 0, 1 or 2; and

Rk’ R^1, R^! R R R’ urd R*' are inee wdentN ίυ·0-·ά-<\ akkU subs'nnted alkyl, aryl, substituted ary 1, aryhdky k 'subsiittited arylalkyk acyl, Mih,sbutied aeyl, heten>.flkyl, substituted heteroalky I h-.-teroievI, Mihsbnned heteroarvl, heieroan Ltlky I or subsbuifed hetoroary lalky I or Jiefnjih e>y R * and R’R⁴ⁱ and R^v R ^:'’ and R” <>' R *' arc R '' tege'l\'' xsitb the atoms r> which they me bonded η-rm a cycle tcteroaikyl or .^uMittued eyi'luheteroalkyl ring;

with the proviso that at most, two of Η, I, J and K. are -N-. By ''at most two of II. 1, J and K >. <. N-\ u i^f < .at Mere ate /e'« ul'w .n atom o te it uetten a >* n ..wo ut.ogn dli'fiis among Π, I. .1 ati>.l k.

In one embodiment of Formula (lllk (Οι,,-Ο is

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of Formula (III), the compound of the present invention has

In οης' onibodtmen structural .Formula (.1.1la):

i of Formula i Hkfi. A is bvdrmmm alkvf. substituted alkvl. arvk in one ombodimen substUuted 3:\l my lalkyl. -mbstnuted ;n\ Ldl-vL acy L -nbsumk'd acyk bcRr-.mlkyk substit’Ucd het» loaiky I, fmerom. R Mtosutmed hcKaomy 1. hek'nn.?'. LX-l, sub-uiited h>-.eicmv iJky -, -< -OR·’. -NO.·. -SiOiJ<^;. -NHOR”, -NR/CGR’t XR⁹R^i?\ -CONRVx -COT/. -NR^'GyR’fe -NR'CG\R^!’’R^!! AR'<’SXRⁱ'R^!1 _>0r-\R'('( Mh\R^!’R^i!. 1‘ick'wbR. A w-OH.All·.

-Midi·. -\{CH ! . -MIOnk Aoi'K . -\H( -MIG.Oh k'H . X|{(

-NIR iS)\H .-NH( ί\Κ)\Η·. -( V-i'll-OH -CH XII .-Cl FA lb Ή-.. -( HX<CI H_?. GGN’T·, ( t AH' Ή. oi ( H-RIH p-bCH

I one ^.nboe.nuo. '*'(000./ dllai. R 1» os .hoOvU. alwi - iK.r.fk'd aXsi <uy lalky L or xubstumcd asy telkvl. Prelcud-w. R k bydn-gcu. u'etkyl, ahyl. i»<mvl, n<'-p>npsl. n-butyL fowbutyk w < 1,' butyl, phenyl or benzyl,

L· wk, owl .x \ikP e; I <mu da dllak 11 w ( fR ') . hs C(R ^ί, I i- C{R 1 , cud & Is -C(R^)-,

L· <>'a omL'C jk? e, I euu >? JlLd Vslweiocer JI Ά-* bam k.’Jkv ai-k substituted an 1, -GN. -(Hi. -NOu -S(OTR \ -NBOlG -NRW® -NR^R¹⁰. -CONR^&R^W,· -CO’R ’ m -NR''CG’R^!<', und R b' hydrogen, alkyl, substituted alkyl, aiylalkyl, or substituted aiyl.Jkyl,

In one embodiment of Form Jo (Illa), A is -0H, --181¾. -NHCH_?? -N(CH;;h, •ΝΗΙΧΊΚ NGCH·. -SH( iO)CH ·\Η('{(>)ν(Ή.. RIK fO)XH_?,

ANHClNHlNH». -GN. -CH XH_?. -CH-AHCH.. -CHXtGGb. <Ο.Ή. -CONHy ’ v’XlK'H a ⁱ 11' -< I b.'t' ’ η 'll , , J R ishytoogen u'etby L ot'od. ptopy I «v.piopyi » bun I. .ό<<· buty L se· bmy k .' bury'l plumy I > s beery I

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In <-ue cmBedniteu? m I <wu-il.. (Illa;, R is ty Jioecu <dLxI x.d <n n.<.l ad.x I hah·, ncte*<*a A I xuh-meted hcteiealkx l· -<' X. -X< ’· -OR' . -SlO^R' - ’COR'\ -\K\ (>P^il, -COXR Ίχ\ -( O?R ’’. \R''V\ -S* tAR^;' P?'. mAR*’WR⁴”: R h hydrogen. alkyl Hib-'bUiKJ alkx k hal>> heteroailx I. xith-mated hx'teroalky I -< 'X. -\^f ?- -OR*. -StOlR •on>ich xr'^ur\-xk^4;( or¹ ’.-coxρΊ<\ co-r⁴¹. so.xr⁴ r⁵ .m-xir’so r⁴'. r Ίχ hydu>ge·;, alky I sabsimued alky I h.do. heu-ioalky \ xansurjuv. ncieuslxy I, CX. -XO . ( »R ’ , •SiOi.R’’. ·Ο<ΌΚ''.ΧΡΊΓ'^!,·ΧΡ⁴\ OR^{}. -COXR^{ -CO P“\ SO XR' R’l m

XR'm up”, oi ;.H x·..·. P ' R' , togetite. a>tr 'he o' p'· OX' nJ' *h.x as. n. tde>l i<·! m a ey ek»hctei>-;dky l οι ,χ·ύ>'-ηθη.·ΰ o Uohcteioalky t = ing. and P.'^s).- hy du gen. alky I, xub.xlnuivJ alky k nah..·. nx’teKvAy k xiih.sotuied hcteroalky \ -CX. X* > OR . XOIP ’ , 0-i'OR^: XR P\ XlxGoP'X COXR^! R\ CO P . SOXR’lC’' XR’SOR·' his ptefc*,.d<L' that R is hxdiogcn. alkany I, 'aibMiUiicd askanx L askciiy L xubstitute-d alkenyl, ex x ioaikany i sbixailaix-J x'Vxioalkany I <·>xOaixx-oy i. xun.-thalx’d eyx ieoalkeny I halo ixck’i'ia-kyl, sub-n:i!»Cxi Ιι,Ήη'.ιΠ y. -( X,-\(>·. a?K ' -μΑ,Κ*'' -ικΌΚ¹' XR* K^il' -XR ‘Ό ;-k' -( t >XR' 'R^s' -( to-R* , -k’ J'XR ^μΚ *. -XR* R( >>R’' Π is also preferable that A is -Xt l:, R‘ is hydrogen, methyl ethyl or benzyl, and R ' , R R‘ anti R are independently hydtegen. fluoro, ebioco, bromo, methyl, triflufomethyl, ethyl isopn-pyl cy ch -propyl propenyl, mertvGpropenyl bntenyl. methylbutenyl. substituted propenyl substituted mcthylpropenylsub-'riiuted buten.yl. substituted mclhy Ihnt. nx 1 -XH-al.kanyl -Nl 1-(substituted alkany!), -OH. -OC Hi. -O-cycloi.iI.kanyk -O-betvs , -CO JI

In some -p.-miit zmboJmi>. mx <*f I <* -mila (Illa) the •Awwound Hus -Hueti'^f'al foi'mtili \>. Ruled from the <^!'>ιιρ eonxixrmg >>1'

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or a tautomer, salt, solvate, and er >tcr rhctc»»f. In some preferred embodiments, the felt of these compounds is hydrochloride »*r troluoroacetar..' salt.

In one em.bodimeni .<f Formula (Bla), the compound of the present invention has structural I s'-rnuda (Blu 11:

(mi) wherein,

A is hydrogen, ,;lky I, sub-mwed .nky I, ;eyl, -uihsntuk’d aryl xryl.nsyl. rehsihuted mxLlkxL are s. to-stouted .icy I. bciensjlksl. .-nbsmmcd m'k'nrekxI hcic;o.usubstituted ’ck reais' hsk'jcwxkf.kyi.sebskruee Lic'o.ux alkx . a \ -OR’ -AO·' -o(O).R\ AoR’ Ain >R^C. Ap/'ί OR AR^-,R’^!\ -OGARfiV'·. -(X\R Au ARVO?R ^!,;

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R R hvdregen, alk'^-i v'bstitutcd alkyl· anudlvk or “substituted aryiaikyl;

X'is (II· .-0-..-NR ' . --S-. -StO) --.or S(Ol· .

λ f-aA-kue sub-rmted . kK, L>.k<>_tdk\ km', ,n sul enukd ictetoiJkx tenc, rn is 0 o? 1;

Y^! is cvclohctc mdly I. suhA-umd ey dohetetvolks I ui

N and .X 3K-adkpviidenHy a cm-aknUs-nd, O -s NR? .

X'bOAR NoR'mS

R' hal·. Ntm CN. -tfli. -Nil -. ally L stibMiltJted aiky 1. .nyl, substituted aryl, ary lull.}l· xtOtaitated ary talksI, heten-.dky i. substituted heteroaikyl. beteroaryl subsfitimd heteroaryk hetero ary I alky I or substituted beteroarylalkyh n is 0, I.. 2. or 3;

FC is hydrogen, alkyl· substituted alkyl, aryl. substituted aryl· arylalkx i substituted ary I alkyl. heteroalkyl· substituted knerodkyl, hetoroaryk substituted beteroary I hoteroarylalkyl or substituted boteroarylaikyL -NR?’’r^!'^!; and each R^y and R¹'* is independently hydrogen, alkyl· substituted alkyl aryl, substituicduryl t'Salk' - Os ο., e< ai-litl - no ero.dkx s roan e> >et uv I h cmi'i “m o' heteroaryl, hetero arylalkyl of substituted heteroiiryMkyl;

with the proviso that, when X is -O- or -S-. .uni -n is zero; then X' is not-0-,

In wu· embodrotem : ΗίπηιιΙί iflla;) X is -CHr; nod Y* is

In one embed -own· ; Fw-rmuki (I Ha 1, X ts -0-, -NR’”, or-S-ym is 0 or l,and Y^! is cye-loheteroalkyl or substituted eydoheteroalkyl.

In one emlfodmicu? oi r-ufuula tlllalJ. X’ is-O-, -NR’-, or-S-; mis L and Y^!

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Id some cirihodnncms of Formula filial \ is mode lerc. cfov kK, pn-ps kmc. dimcihylcfDylcnc. mclhyk'yclopropYkne. m es'cloprnpylmcthykmc.

In seme cmh>-dimcnt- ef FeimaU filial 1. A is hx dr>-gcii, alkyl, substituted ,dkG -< N -OR’.AO MiOX-VR. -MIOR'.-MI COR¹-NR K^f' •(OXR'R'.-UM'_?f •NR'V’0R^!?

In some embodiments of Formula (Illa I ), R^,; is hydrogen, alkyl, substituted alkyl.

b> mt embodmivuts of Formma {^HIal k 3 ^: w csclohetaoaKy I or subf_stmcd e,e’.onctcioa.ky h w pietei.-n,. _S„i s * is pspo-id. wl, *ubst.'med pipe!··, m i. tetrahydrofurany I su'ussiuuted.tefrahydfoiuranyk tetrahydropyranyl, subsitituted teu.thydn-pyiam k dihydiofutanvL subsmmeo dshy d?>-lui my I. pyi.vhdmxI. schsutueU px el e>m . o\„i tm , o s.,.>sfmuco oxetanvl 1'w J ><> ’ ufc si le frat ι κ sul <uted cys.lobcieroalky i c.-mpri<c< one or mme subsriftiem* '-..-iccrod from rhe gn-tip consisting »>f alky I, -mbsl ituled alky I, ary I subsrifmed aryl, aryl.dky I sub-mimed arylalkyl, act I, substi Piled acyl, heteroalkyl, -'mbsdtmed heteroalkyi. hetero.try I. -mbsmuted heteroaryl, hetcroaryialkyl, -mbsimdedhcteroaiGallys \,-OR'' AG -MAX' AR'CQR -\R'R •CGNiC’KM <G_?R\,md NR'CG.K⁵'·,

In seme embodiments of Formula {Hlal), X⁴ is O.

I a seine omhec Imo >is >f b >’ mu' a »11 la ί I A -Cf \^!) A - >s <f OF, -(\i))-MI- \U-{ itei- Al!-C<O)-Ml-, -Cp.'UF, -O-i '(Os- -O-(';Gup-, -Mid FB-Ο- -O-t\0)AH~ -CfNH)- -C( Ml All-, -MI-C(MI)-, -Mi-CiMAMl- -('(ΜΓι-Ο-, -O-CfMlp, -Ο-Ci MIMA, MM i\lb-('-, -Ml \\II)AH- -(.fN-GllF orAfSb

In some embedimenis of Formula (lllal). A is hydrogen, alkyl, siibsritmcd alkyl, or AR R''·; R is hydrogen· and Y is piperidinyl, subsrimted piperidsnyl, terrahydrofuranyl, sbb'rwecc w abwaol', <mx' ', u-d'' c <>^Λχrars -scOsii ole I feti.-mdiopvu rd d, x<b > nr. ο.I -iibshteicd dihydrofuranyl, pyrrolidinyl, substituted pyrroBdinyl, oxetanyl, or substituted pxeianyb

In some embodiments of Formula (Illal ), A. is bydrogcB:, alkyl, substituted alkyl, or -rffiX :Rⁱ⁷ is hydrogen; Y^! is A³-C(X)and AteC(X⁴)-X⁵- is -0(0)-, -C(O)AH, -NH-G(O)-. -Ml-CfO)AII~. -t J u-O-, -G-C(G)-. -0-GfO)-C>-, -ΝΗ-(?(Ο)-Ο-, -G-C(0)AH~, -70

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NlkC(Nlh-(X -O«Mh-MI-. -CiX-OHs- or-OS)-.

In seme specific cmbodnuenis <0* I omuia {llhii), ibc compound Fas xHuelu'.d

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H

or a lauionwr. $ Ji. sdiaie, and -n ibcieuf, In some picierable embodiment hie sail e· these cornpounds is hydrochloride or uifiuoroacctate salt.

In otk' embodiment ot'Formula (111), the eomriound of piesen! nixcution L>.

In one cnd.x''inc'i* ο; I am. da (HIhι λ t bx .bosun aXy k .robstcuted a'Ax k u.x L robsbroiedroyk CX.-\B . -OR'.-S(O),R '. -NkVOR*'.-MU ip . X'R R^l'.-NOR'.

•-CGNR.Vi CO-P. . \R'W-P. ', XR‘( U\R ‘R'.-XR‘CSXP.

-NR/Vi NH)NR^!,,R^!!.

le <'Ά end cd aK.* e. I <una >e (]]] u R b^eioeen II x’. o. v to tn rue <dk J 'In one wibodime.nte^F.'ru'al.. i Hlbk A is hydrogen, alkyl, substituted alkyl, aryk

U'bslRited^J tip . SR . i X, XR’K < < >XR’|> . < ro R XRiteR’ -NR?'(ONR?'Rⁿ. -NR’«?S\R^K,Rⁿ m - \RV( MlBR⁵'Rⁿ; and P?' j» hydrogen, alkyl, or substituted alkyl,

I o'c /bed m. a >' I >ιιγιΛ- ϊ III.R H's 4 .'R ''> »ι X , w {iR ) is -C(R'^?>; and K is C(R '^S)> or -N*.

In one embodinicni ui'I'oriuuia (I lib), H is -C(R '')·; i is -CtR’⁶)·; J i?

and K, is ·Ό(Κ )·-.

Itroite embodiment ufFomrol.i ill lb), R.' is hydrogen, idkyi, substiti teU alkx. aryl, substituted aryk arylalkyl, substituted ary'hdkyl, acy L substituted acyl, halo, heteroalkyl.

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Mibspn-ted htom<><dk\l. heteroaiyl. ,-ubstm-ted bu'KTn.irx L lu'teioaiylail-xl m -idotimte'd hvt> u»jf - uikvl -( X. -\( a, -- *R . 'So n.R . -(<O)R .-XR R” -COXR R\-( O.-P , '-SOeNR^R'''·¹. ~NR 'SOdT’; R^?i' is hydrogen, alkyl, subsiitoted alkyl, aryl, substituted aryl, ayxlalkxl. substituted an lalkx L am I. ^uKttoited aey I. halo, hcterealky 1. -mbsututeu b^ieio.-lky h heteroaryl. substituted heterouryl, heteroarykdkyl or substituted hetes<utiy tolk-1, -CX X- * •or” -SiO;. R”. .((«'Ok'’. XPV ,-COXIER''. CO R^.-SO XlV IC . •XP.ⁱSO.K'’'. R ' r- uxdotem, elk' I, ί-ubx'.ituted alsy I. a.x I. Hihst rated , .ux i.-.ikx I, suhstuuied ap .dsy k aexI -uhslituted am I. hah· ivtoi<fokx I. '-ul-sbRncd hcteuvlky ·, lute?· <ηχ I. Mihsl rated hcterca-y k nctefoaistelkylof suNfruted k-ieu-mxkdkxi .-CX. XO . -OR”, ·8(Ο'<' , M OR* , XR^M 'Λ>XRP -CO R‘\ to'¹ XR‘ P,-\R^!'8^! I R . R'^s e- uxdiig-ur. alto k 'xHw.itutcd alkyl, t x I Ί I’M tote I' 1 . x k ,v I · 1 hum te Isi dkJ t -I . tm ha <> h ten dk 'Uh.fotuted heteioalky I, h-rteb-arx I. -uMutute'd hcteioaixl. nefrioaiy ulky 1 or c-ub'-tEn.tted ncieroars laikxI -( x, -NO . -»>R' . -$(( ?).. R^{ . -Ok OR* . -XR R \ -ί,ΌΧΡ R^(<, -COR^! .

.('to .Sf ;· tel.'¹ P ,-\R%to R

In one omhi-dbuen;. of Formula (lllbi. A Is -XH -, R^: is hydrogen., methy I, tohyl nr ben/yk and R‘\ R '' R' ;md R ' are hrdepcnde-'fdy uxdi w·.·ι, fluoro. cblviO. bromo, -CX. rdkanvL substituted alkanyl, alkenyl, snbstitued alkenyl, alkyuyl, substituted alkynyl, cyetoalkany I. ^ubsututed cyeloalkanx I. cyeloalkcny I. subsumed eyem-dkemk ΙκΊΟ’oal'banxL subMilvfi d heteroalkmnl, cy- lobeK'ro-flky I, snhstuute'-I eyefoh·. te;--.Jky 1, -O-alkanx I. -O(substtatec alkany I) J-.dLcny i, -Ousuhsmuted. all-cm b, -XH-alkany I All-kuh-jinncd alkanyb, -N'H-.ulkeny k -NVI-fsubstituted alkenyl). -S-silkanyl. -$-(substituted alkanyl). ~S~ alkenyl, or -S-fsubstituted alkenyl).

In some specific embodiments ot'Formula (IHb), the ccmipound has structural fornxula selected from the group consisting of:

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or a iaiitoincr. sah, solx'aro, and or ester thereof, In some preferred embodiments, the salt of foes© ioij'p<xed' .s wdnn . ©nee oi i”flt ο.ο,κιΊ,,'© sail hione ©mbodunent of Fonnt-la<JUb), the eompniuid of tiie present ©wen-ion striietural Formula f lllb H:

(illbl) wherein,

A is hydrogen, alkyl, substituted alkvk aryl, substituted aryl, utxkdl.x L sid.-w-kiied arylalkyl. acyl, substituted acyl, hctcrcalkx . '©.ihstituted ncteroalkyl, hetentetrvi. substituted . .· ·. ...... λ . .. .· ;·[ .

heterban i, bote roaryMkyl, substituted heteroarylalkyl, -CN, ~0R‘. -X t >. -Sp. >\ R , AOR \

-NHOR'k AR(XMⁱ⁽\ -NEV' OXR *R' \ -GfoR' or -NR'f O.R¹⁹;

R w hydrogen, alky L substituted alky i, arylullAI. or substduted arx taikyk

X’ is ( II· , G . XR ’ . 8 . StOl .<u HOP ,

X^: is alkylene, subs©-tiled .©l-.x lene. hctcroalkylcne, or substituted hetefoalkylen©;

rn is 0 or 1;

¥’ ss beteo-arx L sid-stnuted hetetoaryl, ex cluhctet oalby L '-nbsUteted ex J ©he ter© alkyd, ©i

X ’ and X⁵ are independently a eovalcht bond,-~O~ or -NR⁹-©

X⁴ is O, NR⁹;N-OR'\ or S;

R* is halo, -NO;?, -CM, -01¾ -XH₃, :alky'l substituted alkyl aryl, substituted aryl, arylalkyl, substitutedurylalky I, hcteroidkyl, substituted heteroalkyl, heteroaryl, substituted hetem-iry L hetei-'.ey lalky I or -nhstuuiAl beteio-my 1-dky I

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R is by dn>geu. alkyl. sulMiUited alkv I. ary Ci hift.i.u. at C. .in kdky L xuhx· mik'd ar, kdk\ l luKbxdks I xt<bAU r_d Kk<> ί C I. hcMoass'. xub^muk'd kck«'.in L :i,-!ue.: s kX.x I or subtituted l:ete'”>an kdky k AR R^!’’i and each R' and Rd'* »s aidcpendcaHx hydrmen. ;dk\ I. substituted alkyl. aryl. substituted aiyl, amhll C. s*u't < tn lake ., i '<r> dA. \.„»»tH r >eto e.-. nJ ho' .©an' substituted hetcromy k hcici·«a·y lai A I or xubsiinaou hcwroury ktlky I.

uituth© pioviso that xvIk'b\^! is ^; > ©i , at'C u iszOiO '.bun λ λί<’' Ο .

hi <ia<. oml-'-dunca? ofFormala (HIM i. V is CH ··. and V^! u^;

la o-te erobodimen· ι i b >rmuk’ id fl b Ip X^: is ~ O -, --X R -. or S™. m is 0 oi I, and Y^s is cyck>hoer©;dkyi m substituted eydobou-'roalkyi.

la ©π-.. enibodiBteU’: Ab>>rmuk’ Hflbl i \ η O-, -AR*'- . or $--: rn is I. and Y^!

:-.y kt xoaie omhodimoΆ ·>ΓΙΆπηπο ί HIM k X i\ aisanyk’n© -ΆΌίηηΜ alkanyl.ene, heteipa&anylenp,_; snhxtnuted hoteroalkanyleoe, alkenyfene, v ib-onoted aitoykrn®, heteroalksnvlene.or substituted heteroalkeBvfene.

la some embodiments of Formula (IHbl).. X' is meihyl.cne, ethylene, propylene, ,'a>-propxlen>.. bu’x km>., <s,-mn -enz, -a < -buiy k-nc po rylono, I'ewlono, hepty'one. dimetbylethylene, merhykyetopropyleue, cyclopropylmoby lene, othenylone, propeny leno,, or buteuyk'aK'.

In utt© embodiment οι Γ«ηηιυΙ&:(ΙϋηΙ ι. X is hydrogen, alkyl, substituted alkyl, ~t \, AO-.-OR’ -S««)i R'^; -NR ? oR' . -NHGRAR^;R ^l. -NoR* -CONRA'¹ -CO-P , AR\ Odfr ,-NR <>\R^hR ^! AR'CWR’ R” -NR'i { NHiNR 'R

In one embndlmen· ef Forinula (inbl), R.^! ’ is hydrogtei, alkyl, or siibsti.tuted alkyl.

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In <-ne enibednnent ο; I mmteu iBIbl i. Y^: i- cxek'h>.'te’<'<ilkanyk sub-tshited eseiobetcrealkain I csd>'l:>.'k<'4ikenxl <« -ijusutok'u eseieboien'dlke'iy I h is pfcktabk ikut V⁵ is mj'cridiiiyl s,-L«mb.ited pipctidiityk tetrahwiroturaovL subsitiiuted retrain· Jrofn> any I, kt:uhxdfcps:anx' seb-'truk'J icMbxdropxrarx L di iJm un.iM, -nbs.i'isted dibMofataro t m f robdinx I. sub-mink J py' iolidinx I owtanx k sub-tmited > cetam i, saeeb.·. ide = mg or its deux uih s\ rebstitok'd suvchaiuL i ng oi its denxauxc

In one embodiment of Formula (Illbl), Y ^! is heteroaryl or substituted heteroaryl.

it i- pjcteiuble that Y^! is ρχιΐθ:η-1, .sub-titured pypdinxu pro rob k substituted gxiu-hl, -uraml, substituted ^ruiuuyb px raio-iyl substituted pxra?.-.-iyl, isoxaz. x I, <ubsiituied isoxazoiy L oxazoly-L and substituted usjznb : it _:s ^k-, pietembic mat flu sub-tuuted exeb--ieteto.i reny. 01 ii< substituted cyek’heteuxdkenyl comprises one or more substituents selected bom the group cotisist-ng -at'aikx L subjittued alkx I. ary I. sub-tiiutcd ary I, asylalky L substituted a- ylaiky L aev, substituted acy I heteroaikyl. -rah-siliuted bek-roalks i, Aicnrex!. substituted beieroary I hek’roary iaikx L sub-sinuk'd betcioa:yUky I. -CN, -(hC -\(j , -foOi. R\ -\C>R-MiOR' -NR Ό ik‘^! -NR’ R' -CONR’ R' -CO R .rod -NR'i i >-R

In one embodiment of Formula tri fill 1. Y is

it is preferable foot X⁴ kO.

K a ro 0 uh 0 mo v ,rd onnak {JIF'O -C(\S-X - is C(OF -F i« fl-XH- μη- -ΧΙΚ'μΟ-ΝΠ-, -C<Cn-()-, -Cs-('((.)?-..-Ο-ί.χόΝϋ-, -MM (fj)-O·. M-CtOl-Nll-.

CfNHp, -CfNIO-Mh, -XIMXXHF, -\U-( (XllbMI- -. (MR-O-, ()-C<NHi-, -O-F ίΜΙΜ »- XiM ιΜΓί-Ο-, -On (NIO-NH-, -Ο(Ν-ΟΗΪ-_: or-C(S)-.

In one eriibodimem of Formula (Illbl), A is hydrogen, alkyd, substituted, afel, or -NR^R*'³: R¹' is hydrogen; and Y’ is piperidinyl, substituted piperidinyl, tetrahydroftiramd, subsitituted teirahydroiuranyl, temihy drops rany i, 'sobsitituted tetrany dtopy ratty I, dfm druturuny i, substituted dibydroflrranyl, pyrroHdinyl, substituted pyrrobdinyt oxetam I subsPuucd 0 sours I. mmiiisaeiflitu ide . iiig, subsPiiitcd mom-saccharide ring, px ridinx I sub'-htuU-d ps ndinx I. px'lolCt stibshiuk'J px ”'<»ix L k': any I, substituted f’T.mx X m ta/Mx L substituted p-> ra/i-lx I .soxu, Mx i substituted isoxazolyl, oxmMyl, or substituted oxazdyl.

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In «me cmBoumenr m I <«n. < Hi n ¢. \ i- bx Jr.gcn. alkyl, .'iibstmitcd mkyl. <.·

ARR^f‘: R^r k mdioeen: Y^f is -X 'tXVX und -X '(XVX’- h C{<)K ·ΟΟΐ>\ϊί-, -Ml

C(OK -Midi’ H-XTl-. -CH))d’-. -t »-C(O)-, -< K (O)-O’- -MI-C«0rto-. -Cd :ιηΑΉ-,

CiNi n·. -CiXi n-NH··. Alk'.XHk -ΜΗ'(\Η)·\Η-. ·<· ΜΊΛΑ··. -Od’tNHK

XH ClMOO Η·<'{\ΙΠ·\Η·,-SiO).·. ·ΧΗ^λ(Π) · sp?) ΧΙΐ, O }j q. < '< \

OH)., or -CfS)·.

in some specific embodiments .of Formula (Ulbl), the compound has structural formula selected fiom the ctoup consisting of

Λ h

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Ο H

/' a lauivinet, salt, solvate, ardor ester ihcreel hi »>nsc preferred enibodnncnts, the sUt of these compounds is a hydrochloride or triflaoroacetete salt.

In one ernhodinient Of Formula.(ΙΠ), the compound of the present invention has structural formal a (Ille)

A (01c)

Whereto D is halo,-OR*⁵, -NH^OR’⁵, -NH-NHR⁵⁵, -S(O)A*⁵, or AR^!5R*-;

In one embodhnent of Formula (Il’le), RA R’X R'and IA are independently hydrogen, alkyl or substituted alkyl k is preferable that H is -C(R '); 1 is -C(R'^!'); J is -C(R'A and l< is ( th AWO 21W1M221

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.VroXHN , and

or a tautomer, salt, solvate, and/or ester thereof. In so m nt to -.d embodiments, the salt of these compounds is hydrochloride or tri Huoroaeetaie salt.

In one embodiment of Formula (HI). the compound of the present invention has structural Fe-rmnla (XI)·

(XI) wherein,

R hydrogen.-UH.-Ml -( A,-a Ή OU et-CO II,

D is -OH or -SH. and \ ts < hi. A H . A H( Ή -., X(( H»A -X H< \ O »Cl L, A Hi t O )0( lb, X1l< V HA H -, -ΧΚ('Χ)\Η·.-ΑΠ(ΊΑΗ1ΑΗ .-CA, ·< Ή -Oll, -CH.XIi .4'11 XH<H-,. CH-A(CH-)>. -<t ML COMI . -( (»\H< H-.w CH MICtOR lb, provide-d that when R is hydrogen, then R'\ Rto R^?;, and R^v ate not Itydrogeu.

L· end ,'Ciaen* e; I mm de (XIL R i\ OIL-SIL * Ά, CH-* HI -Ct ML and .A w -AH , AHCH . - At('ll 1 . -A’IK'(O)CH., -A'HC(O)OCH·.

XHs'lS'iAlb. -AHCtXHlMl·. <’\.·(ΊΜΙ. < ΊΙ-\Η-, CH AHCH . tΉ At< ΊΙ-.)-, -COdl, t'OXH-, COAHCH.O’ ( ΗΛΙΚΊΟαΊΙ

In some embodiment? of Formula (Xi.L wner.R'. P.'. R ' a<: R an-hy dteeen On- OlLanJ/m- { H-H ’.wR¹ i.>:vt -CO/Hor-OH:

wnet R'.f!' R ' R' nydtoec» Du- -'HLandaw \H meuK¹ •COdl orCA;

when R^,f!. R^;i> and R''' arc hydrogen. R'^- is -OMe, D is -OH, and A is -CH?OH; then R^u is not -CHgOH; and

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2017200704 02 Feb 2017 w hen R A Rand R ate hxdrogcn. R' η By ih>>gcu m metlty U»is (til and A is ·· C0₂HithcriR^!;fo not -SH.

In <‘*K embmhmcw ,;; hunaJa illh tiw caumouiul to foe |'Uwni inxentiini bus structural Formula (XU):

wherein

FA k hydrogen. -OH. -SH -CN. -<'H OH or -COti l;

1.) is - SH or -OH;

A is -OH. -MB. -NHCIH. AiCIhb, -AHCtOjCHi, -AHCtOiOOR AHCtO'jAH •SHClSjMk, AHCAHlAll .-( A, -CH OH -CHAH..-CH SIK'H . -Cl k,\(CH Φ, -CO, H, -CONH..:. -COAHCH ., or -CH.AHt it HCH-:

R^% is hydrogen, -t«. IX -Ok til -(X -Ik -( Ih. -C₂Hs, -CH{CHd> -CH₂OH.

-t IHOt B-toA -t ft>r<R⁺ⁱR'\-t <hR'',-M>AR''R^!’.AR’‘mAR·' -B(OR' HOR⁸} -1\O)H ti< * -(OK ’ ·' -l'(O?i R A(OR'’) bf ^bydtog'. n.-OCH ,-<iC,H -OCJI ·( to -C II -(’H(CH )_?, -f Ή,ΟΗ -CH.OCH·., -CA. -Ο(ΟΛΗ’·’Ρ^!.-ΟΟΛ^ζ' -SOAR’ R”. AR^llSO;R“ -BiOR^r)(OR' ’). ~KOHOR^!MOR⁴⁴Xi'~KOXR >< >Rto

In i'ik embodmum· m rfoimnla < XII). R ' w -OH, -SH. A\. -t IHOH m -('t \H. bi one .-ntbodiinen· et'Formt-la (IU). the eonmmmd of tiu· pieseni ηιν,ΗίΗη has stiiiHo'ai Fonnida (XIII):

_RW _R3S

(XHl) wherein;

Γ» ts (»oi S.

A t.- OH. SH . NHi Η., A{(. Ηψ. -AHCf·'HCH-. SH( i(ί)0( Η», MlCt* bAH-.

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-NHC(S)NH.x -NHC(MI)M l·. -CM -CTOIL -< Ή -Ml·, -ΡΙΙ,ΜΚΉ·. -CH.-MCIPro -C04L -<’< ΑΗ-ί’ΟΜΚΉ .or-( ΗΑΠι f< >MH :

R' is hydrogen, aikyl· aryl, uryialkyl, bi one embodiment M FonnuL· i Mil· when .-\b Ml- and R\ RM P and R au: l-ydtogen. ?hvi! R^; w nor tnctbyk c'dty I or pMiw I.

1' -> r.w. xpeciM e in d .neu*· <>f Fe..nu’a t Mil·, me ί,ο.ηρουηΰ ί;η· st?ucuiud formula selected hooi the group sung <0

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<·ι a taub-roer. .-oh ate -md c>i cstei thereof hi «isc pwferred embed ηοοη·-. -he of ihe.-o compounds s» hx di-». blonde or ni’du<»:<».ivCi‘C:C -uh.

In orc ©RfbodimeRt of'Formula (III), the compound of th© present invention has snuclmui Formub (XIV).

X” « A ,hk _..r^;!S

T γ h'-^r·»

A (XIV) \dwn \ -Ml -MICH .-N(CH \.-Nlk fOK'H ,-NHC(t»i KH .-MkrinXH.-. -NHC(S)Ml..-NIk iXHjMh,-ex,a IbOlk-en.-Xli, -CH-MR II-, -ChkN-GH )·.-CGdl. -i/GN'b. -COMk.fli, m -t H»NHC(C';t H-; and R' o; alkyl, aryl, or aryhdkyL

I icme oul' e mo v o' l oin'afefj» ;h,-elu'wesesr. >n roc n’ei I gaud -neJit er anompuu.ud having a strucuunl Formula· (IV):

A (SV) cvhcieur

L is -CHR®'-. -NR⁴; -O- or -S-;

M is >C HR' -, -NR⁴*, -0- or-Sh;

R is- -CHR⁰' -, ’NR⁴⁹, -Ci- or -S-.;

T is -CHR^6:\ ’NR^5!\.--0- or -S’' o and p ar©: independently '0, L or 2;.

R^w is hydrogen, alkyl, substituted Nikyl, aryl, substituted aryl- wyialkyi, substituted

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2017200704 02 Feb 2017 an kilkx b acy k tebsunited acy I. bcternalk^k saAnt ited tvtefot. In L hetetoai C. sab^itu'^d heti tuanl. hcteroary l.nkyl nt Mifonudau hcte’n.in telky 1 A'V As > . -OR¹'? -S(OhR ’, -GCOlCl· -NR'''COR⁶⁵. -NR'Vk -CONR'V. -CO R λ AOAR'Vk -NR'ASCTR''·. -Pro >R^; foOR' UW^W- }m -P(O}tR h{OR ')

R w bxd.muu alky , substituted alkyl· aryl substituted aryl ary k'dkystilMituted an lull \l royl. stil Mr.uted -uy L Iteteroalky g substituted ucteuAkvk Petero^n... -tebsiituted netefo.tn L Aleman lalky I <> '-r.hxlifuted bctc.uan'.alky I , ( \, \s>-, ; )R ¹. -S· i b(,R . • t iCCKA Ak^;'^;\ OR' . \R^llR λ ( i A¹ RA -i A iC'k A i ΝΚΑ< \ AlC'Nf nR'\ RROR )<OR'~S Pn'ntCR lVn_kR_tlOR'k

R' o hA Act·. alkv L substituted ;tlkv L ar k -«ubsiftutev. an I an kflky . -teAtituted an talks k ac>k substituted acy k hetciojikyt. substituted heteiOsbkyk hctcroaryl· substituted ncteroarvl. betai\x?nltdkxl or sub'-ntated Itetenuny AkO ,CN, ACC, -OR' , A(O), R‘ , ACOR¹’ AR'X'OR'' AR''R^C'.-CONR' R*',-CO-R'\AO AR' R^J' Ah'80 if 'IfiGR' Kith k P<tntOR”jfpR' Ί <α -IA »><R' }{OR’ 1

R ' s bydrt>w..n. alky l· Mthsibuied alky l· ary i. substituted ary t, ary iaiky I substnatvu atyl.Jl.yl aeA substituted acyl Iteteroalky, l· substituted betei-« dky I hetetoai s i substituted beteteary k hero·'.ay kuky I <x tehstinucd betetoaty kdky I, ( N. Mb. <^R ’. S(Ot R ‘ OCC-R \ Ni< COR NR' R AAR R . t OR ' sit NR ‘R \ NR \θ^< I -RtOR '}t()R'^;i -PtO)tOR \OR’hm 4’tORR''){OK ’ i; nt alt·, rnativdy R^!:Amd R^; R'Amd R \ ·>·. R >-jid R’' logetbe; uith ^;be atcris ro \\hteh Ι^μ?ν ere bended four» >ι·ι ary, si'Ostinitec aryl., heteroaryk substituted beteroaryl, eycloalkyh substituted uydoalkyk eycfoheterbalkyl or substituted eycloheteroalkyt ring;

C u_s v and x are indepen-K nils n, I w

R''⁴ to R ' we indepl· nJenth hydrogen allyl sii Auroted any I aryl, substihited aryl, arylalksk vibsuiuted antill y > hex roalkO substitutes' -η'ίοΆχΟ he'eroaryk substituted heteruaryl . heteroary Italy I m subsiitnu'd hetewoary Ulky I or .ilternatively R^M and R⁶' R** and R^i>:, R⁶* and R^Ver. R '''^! and R together wiih the atoms te which they are bonded form a cyctoheforoidkykor substituted eyefoheieroalkyi. ring; and

R^! tn R arc iiidapenJeulN hydrogeu, alkvl, suNntHtad alkrl ary I. -ta-sOnded an t.

a v lalln - rail. .A an talk-, <u O sjA« .and <u O hA'seaPn ) * tbxjljt-.il tnu< i.. -A,

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2017200704 02 Feb 2017 hcteromy k substitutedheirroars I. heteroa* y kilky 1 o? substituted kHe’<‘arytelkyl;

w jfn the p*<'·. i '0 that at m<-st indy one of L. M, R and T is a keteroatom.

In one cndk'dnncn* ofFornmla ilV). B is -N-. ars-J F. is -NR' - or -N-. 1( is preferable that G is -C-.

in <»ne e-nb-'-dirnen? of Formal.; *J\ k the eompeund of the pjesen? n-sentmn h:^ structural Formula (XV).

XV wherein G h -SH ·» « hl and A is -OH -Mb -XHCH -MOM -NHC(0h lb -NHC(O)O('H-NHC(O)N.H;. -NHCiSfNll·. -NHClNHINH?. -CN. -CH,OH, -CICNΙΊ_?. •CH NHCH -t H Mlhb -CO B.-CONH -( OMR IP m -f 'H NHCiOX IP

In x.'ise spenfu embodiment of Formula (\\ } the compound h a- sinYteral formula selected from the group consisting of

HS^N^ Πθχ/γΑ

N.v. JL J γ ., γ - .and Y

NHj OH OH .

o; a iaulenixr. ·* ill seAal.·. anJ » este* iSyssC In senK ptetern'J embo.hmeub.. *bo <sit of these compounds is bydiocbloruk' or lritluo?oacfia^e salt

In one embodiment of Formula ί IV?, B is. -N~; E is -NR.⁵ ' - or -N-· A is_: hydrogen, alkyl, substituted alkyl, asvk substituted atyl, -OR - SR⁹, -CN. -NR⁹R’ ,. 4X)NR⁹R^W,. -COM -NR't'O.-R⁵ '. -NR'’CONR^fC‘R^S5,--NMCSNR⁵'R^H or-\R\ i \H}NR^ii:R^;;; and D is -O, -S . -n-orO

In one cmbodin'Ko. e*'I etmula (IV), the compound of the present invention, has structural Formula (l¥b):

wherein L is -CHR^’s M is -CHR*’-; R is -CHR⁶²-; T is -CHR'w.

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In seine spcethe cmbodeireni.s <d F<.iniitia {IVi. Uk conqeitirJ lore so udntal loitmra sekeuJ itot’, the t,u>itp re-ns s;n g of

or ,i tantmner sab', sobrate, and or ester thereof In some p-A'ncd cnh-idcncris. die ss'u ol these compounds is hydrochloride or trifluoroaeetotc salt.

In oik embodiment of Formula {IV), the compound of the 'present mvc.ntion has structural Furniuki t l\ar

In one eniboj-munt ctTurituiLt tlVa), I. k ΊΙΙΑ-, M re -< 'HR* < R re -«'HR*'-; and Γ is -CUR It re prefeial'k· that \ is hydrogen aheJ, sidrettjuted alkx b ary I, substituted arek -OR\-SP ', -CN. -NR 'R^!1. -CONRV'. -( O_?R, AR'k C_?R^{! >}, -NR*·, <, AR^1-'R^h.

-NR‘( SNR^hR^u or ARV< NHARA'rA lu some specific embodiments of honmila (IVa), the compound has sbnctural formula selected from the group consisting r>f.

or a tautomer,: salt, solvate, and/or ester thereof. In some preferred embodiments, the salt of itora- compounds is iredroebh-riile *-r trifiuoroacetate salt.

In one embodiment *>f Formula-(11.), the compound of the present invention: has structural ΙοπηιιΙ,Ή* u:

A (Vo;

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2017200704 02 Feb 2017 uhoon 1) ^b’.Jrega.Jy 1, uni lull·,·, -OH, -Ml., -SR' -CH . -< 3 >-ll.- -< 3'>Ml·: \ w -Nil..

-NK( Hi. -\f( Ute. -Mb\vnCHi,-NHCf< >)O( II·. AHA RMK AHAS.sMl·.

AHC{NH)Nll·, -<’N -CH.< >H -t liAH-.-Hl MICH .-AlAil’IhK-CO.lk-COMf..

-< ’< >NHCH . os -CH.NHCfi Μ Ή. .md P^- w hy dr>>pttj. j Iky I. substituted alkyl mxlalkyk hs mu cml-'-Juncn? of formula(Vat 3’ terms a single bond v-ifo W and a w-i-bie

00:0 Alli· Z. 33 A ·( )R 0- O: C(R''>oi N-,,;uUZ:s s.,.N(k'gos <?

in one embodiment of formula (\'a i. 3’ terms a doable bond with W and a single bond with Z: 3\ i >,-N(R“)₍of -O-;Y is C(R Ό- m N-, und Z is -GR Ί- ο, N-.

Io souk cniO-dnncnts of Polinina i3\;). x%he?c.n K is C(i< >

- o„. >..nboj m „ Άη'.ιΙΟ a. *he con. -ound ,>'N w pscse it bcrncrl t>

structural Forme la 13·’ i

wherein:

R'^c is hwho-gen, .My i. hate. -CO R '. -CONK A . -SO2NR.^:V\ -NR^{: :}SO;R^:'\ -RVOR ,x,OR'i -P.OjfOR kOR) n -P<OuR^s,){OR },

R' is hydiogen, MF oxy, alksL subs-mited alkyl, hulo. -CN, -C(0)NR”'R'\ -CO.-R '3 -SOAR ' R ' ,-NR'’S( J-R'' -FfiOi-; 1{OR^X 3 -FYODOR ItGR ) or -F’('(JXR'^sf )(C>R'' }; or alternatively R '* and H iogvtner -,sirb rhe atoms to which they are bonded form a eydoheteroalkyi. or substituted cyck>heteroa!kyl ring and

R'⁴, R'·'·.. R^s%and R.'¹' are independently hydrogen, alkyl, substituted alkyl aryl, suMitiiuJ ary t. aiylteky I sub-umm.J ary kills!, aes I xubsuniR'd aes I in.ierealkyl, substituted hete>->aiky I hetemary i, siihoimrcd heir· nary 1 heteroa?yl:dky I o: xubMinied hereroarylalkyl; <ir alteinteudx R'' and R or R ami F<? tegether with the atom* to 'ahici: the', aic bonded f,>nn .i ia eiohcteioalkx: or s-aostilute^l ey ciobeteroalksl ?ing' provided that when R^ and R²’ are hydrogen, arid D is -SH; then A is -NHy.

In one embodiment of Formula: (V), n iitn D ;s mete) I -\ is donethy kirmn-i. :tml R i- hy Jrom-n; then R ' js not mi.tU ah', I or carboxyl «iiu? 'i'eiJ \ is d'u,'iislan > cm. R i-mub, hui? <>♦ irJ s

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when D is h\d><'gcii, A is duncihyliumrio and R' is methyl; then R '^: is not inethyh wbut O :- hxd-ogen. A is mctnykrnuib· and R :s byd-©eon, the© R' i- nor inctlp i, etf.yi or carboctboxy;

w icn a ' Iwu.Oj^n X is i„ci Ό ,ΐ'ηι» and R si:,.’ wl *ί > Runner ncflixmi carboethoxy;

«hoi O :- hxdiogen. A is lucinykrninb- and R :s ·( H We. the© R' i- nor inedq i carboethoxy;

when a i- phenyl. - nietoxb- uiro ©nJ R ' j-bxdie^.-i' *h,-r R^s is nor methy R ©nd when I> is plteiix L A is -XHtCOX 10 and R is incibp i tiien R is no- easoonterhoxy in one cmh-odlment ot>ony:iiL· (V?. -he compound --f the present invention hestructural formiki <, V B:

wherein D is hydrogen, -¾¾¾. phenyl er benzyl.

In one embodiment of Formula (V), the compound of the present invention has stiticniral formula (VH)'

wbcieih X is hy Jtogot, -(Ί b. \ΊΒ. phenx I <u benzyl

In one end-eminent <n Formula (V). -he compound of the present inxcmto-i has strucmtal formula. (VIII);

wherein

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R¹ and R ’ are mdepciukuth bx dr.-gen, ·<Ή,. -( ,IR. pbenxl -.r hen'x k and provided that both R° and R^!<> are not hx drogen.

In < me c>nbotbnio0 oi I mnulie < V). ’.he c<mqn acid of H,v ptc.-eiΓ mx cut.<»' 1 ha-nuetwal l<•uDiila (IRi

(IX) wherein

R^: ’ is alky I. xubMiiaud alky I. < X. R'lOIXR ’R , -CO.R'^!. -SOyNR ^SR -NR^SOjR⁵\ -B(OR' ^!}(OR^s\ T(OXOR'^jXOR⁵⁵). or -IhOXR 'foOR· Ί:

R' Balkyi ( (M¹ 01 -COXR ‘R ’ A() XR''R'\-XR XiJ-R -RiOF 'UOR''j -I'lUpOR¹’ MOR t or -ΗΟμΚ'\( ?F k ,md

R ^s to R arc mdep-.miciniy hydrogen alky L < liBUtuivd alkyl, aryl, subMiuiied aryi. arylalkyh MibOinilcd mxl.dkx i acyl. Milwinuted acyI. hetensilkyL subsrimred h-.R-ro Jkyl, hcteH-Mryl. subsiikned hcrcroaryl, heteroaryhdkyl. or substituted Itoteroarylalkyl: or alternatively R'^s> end k' iogMi,T -xuh the to xxlfli-h ih> x ,u·, herded o<-m j q Joneieiou.ky I or substituted cydohcte’'Mky I ring.

la one omhvdhneni of Formula (V), the cornpound of the present invention has structural formula (X):

(X) xvhewin,

Γ» b -OH, -SH' or -NFh

Κ^ζ'χ alky :.vi>ijt.iM alky kaXoM, (X, CK^XR ^sR. CO R -SO XP ^!R , -NM'SO-r, -BiOR fou >R'\ -ΓΚ >aOR ”>< <'Ί. l\< ΉΓχ^^ΟΚ'Ί, und R‘^s' arc indefxnmculh In drogen, alkyl, substituted alkyl, aryl,, substituted aryl awlalkx 1, substiiat·. d an lalky k acxk subfortUed ami, hclmualkvL MbfokiKJ hctciodkx L kstcoMiy h ^no.sututcd hctcre.u'-k heteiomylalkx 1 oi suSnuneC hue' o-.ny alsxk <r alteir-atncly

106

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R 'and R’ iogefocr wuh (he aUnnx (<> ©hieb flsC' <ucb>-n<AJ ioini a uxcbUteiebudk'd >·» '•ubsPUiK'd O' dohcteUtj'x'J i ·.ng

A sente xjveife x'mbod.nrrix cl I <>fnnt a {V t). Hr u'«!jX\ nd h.-r Osburnd ibi inela xekcted Rem ihe gump <<Ήχ:χϊΗ:;.^! of

107

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108

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wherein,

R OH -SIL-* \ -CH<’H e~ 0041: and

R' ;s MK-CHU IKmmzu m «Ή(iChCH ( hl·;

o; a taulen^r. -ϊ ώ sehaL·. anJ » esle* thcKuf. In senu pwicm-J einboJinu'hK ihc <sit of these eompoends ts Pybodd.mdc or tritlno ο,ΚίΚΓ? sab .In- another embodiment of the present Invention, the chentosensory receptor bgand tu>'duk'i is e<’fup>Ond bavrop ,· .-t'oekne I otnada {\\ I)

109

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'wto A >~lA

Y' (XVI) or a tautomer. salt, solvate, and/or osier (hereof wherein:

n is 1,2 or 3;

each G is md>.pendently -C(R >(R )-.-CiOs- -YR -er -8(0).-: provided that when n is greater than one rben tmiy one G is -CiO)-. -CIS). -S(Oi>- or -XR -:

Y is-GO)-. t Sier -SlfJjy

R is hydrogen, alkyl. substituted alky l· aryl, substituted ary l· an kdkyl substituted awblkvi, itevl. substituted acvl. heteroaikvi. subsututed bcieioaik) I, h«‘ie-<< no , s-risiiteted .ete-oan ncteu .,λL Ixl sid>.mit wdbete.oan-.alk^. -t A -xO -< »R αιιΉ ' -AR R -conr'--r'-\ -co>r⁷', -nr^k'C0:R⁷-\ -xr’-coar' rA -xrA snrA'a XkAt \H)XR'⁵R ^J -So XR R -\P SO AR ΊΑ -Bit n? )<t)R')

-P(i )1(OP~' ;{i )R''1 U- -Piί Β(Κ)(< i, ii and b arc irtoepersdentiv 0, I or 2:

R ^: is bydrogcu. alky ΐ, substituted .dksl· aryk substituted aryl, arylallvinsutu.ed .arylalkyl· acyl, substituted aeyl. hetensdksl. substituted lictemalkyd, heteroaryl substituted heteioui^l· betelearyknky I, substituted bateroarx ialkx i. -< A. -At -OR \ -S(O)t.R l· -AR ^fR ' d?O\'R‘‘R‘ .-OCtiR^-ARA O?R‘‘. AR A OAR 'R -NRA?SNR^v:R^% ,qrNR?C( XR)NR-'R.\ -SOAR’V -RPAS0?rA -\^fRA;O>XRAf'\ -BfORAiOR⁷³), -P(O){t)R ⁴}(OR ;,-P(O){R 'XOR ') or altetnaPseh, R ’ and .together With-the atomstn nb-eli they me bended Run; an awl. Mibt:Uitud .in I. beurea?)I. sub-limiuJ heletoaryI.

oetoa Ml sul wtoxd v'wk\iks ea oluisn alM.<u wio-tr. e.e ocluhcteexIks nut 0<Lv..e .’κι te w opts'uteb L^di'iUtL· m ^lAttt.ksi aw( L_ulc up -, lAuXited aeuiea^. cycloa LU. substituted cycloalkyl·.cyelohetetoalkyl-.of substituted cydoheteroalkyi ring;

F t«> R.^;>i are independently hydtogen. alks I, xubstnaR-d ,dlw I, awl, substituted eryl, <!ixlalky hsuOs'utuied aishdkxL avO. sul-stuated ..el. heteroalkyI, s ibsutjted betcia?Iky 1. hetefoary l, substituted hetemary l· beton-un laiky I <·» Htostiteied heteroaiyh.dkel or alternatitely. R and R R'' and R l· R * and anti R' and R * together with the atoms to which they are bonded fonu ·.; ey elobctcronlky 1 or substituted cyclchctcroalkyi ring; and no

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R io R '' 3fc uniepviiik'uih Indrogcn. alky k -ubsuntled alky; .. J sub-muted royk asylallr s. substiuiled arylalkyk acyl, substituted aeyk hctcroalkyl, sub^nnted hclctmJkx L hctc'oun k substituted nelcrmuy I, hcteroaryialkyl or substituted hetcroaryialky j or alternatively, R and R ’. together ά :lh the rooms to η I ich they are bonded term a ·ά el<udl.\ 1. sub-thulcd cyekndkyk eyclohctcio.nky I or .-ubomued vydo.bcteroidk.yl ring.

In bwiiu- umbodinK-ms ol hernm-h. (XVI), when G is -C(O)· and R ' =» hydrogen. R ^; and R do not fowl a pbeip i = mg In other embodiment, R ^!' and R logethei o uh the atoms to uhieb th>.y aw oonded foim an ar u «nsimncu aiy 1. ecto oar , -absufutec betere-nyk cydoalky L sub.-totuted cydoalkyl. eycioheia>-alky i or sut>atnu?ca cydoheteroalky I ung nhvtc the ring r opu-'-nally fused to another ar, i, sabstutned asy k betouoar, k suusuttned beteroary L ey clouiky L '-‘uhsthuted cycloalkyk cyclohcteroulkyt or substituted eydoheteroalkyi; ing.

in still other on sbodnnente of Formula (WI), a νχ.ηη-und of structural fortnulu (XV Hk (.XV LLb., (XIX) or (XXs is provided:

(XVII) p?8 A-.O ' T*

Ji mr r'O<· ci' o (XV lip

(XIX) (XX) where ϋ is I or 2

Io some embodiments, R* and R'^! together with the atoms to which they am bonded form, an aryk substituted aryl, heteroaryl, substituted hcter&aryl eydoalkyl, substituted' cyeltsdk J cycloheteroalkyl or substituted eyd.ohcteroal.kyl ring where the ring is dptionully fused to another aryl, substituted aryl, heteroaryl, substituted heteroaryl, eydoalkyl. substituted cydoalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.

In anoihe.r embo dimeut of f o nuula ί X VI), th e elwnosensory ’'ce.t'ptor 1 i.gan.d modifier is aroompound having a structure Formula (XXI);

WO 20(18/154221 .PCWS2(H)8/065050

2017200704 02 Feb 2017 wherein;

xvfih Use pi. ί-c ihm pe mule than 2 of H. I .4 οι K are -N-;

R hydrogen. alk>>\y.-Gt 'Il·.-Gt'Jl·.-O( II·, alky). -Cl l·. <-H . -( Hit'Shi·. -CbhGH, halo. chhrx Euorx -CH -OCHL -CN, -CfOlNlV iVh -CO .RΛ -SG.-NR/'R^, •NR' SO.R'l·-Bi* >R'\(>p^s ), l^>i())f(H<Si_vOR^s )os P(OhR' hOR'L

R λ l'.M’'<»ger„ alkow. ’’CH ’’CH . «XhH-. alkyl, ¹ H. t IL, CHi( H,l·, Gib’ >H, hale, chime. demo. -( H-OClb, -CN. -( (O)NRR'' t O-lV ί S0-\RR^s\ -NR?SO-R“'⁷, -BiGR^XOR⁷⁷),-GG}(OlV> Hk'ier -IM u(R XOP?\

R”'Mwd;ogei\a)k.-xy, Ot'll·, Or 11·, 0( Ik dksl.-OH .-<'dl·.-ΟΗρΉ-,ι . •CH'OH, halo ehhr·:-·, i’iuor-:<, -CH iX'Hs. -CN, -CtQ'iNR lC\ CO R bO NR ‘'x/', NR’SOR\ Bit >R'^V»{()!/'), P(O>!>' JR^a 1(OR^S ) _ot P(())_f R ' ){OR Ί

IV¹ -s hydrogen, alkoxy, -f fCH.. -OO H.. ·Ο('Ή . alkyl· Clt. ( .bl·. -CHR'Hm. -CH_?.GH. hat', Cnloco. fluoco. ·( HOCH». -CN. -CiOlNR-’R' . ·ΜΗ?\ -SO.:NR⁰“R^f>l, NK?\(hR’, B^OR *' 'M >R*⁵ l I'fO^OR )N flV⁵) oi Ρο?\Κ* UOR Laud

R^ss to R·⁴ ms iMependehtly hydrogen, alkyd, subxututed alkyl, aryl, substituted aryl a.'y ktlkyL subsumed ary lalky L acyd, sub'-tifuted acyl heeb-ailky L substituted heteroaiky I, hetmoary L sabsututod beleroary I. heteroary kdky l or suSnU/cd het-ro ^fry 'sKy I oi alternate R^s and 8^s , lV' ami R^s\ K^v’ and R , .»r R ' md R h>gi'thei with Mo at, ns to w hien they bonded form a cyeloalkyl, substituted cyeloalkyl., cyc.lohetoroa1.kyl or substituted cyGteheteroalkyi ring;

provided that R^i>s, R^b2, R^'' and R^M arc not all hydrogen.

.share

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In seine cnjb>'dnncnt- of Γοηηη'η (Wil) R'¹. R^x . R^s' roa'i )C' roc ιηΧροηΑ0Α WreccmalUv , -O<’)U,-O( 4R,W lb, alkyl -( H-W-ll .-( Ito Ui, -( li-Olkbab·. ehfoio. tlmne. -<’H C-( Ik.-CVl iOiAHMe.-CO Ιί,-GH lh M > \_u lh) -MISO-OIK

-Bit Ή) <·> -P{OhOlb in sub other ronnodnurous . I hrauula (.Wilk conu'<’unds has rtj. the WHtouubefow are prr-vkled:

In another embodinient of the present invention, the chernosensory receptor r.tln.e ??» i- . .οηηχ . v u. n .-4 re Metin

or a taricener, salt, soKcc. and or ester thereof wherein:

each G is independently -CriV KR·⁵⁵)-, -C(OK -NR⁹⁴- or -8(0).-:

η n i. .2 or 3:

pi-.n -Ocd that wkeij n u ereato' ihan one *b-n <-nly orc G ss (-S(O)’· et AR' Y !- -Cith·, -( (Sl· or -S(O1- .

L w -« \ R ^H}{ R’ ’Ί-, -O-. or -NR^m-;

R‘‘ hsdiogetn alkyL substituted alkyk ary l, substituted aryk aryblkyl, substituted ajyhlkyl, acyl substi-uted acyl, hctcroalkyi, substituted bctcroalksk heterouryk substituted

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2017200704 02 Feb 2017 iido<MP. k buteo-aix lalkx I. ubs(itete>l hctetoas y lalkx I, -( \. AO;. -('»R‘ . Ac >),R’^f AR ^XR'''', -f ’< >NR’'P. , -< '< > R* '? \R , AR'' CO\R“ R -NR N ’SNR ”R’'^: <u

NR<’t NHiNAR⁵'*·'. -St) NR''R ”, -NR ^>sS« * R ’. AR' AtoAR'^R -Be ?R'^vi<OR A. -P(O)(OR⁹5(GR··’) or -P(())(R ^s)(< >A'S

R* ' is hydrogen. alkyl, subsist-trod alky b ary I. .substituted un i. asy bilky I. sub -muted atylull \l a-rel, sub.stnuted -u.yk hcteroalky g substituted ucteu.Akxl. ixte-<’ar , --aOMftu'.cd :Vteru,ii) L h.ici» a_:y lalky I. sf.hsun.te»'. In'i.u’urvbill y( N, \(*>, toR A

NR^k'^!R’ UAR^;' R -CH // ΝΑ ‘’(.'Ο R^! NR ΛΙΝΗ’¹ R¹ ,-NR’'SNR¹ P^!® or --ΝΚ^<·\χ-ΝΗ}ΝΚ’^0?Κ^ω·⁵.·ΑΟΑΚ^ιίΗΡ^ιίΑ··ΝΚ^μ’Α«·>.Κ^,'^υ. •NR^1,JSO>NR^,'^vRⁱⁱ'·.

Bt< >R^f'\()R^!l l.-PuAe-R^^KOR¹¹ I, PR AR?' hOR'^!' I»-; alternanxoh. i<' ^; and tug-mhci u uh the alums to '.xhteh they are banded f»-un an are I, substituted .ay 1. hot».roars I. ml'AMted hcte.uuix . m vlua ky I. reub*i.t.uicd cy cloalky , ex ch lictere.dlA. ei sul -muted cyeloheieroalkyi ring where the ring is optional!}· fused to another aryl substituted ary I. hcleruaryl. substituted hetoroaryl cycloalkyl. substituted cycioalkyΊ. eyetohcteroulkyl or sulretitutsd cy-.'lohetoroaiky I erre;

y and z are independently 0, I or 2;

R^9!! to R^:'' me tod-MKH-iently hyAoli®» 4kyk substituted alkyl, aryl, substituted aryl, aryhtlkyl substituted ary lalky I. acyl, substituted acyl, Iteterpalkyl, substituted hoteroalkyi. netetearyk substituted hctemjry I hotsroarylaikyl or substittited heterOawfelkyl or .alternatively, R ^Λ> and R^>;3, R''^s and R. *^K, R ^u'^! and R^{\ br R.*''*'* and R.^K,? together with the atoms to vx Inch they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted eyctob.'tei· Αχ» ^:’’^ηΑ

R * n> R av injopervendy Uy dn gen, alkyl •subswmted Rxyl 'o-xl suburiited aryl, are l,dl y: subs’ii-Uzd anlalks , ueyl, sulmwmed .eyl betewvili-yl Ά·Ά;ΐ_κ\1 beiero.dk> i, hetoroarv·, sohsmuted hetem .ry > hen re.uxI.bl x< »>·' simMiten c betom-irs <dks I er ghemjuv-dx R'^s an>( -ogedu''-'.uh meί<> χ-,ο b ih y ,u heree l ''ο>'·η a ex »k>ai>-y) sub-smuted cytdoalky 1, cycloheteroalkyl or substituted eycloheteroalkyl ring;

R·'⁵ is hydrogen, alkyl, substituted alkyl, aryl, substitutexi aryl, arylalkyl, substitutod arykdkyk aexI, sub-moited acx I. ho-euxilkx I. -Asteuted hcteioalky), lwtero.tr> i. subsilnned .ik'oaix beteio.. L· I xl <’sub-un hob oais.aikU an I

R ‘ * η» P. ¹ ο» n di peneew \ Όώορο'ι ulAl sjb<u.nkd . xxl -rxl -iibstoiile I a, G.

ΓΙ4

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2017200704 02 Feb 2017 ary lai ky I, substituted aryialkyb acvl. substituted acyl, heteroaikyk substituted nctcroalkyl. het>reaf \L substituted h'.'teuu-n k bcicr> an laikv. ΐ < -ubsuuucu hob-teaty laik\ I er cite’ n-.-.tu e R^!i!>i and R^kb, together with the utonts to Khtclt they ate bonded forma cyefoalkyl, substitute’ cyekxukyk cyelohcteroJl.-, I >.·> substituted cydoheterealky I rnig.

in souk 000-(-5:100:0.--. ».hen i. is <\ R''' i-- h\ drogcn. R¹ u- tnctby. I and tlx bo connecting the carbon atoms kneed to R^? and R -s a d-mitoc knu then Ris net hydrogen lu some end - >.' no to-- of Fo'.mtd «. t.Wlb. a οοω'<ρ-ό id e'kttuc'nial 0 unula (Will) -. a.'oridcd

(xx th;

where when R⁹ⁱ is -CFL then R*·’ is noi hydrogen and that both R^: and R¹' arc not hydrogen.

In some, embodiments ofFonnub iXXIIk R ’ and R“ a=e independent v .-.ie mdcpendcntlv kydrogcu. -C<ib, -Oi Ik-Oi II·, .ilkJ, -t'H . -< Mb, Λ lb^f 'll·,»-, -( IbOH. hale, eblete. lluose, ·< ΊΙΌ·( Hu OX.-SOU . (tO)XH\k, O'* Η, <'ί» < Η Ά(ΐ IbK XHSO-’db,, BfOlb'Oi I'm u-tC-Hl-, le </ba unboduuuits, R and R Ugctrci wnb Hr atoms to which they arc attached forma cycloaikyk cyeiohcteroa&yl, aryl of hcteroaryl ring.

In other cnibodlmcnts Of Formula (ΧΧΠ), compounds having the structures hr me pro\ ided.

;low

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F .

The definitions and subsHtucnts for various genes and snbgunK ©t'tln. present compounds have been described above in detail· ft should be tmdetstaod by one -kiHed m the art that any couibm.:luin >>f the defhntb'iis and subsitacnm desuibed above sisuikl not tesuh in ; inoperable species or compound.. By “inoperable species or compound-,-it is meant a compound sBuUuiC that \ Mates the Movant se'eriF'e pimento isieh as, Tn ewtrnle, a -a.be» ;.t©in connecting to more than Ms e-waLn; »©istol m is ,-o unstable .h.© scpumton oft ic ο»>ηη'©ΐ’»ΰ l©-m ..: ic.iUi<m is nup©-<sfok (such a-. M ex-nuple, m©m than thtce carbons I groups connecting i© each other continuously).

In one embodiment, the present invention provides a process of preparing a compound having structural Formula (a)r

R

comprising- reacting a compound having structural Formula (b)

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RI

nh a ίχι< xs heroin D *' oxseen ei sinlui. \ is -XH oi OR R' is h*. Jiegen ·. Lx L substituted alkyl arx L ^nbMittaed ary1, ats Ldky L ot Mib'tiuiteu anlalkx^!. P “ and P‘ ax mdepcmk-mly hsdiogen. alky k siibsisiuie/i alky k arxl. substiintud ,m L aiylail.sk sulwinited aix lalkx k aey I, mbstuifted acy 1, hcterrodksL salon ite-d κΊοηκ. fx I. heteioai s'. sabron.r^d heteroaryL heteremy blkyl, μ;Ιήtinted kcie*<>an hilky I. -CAG»-. -OR'k -StOKR'k -NR^R'k -CGNR ’R \ -( ()_?R'k -SO.X'R '‘R; or AR* v > -R*^? or aliernadvely R^;6 and R'⁷. together sxflh the a(*»ii' le xslnj; (hex arc bonded, num a ^xel> silks'.. sab<u-.r^e ex Jo ·. A L

I tele* < xy cloaikx k or sub'tilntvd helerocy u loaikx I * mg, \r ro aty I o> M.bstiluteu aix· L and R is -^f 'N, -(\O'»R^f. -<'(‘ ^lix)R^f. -Gt' ^}AfR* l·, caGi R^f k nidef'cndcittR I>xdi>-g-cii. .'.kG, substituted alkyl, an I. saiwutulcd atyI ap lalky 1. wibstit'atcd atylalky L acxI. '•til'·.-) ruled aexI. heimwkyl, '-uhst'tiiiod heteioalky 1, Ιι·.-ΐα>·χη -πί'^ϊ ίυΐν.Ι hefotoat<I. note oa»y al\y’,, ? Mil-tnurod i'Ctetouisialkyl. k Rd. i --r 2; and R ^! and R ’ ;ue indcpusdcnih hydi'o<aen, adkyi. <ubsutuie>J alkyd., ^ry 1,.substituted aryh aryhilkyl, .substituted arykdky 1, acyl, substituted acyl, hcteroalkyl, Mibst.ti.ts'd Lvic'<MiksI. heteioatG, .'Ub'ifitt.ted Ικ,οοόιχ L reteroaiGJAl sul'Muuted heteroatskt Is I o; akviuauxeis R ’ and R , k'gcdK sv.h the ekuu.Go win Ji they a' e boosted, te.rm .. cy dkA.-ero.dky 1 oi xub'-ntak-d exGohetet'oalkyl 'ung h is pt'eter. hie i t-it ‘he tet.ro is ,n inorganic base, Mid; as NaOH.

In one enlb&dinietlt. the compound having structural Formula (b) is prepared by Cteting a compound hro-ieg MtWUral R.-rruula (cl

R¹’

^x '^C;. X', ^Th > e>>mpouul bus ng struc'iind I otirrb pj

Preferably, the above Ar group Is phenx 1 »>r suhMhju-J phen' ‘

In another embedimeni, the pr- s-.-ui tnx cnti> m prox ides a process of preparing a compound having s-ructund Formula {el

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win prising r.mcfo-g a emnpoimd ha-nig Mi uetw al Fain ink; ih

R^3$ (f) with a base. wherein A is -NH? er -ORR’ is hyelro-gen :Jk\I subMittiud alky I aryl, substituted aryl., arylalkyl. or xubstituu.d mylalky k R’\ R ”’ R' . and P are each imicpendcnHy by drogen .ilk y ΐ <·ιΡ<-ιΐtmed alkx L ary I subMiiutcd ary i ary ialkyfl. subsfouted ary lalkx I acx I, substituted acyl. halo, heierotdkyl.,-substituted beten-elk-l. hetema\l. $iil'\icttted heterojtv.L hek roarylaiky I or substitmml hetetvaiy folksI, -OX. -NO.. -’.^SR'^}, -fot>\R'^{, -XR M fo -CONR^rR \-CO.P.‘^!. -SO.NR ^!l<\ md-NR ’$O_?P \ -n a?eirame'.y R’ .md R^v. R’^e and R' or R and R together xsitb the atoms to which ibex are bonded form a ndv'Jkyl sfubstituiedcycioalkyl,.heterpcyclonlky t. or substituted Ik'teroeyJoalky I ring; R¹ fo i< -CN C(O)R.^!\ -C(OK)R^b, -C(O)N(R.5'' eae 5 R” is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, ary-lalkyl, sub* touted aryfolkyl, acyl, substituted acyl, heteroalkyi, sub-mum d herei wdkx > bet-, roary I, sub-mum d ho-ere-iuyI, holer·taiy lalkyl. or subsnuuo.i hcleiuarx ialky I: and R and R^k ,ue u-depe-aRuHy bxdrogsm. alky], substituted alkyl, arx i. subMiiwd aryl, aty ktlkx'l sub-niiated ary lalkyd, acyl .substituted acyl heteroalkxl. substituted heteroalkyh. heteroaryl. substiiuted heterearyk heteroarybdkx I or sub-um-ted hetetoaty folks k or alternate eh R⁴ⁱ and R⁴C together with, the atoms to which they are bonded, forth, a • < _: ,. :·; : x.. ; - : : ' ·: ' :

ex eb0i> tenn. I x I < m. mH. ai.--·. obeu ιο.’ΧΌ .m» u <*> ^’efewL e ibai . i. Κι-e is e. isott’anic base, such as NaOH.

......XJ ..... · ..........

In anofoer embodtinem, flic prcserit trwsntion provides a process of preparing a Compound ba-mg struciural Formula (e?.

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A R³⁸ (e) ' X, <„eiH prising reacting a compound hmiug stiuelural Fotnrak; <gi f^? ΜΗΝ, ,.Λ, ,.H'^y

Ίί w¹ h .J

R³⁸ (g) \Jh Χίί'ΜΡί'Μΐ: ot Ci-S(O\-N’H_ re tbi prereuce Mabuse to pnuM dra-edx a enn.po rid haring structural 1 e.eiuh <M\ '.a ahcrnatixely re provide the iompouf-d basing striictural formula (f) of claim 221 which is further reacted with a base to provide a compound having sbueninil I efmnfo M It is pief.'rabk tuat -’be base 5$ an -u jame base. --i< Is .,- DB’t

In general fisc compounds of the p> e-citt fin cn$<<<'i . g . Loitipoi.mk λ uh the foi molac described harem can be sy mhcG/ed according to the processes dc-cribed al·, x ai-.1 Hie following exemplary procedures and '(.hemes.

As discussed hereinabove, a sa l t of the -compound o f the present Invention generally can be formed by reacting die compound, with an acid or base. In erne embodiment, the n: esent (mention l'mrl:..-rpi'Uklcs a ranibcuc mcihod for preparing a salt of ike compound having any of the above-mentioned structural formula at a large scale. The synthetic method enables preparation of a large quanthiy of a salt of the present compound quieklx and economically. The synthetic incflicJ can be applied in either'&laboratory setting or an industrial rotinig. One example of the synthetic method is described hi details os l·.'sample lr>5 hercnibciow

In general, the compounds of the picsem invention, e. g.. compounds: xxdth the formulae described herein can be synthesized aecotdmg to the fb I lowing exemplary procedures and/or schemes.

Fx riimdiisre B iucladiug, te-M pynirndmc dc> n ath as such as -.:0(00/0)1003 and pyrido[2.3“djpyrnmdincs aic a ntbesized from 2~armuo mil des. 2-amino ketones, or 2-anhno: carboxyl dcrivatix-'es A by reaction xsith the cbfrespoudiug carboxyl derivatives as illustrated ra Scheme 1 (Kad-Moghadarn et al,,A «/ /fezenuye/te Chew. 2006, dd, 013; Roy Org;

1.1.9

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2017200704 02 Feb 2017 </?<'/?>' 2000 k 382; Jang , /,//.../. Ά/ <//,,'>' 2006. --½ 055; Kiial’iKidiJclt <.·' M, Sfomg. A/s?/. ( A, p<. 2005 .-) 2<\Α the jran;·- gtoup ni (he state ng nhuerfa'. A eai. be furthci 'uiivte-uakwc hy alkylauou ίΒιον,η e/ o/., J. Med. Chetn. 1991k 1771) or reductive anunation?(Uehli.ngtei ,/Z , )/<</. P,w. 2006, 49, 27SX, ,.¾..) Io provide the corresponding .hHuouo-mhs-iUited

2-Minino imrdes,2- amine- ketones or 2-amino carboxyl derh-am cs ('. The coupling rvaehon of A or ( vs tth Lteii -s kvanatcs such as, for example. benzoylisoalnMcyunmes end subsCGUcnt cyclization m ncanaent wn ΎκΊΙρ <»- U ¹ rhe p-. im dm ?s His p .ι'>οό Juo.'tnes F iachklmg. out n>-r feasted to, fused pvnmidin-Ji I HHthikmes such qma.izohn -2(1 HMthfmite and p\!':dol2.3-djpy,smtear 2HHhiihte-uv date-.mo-..·-- i H-kha ivuy ,/</,.. 3/<·/ (7<w. iter. 2000. Ή 122 and 5ofcieno. Med tho-cnu lG-ααχ .-/m . f -,/.7.(< <'»»///-(.,--, I9S0. ?V, A, Wilson, Ο, I .fee 2001. A 5,x\ utaejh.cs cued inacm) Ih-sM cycheafien > I Λ et ( with iihi>-)a:cj'^: in the presence of MaOH aisc rc-nths in the formution of py bas-din-Ji i Η h thiloae da ham. E {Scheme 11 <Nagana\xa ¢/«/.. A>;>/y khv/ (.Ά·?. 20()0, /4 71.21 and reference* cited therein).

Scheme 1

Pte CN.COR’.

GteAte. CO M.

C0NR-R”

R*

E

X ~s,«

HaN Nth

Pyrimidines B and pyrimidm-2(I HkUhihmes E can also be pu-pa?e-l from corresponding L3-dicarbonyl derivatives and rtd.'-unsalurated carbonyl .derivatives by condensation with guanidines, amidines, or hhiojt-rea derhathes as shoem in Scheme 2 (Sharma

A W., Am 1 Med. Chem. 2006, 4/, 83, and references cited therein; Bellur el M.,: Tetrnkedixm 2006, 62, 5420 and references cited flwrem; Hatiser si al, ..I, {feycOsm. 1953, Id, 388).

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Scheme 2

AH

R'* i

Various pyrimidines .M px iimidin-2f 1 H)-(thi}oncs as well a- dicii' Insed ip iHindibc and psnmnhn-2f IllHforione Jem tew es as quma/oliuc- and θ©ιη.:'οί:Η-2(:Η6©ηο- cau be -ο mhc-ι/cd horn px ina:dn:c-2.4(! H3M)-di©ne Jet © aims .:-.

a-. the fused |'Sii:nidhie-2,4iJH,?-.H:-d?©ucs such a- quina. ©iine-ij-^lH^^Miouc and pyridop 3-d]pyrimidi.ne-2,4(lH,3_:K)-dione dem arises /Scheme 3). Reactforiof p\ Hu.-klh:c-2,4(: H,3H)-dione dem Awes with phosgene or P< >Cl· provides the eorresnonding

2.4 Jithkuepxiuunimes (Lee © <i;, 5- v, W 2006. (>5 and sdeunces uted teu.x υ .'sobscotiem displacements > 4’ ihe ϊάo dnoridcs xv Kh χ .; ious uncle»-philes resulted in the f> - uau©n of n\ruuldines aud py/madm-di sHi-(thi)ones as well as fosedipyrimidine and py>/undni--2/11l)-i du j«-no de: h c-> i Kanurna fe? aL, Bioorg. <V Med'. Chcm. Pelt. 2(M5, /5, 3853 and tefe/enccs cued the-cun I 11 «Ί,/i.-oO'C d’ 1'<ο ( Ma. Ζν©'. 2M7. ; ~ n6S, Vx-is©u v i\ h'·Mo 2007,/5, , n»'urland -.' a;. 8 ('unei X\ H51, ,2.sj

Scheme 3

u.a/X | ’.ohm a» ./me ' Jjo^ des a J’used ' i'duadi.te re 2 e <x\f»k derivatives such as, for example, lH-benzw(c][l,2,6]thiadiazine-2,2-dioxides arc also

WO 2tWiS4221

2017200704 02 Feb 2017 synthesized from 2-arnino nitriles, 2-annno ketone··, or 2-amino carboxs-i derivatives A or € (Scheme 4), by reaction^ with NffeSCACl (Hirayama. er M. «£ MM Ch&u. 2002, Zfi, 150°; Kanbe ¢ / M, A> > >< X fox/. < iwi. i e i. 2006, h , 4090 and refcicnees cited tbeienO or Ml S‘t\ki:s,in <><<?. > ( 1 m 2906. A< Mhc and sMeiet.ccs c'ted ilk'wm· aid foilexvcd ip exektofion m the piescjue of AM Hl {tsoxu: er .>! , f/.w >-<>c t I Ma, 24, 345 I.

Xib'.vtos' '<' ed . .1 t ^}'g ( 1*170, At, 419 i, uox a cl ai, l't^1, Pi\<'u > 0 < ’> >'. f> i 1984, '/7,

777 s. fhc eoiKknsateHj of the u0,,cs.OuJu'g 1.5 Jicml’·. re ] dci x.mx .-·, η β 00,-..00,.004 e.i?b< :p I de: e:mvcs w =ib suhauudo de:nauve. tSclurie -O :dv? icsul'. 01 tac ΰ ηΐι,η en of iL2,hhh:udm/:ne2,.Adios.cedcrnuii'e,f\VngiU, My; Ctm ΜΜ.Λ','.Ws

Scheme 4 ot rhmg-.no ₂/dbu —“------1

c

CiSGyHCO

Of

NaOH

R ~ ON, COR, {JO A'i:, OO;:H, COMRR-

R^biH$O₂hlH₂

Y~Cl8r, LOR'

W.heds .et the .smh>.sss ,>ffl.'ene|2.3 d|'wrmnd.'it dc'A.'.nto mec.to.enb> d m

Scheme 5. 2-Amino thiophene denx .ones 30,1 are syntbesiited vm the Gcwakl reaction (Chun el al., Synlheiie CorrimtmiciMkm 2004, 34, 3801 and references cited therein; Elmegeed to ak AM. J, MiM Ghm. 2005. M, 1283 and references cited therein). Compound 303 can be cyclized \M?h t^!,c vW’c.p'mdi',-' c..o<'KsI ccmxujxcs '.e g-xc the tb.sUop? dlnxiu'iidmc dueoroc-klM iRsd-Moghtidatn../, Cheat. 2006, 43, 9M, '•cigw <t <.?<'. fooMv-Av» 1.6 2000,42,

2215, and references cned therein; lung et M, *' 2006. ax, Oyy 1

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Schemes

HAR⁴C(OEtg or AOOCI or R'^:CG_;H or R'W o

301 _v..R

303 r: r²

303

R - CN, CC₂Me,

NaSHtCAcfe

ft’ PhCONCX

305

N :: C'-i CO We.

CCRΑ⁵ΐΤΓ

O ^X R R·

300

X :» S,G

R :: CN, CO Ale. CCA⁵ •S.V -J

Ν

A i

•N

R^;W, NaOH

ΑWhen A ~ H

R²

3»?

X :: S. O

A

300

X - ft , C:

WiW R~ :: N: :

RCO_?H or RCOCi or

RSVC· a RCHO >

RNCO or RNCS

X-S, 0

2>Amino thiophene derivatives 303 can be further alky dated by either treatment With k 8? Rx ¹ not \utl· Rt IK) \aBllij »\e>', te g've the Λ-ulk C.ated 2-Wiihi> thiop-ttJi.· derivatives 305 (Brown <?/<..’/.,./ AW. Chem, 1.990,93, 1771; Uehling AW, Chem. 2906, 49, 2758 and references cited thereihh which ate then reacted, for example, -with. ben;foyliso(thio}eyanate to give the corresponding Wve\ I (ths>puea derh auxcs 306.

Ci'Hjpouiidt'othb max be eschzcdm te.ailmert v<ith NaOH <<> ptox tee dronm 2, W jpx timidme derivatives 7 (ERShcrbcny et r?/., AW. Ckem. /h· 2999, ;0. 122, and references cited therein;

Reddy et«/,, Sw/Wc Crxoinnm, 1988, /f, 525; Wilson, Ory. Lt 2901. .< 585 and refer cnees cited therein). \x heii R' it cwijpouuds.'5Γ m.o. be reacted xxtfn R-Bt NaOH to give the

WO 20118/154221

2017200704 02 Feb 2017 afeyUtskl proUucis 8 {Hm-ro a ro . b‘<v m 20O3. ί ί. 2~ i 5 i W hen R * Ml·.fee auihw group van b>- birther liinchopali/cd ui else the pn?dih.Ls 309,

Snxidatb qurui/c'm-^t I iO-ore arc i ini.:robn-2· Jh-ri.'oue- derivatives 402 <xto.e -told cswcd rt.-ir ' aliens 2-an 'irobtovoiv u:d drois toises. 2-amm.d omrtnc de' tx aax uimnoacei<>nhtob'nc deux sin -a and Z- ;mim> 'benzamide denxanxcs 400 as s'nuxxn in Scheme n. Couphng inaction ? e<»nip'>unds 400 x-n-h benzoyl i.so(throk’x.an.ne:- lead n· ihc for-nation J ceii n>:,'ig be r ) tthiokr»? d.ttxat.xes 401 lhe. c)sb/.mep · r.hc e.c-roce of Ν.ΌΗ proxidcs the quinazohn-l·, I Hi-rdnieuc· dem anx c> 403 {Ll 'tojerbcnw VGA <): η?. &'χ· 2000. fi‘, 122 and rdefences cited thaiem. R.vddy ·'; u/.. n't ('>'?;??;«», 1988. Ze, 525, x\ iisom ίλχ /.«. 3001.5. 585 and references cited therein).

Scheme ή

CM, cor’ * - '>

COrMe. CO-sH, ^C<-R

CONR’R CO^Me. CO₂H, ’ ’ ’ CGNR-R·’

402

X * S_: 0

IH-benzcfcJi 1,2,6phia<jiazinc-2.2-dnixide dcrivaiives 404 are sy nthenized fi’om ‘Ί. sa>'t. sia't ig 'xia..-',i s 400 «'-clk'nie ”> i« 'ik' teacher.-x\itb st rt »mideO' R <;.\>χ I chh'ride. tolkmed by ewhzation with NaOH. Direct reaction of eompotmds 400 xvith sul&midc in the presence ofDBU at the elevated temperature .also resulted in the formation, of

IH-hen oic|p ? h(lhiadia/nv~? ’-dro-nj.' .'cnxat'se- 404 iMo'yano^'t t / th <; < a.',»’ 2006. '49. 3-190, and refcrcncsto cited therein).

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Scheme 7 »s R-* R¹

R⁴ 4δ3 R⁸ R^{4 400} H - <X -OR\ _4G4 p .. .-μ w CO-Me. CO H.

AAh <*»« '

CC-tdR'R [___________________NH₂SO_gNH_2> DBU_______________________| \hmia. <'hrc fem m.'Ca <« »dso s»xkv..e i'<’m <μ .mi/obiA-feu H3H)-.houcs fScbemt xl. Pc.ienon <4 quina.'vhne-2 4f l Η ?Hi-di.'iti> uidi PO¹' Ί pnvulcd fee LOiiC'puiulme d>chl<”foquiiuzelnK'S (Znnszain e/ a/., //<”< vg. A Ifei 2005, /3,3681 and references cited theism), sub-eguem dfepbcement- A( io (άο chlo .des xvitn various nucleophiles resulted id formation of quinazoline derivatives i Scheme xl (KannmaWol, bhwrg, $ MW. Cherm £mz. 2065. /?, 3X53 and isfcmne·..'- cited thmeuu Blackburn. ,9λλλ''<. A U·fc?/. 2006. /'?. 2621 i.

SehtUM 8

R¹

r³X R^?!

4--Amiu>.;--5,o.7„'6 icn;ih\ du>qmmi '>>un-2iJ 11 Hfeiloco dci o ..itu ca and .mu'.io 5 n.hS cuahiuo? IH bcnA-Rd|l.2.h]thu'.dij.’fjK' dx xids deiixal tea. u-.-'d e.a straeftor analogs with different ring sizes, as shown in Scheme 9, are generally synthesized according to fee methods described feerein. Thorpe-Ziegler cyclization of dimtriles in -the presence of base provides: p-aminu--a,pUnsaturated nitrile derivatives ( Winkler er «I, Twm/i.xi'2005, a/. 424’k Yosbizim.» .v <</.. ( ».'>/?, 2002. 7. (>;-., .md reference'; cited therein; Rodrigucz-Hahn <.,? u/', .’hwAW»· Gwmiw, 1984, ./4,967, and references cited therein;

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I'sami- > <' <?/.. / l/><; <'''?> n> 1001,3-,2890)- I he fi-anmt. -a H-imsatt.mU.'d mnsk·, may be reacted, for example, with benzoyliso(tbio)eyanate and subsequently eyebzed by treatment with XaOIl i<< p'.oxiee 1-jnui;>--5 o,7 d'tch.ih'-duxpuDa,>- m~2i Uh-tOnlct'c iL·u(I l-hMd'cm <// η/., Ak-.i ((;<>;<'. Txer. 2006. 7v. 122. and refmences cited thcrJm Reddy tom . Sew.vwd < 198A /.'< MS- ;λ u JI as ?hcu stmuural .maloes unh Jit'tercrJ ίmg s zm {Sci'.cinc 0).

Snadartx reaction '/ ^-annno-adv-unsatufattd aitrde derivatives wnh suitamoyi enhride. Bj-HoucU b> treunnem xxnn \\i< >H pj- -. j j·..·-1-ammo--5,6.?,8--etrah\dro-1 s.d.t'hhmduizjiw'- M'-dmxidctieruaMw. as \’-eti :-e st» netural analogs u sth different rma mzc tSehvtne^,s) (M:^; ayatna < ·', bM. w. <9 jHW. t 2002. < o’, spa Kmibc < f ui, &>„ <\ >A </ ( (₍<< >' 200K i \ -H’9R and i .fcicix,^ cited therein).

Scheme 9

Π ~ 0-5 n-0-5 X~SQ X - S. O n - (};> rt - 0-5

NH₂SO;NH₂ or QSO.NH-

π - 0-5 n - (85

AteSuliame and fused aeesulfarhe derivatives € such aS bcm« >.. Π- 2.^;)> ν.ηΚ<.ί' .η ·»ΗΗ) > w 22 dnwvk^ vun be m Guv ,cu w,< -Jk <c tea» n ot 1.3'JicadH'uyί dcn'.atsXv.s 'k m 2-hywov e..'0n\G ccHvatisce B -.mdD unh SO- <»' < *tS<'»-AHn as described io Scheme 101 Li-wics ,7 al, 1090, 40? ami r-rfetcnees cued tbcreim

Ahmed «/(9¾¹. Oas?. 19R8, 33. -111..\ -\bmed e<* <<?'., FAw «·,/<. < As 1989 20. 13 »11

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Scheme 10

C so am

OH O .-M J-L. R r OM&

R⁵ D

Xitesal vnu Cuixal'xes { x. a <l· be ο ri <.ro l ate* * to , kx i .> o enols xsitb FSOjNCO (Glauss ei aL. Tetrahedron Lett. 1970, 2, 1 p>) «<' ¹ 'Is* ».\« \ »i Rasmus<n ah. J. Ure. Cheat. 1973. .??. 21 14; Etter etal.. J. <:.Λν. Chem. WRu. M. ‘~-p\ hm-tibi < / u?. Ifiaii!'? J. Chent. &to. ?9 1987, 7(3, 1082.; ax shown in Scheme LL

Scheme 11 %p

.., ........ , FSOsNGO CiSOyHCQ F¹ , e

Saccharin derivatives may be synthesized by direct oxidative cyclization of N-alky i-o-meihy i-arene^oh'-nannde^ as xia>\xn in Selieme 12 (Xu ·. ·^Γ <ίό, ΑαλΜΛ ;? 2U(h>, 6.\ /90.:. and referenites ciie-l then-m· Pre eu;.· AtoUM ·« .’>/·;;<» /λνρη ,OR.Pivre 2005. ?.?>>.

Cydizatii'n of o~ear^sx>\'Laics-cmPnapi chloride derivatives w ish mimarx amines can also provide.«.iceharnt dematsv·.'' (Robinson .../ /?.'.'// ,/ ΐ'/'g (.'Λ·..'/? 2080, 1483 and »eforences

Cited tret·.') Seneca <''<7 / E^f . Ct<m 2005 Α,7Μ·\γ< i V.eiki s <. fed tnci-. a IL ΜΊ,ήο >’< , / »/>’<’ ( Lw 2005.9^s t'vi”'· i. '{net Is. .coaiemat e fo-u.

,'O;h aAn-fi2l iK'ue-Ll-'bovde d. lutouro'mu s. sxntbes, _tJ ^mdelx

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Scheme 12

H₅k\,

CfC>»

R⁵HH₂

According to the present invention, chemosensory receptor modifiers or chemosensory receptor ligand modifiers of the present invention can be used for one or more methods of the ptCiOitr invention, nt- dmauug, a chcmoseii.Orx receptor and. er ligands In general, chemosensory receptor modifiers and chemosensory ..ceptor ligand modifiers of the ρ·νχ·..ηί iir-enuou .nv n»ov sled in a compoxiimn, <»oeh ax, < g.. art ingexuhlc ».ογοροχ!1»·>π As axed heroin ί·ί ”mgx-bblx’ x'-impo-ms'-a' mciudox any <ιΦ.Μ;·κ.ο inlemlxJ b't >>r.d ι.οη<ιΐιυριίο·η eiih’.r .done os u-gether w i*h .mmlvf sabxlara'».. fb·. i-igx'-dble e-imp»>s:n»'-n inelnde-· both “food or b.„xoi>igx' products'’ and nomcdihlc prodnc-χ;. By *T'i».»d or beverage products'' it re me.mt anx ed-ble produe? mt>..ndod fn correuropfom by htimarre orammal· mt lading <>hdx, scroixolids or liquidx (e.g , bet erages? I ho -erat n.-n-edible· pr»»duxtx ' <>? ''nmicomextihu. composition includes supplements. nutraceuticals, functional food products (e.g., any fresh or processed food claimed to have a health-promoting andfo? dixouse-prex entmg properties beyond the ba-ac nuwiiion.d function <>f supply »-v nutr»·, nixl, pharma.-piru.- are oxer d'e eeurrer Ί... <. i, r x oi.d o » - > <xe.R re su .w ,Ι.γ dr ex ..»I n ¹ h” .ifoex eox ten. p od u lx xuen «nxcetoned itp balm*- .md other personal care products that use xuriarase ahd Ot other sweeteners.

The ingestible compositioti also includes phar nacenno.d, medicmal. or comestible· composition, or alternatively in a formulation., e.<g., a phannaceatical. or medicinal formulation· or a (bod er box crag, product c^f fromtdabx'n

In one embodiment, the chemosensory receptor modifiers or chemosensory reteptei hgaud mcJulrex provided hs fk-pw'Ki.t n xunt.'-n can be treed al wn low iroiicetitratfons <_:i tiie order of a few p per imihen. in eemhraaium xtilh <me m more known x x u- tai.» d o al ni <>. x to -. km ^fl. i. n tor lu. k e<u χ'.ι x'u required to prepare art ingestible composition having the desired degree of sweetness...

Co-nutonly used known or artificlui sweeteners for use in such combinations of sweeteners include but arc not limited to the common saccharide eeteners. eg., sucrose,

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2017200704 02 Feb 2017 liiifksj, glucose. aud 'ΆΛ’ίοκτ c<>nip>Ki0{w compsremg natural sug.tr-. such re c<un --roup suwiuding ingis fruet·-re c<-ssi: χχ πq'i or <nhcr s\ tups m swecu u >. ⁱiit.enru.tcs ,kt is rod fturo natural fruit and xegetuble Ourcex. αίρι-χχ uthelic ‘xifgai alcolre sweeteners such as erythritol, isotnaU. uscistoL s-sus-iiituM sorhit. J, xx hick rmfoodextrir). .uni sb·;· hke, and artificial sweeteners such a- reparnnm, .recvluniu. uecsulksiue k, exekt-nate. reuralrec, and aliusmc, Swectenctx als·· in Jude reelunnc acid, -ηο-ΟΓΟΜύο. t:tgat<’sc. snuhree. gasaetose, mansiore·. sucrose, fructose, iact-'sc. uvotaare and oinei aspnitauie dess\at:xre. gb\-,>re, D-tiy p^f->p-hu.t, Jycm., ,na tnoi, huistok -soousi·, hxdiOgesuucd ghuore- sxrup (IIGS), hydrogenated March hyd= <9' < ,uc (HSHk sire iosule. roh.mihossdc Λ ;md other sxxect bk M-bascd glxeoxides. eauekwuc and odicr guantdinc-bascd sweeteners, ete- The term sweeteners’' also includes, combinatians of sweetenem as dsredosed herein.

cnemosensosy receptor modifiers and chemoremretry receptor ligand .neddkre of the present im cuuvs· can also he pros. ided, individt-ally or in combination, with any uxgcreJ-lc compos-men known or kuer disco' cred t os' exampl·., the •ngcstd'dc •.omposihon c m no a comostibie cornpostion or noneomestiblc composition. By ''comestible composition' i* j me.mr any composition that can be consumed as food by humans or animals, including solids, gel, past·;, foamy ηη·τοί'·,ιΙ. re-ms so'-sre. lkpsid'-,ot mixture thes'ro-t By m.-ncomcstihic composition’’, it is meant liny composition that k intended to be consumed· or used by humans c»r animals not. as food, including .solids, gel, paste, foamy a-akri f sesnl-solids, li.qiiids.or mixtures thereof. The noncomestible composition indads, but is not IspiRed to medical composition, which refers to a noncomestible composition intended to be used by humans or animals tbstherapeutic purposes. By “animaFf it includes any nors-hamasi animal, sueb.as, for example, farm animals and pets.

In one embodiment, the chemosensOry receptor m.slifiers and ehe?nosenM<rs ie.opu-r Kgand nu'd:Ho?\ .re. add·, d n> ,s mmeomes’ibk' c<xmpreiHers us ·ν>η~.·θ:Ηη modure -u<h a> supplements, nutraceut.ical.s, functional ft>c>d preduc - (· p , any fresh s r process'd food claimed to have a hoalth-pronioimg and/or disease-preventing: proper lies beyond the basic uutriiioual function of supplying· nutfiesits), phaMaceutical and over the ebuuter. medications, o;ai ear..· products such dentifrices and ntonrhxx.udiei' cosmetic products such as swcoicsicd lip balms and other personal care pro· hires th C axe -mcralcs,: ,md m elhet ax eel oners..

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In general, over the counter (OTC) product and oral hygiene product gene rail· refer io product *'»>r household and. or personal use which mu- he sold χ- ifo-mtr a pics^uptimi and «η xwhmd a - s s (<> a ineJfi.al ptofesss.-iul I -an.pks el foe «11 C moJiicls me'.adc, hm .m.· not Innitcd to Vmimm-and ibclarx supplements. Topical aisafocmA and >·· anacMiuiit.. < \-ugu cold and allergy s-;raeJ:cs, xnt;biMammes ,md oi adcigy n-mefoes, ,;.jd c iruinanors theicvf Vitamins and Uicca'v supplements include, bm ;.ii·..- n<»t limited te \ -umims. -henuy supplements, hmics bottled autf.t \ς Ji'.M dn.d specific \it.im.ns, dictoix supplements, a v- -ul et pi- m\B of oe relating to m prox iding inttrithm, jnd c.-rnbimmcm memof. Ih-pieto analgesics jndm auacsihctic include :my u-pieal c-canis onitinents gels used to al lex rate superf-eiol or deep· seated aches and pains, e.g muscle pmn: tecthmg gel. patches with analgesic ingredient; and cvinbinaticns t het eof. < ougb. cold and al ferny ;emedies include, but are not limited to dcc>:-nge.'i;m':s. cough ic’ncdic'-, nnaiyupeul p-epaottmns. medicated cvir.et emrx. antihistamines and child-spce:de cough, colei and mlergx remedies and combination pi * In-’s. Antihistamines ,md or alleigy rem·..dies include, but arc net limited to any systemic treatments for hay fever, nasal allergies, insect bites and stings. Examples of oral hygiene product include, but ,x;v }vj limited to m--m x eleanmg strips. icothpasu.. lootl'fomxhes, motjihwasni.< JentJ iin-'es dentine muc, mouth hvshenm at h->me teeth n hneru-ts and J..-rt.i tl> ss

In another embodiment, the chemosensory receptor modifiers and chemosensory e-ep-rm I m- / no s , . >11 t > oed , r Uxen.g p^r<«-d c h iiaaioi- lx.’iflesot food and beverage products or fermulaimns mchtde, bin arc not limited to sweet comings, frostings, or glazes for comestible products or any entity included in the SoUp caiegoi'y, the Dried Processed Food category, foe Beverage category, the Ready Meal category,, the Canned or Preserved Food category, the frozen Processed Food »at \ foe Chf l> d P m ess J I eed caiegorx, ihc Snack Food category, the Baked Goods eirogo~s the ( eofo-ronan e.uegeix ibe Dairy fo h\'t - aieg'»y foe h o k'u-ani category. tm> M al Ko^rtl wemeiU . ’ go x.foe Fb a * id Noodle category, oral the Sauces, Dressings,, Cond»m m\ - n ⁽h 3,t ix !'<»»» I,-,i ego^fand/or the Spreads category.

In ptnotai, the Soup LUtceerx Eekm Io canned ριν-.νιχ cd. dehydjated. instant, chilled, UFIT and frozen soup. For the purpose of this definition soup(s) means a food prepared &om meat, poultry, fish, vegetables, grasiis. fruit and othei u-gtcdiimls. cooked in a liquid xxhiek may incl ude visible pieces: of some or all of these ingredients, h may be clear las s, broth) or

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2017200704 02 Feb 2017 thick i,.: chowder}, -mooth. :>me.'>l 0; chunky. wtedx -to-scrvc. senn-condensed ©’ condensed and may be served hot -.-r c<-ld. a- a fust course or as the main course of a meal or as a between meal snack /sipped hke a ivn-iazc) S>-np mm be med as an cr-.-s,hejii io: /sp. une , the/ me'd e<wi:p<-ucni' and may lange from ©©-th- {1.0-1-,-1 rune 1 to -auces (ew'ani 01 -iwe-_-based -oops}.

'Dchy Crated uitd ( ulntuiy Food 1 .-.tegoty'' iisuadx means. fiH'>-»-knig a:d products such as; ppwders, grantiles, pastes. concentrated luim-J products, mdudoie concentrated bouillon, bouillon and bouillon like products in pressed cunes. tables or ponder - gianulated form, which are sold sepatarch as a finished product or ;.is an mgrcdteitt -valim .-: product, sai-cv< and recipe mixes (regardless of technology); (ii) Meal solutions produce such as· dehydrated and fee/.. h <. J wmp-, it'cli > . de we jated-oup 10 \es de-wd/eed w dch-dt..> t seedy -:O-c>-©k soups, dehydrated or ambient preparations of ready-made dishes, meals and single -W: vc enueet» including paste, potato ,-ud tide dishes, and (=1:) Meal emhelltshtnenr p> ©ducts -^;iub as' te-ndbnonts. m.irmadcs. saiaJ dressings s;ilul ι-tppmgs dips. bren-lmg. butter mixes. «helf stable spicads. barbeette sane-..'·, liquid rectp-.. mixes, concentrate’-· s,mc-..-< or sauc>..- mixes, ouhiding reem·. mi'os h-r s.d.td seid a-· a finished pr<-.in-1 ©1 -is m ingredient v\ nhirt a proju-.i whether dehydrated, liquid or frozen.

I he Bcveiiigc >.ateg-.-n u-ttelly moansbexpmg.--, beverage tn and concertt/’ates, including but not limited to. carbonated ami non-caibonated beverages, aleohctlic andnou-alcoholie bm emgps, ready 10 drmk beverages, liquid e-'-neemtatt- formulations for preparing beverages such .©- ,md dry powdered bus01 .pc pros uiv»i m 1'hc Beverage sateg <n Jsoi tltde leahohel» » 1k- ies>4 ,hs s,>o tsd inks so-onn. eev a-te's aid hoi drinks;. The al con- >he drinks include, but are not limited to beer, cider/perry, FABs, wine, aud spirits. The soft dnnks include, but are. not limited to carbonates, suuha as colas and. non*· cola carbonates', fruit joke, --wb as juice, neetmx, jtiice drinks and fruit flavoured drinks; bottled η .η·..-·-, vs huh me lades sparkling water, spring water and puriiled/tabie water; functional drinks, which can he carbonated or still and include sport, energy or elixir drinks; concentrates, such as liquid and powder concentrates in ready io drink measure. The hot drinks include, but are not limited to coffee, such as fresh , instant, and combined coffee; tea, such ax black, green, white, oolong, and flavored tea; and other hot drinks, inekidlug .flavour?,, malt- or plant-based powders,, granules, blocks or tablets mixed with milk or water.

WO 20(18/154221

P:CT/l.sS2(H)8/065050

2017200704 02 Feb 2017

I he Stuck I ood uk's.x>r> gencuilh. rck'r.' to aux rood -bci can be a light informal meal incbnbuo. hm nol limited (>.· Sxxect and .wwy .macks and ,'nack bars. HanipLs of snack; h«'d inc ii.k,bu‘. a e act routed to b ut mvrA e up- Jb^s iMi joed -fufr \ ltd a <.uiu Tuppopcorn, pretzels, nuts and other svect and savoury· snacks. Examples of snack bars include, but ,ii·. R<>; binned ?·.> crowd.; nincsh hoi , n.c.wfast b u.> eiu.gx '•xas. ;ru.' lx·, s a.sd obtci swrok bars.

The Baked Goods category generally refcss to any edible pn-duct the process of .s.cpe sue v Inch lexolxes <\|v..?ie i<> hro' Of .sccssixc m nhgb' f sump .s ei’b. .uJ g- <·>.·λ suelude, but are ιοί hunted t»· bicA nuns, cookies, nuHiniw cciCsd, teasici pasuros. pro-tiros, a, dries, ran Ί is row s, pros, baec > \,<ix ο,,κ \>% < u. a w I 3 cd t » Λ .; <j an, combination thereof

Γη·,.· kx Cicam caftceix geiteral’x totes - :o ^f'i> sen dc-sc ' c<· r.-.tung cicuui and sugar and tlavormg. Examples of ice cream inck-de. hut are not limited to; impulse ice cream: take-home ice cream: frozen yoghurt und artisanal icc cream; soy, oat; bean, (e.g., red beau and nmng bean), and rice-baked ice creams.

The Confectionary category generally refers to edible product that is' sweet to the taste, Kampies oikonfeeoonaiy include, but me nm limited k> candies, gelatins. choc>3ate confectionery, sugar confectionery, gum, and the likes and any combittatioa products.

The Meal Replacement gategroy generally refers to any food intended to· replace the normal nteals, particularly for people haying health of fitness concerns. Exmnptes of meal ;cpku'p;cul mchid>.. bu- arc η·η Hrmkxi to shmrmngprodn>, is α-sd ecrx.ilosccnc,'pro-web'

The Ready Meal category generally refers ip any food that can be served as meal Without csicusix c p>>. poomon or prs>ccs-₍iug Th·..- read ηκο.Ι include prcdiuis thur have had recipe “skills added, to them by the manufdciarer, resulting in a high degree of readiness,, completion and convenience. Examples »if ready meal include, bin are not limited to c.ipfc-1 prosetxA ho^en. -hied ehdled rowly ireu s, -Ικόργ ro xcs· fro -or pi/e : i h> led piz/ >, and prepared salads.

The Pasta, and Noodle eategroy includes any pastas and/or noodles including, but not limncii to canned, ikied and ciulkd fresh p.wia: and plain uiMaiU. ehdlcd. uo/.cu and snack noodles.

WO 2008/154221 .PCWS2008/065050

2017200704 02 Feb 2017 (he tanned Ptescnud Food C3teg<*y inehiJc--, hm i.' u-.it limited to cairned piescived meat .md meat ptudii.is. fish seafood, vegeRihk's. teimit pears, test ica-.h meate. soup. pasta. ,md oiha e.mned ptoses v cd food' fin.· Γπναι Preuas-cd Food catep<«y· mehuku but L· ii-.:i limited to Ρ<ν>.·η '>·<><, -iteu .cd nreat, gsotesteu nnibiy, pn-vc.sscd fish sca?'>-d. potevu-ted xegctebk’s. num -dht w ptocsX'sed p tab >.-s bakery products, desserts. ready meals. pizza, soup, noodles, and < 'h.. 1 ο?..j food

Πι·;- Pris’d Γρ-vcssed Food entcpoiy inchides, but is m-t limited to = uc. dessert mixes, dried reads sneak, deny dialed soup·, instant *oup. d· fed pasta, pfam noodles, and instant noodles.

I he (.'hiti Froecs*ed Food eategr-'-s mdwks, but is not limited to chilled proccs-xd moats, proes’.'sed t'i*h seafood po'decK hmeh kit*, t'rrsh cm fruits, ready meals. pizza, prepared salad-', soup fresh pasta .md noodles

I he x.uie.s, Dies*irg* and Amltmems t.in.-gory nt·..odes bin u net .imite-J to tomato pastes and purees, bouillon/stock cubes, herbs and spices, monssodium glutamate (MSG), table sauces, soy based sauces, pasta sauces, w-.t cooking same*, dry stmees/powder mixes, ketchup, mayomWe, tnustmd, Mad dressings, vinaigrettes, dips, pickledproducts, and other sauces, dres*mg$ and condiments.

The Raby Food categrey includes·, but is m> e ’imred to m lk~ or soybean-based, formula- and prepared, dried and ether baby food.

The Spreads category includes, but is not limited to jams and preserves, honey, .chocolate spreads, nut based spreads, and yeast based spreads.

The Dairy Product category generally refers to edibs.' product produced from mammal’s milk. Examples ef dariy product include, but. are net bmited to drinking mill; ivodueis ch/cse (00,000 <n\; sour mils -hirl- atdoU'ci da >y produc's

Additional examples for comestible composition, particularly food and beverage products: or formtdatiens, are provided as follows:. Exemplary comestible compositions include one: or more eori.feetioneri.es, chocolate confectionery, iablefe, countUncs., bagged s.;l-line.s sodlmes, ϊι<καί assortment*, m salarJ hexed as^Hhnems, ox ist wjappt, J miniatures, '(..j-o'id JihoL’.' < iM'&iut 'Vs a da on's otKj.Kx ’!,>,·. <. ,η.Μ.ο ui, ’.nt .s sUirJa J mints, p/nver mint*, boiled sweet*, pastilles, gams idlies -mJ chews, totTces caramels and

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2017200704 02 Feb 2017 nougat, medicated o.rnfi.em'itew. R'lhpop'-. κμ.οιικ^. elhe¹ -η’.'.ιΐ co’iiuli. !.e:\, gum. ebcw.ua gum, sugarizcd gum. sugar-free gum. functional gum. bubble gum. bread, packaged '''industrial bi cad. unpUx kag _d ji nsanal h« cad, pastries, cakes, packaged/industrial cakes, unpackac-cd. .cUsamii cake--, κθ-Aies. ehoc<>latc cwticd bisi.mb, sandwich hiscuite. ill led biscuits, saxuty bi-vtnts ,md mackcis. bread <ulw'mulcs. breakfast xercuK, ite cescuR. f.mtilx breakfast ecb.als.fiik..'-. 'ju > othe c>. ..m J Jtc A e„Afast>cictK, h> rc.»<'>. ccefctir Bp >< ,<.oetcur. > >dc.a> ’.<»' dm > we cicum s nels port .><j u .net u. >. .e. n, mil pn.\Ua >k\ cica-m multi ped, waici ics. cicam, rake·!>·ηιζ =ec cream, i.ikc-homc -Jujy ice cw’mn. U umim dessert.', bulk ice cieurn. mM-borne umei ic-c cream, fb-?cp yoghurt, urtisauul we cream, dany pi miners, tnuk. ii-.'-h pasteurized milk, foil fat fresh, pasteurized milk, semi skimmed.

be.'h pasteurized milk. Im-g-hfi? uht milk, full fm bmg liic ubi imlk, semi Aimmcd lone me rilit nrk faidrcc I--ng lm_- uht mtik, ge;u imlk, xxmd-.iu.d csapuiaied rids., plam c>md-.mseil ex-qx-med inds, fknored, tbnenomil and other condensed milk tiimnvd milk drinks, dairy «mix Ike cred milk Junks, fkisoied milk drinks w bh dm) mice soy milk, sour rmik-.h inks, fermented dairy dunks, coffee v.inlcner-' p.m Jcr milk ihuoicc. powder mJF drinks, cream cheese, pr>aessvd die-..->.-, <prvaJ.ible pree-wsed cheese, unspren-iibie precessed cheese, unpmeesscd cheese, spreadable unptocesscd cheese, hard che-z'-c. packaged h-ird dices,\ uopaekaged hard cheese, yoghurt, plaiu/natural ywtort, flavored-yoghurt, fruited yoghurt, pfObiofi'c voghwt, drinking yoghurt, regular drinking yoghurt, probiotic drinking yoghurt, chilled and xhelf-siable desserts, dairy-based desserts, soy'-based desserts, chilled snacks, fromage fr.iis· .mJ quark phtin irc-mago Raw mid qu.uk fl cum J ire uago fix's an-I qtte's smery tioruge fi >w and pi.k,-oxoer nd saxci, smuks u* ί s i a ks, ibms <.ru| , ex tiJeusmuks k’ Ί.. >i chips, popcorn, pretzels, nuts, other sweet and. savory snacks, snack bars granok.» bars, bte A fast bam, energy bars, frn.it bars, other snack bars, meal replacement produois. slimming products, convalescence drinks, ready meals, e m to J r.-aJy wea s Γόλ-ι wwdy m xds. Jne I rc.i b meals, chilled ready- meals, dinner mixes, frozen p»? a chJ-eJ pi// a soup > .inner soup, deh' im cd soup, instant -< >>ip chilled soup, hot. soup, fiOzen smip, pasta, canried pasta, dried pasta, ch.illed/fivsh p.tec noodles, plain noodles, instant noodles, cups/bowl instant noodles, pouch instant noodles, ebilied noodk'S, snac-k noodles, canned food, cairned meat and meat products, i,.mrcd fish s. .i.e. e, xai’iu J χ>.<η l>. i .'s x mmci. iemakc.> c .. i-.d beam >mmioi. fiml ecc.iJ tc.idx meals, canned soup, i,.inm'd pasta, other cannce foods, dozen food, fix'/cn pr.'iesv.J sed

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2017200704 02 Feb 2017 meat, frozen process'd pooluy. h<> 'en proc.> rod fish seafood, fro/eii pioec.ed \ cgcUibies, Dozen uie.it mbsumuxs, fiozen potatoes, >·'λό baked potato Grips, .-foci .·', cn baked potato products, non-oven frozen potatoes, frozen ba et> products frozen dc->ron. luvui ready meals, Gown pi va ιι,'ΑΊ. ·>·’.ρ to-s-j ooodks <.foto !'<>/_{' Io<fo, di;td ..'.'J. eessc:. seise¹. duc.l waJx meal·. deity fo-itcd soap, instant sot;p, Jucd pasta plain lu.-dtev uroum noodles.

cups bow I mutant η· - Jks, ρ· meh. instant noodles, chilled food, chilled processed meats, chilled ik.h seafood products. ciullcd precessed fofo, ehilkd coated fish. chided sto-'ked tiJt. chilled luncn kit. dnlk-d roady m-.als. c uf.cd p. ru ctol'rod soup', cnl „d I c.-di p.roa, co iked neodlc.', oils an,d fins, obi u mi, vegetable and seed oil. cooking ibis, butler, imuganue. spivadahie fols and fats, fuaotiofial spreadable oils and fats, sauces, dressings and condiments, tomato pastes and te-mllon -ck cute,'. stock cube;., ma\y gianules. liquid stocks and loads. hu'b-- and ptecs. tetmente.i '••iuccs. ro based rouccs, pasta ..nucs. sacce--, diy rouccs poAuet in.xto. ketchup may mm,a.·..' logular maymmai'.c mustard salad dressings, regular s<daJ dressing.· low fat .-.J.u· drcs-mi.:.^ x in.dgiettCs, dips, pickled p-oduci;-. miter sauce?, ckessfogs and cmidtnwms, baby food, mi.ik formula, standard milk formula, follow-on milk formula, toddler milk formula, hypomlergcnk milk ifonuda nmp.m.J h,toy food, dried baby food mher b.ihy food, .'piead.jams and preserves, honey, chocolate spreads, nut-based spreads, and yeast-based spreads, Exemplat y comestible comppsitionsalso include .'confectioneries, baker/ products, ice creams, dairy products, xwzot and savory’· snacks, snack bars, meal replacement products, ready meals, soups, pastas noodles canned foods, frozen foods, dried foods, chilled foods, oils and laN, baby tends o \pc. c\.r? n x iti i ie t\ n ' x.rus u υίγοΜ n ’ s als > aIu? breakfast cereals, sweet beverage? or solid or liquid. coiwenlrate_: compositions for preparing beverages, ideally so as to enable the reduction in conesntraiion of previously known saccharide sweeteners, or artificial sweeteners.

y ptcalte as le.ro a chemos·, iw. ry receptor nu>dn!a'mg aroouro a ehem-i,wn,^oiy receptor ligand modulating amount a -meei dax or nrodtd.umg amount, a roroei ''avorihg agent amount, or a sweet flavor enhancing ammmt of one or more of the chemosensory receptor modifiers Or shemosensory receptor ligand modi fiers of foe present invention will bo added to the comestible or medicinal product, optionally in the presence ol known 'Oxceteners ,rof.. so that no ..Aee* (foxor m-folded * omestfole or mrdiemal preduci has an meteased svxeei taste .k compared to foe comestible or medicinal, product prepared without foe modifiers of the present

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WO 21WA4221

2017200704 02 Feb 2017 mveaiion. as judged bv human bcmms or aumuds m gcucud, ·.·; .n the c..se of JmB.uL-u.-ns testing. as judged by a majority of a panel of at feast eight human taste trotero. rm procedures commonly known in the fldd.

The uoir emr.ilb;?: of .sweet tl,r. > ·> ing agent needed So niodulaL·· <* iiupuwc the H.;\er <4 the comestible m medicinal product m rommrotron w di of c»mise depend on many xanubk's. including th·: specific lync ot\omcsuHc vomposUion and its various other ingredients, C‘ k. ihfcpi··· lecofou.» >\bow ₍ \w<„* th '<» mg .menu a ui the ee 'cet r..ii 'iv'bce>' fie uabmd genet··; smiabihp and mdixidiml piefetcnccs and nimbis cmuntions of various human hetm>s tastmc the e- mpomtrons. and the .-mbivmiv·.; effect of fee p-articulat compound > -n the taote of such chemoseosory compounds.

’ htu application -.r'die cltemoror'-·-’' .eceptm m >diftc’s .,edm d'eftb·^ismy receptor ligand modifiers is for modulating (inducing, enhancing or inhibiting) the sweet taste or other t.wtc properties of either natural or sxcrbeiie sneer lactams, and comestible compositions made therefrom A broad but also low range of eoucemrations of the compounds or entities of the piewnr nv mni· n md typ^alh he uxnrovm . < from .room h bbl ppm n> I GO ppn\ <>i uariov.’.t dlentause umges from xhout 0 I ppm te about A ppm horn abmn ^f> Of ppin n> ahom 30 ppm. from about 0.0? ppm to about 10 ppm trom about I» 01 ppm to ah·.·!.:* 5 ppnu or from about (».02 ppm to about 2 ppnu or from about 0.01 ppm to about I ppm.

In yef another embodiment the chenioseiwry receptor muddier mid ehciw jsenroty r.-tepn»’ I gam; m>>·brer of nt· pre-rom m.-rri, r can bo pro'nled m pharmaceutical compositions cob taming a tlterapeuticany effective amount of one or more compounds of die present invention, preferably in purified form, together with «suitable amount <>l a ph. ti. <. uti> al \ .ro cp ab’e '· e i · e s? .·, n> m >' fm foe t ni” to pi spx a In nnihit on fo >i patient..

fob?' ado mtc'edtw q> sett iciompro ids I Vj^ β'ιβ,οι o .nd pharmaceutically acceptable sehielcs are preferably sterile. Water is a preferred vehicle when a compound of the present invention is administered, mtraven· msh· S-, me solutions ami aqueous dextrose and glycerol soluifotis can. also be employed, as hqmd \ eh xks. particularly· for cm etable '<· ul.rois X.,iLible phrntmu eareal w reh- s' re inehi k cw .'iei‘- - i< h ,b -taicb. glucose. Lu.ie-.sc» snerow. gel.dm. mud. ike fmm rhalk... silica gel, sodium stearate, glycerol monosiearais, tale, *>dhun chloride, di led skim n.mk, glycerol, propylene, glycol, water, ethanol

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2017200704 02 Feb 2017 aid Uic hku Γυ-„· pwseul piuirtrav-cuifcai ceripoMnuu.-. F'dc.s.'eJ, >.an aKe v.>ίΛι,ί inni<u anim-nw of wetting >-i emiilMh iitg ageisK <>r pH butfeiing agents. hi addition. miKiharv, Mobilizing, thn kennsg. hihriearing ,md e»doting agents may be used,

Phanitaeeniie-.ii compo irons uompiismg a compound of the present inxention max « m:mufeeimvd by me-m.- ·?' c<»nxeufioaa] nnxing. dis$<4x leg, gnmuhttrng. dragvz-making·, s' roim > nu'sBnj c U. ps , .nng cmi ip mg > kopb n.n „p oc^ss^s ^uh, '₍.>οιχ..Ι compO'drons may he formahicd m vorocnu-md mannei U'mg <me jrmvu' physrol>-g:eaUy ac».cpiui'iee.-a:ivis, diluent. cscipieiite m mixilfaiies. χχInch fjciiiiatc processing <4 compounds <1 the picscnt im canon mk> -uepaiaisoit.- x-Ash can he rocd pfomaaceuiRulIx. Proper formulation.: - de wudcut upon the route ofadministration chosen.

I no present pharmaceutical compositions cun toko the form of solutions, -nspeasrous, cmvdsi··». tablet', pills. pellet.--. C'q'-nh', vapsulcs centaim.ig hq-.iid', p> xxdern. su-muned-reieijsc fornuihui-ms. Mipp->sitories. emuHit>-w, a-..-n>-ds. sprays, suspensions, <>r any other form suitable for use In some embodiments. the phamiuteoiicahy acceptable vehicle Is a eap-mie {sex', g , uro-'-snal-l w ?< , I mod ktees Patent ? <><·>' jOihei o\.imp_:es .>f suitable pharmaceutical vehicles have been described in the art (see Remington.: The Science and Practice of Pharmacy, Philadelphia College of Pharmacyand Science, 20^!i' Edition, 2000),

For topical administration a compound of the present invention may be formulated as -chumm g/R, oint n.- vs, .οο,ηγ- suspensions, efe as is. wen-known in the art.

Xy-a-iu e ·, nvuiwnws xclbtle foose designed for administration by injection., >'g subciinmoous, mt:,ix .-mm* mnomnsenkn', mtnahoc.;': -n irmjporinmeal mh-ctron. as eel' as those designed for transdermal, transmucosal., oral or pulmonary administration, Systemic fotnmialRm- may b>. made m . ombin.tmxn xx uh a further acMe .-gem that imp'oxc,·. iriwoe.han clearance ot'mnx ay mucus .xt reduces -mucus \ Ue,-Mty These active agents include, but are not. limued io, ro-duim ehimncl blockem anubfoncs, N-jccoJ cysteine, humucysteim’ and phospholipids.

In some embodiments:, the compounds of the present invention are lormulaied m: aceordauce With, routine procedures as a pharmaceutical composition adapted for mtravenous administration to human, beings. Typically, compounds of the present Invention for intravenous aJirou-ria. <·'. .ικ « .Η <ί- 'u s'.cde is.-to-'u a-ρι.οι.- b’.fh i 1 oi r .Vice a com]' mod uf .Ik present invention.may be formulated in aqueous solations,-preferably in pltysudagietdly

WO 20(18/154221

P:CT/l.sS2(H)8/065050

2017200704 02 Feb 2017 tA'inpaVblc butte!·- stub as lhml>s‘ M>luti*ui. Ruigcr'· sol* aim*. ot physiok.gteul subiro bail os. I he ^•lutum may cx'nuan hmimkiusy agcn^snch ax-uispenduig. vahik/iug and or dt.'pctemg agcmx \\ hen nceexsmx. the pharmacealkal companions may aL<< include a sohibih/i>ig ;ige*U.

Phanitacc»nic<d coinp<-*u>>>ix for infravcuous admimsttinien max <»pdonaHy m-elude a local anesthetic Mich ax lignoeimtc to ease pain at ?hc xn·;· *4 the iniceimu. Generally, »tc >Uic> -t'is u suppj us’iPKi s pauub ,> m \..J κί ijniiuv»!.., l· u cample us a lyophilized powdci or water ficc concentrate in a hetmciiedly scaled eonbrnicrsudi ax uii ampoule <*i 'techcttc mdtoimg ihc quantity of acme agent. \\ hen the compound of the proront iincnii»-n ix it-Jinmibtcicu b·, infusion, st cun be ώ-ρ-οη-Μ, foi example. w i?h an infusion hettle contam.ng s'-.nde ph-unuceiitmul giadc wate! > i sa.m. \\ hc.i th. v. iiyoimd of tuc picseiit inx-.mu>.n is ajmintxici-.u by intccti--n, an mnv-dc to sic* lewatc foi m ec'ior **r wdi te c.m be provided so ib.n ike ingiediem.-· may be mixed prior to -idmimsiiatfon i '-r ttemsmaeoxai administration. penetrants appropriate- u> tiro barrier to be permeated are ιρ·..·ύ in ihc tbrmu.lat.ion. Stteh penetrants are generally known hi the art.

Phnn-nac-.’uueal compositions for butl delivery may be iti the form of tablets, lozenges, aqueotH ot >-it\ .su-pmshms. granules, powders, emulsions, capsules, syrups, or elixirs, for example. Orally jdi=wtnisi-.fed ph:nte.iceuticai compositions may contain one or more optionally agents, for example, sweetening, agents such a$ fiuctoxe, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen.,. or cherry coloring agenix and preserving agents, w provide a pharmaceutically palatable preparatidn.

W-rcO ,-i\ \',he*'. »1 tabioi or pill fo*'m the pborruceinieiil xompoGn-m'· may l·,· coaled i.o delay disintegration, and absorption in the gastrointestinal tract, thereby providing a Sb·-'rained action ox» r an extended period »>f omo Selectively permeable membranes surrounding an -·χηκ'·ιίί.ιΙ1χ aetixe drix ing κο-ηρουπο m» uk·» suitable-for-orally administered compounds of Οι·.- p;C'Cnf i*u .-wiem In these Ivor pknhunw iluid uvm the em r»>nmo u nin. iii'r ng the capsule is imbibed by the drix ing compound, xxhich swells:'to displace the agent or agent composition, through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time delay material such, as glycerol, monosiearatc or glycerol stearate may also be used. Oral i.'omposiilo:is can mchuk standard '.eiih.le·* vid; as mannitol, laetoxi.·. xtejch. magnesium

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2017200704 02 Feb 2017 sb-aratj, svdmm stio-hmmc. vdlulcsc. nague-·Hut cmbomite·. e>t Such v chules ;>:e prefcKihh of pbatmac cu ti e a I gt ade.

I oi cud 'i.prd j)h‘|uulk>!i' * ich as. io: ex.,mpk, s isncnsieu'., Jis'-m and -Multons. siiimliie catiiciv xwcipscnls οι fukient* inchaic wok···, Mme, alky k i ugly cob sy. po-py lv-sc ayeol j nob,ulkv kmc gb vols ('g . p-:y α^:Όknu g y cob oils. akobvk, digl -Is acidic buffers between pH 4 and pH o ie.-.. accuitc. Μονο. asc<ubate ;n between about 5 0 tnM to ab- -nr 50 0 m\l) e<'·. Additionally. ilm -i mg agents, pi-.-*erxatix coloring agent.-., bm.- .-.aits, <ko leaininnc. and the hkc may be add.-n h-ι buecid .:dininH?i.nh-n. ?bc pf-auracetUical eomn-s.'ions m<, take the foim of tablets, lozenges, sm formulated in conventional manner.

I uiuiddtug M•uulatio.i- stmah\ I» i u-< with rebul re s and l.quuApmy devices and LHP jcioso! devices udi lyprealb sncUidc a c-mpouud of toe present ηΛνηιηιι wnn j phanmjceutie.dl\· aacptaNo vehicle Preu-rably the pharmaceutics Is acceptable'.chick i< a iiqmd stub a* alcofo>1. vs aes, polyethvlen>. giy-.oi m a pcrtlm-n'.e.irbi':'i Opfom.ihy. aneaher material may be added to alter the aerosol properties of the solution or suspension of compounds of the invention Preferably, this material is liquid such a* an alcohol, giyeca, poly gly ee-l or a tatty acid. Other methods of formulating liquid dtug sdkitlouo οι sm-pen^ion suitable for use in aerosol devices are known to those of skill in the an isvc. <.g. Btebafcki. United States Patent No ' ΙΓ b . Ak i me.'Sia C--^r. eni N>> s o t< I»

A: compoimd ofthe present iiivema >n may ake· bo formula!» J m rceud or vaginal pharmaceutical compositions such as suppositories or retention enemas, e.g.. containing convennoonl suppository bases such as cocoa blitter or other glycerides,

In .iddiri'U· >o rbe u-rmuteiiom' described ->ie' mssly . c. mpmct-l omhe pn-seni invention may also be formulated asa depot preparation, kuch long acting formuMti- ms 'may be .idnwmsteu J hs m’pujntanon r example sUvma v. ouHy <v im'amuscuU'ly; or hy intrmnu'» u’ar 'me- t-on I h_v»s^ lb- esanple a compound of the pn.-*».-m inwntson may be formulated:: with suitable polymeric or hydrophobic materials (for example, as an emulsion, in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

When a compound of the p e.'Cni mse-mon >* acuhc. ii 'may he induded in any of the above-described formulations as the tree aetd, a pharmaceutically acceptable salt, a solvate or

WO 20(18/154221

P:CT/l.sS2(H)8/065050

2017200704 02 Feb 2017 hydrate, PhaiinaceutKallx acceptable salts siAtamkulx retain the activ itx of rhe free mud. nciv be prepared m w.sei'ou -a uh bases .md rend re 0« nwra soluble as aquc-'ta- «nd <»th>.'i prot'e sohauR ihau (hs c·-* resend ng fiecacij bun.

\ uompetiod <4 the pieseni invcnuon. ami <u pbeimaueinn-al croup. .-iireu there·'!, xx !! gcucralix be rood m an anu-nnt cliecirx v b· aclncv e the intended propose l-w use to treat ·ι prevent disease.- 01 disorders the aoinpounds of div preset:' no eutren jog orplmumiceuuval roniposnrens dKrcof aw administered or applied in a therapeutically effective amount.

The auioum 0?'a cun-pnnnd c>rdie present invention that will be effective ui the treatment of a parneuhi' disordc- or c- -ridition disclosed hcreni vs ill depend on the nature m' the disorder w condition and can be determined by siatuknd clinical iccumqucs known hi the art. In addiib-n. ,ν >.··ίι·<. or ro n\n rosaxs may optionally he employed to help identify optimal doropc ranees. The a-nouni of a conipound of the present nix ention administered wife of course, be dependent on. among other factors. the '-uhioet being treated, the weight of the subject, the 'tex_l.iuy of hi·., .affliction. the niamb.r-d adrmmwriroo··. and the redgment ot ihe prcsciihetg physician.

For example, the dosage may be delivered in a pharmaceutical composition by a singh- ajimtiishatreu. by multiple appluatrons or controlled rebase in some cmbodimcin. the compounds of the present invention an delivered by md sustain .it 1 v lease administfation. Dosing may be repeated intermsno uix, max b pros 11>*U done us in eombinatkm with uther drugs and may continue as long as r.-i,U'too R> e'tect \» r_s a’ment of the disease state or disorder,

Suitable dosage ranges for Oral admmisiratmn depend^ on potency, but are generally between, about 0.001 mg to about 200 mg of a compound: of the present invention, per kilugfum body xveigh'i Dosage rouges may be readily determined by .methods known to the a-ds.m .,.f ordinary -ikill the -nt.

Suitable dosage ranges for liWavenuus :(i.v.) a Im mstrat on are about 0.01 mg te about 100 mg per kilogram body weight. .Suitable dosage ranges for itaranasul administration are generally about 0.01 nigfog body weight to about I rng/kg body weight. Suppositories gener.db, contain about 0.0 j milligram to about 50 milligrams of a compound of the, present nxcnu h' m nb Js \egbi di.kn npiis. uj\i num Ju Ά’ Jk ran r ol ah. 1 * 0 s·', u> about 10% by wtagni. Rceomtnondcd dosages for iutradcnnal. intra muse mar. imraperuoneal.

1.40

WO 21W1S4221

2017200704 02 Feb 2017 stibcukmeous, epidural. t-ublingual oi intracerebral adwinretixition ara in div ttaigc afabout iiOOl mg to about 200 mg per kilogram of body weight. lOfenx e threes may be cxtrapoL-.led m.-ns dose-tcsponse curves derived from m vur<? or animal model test systems. Such animal models and systems aie well-known m die a-r.

Piefcranb, a therapeutically eft'oetree dose of a compound of the present invention described herein wdl provide therapeutic benefit without causing substantial toxicity. Toxicity oi compounds ut the present invention may be,determined using standard .Gam remrae,· mocxdut.-- a w n.-s .. read h .receitat-ied b- 0-c -stilci astsa, |·\’4ο-.»μ:< between toxic and therapeutic eflccr re. die therapeutic index, Λ compound of rhe present invention w dl ρ» cforably exhibit particularly high therapeutic indices in treating disease and ds wmJcis, Hse d.-ragc of a <x>inpwuud of the pi-re-zui inxeni-uu dese tired icr.in w d( praferanh be within a range <0 eucidaiing c>mcent rations that include an effective dose w-ttn lirtic or no toxicity.

In certain- embodiments c-f the present invention, the compounds of the .present invention andbr pharmaceutical compositions thereof can be used in combination therapy w ith at le.ret one other agent. I he compourid of the present imx.mi.-n and m plujrm;i-,.euucai composhhm - hereof and rhe other agent eau .κι .aiditre eiy ore more preferably, synergistically. I' so wo e.nbvihmea.;.-». .·. compound the pte*en: -» -, ent on -ed οι ρλ.ρρ. cot 'real com-* ^s ίο ' iiizreof re sdmmrere'red rewcurr.-wly wnb the vuroir s'ratk-r ofaiieiS-t went, winch tv.iv be part of die sum,· nhajmaeeiit^!C.h <omnosit-.'n ,re the » ompound o-l ^vho pres-, te inxemsoa o* a d fferoot pharmaceutic./: corapox’tum in can., r embodimems a pi-.smacreric;/ compos'.tarn of the present inven tion is admimstered prior or subsequent to administration of another agent.

In still another embodiment, tfo »heiyesO'Wt»·''. v^epier modifiers and chemosensory- receptor ligand modifiers of the piesou Vscmrem vud or pharmaceutical c<>mpi-':n.-a\ bi, roof may :·,- 'ahanlagereusly ire-. C in human ire-licinu

When .used to treat and ·« prevent d reeases o· dreetdots, me compviinds described herein and/or pharmaceutieal conipoxiiimre may be administered or applied ι-mph, or in 'Combination-With other agents. The compounds and/or pharmaeeudcal &imp< rebions thereof may also be administered or applied smgh\ in combination with other aetdre lunrols.

\1.:ihads a-die.nnieui .mil piopbx lucre bx tuliimireUanon to a patient of a iherapetrii.cnlly effecti ve anio tmi of a compound described herein and or pharmaceutieal

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2017200704 02 Feb 2017

i.-ou^O'mir.-n dtoreMare prex-Jod heicm I kc patiei.' max bcan3?'.m.J η.ι·χ prefer. bh i, niamuud .Bid uiosi preferably, a Iranian.

In one example, the νοιηρουινΚ deseiilred herein and ot pharmaceutical compositions thereof are cidr'ihi'-'-tcied orally. I he c<«up-,'iBid- Mthe present imcmion and oin.Pnrmaccutica.1 compositions thereto nup aM lx administered by an> ->tbei corxenieut ι*·ι??ν. fbr example, by infusion or bolus injection. bx :il”><>rpt:on tini<ug?i cpnlidiul or mucocutaneous, linings (??.g„ oral mucosa, rectal and intestrnol mucosa., i AUinimshation can be systemic or tec d Vs-ann d.nx.,y sX'.fcn’. a.e Manx a. i< c . cncap-iUai on m '.fp> •scries. nneropa tides, mic-ocapimles, capsules. <-·<'< te iha? on be used ?.· adntims'rei a compound described herein and ci pharmaceutical composition thereof Methods of aduunistrutfen include. but are .not limited, to, intradermal. intraumscular, intraperitoneal, imrax-enous, subcutaneous, intranasal, epidural, oral., '-ulfengual, ; man.is-d. iniotccrebiaL ii-fiaxagm-d, η.msdeim.il. revi-uly, bx inhalation, or topically. particularly to the ears, nose, eyes, or skin. The preferred mode of administration is left tc· the discretion of the practitioner and will depend impart upon the site of the medical condition. In most insta acre, .idministration xyi.11 result in the release of the compounds and/or pbarmaceuticai compositions thereof into the bloodstream.

to ;m-.'ther •..-sample, -t may be desirable ?o administer one i<r more compounds <4 nc present imoi-noi· and o? phamraccut M eomposit’on thereof kxaliy ?>· the area, m need of o ment This may be a> moved k r example.. and not uy way m limitation, by leca, mtiuhT i.sngxuigO’. top > ,d applieahon , χ in οη-ρηοοηο-χ x-, rtf a wre.i id dressing iftet re jers to mjeeoon by ru a cl a . ethe-er m mean, ·>}' a roippe.sm.ry rem. nu-ans of ar impkir.i said implant homy · >f a porous ton-porous, or gelatinous material, including membranes, -such ns sialastfc membranes, or fibers. In onO embodimetit, administration can be by direct ipjection at the site (or forme?· site) of -ho eonditfou.

I ,se? ,i'i ? .or . romp > , tv i\ be UesH.mk » _t ui idn> e <> <>^f mere > o· mounds of she .present (mention and or nharmtootitical cemp.^iifon^ the» of ninth e ot'alnownus system by any suitable route, including intravcnirieular. intrathecal and epidural injection. Intraventricular injection -may be fiicil itntod. by an intraventricular catheter., for example, attached, to a rewix ci: snub r.- an Ommax a resetx on

A compound of the present invent vm ami/or pharmaceutical composition thereof may also be. administered directly to the lung, by inhalation, For administration by inhalation, a

1.42

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2017200704 02 Feb 2017 coinpound <4'the present inxenbou aim or pha'njueciincal compos; mm -hereof mm be e<mxcmendx dchxered re toe kmg Ry a number <4 dine·cut Jex iocs, I at c?.anjp'C. a Metered Dose hdiak'< I'M Di;. wbu.1. uldi/es eaubaers that wteaht a ratable lew boiling propellant tc e·. J:chio:odihi<u<mtciha>ie, t> tchlmxuluoioineflKme. JtchloroK'Raih.;<»r<xcthane. carbon dioxide -'?· any·· etho? smrabk- past may be used to ddtxer compounds ,>fihc present indention and/m pharmaceutical Cvniposfoonx tlictcof dneefiy to.the lung,

Xhcsmrmdy, a Dry Powder h-l-ulo; (‘ΌΡΓΊ devue ma- be used to administer a compound of the inwidmn ,md <n plui mae^utKal comp- smon ΜμοΎτο t;_}(, DP) dex m·..-txpseadx use 3 modumsm such as a bur-t <4 $.,b t>- create a chrnd o''Jr\ powder uwitie a container, which may then be inhaled by the pultent. DPI devices arc also well known in the art \ p> p.'la: '.anat on b the inu'.tuk' do-c DPI t '\1DDpl ''> -.wto u, which - lo'-xs fm toe Jccxob of ni-'iv than one mcrupeutrc >.!>:-so h;· example. cq·-ah'- a id e,·. nidges <4’g·.. .Mm \>i u-..- m an inhaler or hisutVb-.tor may he formulate·! containing a powder mix of a compound of th·.- present invention and a suitable powder base such as lactose or starch for these systems.

Another type of device that may be used to deliver a compound of the present invention, and/or pharmaceutical composition thereof to the lung is a liquid spray device supplied, tor example, by Aradigm Corporation, Hayward, CA. Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be directly Inhaled im»· the lung,

In yet anothm example i neHi'κ used to deliver a compvnnd of the present invention and/or ρΗ3.πηηοοαΐίούίοοϊπρο&ίΐΐοη thereof to the lung, Nebulizers create aerosols from liquid drug fbOTulatisns: by using, for example, ultrasonic energy to. form fine particles that may be readily' inhaled (see c.y.. Verschoyle at, BritishCm?< t r. 1499, SO, Suppl. 2, 96). Examples df nebulizers include devices supplied by Shelllekl Pharmaceuticals. Inc (See, Aimer e! a/.. United States Patent No. 5,964,047; van dor Linden e/ of. United States Patent No, 5,95(}λ A); _Van der Linden re aZ., United States Patent No. 5,970,971). and Batelle Pulmonary' Therapeutics, Columbus, OH.

In yet another example, an electrohydrodynamie (“EHD”) aerosol device is used l·» Jclix or a eunipoiUiil of rh.; uu-tem iijx,;nii«>:i and -a- pba:m:u.em;eal crarmo-hsiH thereof to the iuu? Fl ID .wie-'tl det n es use ck^ uic.d eneq-y to oeres.-li, c liquid dreg solutions ;>r suspensions (sec e.y . Noakes».’,«« . I nit,-d to,cos Patent No 4.7M.Ύ>0) The eicctrocbemical

143

WO 20W1M221

2017200704 02 Feb 2017 picperite.' ©f th© t’otnml.iu>w niq. be irnpoiuaH paranicteix ?© opittm/c when nebxerirg a e<m.p< ind ©f d >. pu'k'f n - mP.on ©re os pha;m,..<„et Steal c<»'tip. /kt floem to Oso .nu witk a:i Fill) ^©-‘i Jex near© see ; ©pt.nn/.hmc w tmit.'KM '/.t Mined I·' ore ©'\ki'.l et :he ait EMI) acr>devices mux mwe elliucntly dcltxcr ©>>mpmtnds to the king than odter ptibnonary delivery RvbnologK.-.

I > xu anotnei ©xamp.c. w© ©©.npouce- of *hr pjc»ent nx .rit> i: and <s PUmmaeeutfcal eompoMi:©».- th©:©·©can bo dcbxvied m » xc.-tcle. m pa 'icula: a Ιιρ> ,-otne ί I .mgei, 1900. v ?</:η 24A 152'J s-.y, } j©©· . (:sj' bpo- ire- in ϊ=κ 1 nci.ipx ©f irttectu>u> D-woa.-© and t'ancei,” I ©per •’•kuxtent and I idler ua-.k ί t.-s, Rex- Vux. o© /©5 <J9.x9), see gerteralk Liposomes in the rherapx of Infectious Disease and Cancer,’’ Lopez-Reivstcin and Fidler teds.). Li-.-. Nc« Ymk, ρΐ'.353·3η5 (Μλχ'ΠΕ

In xct another example. the- compounds of ?hv pi ©sent htxvntf>-n and oi pharmaceutic:? eornposhknis th©?cof can be delivered '.'in suxtained release systems, preferably oral siist u'ned jsde.^e sx-noms. bi on© :.mbodim>.m a pump max h·.. cs©d Me·. J angci s'/pus, S©L >n 108 CM < t i lie C<’-m < me : ?tH bmuel e ' 1989 \ ear' <’ M ©’

3.; 1.57=1).

hx yet an-'tbci example, pob inx-'ie :no\n.ai- ©an be used (ua 'Medte.i'. Applications of Controlled ReleaseLanger and \\ txc (cds k CRt,' Pres,, Boca Raton, Florida 119 M < onto kx D © Bi© s.n . h I © Drt j I'n qa! D©x i mt l-M*© n an © x ne’en . < Bali (edx t x\ il_ey, bee York I -mg· r· <<«' (983 ©' tka oexV. Set Rev.:Mrmwo/

23:61; Fee a&o Lexy er M,1985, Sfefence 228; 190: Ditring el £?/., 1989. iVewI 'Al How ill - <, 1909 / \te<> X'y / Η)Ή

In xt IIt -nbot >. ixmodimcMS;. polymeric materials are used for oral sustained release gcI x tx I tetened poke. © irJue vxdmr.i. a «>xxm©ihx re In os© hxj’oxxp ©pxlce, uL ©e hydr0\vpropxlote:bxkv':liih>se am- hyd ©s'<> tixyb ©UhIo-v (m©,-t preterred hy»ln-\spr©p\I mcthylce5hil''xe) Ottur p:ef« nvd cellulos* e^rbe?x hux'. he©n described (Alderman S.·? J PEirm. Ter/?. <$ AM. Mfr, .1984 rij) I-91 Factrns affecting drug release arc well know n to ♦he-L'le<L»tidn and box© been dexudxd n the ait ,B.u\ io ri >< bi’ ./ M n-<r J079. 2Mt»⁷)

In yet another exampk. cnieric-eo.dod prcp.naPons can. be used for oral snstamed idea-© admmisiE:tie-n hektved coati-sg maku inis me bide pt'ix mers x% uh a pI Ldependen t xoitibi lily pH-uonh oiled ©ric.Aek ρ.>|\ιηο/χ xx Hit a -1©ν or pH-Jependeut rate of swelling.

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2017200704 02 Feb 2017

Mx'lunou <u cnrooti v >., l:me-emic<'lied ινίοΰ-ν}. peixmcr.' that aic dcgnnk’d by cu/ynu ^; (m.. enry mc'C<ui;roHed release) <md polymer^ that huni finn layers that are droiroy cd by ;m mcrea.'C in pressure (Λ-x. press;rr e-contrel kd ;ek'a<;.

hi '-till ..mother ro.ampk'. O'-moPc delivery sys-enw aie iwed im or;.d siisUimed ideate adnmnstnuion (\ ermu e? u/ . /hug M . h <.1 l'>i t, m , 211101, N fosi i.j vet mhei cmh»>fomcms. OR0>‘'' osmohe dev ices, are used fomml sustained release delivery devices f i h.cavxvs .'< N , I need Stales Pu-cir \·.> 5,6--m”0 1 l:c„uv .- <<’ <.?<., I 'r. ted S\nes l\uc-n 3,916,899).

hi sidl anoihci cv-mndc. a e>-nncdled-irlease system van he placed m pi-roumty <4' die laiget --I tec cemp.-niuk und ei peaimac.,utica 1 con: κχ,ιημ oi the nnc r>o.i. dnn- roeanew < :ly a f.ac'ioi' <»l '.he >y mghk do^. {See, a g., G> miso.,. in ' \k*dica< \ppluai->ii. <>f ( cnuolk'd ReliAwc. 5u/v,<. \<'l. 2, pp I 15-136 ll9sdi C-ihci eent rol led- rclea -u wS'ib discussed in lunger H 990, \,<·'<<.. .61°' I y.??-1533 may also he Used.

Having now generally described thx' inseniion. the <iime will bo more readily endei.sis, q py lek'rcnee L foe fofo ning roampie··, vvnuh ai·. presided Py way ofsllusKanon and arc nor. intended as limiting. It is understood that various modifications and ebanges can be made to the he-em disclosed roempiaix embedun-ems ν,ηήο.Γ deparnne ti. ro *h.e spent and scope of the invention.

EXAMPLES

EXPERIMENT I: Modeling and Identifie-atiou of Potential Chemosensotro Receptor

Ligand Eahaacer

The general procedures for identifying .a poicittial chsmosensory receptor ligand enhancer isst-nimaii/Axl :;-'· the follnwing.

Consirm -mg a model pt Ln- .slrocmre -6 the \\ m>-· rlyimp 11 R2 domain

Docking a chcrnosensory receptor ligand, a sweetener into rhe actix e site of foe sinictureoftheXtenus flytrap domain of TlR.2, with or without T.lR'3 present . Docking a chemusensory receptor ligand enhancer, e.g., a sweet enhancer into die active site in the presence e-fthe chomosensory receptor ligand, e g., the sweetener

Sck'ctmc a chemoseusorx rovepha Ih.-.md enhances ’ e , sAcet enhancer eabduhtc. based on txvo c; ihma: ;d it I in the active -tte m foe model, .md h) it forms productive

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WO 2lW154 221

2017200704 02 Feb 2017 iutertteu>-us with sks X cues fl'.nap il>-maei of 1 IR2 ami with ti.c ^.l.cmes^r^ci'. mcq to> -imrid e u. the wccicuci hiRtacnem can be vac du W.sals. butul <u In Ji.'pi.>-iMe uteris <>i aU-uue groups, hydrogen bonds, ring stacking interactions. ot >.alt-budgjiig eleem-teuic interactions. Kes »emines for sueb njienu-tioiK inehidc the hmge fc-mbes the near acm e stie. the pincer loidiiew ; r , micmclmg icsidues dc-uiibcu in the i-iucst inxeniiou. ( anditiatcs arc r»-f restricted to mung completely w ithin the active site, as a is open and chemosensory receptor ligand enhancer candidate* may extend My -nd the acto e Gte as long as they partuily extend into it

WOtoste

A model of the structure of the Venus Flytrap 11R2 domain may come from crysuxl structures of Tl R.2 or of ΤIR2 complexed with fl R.3. I ne domains may be in open or in closed foiin. and may oi may not ue ,\1*<⁵ or c-mam a tig-md -Xite; 0,.0000,- a model <d ibe structure >;'the Xemn I lyrrap I JR.2 domain mas be built -sing si.um.nd homology modeling metis>ds using er>sial structures of m aiiable X enu-· ily u ψ eiom.ems such .o- tiie mCuuR i-.ceptor Venus flytrap domains .as templates to construct the model.

Au example of a procedure for building such a mode! is io use the commercial software Homology or Modeller 'from the Ae^ eh y > Corporation iha t is v. el I d> ·». urnented ih^: foe literature and available commercially. Alternative conformations of the model may further be explored using additional molecula» meeh.uik.il techniques that may -nclud·, hut are not limited to normal mode analysis to explore »· l.inxe mroemenl >>f the I>-bes of die ni,.,!el. loop generation techniques to generate alternative conformations of loops in the model, or Monte Carlo and/or molecular dynamics simulations.

Hockfo^.

A ehemosensmy uv· pt<>‘ ligand, ?g ,' new ·-< r w,is f κ .½ ,wu into the active si:,-s'l s _;R ' Rs •noJck'J pose in ito v, on. was < ecn c hs its aiil w io form pfodueme van der Wuals. ring stacking, b\<t-<>gen boiwng .- id m - v ' brdging mte'actions with iufetevting residues within, the active site of the Venus flytrap domain of TIR.2.

A. candidate for a cbemtiseasory receptor ligand m- Ji ties.(.-/. .sweet:enhancer was then cfoeferf' into the active site in. the presence of the ligand, eg.. the sweetener described in the previous paragraph. Its active pose and its candidacy as a potential dhemosensory receptor ligand, modifier, sweet enhancer was based on its ability' to form productive interactions in

1.46

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2017200704 02 Feb 2017 the toon ol \.m dcr Wauls, une. Mackin,’. hydt.'eo'i I eiklmg, one or -.ail hieying ujtei.iclk'U.

nh imci <i<mue iosiduV' Jx'iibcd in the ρι\χ?>1 κχηΐί, u, w itb ,t,ld'ti<»'i ii ' e u.liws of Μ Π Rd domain, and optionally with, the cliiunosensory receptor ligand. the^sweetener placed ih the active site as described above.

R^m«QgMd.Modifim

Λ nmlccule xro,-. comidcicd a candidate si ii can be docked mto the aeiwc site in th·. picroiuc o?'a ehcnsosciKOiy i .ceptoi beano. < c . xxvectcne., foim. ic pi. ducix inter.Khons with iuteiaehiie residue,' d-xribed in the ρηχΆ iuxcnii-'ii. We defined oxo spaces ά-thm the hcihc s_:t·,. pjs? space occupied by a chcmoM'usoix icecp'oi l>anu.<_ c . sxetenc:. ami a •>.cond 'ρ.χ. > keup.cd bx idvnxi'.n .ccc; *oi tea xi uxx’ific,,. c-cnKnc..· Meuobus and iiuitaecnc.Ms louib estubbsbed Ux icstehte.ih.tr were considered m M likely w line these -p utes ;, - nic cik'i'ioss’ii.Oix i .cepr.>' I ganc, < c . sv,exn.,s a id J cm. scnsoix ,c..coi. * hg .ad ni'.difier '.e . svxcei enhancers, hi die coolest r.f »>ur study, ''residin’ lining ihe .space” moanr Hui be residue had backbone and or .side-chain an.nw lb..u wore posili·med so th.n they can nowmitels mteiaei with atoms ·>Γ dm dvmosonson re·, enter =ig. in· I eg , •mee-OHcr b-pace '> andfor chomosensory receptor ligand modifier, eye., sweet enhancer (space #2). XX bile rho chetnosensory receptor ligand, e.g., sweetener and chemoscnsory receptor kgand modifier, e.g... sweet enhancer themselves cannot oecuny the same space, fheir corresponding spaces may overlap ditet-i the ability of iesiducs..to cont.i a h.»th the ehomosetiRory receptor ligand, teg,., ‘.txeetener and die cbeni.»sensory recepn» bgard ma.bfior., o.g.. sweet enhancer, due to protein, tiesibib'ty.. due to ligand flexibility. ami duo to the potendal for multiple binding modes for a chemosensory receptor ligand, e.g.. sweetener or chemosensory-receptor ligand modifier, e.g„ s'A.-ot o '.-an. er btterr.ah. n on mipo-tert .estoi'es hruy space '' I .nd space ' > awe bow nodobng and docsinp .· A from so,-,- ·. e'.-u 'vucgcrcsis

Λ’ ay ) i VVX' («. Ο>^!Ά,. ’ } \ <.<< , s ’’<^f <,<' .γ/,

XX o nave J^;st oxo ed t w ore o-'i w spacer occupied chcmpsensory receptor ligand, < g.. sweetener is partially lined by residues herein, called hinge residues. Maiw Vemis flytrap domains have been crystallized with agonists includingmiGluR I. mGluR2. and m.GluR3 that show agonists forming mk-raGtens xnii how.fiogmis residues to those identified heroin for T1R2. Many cbcnioscnsx'ix jctecptm fot aids e.g.. sweeteners docked to the model of T1R.2 can be docked to this region t >ur sue o-rox ted mutagenesis also provides strong evidence to support

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P:CWS2(H)8/065050

2017200704 02 Feb 2017 the rinding fom ;_t won. > o; 'endues qvteaHy ad.<uc'it i<> it ate km ras'docs ?. the actw mirn id a chen:>>scnseix re-..ept>a,»' g, Π Rd related teecpioE Sime cbejnc.'C'.isoi·'. xcccpt<>> i^’ids i'f.w'wAiroidh’is.\ ‘he's ' t .< ra re ..¼ hn'η. t J» lust'Px<-c h * I * >_i residues x'hcre dw list .n these additional residues r dependent, partially on the st.v id trie clicmoscnsi>ix reccptot Lg-iiid, s./ , .-''Acctcnc:,

Prnt’er nwMras arg «wWW iq be associated with the seecpdspacs (space #2J. Venus flytrap domains arc known to transition from an “ope»’’ state to a “closed’’ state on agonist bsiidray 1 Ire th nap .a-nunn w ^.mpiwcd o· tw- l<>bcs vorann·* y reicucd \> in the liicraiuic as the ii-w l<>he and lower led·-.;·, tn the ‘Opea” sta?c the tel ·> m- ’urtker apart, while •n the cb-sed stare the b’bcs iindurgo a rebin, e nu-tion fuel bungs die uppe* and Awe: I· be dose; together, in addition to dneet stabilization nf the closed state ofTIRd by the agonist, our modeling study h.;e dcm--iistiuted tba? iherc is additional stabdiro-ira· of the closed slate through interactions ol residues ,··η ;be uppu' h>b·.. with corresponding residues on the lower Jobe that are herein eadk'd ths- ''pln.io: residues. V, e h/c du\o\ >.red that an interacting site. < g. interacting space lor a ·. hen-osensrry receptor ligand muddier. t.g. sweet enhancer =s the '-pate· 'dun is partially' lined, by rbose pincer residues, siuc<“ aoeiiiional interactions in this -region can further stabilize the closed, agonized form of fee Venus flytrap domain. Our site directed nimagenesis study also prox ides evidence to support the finding that pineor residues and residues spatially nfeccenr io them, arc key residues associated: mth modulMlon of chemosens· >ry rec rpror ligand, < a cwban> etnent mtn Uy , · ί^ν 1 c.md.

?fey>s' />.<. <><«» ,< - abeiwppetf In the abovedisotissiou the ehemosensory recepi> >» modulo* . v, sweetener Binds to the binge:while the chemvsensory receptor ligand modifier eg, swscf enhsueer binds to fee pincer region This n jxtst one example and shoted n>>t hs’ cersraed rest Hens eh b'or esji'ufe-, ran m· coring .mu i'-c-eki>'s study has also demonstrated that a rikely binding mode for saccharine as an ugsmht (\wecu.-ncrl involves binding to the pineer region. Such result wus further supported by our rate-directed msitagenesN \\ uh a dicnrasensoix reraepror inediuet. c g . w^Ttehr hound η- tli«. pn.ccj region there is opportunity for further stabilization of the closed form of the Venus flytrap domain through binding of a ehemosensory· receptor ligand modifier, &g,, sweet enhancer to the hinge region.

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Pt oecdsuas Defiι: ί tu-i is.

I >> dure > qcmialb .ormA'i.u a- du -r< - i.hhkjk andi-toUin l x candidate' mok-cnk· rehiOxe fo a clicmi'-cma-¹', receptor, <.· s;., I I Rd Άΐαίιΐί to nu-dd while sHiiiiluinvously .-dhtooug internal u-u-mnal angles of the candidate inokculc t-· fit ihc candidate molecule into the aciixe -fee of rhe ».hcm>-.s-Msory tcccpi»··. 0.7 , ΓΙ Rd snuctural model Poses of *t x.u\< date ii'okxJe f jo to <m-, cl-Me Ofte it.u <> 1- tod¹ r > ml 'Oi-ten-) roe -eketed ba-cd on whether the no-iecuk- Gts the aet-se she, imd whether the m-iteeuk- can fo:ai productive van <Jer Vro.rols iutetacu>-ns. hydrogen h-.-iuis. ring .-lacking inierac?ion«. and sob bridge interactions with K-5iduc< of fisc acts', g sne and w ith the chemosens: uy receptor ligand, *?.&, sweetener. Key residue* can be identified \ candidate is vOis-aicred more likely if n. interacts with sets of iCsidnes sn the .iviixc site a_;- the hinge rcsion, tiie near aciise site, the pmcei residues, and the itoalhy ro the acme site ll i< ala-·· considered more Rk-..-iy if it ix-rms direct iiuora-,.ri->ns with a ener ->;-ensory iveepim hgand. < g.. a sweetener

2. Homology Modeling

Hornol-te,;-, modeling k- g-.nci.ihy -rorsMdered a* tlix' process ,-t ccmstritoting a m<>dd -a the \ 'dyn,n> domain chemu.-en.-Oiy sveeptei,. „>. ΠΡ2 Irom ea ,nn no acid sequence and fiom the three dimen.-k'nid coordinate-, of one or ntore homologous Venus fly trap domain prate ins. Hon>ok,«gs model mg may he peth'-rm» d usmg st andard methods welVdescribed in the literature and available m Cvmmoseial '-'-mxsme ,-ueh as the lloioology program or Modeler bom Ute At w’ln-l omro-ah-m M- dels haw-¹ on experimentally determ ·ι·, J -tr.jcn.tes ofrqx u and closed forms, us well as animation of models using normal mode : analysis,, were used to define the pincer residues discussed above,

FfiemmmX.lihiStebA^

F Igurt-s 5 to 10 illustrate interacting spaces and residues associated witli one of out ηκ'-lt-cular modeling studies.

EXPI- RIMPX Γ 2: Mutagenesis Study for IdcBtifieaiion of C hemusemson Receptor Ligand .Modifier: Eohaocer

In our previous patent applications (International Publication No. WO^:07(M79fiR and luiernafional thibncation No WO07(}j 0471)9), we described a mv'tliod using hur.<m-i.A·. chimeric sweefumami chimeric receptors to map the binding sites of sweet and umami instants.

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Ger data demmisuated that a umtfoet >>f swcctaicrs. hscludmg sncrosc, fructose. mspaiUtmc. ncotatnc. D-ϊκptophai: i 11-ftp). AccsuHhme K.saccharin and didcm, all mterac? with the TlR.2 Venus Πνί-ap d.-mart A’l It whd>. sh>. hilsh UUanis, mehshue 1 hdam. .e uiosine-cknh.-iiophiKphmi.' HMPi and gmmosnu'-SMb a ,<-phosphate itιΜΓ'·.ah interna wttb the Ti RI Venus fly pan domain.

I nda the j.umancc ol moxsul· .nodchcg. we pa Im me su·. c.tcaen wutagenssts on human 11 kd V *- I The nnmig.-jesis was done osi.u the <nn .ie Pt K based inabod Human I HC uufams woe n us .mb ι .insieccc. mu HFK..A3 -.ell u^.na wnh fl e immm> 11R3 wild tv pc eDNA. und the franstect-zd cells wa-c eharaaenzed using an autonuoed FI IPK uk-.ehmc m * caseuim uuagmy sy.s-au as dcw.nbev in . m ptev u-v.s purar app icatams In <srda- (<> conn el for ph^ma memhjane exposum. n:<’?cm folding ;md ·.? tiaoix hat might conhibute to J-kmgcs m receptor uetons. we used ? tmeetenejs winch interact with otha dom.iirK of the human sw eei rc>.eph -r a< nosh w...- controls. 1 six’ ?. ccnti'ol <w c-..-roners vsere eye irnnate ami com pound X (Senomyx). h is known from our previous data that esdanute interacts with the human fl R 3 tran^membmue domain, while compound X interacts with the human T i R 2 tmusuiembrafte domain.

The mutagenesis data for a numbe* of sw ecu nets a-e summarized in the following tables. Based on the data,we concluded that n te-nducs tS4tl SI44, SI 65, Y103, DI4'2, P277) are criiiculfbr mteraction with those sweeteners

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Mutagenesis data <m FL1PR

	Asp&mme {15 Mm)	D-Τφ	: .Fi4.iCtOSt4.:· t?<k' >:)M!	(2ίΧ) KiM)	SrotJ-w i w.-l..nA 0.2 mM ) : (80 rtiM)	S3819 , •'S .Λ - >
V<T		4-4-4-	4 44-	4-.4..4
	.....'	3t:	: 4-4·			........rr:.........
V?<^4 A		4-4·-	; -4-4:	4-4-	4-4- ! .-4-44-	4'4’4
F-332A	$0000000000000000000000*			00000000000000000000000* .»<><><><><><><><><><><><><><><><><.....		4-4-
SI 651			-4			? 4-4-
0278 A.........	s.................. .....	4’4·		.....		:4-4-4/
		........44-.........	4-		L f '	4-4-
...........	$0000000000000000000000*	4--4	<+<	OQQQQQQQQQQQQQQQQQQQQQQ* -0-		4-4-4-
;6?A	τ-4-t-		; -44-2-			44—H
M143 A	.....	3t:		4-4-		VH
S3?>3A	' 4-4-4	-4-44-	i -4-4	4-4-		4'4’4
		H-i-		90000000000000000000000* : 4-4. γ- .»<><><><><><><><><><><><><><><><><.....		-44--4
T · 84Λ	4-4-4-	4-4-	: 4-44-			4-4-4
T2.42A		•y-y	; ...5:.4.	: <4.4.		-4-4-r
.1..2 ?M A		-4-4-4	i -4-4	: 4-4	.........44-......... :.........-4-4.........	:4-44’·:
nMA	4-4	4-4-	i -4-4/ KOOOOOOOOOOOOOOOOOOOOOO9	i -4·4·

Mutageaesis data tm calcium imaging

	Aspartame (IS n:M!	ΓΚΓφ 120 n$d ϊ	1	12'00 jiAl)	ίλ ? rAB	ί8ίΐ n \n	p4xKl
WT '		4-4	: -4-4	-44-	4-4-	:	w:·
	-4	-4-	4-	i 4-	-4 :	: 4--	γ
Y103 A	-	F	; 4-	i -t	-	i 4'	' 4
027SA	4-	7:		i 4-	-	; 4-4’	-44-
ί}«ι:·.\			; -	-	4	: -4	4-
r	-	-4	A-	i 4-	4··	: /’Τ’	4-
Si 651	«.·	-	4'	; -4	-4	: 4-	: 4’
S4i.0	—	-	-	-	-		:4-
bi 42A '		-	-	-	-	: -4	-4
A	-	-			-	i ~
.A395F	-	-	-	·-	-	: -	' 4

WO 2lWlo4221

KWWMO

2017200704 02 Feb 2017

Y2 : 5.X	~·			-	!	·'
......dI/J......		Ν00000000000000000000Μ Meeeeeeeeeeeeeeeeeeeeea	-	«xxxxxxx»^^	Meeeeeeeeeeeeeeeeeeeeeec	-

Additional snutattons na R383

	fo to ehM)	<S<j :M ·	Sucrmv ί?<λ:Λ:ΐ	Sucralose {3.2 mM)	D-Τφ : lO’.lV.	Cyclamate {80 ιϊϊΜ)	c
WT	; 4--1--	4-4--T-	i 4’4-				, Λ -
rre'foh..........			F	: ·<··Η·	.........-..........		...................
ICX/O	; Λ·	A	-	; :4	r	4’	: 4’
ί	: -	-					*·
RWU·	: :*				-b-	-T·	4-
I-rerej.;		•l·	•	: -V	t·		-I-
RStoN	; Λ':	ri-	...	i '4	' -r	4->	re
isWS	: -	V		i 4'	i-
R'-S-.x	:	-	; '	-			re

The sweet. enhancer, compound A. is selective for the human sweet:receptor, and inaeriw on th», r;u sweet re^epb -r 1 sing rhe previously described human-rat chimeric receptors, wo mapped the fending -me of e· impound λ :> bl IR2 VFI \s shown i I ignre 11 eor'ip-mod A enhanced the sucralose activity inhuman sweet receptor (h2 h3) hut not rat wwet receptor (r2/r3). When/we'replaced the rat receptor T1.R2 VFT with its human countorpan (Ii2-r2 --3). rhe receptor can. be enhanced by oompmmd A. On the other hand, when we replaced the human ;e>opte-r I IR? \ l-'l v itP ire rm o<rerae^:'pm'l (•'’’-ΙΓ bΌ, foe recepte’' cm re loogc -1.-χ-ι^!ιmeed by compound A. We conclude that compo und A interacts with, human. T.l R2 VFT. Ehie t-»tee different -'ensitiv itv of human and rat receptors to sucrakrec, .different sucraiose eoncenteat-ons were used ro .-sehiex >. -l’C2R of di·,.- ditforent receptors.

I elk-n rag e>ui:p«'Uh>,l X, 8 niese aralori.es \ue beet de> -il't d n> erba-ire foe sucralose activity of human sweet receptor. The same mapping experiments were carried out on these & analogries, and: we observed: the same activity pattern as compound A as surnmarized in the following table. We conclude that all. 8 ecinipomid A analogues interact with human TI R.2 VFT.

WO 20(18/154221

P:CT/DS2(H)8/065trf8

2017200704 02 Feb 2017

Alter mapping the euhuneers to human TIR2 VFT, we performed mutagenesis .w'-xx to mrt.'Ki eofm. sh- suter.u’jo'to'k' ,X- -s.mres.u. .d n< ί κ reJlewsir. (al to. six fFj-5.1)2“n. L2~’>. Ε>30~ R3-S5. X'jyfo} were identified as criui.al fm Hie acioiocs of emnnouuJ Λ and anulcgouM There conipuuad.s, namd-. compounds Λ and XI ?>· Ah’, are represctiianre eompvnnd.s A the piCs<.m itt’-cmiou nreludtnq comn<nmd\ oi ,%?incmral Formula i B and m, subgcnci se l··ι mutes Iniucstmgb , \ A4 :-- tore import tut h·· :hc refo mes to 2 so jcturally related swcercncis {a·- sh-an in Figure' 12). saccharin and actsi.dfmn< R gXceK.’L u'dii-aim^ that these sweets;nets might >-ccupx .reuilai· space sn the htnnan Fl P.2 XT Γ. The con>.ennati<\ns tot me 'oxccte.'.eto utc X\pa tome t^! 5 u\Vu D bp ( Ό uAl), s„- ηΛΠ, S»K„ih sc re 2 :u\i > XecK {S mXP>, Saccn,» ;-_s tZ m\ll * Telamcre :nXI), S -<x 1 -125 ,ΛI)

	Wb/l	ΐΑΚ!	Ι1?.:ί.^ί3
Ccinpowiti	•J'·.		rb
Comgmtnd			4-
Alf25uM)
foSSKifiUSrl ASmuMl			y	7'·
Compound
Cmnpcunrl			4·
A4(25uW
fdpjiytnuggl A5 (25 pM)	: 4··:	—	y
Tunmonnd	X		rb	-
CpmjHmmi A7f25uM) ^vvvvvvvwvvwvvwvvvvvws	F:		4^
CAtnjWiml		-w.	y

ALG.QO

AT;

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	Eaiwceawt .Activity (at.25 s+M) for Cornpouad A and its.«aaks^s-
h2'lR2	Mcratee A A4 Al A5 A2 A6 A3 AS A7

\X Γ ·ί+-i+

X >M X ++-++

H-2X ++++

YI02A -+;> ; ' \ ..(.. .(..(.

o:”s\' -++'

Kr+X +fofo ++.

V3S-U ++-+gin's ++++ :<·> ’ \ ++++

SU'.'.X +++

NW A +++ ; X'+ X iO·++ • i’X ++++

*. \i'\ ·ί·+++ i ’i?'''4fe' ; +-+ ++-++t j λ<» A '4444-X η·Λ! ++++

S'<+;' :: ::

«X· XU ++++ s-+·:.? ϊ +++

IN>7.\ ++ 'Ί2 A ++

R+SR +Π307Α +B)-» X -+SXV\ ~+·

R383A -+ \x<'5E -V j. t L. . L t ' J < t • 2 : t r y. ^: ' 2 ’ >

.1 -L·. : Lt .2- _i_ a. '

'.'re R ' N,TTT ·:·£ -y-r·:· Mb4.444 44 -.4-. —T'-re ’ ? !· 2 21 · ‘

,.γ.. (4'tt

4· 4- 4-.4 +4 4'1'42'4

·. +. λ . ·. ·. .:. .<. ·<.- <_· -+: : 1 ’ ; ¹ ί· · >

'2'4 42^'2' 444't*4

-.1-.-+-. .+.·+-. J.-. .+..t. .-+.+..4-.

,:.-E, ,+ .1.,+ . >.. 2. .:..... >.

• · Π > · 2 2” , ;

f'y {?' 4’44-44

..<;+. .€.+.+. .:..4. .4..:..:.

τ 2 ? !· 2 t <2 : t >>.'4 444 4'9. . j..;..:,

449· 44444'

x.rt-. ^44 '44444' ''Y'4^; 444 44 ·+··':··4

.... ^. -.i-.·.·.— MMs 4M4

--:--4 44’··:·· -44·444 .-:..+ +,-+.+ +- j. ,i, j., v

4. -.-(-.. W + ++ +++

A ++ +++ + ++ +<+-+ ++ ++-:+-+ + ·;··: +++ + +: :^:++·:++ + + +++ + : -: -+, ++:++-;:++ +: ++^:: +++

-A-- ...,. ....:..(.

' .i. -t- · ·.- : t-ty : y ' < y :r :4. 22''

2 < · ' ‘t re'?’ re ’C'?'TT”y

4Ύ'*· ,4,.(1. +:, .-T..4, f. -144 4-· .444 y+’ y 4+1 y

4-$· 4 4:4444

4^:- 44 :·’^4Μ···

:.4-- -.-:-. .444

4 444

* DS78 is a critical residue for the cahanccM because all enhancers: in: foe above tabic shoxv agonist activity on D278A mutant,, i.e., they activate the ..mutant receptor in the absence of sucralose.

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ENPERIMEN Γ 3; Chemical Sy a thesis of Use Compounds of Use Present ksvmiion

Example 1..: 4 -Amim>-5,6-dimethyIthkmo|2,3-d|pv rimidme-2( IH Mhitme

nh₂

Λ v Inof N-ι 3-e( aa<>-4.5- diinethyhhKpheij--2-y !carhumothhyj)bcfre;.m'.idc icxsoupie ia'> {1 ‘Ό g. hdb mml> and N,n >H t2 N, 8.3 ml ) us En HI {25 rd ) wa*- xt.ttcd at lti<) C imd-.ι mtiogen ?'? bah an hem. Afku coolme to i m reripeiatmc. 'he ck'ai rcacimii seliitiot) wax tiiterad _md the fihiatc wax cate talk nemrnli/ed with 10 % Act til w ah \ jg.-r-a^ .stin i ng at 0' C the texiiluml' r ee nutate w ax a> Lx ted bv ‘1 ti teior, w a-a x J w it ι w at m w ;.t.: ami then 20 % EtOH in water to give rhe final product 4-a.mmo-5,6“dimethylthiono[2,3-d]pyr.imidine-2(l Hj-thkme (1.,.1.1 g, 87 %).as an ofi-white solid. M p.· > .260 'Cl ^!H NMR (400 MHz. D.MSOM-.) 0 2 25 (s, 3H)., 2.2<S *. 3H) MS 2.12 (MH 1 bxmnnk ia \ {5 Cyano 4/-dni!-.'thyhhiopben-2-vRaibanualnovribcuzamjik

To a solution of 2-amino-43’dimefhyith_;iophone--3~carbon:itrile (1.52 g, 10.0 mmol) in 1.4-dio>:ane (20 mL) was added benzoylisothiocyanate (1.63 g, 10.0 mmol). The reaetkm mioure wax then stirred at roosn temperature under mtregcr overnight. The predpitabo··! wax c-:-1 lock'd by ftltratiou. washed with E.t().\e Hexanost 1:4), and dried under vacuum overnight to give N-(3-Cyuuo-4,5-dimethylthiopbcn·2-( lein’bamcahioynbenzamide sa & wbii-. solid Ή NMR <300 MHz. CiX hi0 23 (χ. 31b. Ml tx. MH. - >8 ? I (m, .’ill.

7..X /t'i'im ΙΗΤΜ_{χ./ .'Hl,') 3 (fo HL Mu.MhMH )

Example 2: 4-Amimqmna£oMne~2(I HHhkme

bib?

183

Prepared ax in example I fem Nⁱ~(2--cyaaophenyleatbanwthioyl)beuzamide: (Example 2a). ^!HNMR (400 MHz, DMSQ-iC) d 7.25 (dt, J- 1 < 8.2 Hz, 1H), 7.35 (d, 8.2

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IU lH).~.6S(dt. 7 j,G.82H/. Hli. x.O5 (dd. 7 J.O.x I Hz. )lh>30(s. !H).8.35(s, Hh 12 34(:-. HI). MS ΓΧιΜΠ I.

Esampk 2 a N-{2-«''.aik>piuTdc.nl-am<>diOvDben'unifik

Prepared us in Exampk' la bom 2-animobcnzonUrie and Lcivoyl ΐχοΐίικκχ anate ms a pile-yellow solid. ^lH NMR <4Q0 MHz, DMSO-<M 0 7.35-7.56 im, 3H), 7.67 ({, JH j, 77-=7^(1./ 5 2 IP, 2H). 69 '•’I _kd.J 7 2 Ik, 2ΗΛ Sfo X 01 <dd /1 ’..vH;./.’ 6,2 Hz, 2H), 11.90 (:-. ;H), 12.54 (,--, ; Hl. Ms 262 {MH j.

Example 3: 4--Mmrto'-5'-meihykpnim/i'dine-2nH)'-iiikmo

H

155

Prepared as in. example I from

Ai2cv-?> 'tn nfop'em le-iha noinu ' >}. rs-muJe d 'η <c > 3 a-an >11 wb. sold V. | '' 250 r ‘H NMR (400 MHz. DMSfo-Λι 3 2.56 {.-. SH), ’.OS (d,./ 6,X Hz. 1 Hl, ‘1 13 in. IH), ³\d .7 0 6 It, Hl) 74x(t 7 OMH Hl), s 50;b HI), >(s K|^l\\Va (PMSO-dfo a23,2u k)0 30, H-l 27, 12- ro. j’43; ; k-97, MiS. MO-'s, I7m»7 MS IT* (MH ).

LxampIOT N-(2-CvanophcnGearbam0thioyI)honzamids

Prepared as in example la from 2r^niup»6mdhylbeWQn.itnfe and benzoyl isothiocyanate as a pale-yellow solid, *H NMR. (40() MHz, DMSi W, i <’> 7.40 (ni, 1H), 7.S2-7.69 (m, 5H), 7,98-8.01 (m, 2H), 11.99 (s, 1H), 12.54 (s, IH), MS 296 (MH j Example 4 : 4~amisw~5,6~dimethylthieno(2J~d|pyrimidi8r-2(lH)fon0

i

A xokilion of N -(3 -ey a- >.<>4,5- dimethrinuv)Ten- 2- x lem I Mino x I ibei izandde fe\miple 4a) {44 35 y, U6,. mnic ) ami \.i( nJ (2 N, 204 mti m I iC-H(*00ml Mw' -ijiueut

100 'V? under nurogeu ibr bro; horns. The ekas uacOon solution was Jikeud rod die f.P.au. vs

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2017200704 02 Feb 2017 <.©©lmg io ©·<«η temper teur., and then v< .u ea-teu l\ is_©©;. i. ©J w u i ( ’< > Ate Hl /- 120 ml ) with vigorous stirring at 0 (,. After stirring overnight from 0 '^:C to room tempera:arc. rhe nsitham picvphate was coilctecd by filtration. x-.u-hed with xsann wai©'· (m.i-ti '<. ’. i 5© nJ x H and .70 ^u.> hX’Hl in water (200ml, x .?). and th·..r= dried at 50 C un-kr sa-tehni ©x ern-ght to yne th© final product 4-3niiri>>-5.o-ditriclhvlthieti.i|2.3-<l|p\.rrinidui-2(l H)-©ire (27 7 g. ©c %) as a Moie-dd it \MR GGO MM/. ΓΛΙν* > ~‘hr < hx Mb 224 (x.3lh 2 HpMh MS i‘m (MM p l· - amp v 4 , \ /©s m <- © me’hx obi©© >..© .2 s w , ©aim's b K-tza uh e lo a solution ot ΐ-arntn·· 4.5-dmtethx Hli-oph.re·--eml··>nr.rt e {.·χ©η·ηΚ 4hi /25 g, 164.5 mmol)in 1.4-dioxane(600 ml.) was added heuzoxl isoexanate (2-1.2 g. IM.5 mmol). Th·.;:auction mixture was then stirred at room temperature under nitrogen overnight. The prccipitufc was collected by fiitrurton. washed with 1,-1-di oxane 121» ml. x 3t. and dried under xaeeumte 10 t M 3 hoaix ;© gtse \-<,.Mxanc»··'· '--c methxbbn’pnen- \\ .© panxox ilbenz mu,ie (44.35 y. 9(/..) ©-> © Mme ^ohd. ^!H AMR 14t>0 MH/. I'AISOM. 1 0 2.10 (s. ©Hi. 2.24 H. 311). .52-7,5^ (rn. 2M>. 64-“ r-9 tni. IM). 8.0=4.03 tm. 2lh. = 1.5/bis. Mb 12.(4 (hx, Mb MS 300 < MM }.

S(9Wlg;4fe 2-amino-4.5’di.mmbvithiopheug~3’Carbmiltril£

I© a .-©Intion M'bii(tei©m ()o2 0 ml , I d m©0. -iilfu” t ).9O g ; g mol), and matbno.miri.le (119.49 g, 1.8 mol) in. anhydrous Ethanol (1.2 L) was added at 0 C triethylaniiiie (251 4 a© . I x snob The uateten x- λ Mute© Μ O ( f> i 15 'mr©{©s tn©r i.eat©J te MFC icj ~O mimites. After cooi ing to room temperature, ethanol (920 mL) was removed reduced pressure and .©::©c©u.- XuCl t?(!%, 750 nd© w©- added 1-te tesdimg ncxUi.e xxu- Mined ?©? 0 minute.and cxu.;ued w ah metiix I e*b©s {IL). I he ..qac-oui- sa-©' h© Jiei exKieted wn i Jiefljx·i uher (500 ml i and the 'u-><Jul4e Mid- w-ie uoimed hx li u dier ©6©' whier die ©tguine koci was separated and combined with the first diethyl ether extract The eombiued prgauie extmetwas dried ox er MgSO.:. filtered and concentrated under reduced pressure. The residue was stirred tor 2 hours in dichlorbmeth&iae: (300 mL) and a solid Was collected. More solid w as isolated from th© ,.hebk'temc;hanc suluo-m cook'd ι·> 4 C I he c©mbmcd <, hd pt» duet was lefluxed m diohioromethune tvlH» mL) for 10 minutes then stirred at room temperature for 3(f minutes and cooled to -78^SC. The resultant precipitate wa,- collected by filtration to ghc the crude product ί Uo g'i The nhiatc w.w concenttaud ©nd the to.-tdu© ua< ch>sun.:'.ogtanhcJ oi' sdic© g-4

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2017200704 02 Feb 2017 (dt<cW'. dichlaiomHbane;- w pr-exMe .1 solid that was c.-tnbined Mth foe pre’- ions crudi. puniuet. The resulting residue was purified by flash chromatography on silica gel (dichioromcthanc) io yield 2-animo-4,5~dfmethylthioplwne''3-carbonitrile (I05 g, 38%) as. an off white solid. ^s H NMR (400 ΜΗζ,/DMSO-fod d 1,93 (d,J==* 1.2 Hz, 31¾ 2.07 1.2 Hz, 3H), 3.33 (s, 2H), MS 153 (MH s

Example 5: 4Anrim)~.5,6-'butyleaeihienu[2,3-'dipyrimkHne-2(HiMhione

nh₂

Prepared as -in. Example I from

V{ 3-cyan--4 5,6 -tetr »iwdr>>heix'e>[b|{hfopheri-..’-ylcarh.imoihi'-y fiixn.ram-de t Example 5.9. ^lH NMR {400 MHz DMSO-Jjd I.”5 <m. 4H). 2 <>.; (m 21Π. 2.71 tm. 2Hl. Ms 2 A {MH ) kkan?j>le.M:

\-(3-Cyam-.-4,5.0 IMcnnby drw\nzo|b|ih:->pheri2~yk'ath.im0{h:->yl'>--benz.irmde

Prepared as. in example la from 2~amino-4,5,6,7-teirahydi'obenzo[b]thfep1tene~3~carbo0itiiie (example 5bl and nejMwhsotu >\<sw· as a p /e-yedev. sold M's el’(MH 1 s_(Jmpk 5h- y-Amioo-1 s u 7-ii'tra!iy>k.'ben/o[bphii)phene”3“Carbonitrile

A 'sdinion >>f ey> lobexam-ne (I ^C)i> g 10 0 mmol), mak-HomtnIe (I 32 g. 20.0 mmei), sultm Mfi nig 20 0 mmol), and tnethy Limmo (2.0¾ g, 20 mmoi) in EiOH (50 mL) was jctitAed -r 6 !' wider n wage > fka sob. .t' w .b w nwee i -ider redu· ed pu vj\'. nd rhe C'iJtiexiiMote n weei I a^-» x< are w > · 'h r mu I w er -,. \ pitas J a * Kd ' 0 brine, and. dried over NaiSOn Afier evaporation :of ibs solvent, the residue was purified by chrornatograpliy on sifiea gel eluting with EtQAcfi-fexanes (2:3) io give the title product ax a yellow solid, ^!H NMR. (400 MHz. CDClfi 4 1.79 (m, 4H), 2.50 (m, 4H). 4 59 ts, 2H). MS 179 (Ml 1

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Example 6: 4-Ami»o-5-methylqainazeO»-2(.lHEo»e

157

Pscpat cd as m example 1 roan N-{2roxane- s-medn Ipbenxkatbam. \ -)l er/.amdc (example 6a). Ή NMR (400 MHz, DMSO-dJ <> 3.04 (s, ?Hx 7.43 (d,./ === 7.2 Hz, HI). 7.5 = (d,./ - 7 2 H,·. (Hi. 7.97 (t.J- 7.2 Ήζ, 1Π}. MS 176 (MH).

Example he *x -(24 x ano- LmcOMphenylcai bumox Rbcnzamide

Proposed as », cvu.mlc la *i. i.x 2-CKnno~e-mctbx Iben ei.'lt * I- .mJ ben ox i isocyanate as an elf-xJme s«did Ί^;Ι NMR (400 .MHz, DMSO-M) <> 7 I 9 (J. J b 1ή. ΗI), ' 52-~.tex (in, 5H1 MCXGk (m, 2Hi. 11.32 w, I Hl. 11.40 is, 1H1. kA 2W iMH ) Exampit 7: 4Amine~6'ethyE5'methykhkmo[2,3~dlpynmidhi2t Ullmnt

Prepared as .in Example I from \-P’-cx.Ui<' 5 Jlw A-mslb ΑΜορΙίν,/ί-Α x IcailOmosbaeu/ancJe (i.xamk 7a). Η NMK (AJO MHz, DMSOMs) O l d I (6./ === 7.6 Hz, 3H)_? 2.26 (s, 3¾ 2.60-2.67 iq. /=== 7.6 Hz, 2H). MS 210 (MH ).

Example Vo: N«(3-Cyano-5-ethyk4-merhyW^teph8n-2-yl:e8rba_:moyl)benzamide Prepared as.in example la from ? atnmo o .thxl 4 m.ihxlihiopheae 3 otbomi' de (examp e ?b) ami I'creoyl .soeyar.ate as a pale-yellow solid, MS 314 (MH').

Example 7b:: 2- Amiw-S-ethyW-methyltlaiopheae -3 -car hominie

Prepared as in example: 5b from 2-pentononc, malononitriie, and sulfur as a yellow solid. MS 167 (MH),

Example 8: 4~A.mkm-h-mrt.hs hhieiiap..3-d|pyrhnidin~2(lH)~<me

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Prepared a* in Example I from

X-(3~ey .a-:: >-5-m. ihy h'biepben-2-y uurbamuy Dbenz.mnde ί I x unple eu) 11 X MR l u)0 Ml L\

DMN M M to- 31b, <>'.>? (- J lb, 50 to- His MS 182 (MH 1

Example 8a: N43-Q.an{>5>-methylthiQphen«2--ylqarb^rn.<>yl')bcnamIde.

Prepared, as in Example la from 2~amxHO.«5«methyllhk>phw-3toarbonitri.le and ik'uzosI ixocyanate as a white sto-d. Ή NMR(40o MH/. DMSO-<i. 1 Λ 2 )8(1./=- I .? H e hilt

I 2 IL\ lb), ⁷'-Ml / SOH ,2Hk<V-(d,./ 2 IL\ = H), 9.0 --8 hl tn 2H),

60 (Hs. Illi, 12 05 (b-, = H} MS 256 (MH 1

Example 9: 4-Aimnto6-(hydroxymethyl)-5-methyl1lHeuo|2,3-d|pyrhmdiue-2(HI)-thimie

H ⁸γ^Ν·-χ-\ pH

Ny.,/“

NH₂. '

Prepar'd a- n. Fxarwk' I trom

N(3--cy<mo~5-tby dioxyiiteihyl)-4~mclhylthiGphen--2-yk-3rbameth.ioy4)be.rmannde (Example 9a).

^SH NMR. (400 MHz_? DMSCWfo 3 2.30 (s, 3Hk4.54-455. (d, J- 5.2 Hz_f 2Hk 5.54 tt, VH). MS 228 (M.H ).

Examule 9a:

N~(3~Clyanto5--{ hyds < j -> tucihy 11-4 -mcihy lda0pben--2.-ylea.rbim.tolidAW0“bensamide

Prepared a- in example la from

2-aniUj0-5-dAd'M\xmtohvH 4 m-Mi-Plmmhcae 3 carbene de d xanip e OR) and ismhmeyawtte a- --. yel <w -χ·'=4 MR ,-,-, ΛΙΗ '

Example 9b: 2-A.miw-S-ihvdroxvme&ylM-methvfthinnhenefo-earbpmtriig

Prepared a- tn example 5b from -Fbydiexy l-umn 2-etie. ma letter tin lc and xulfur axa-edcwvdd H NMR (WO MHz DMM i a ;.- ' W(-.3H* 4 ?0 I H {d / -nil,' ?;h, y l0<\ 1Η i. / Otb-. ?Hl

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Example J0: 4--%mian-5.6..8-tetrahsdroa»iaaz01iue~2( t Hl-lhione

H

Prepared, as in Example 1 from \-(2-ey .ram. χοΙΜιοχΑ-νιη k'.id->amed»oy ilboroxm-ide fix enple lOa'i as a xxhite -roild. Ή NMR. f 100 MIL·. FA1S« iff 1 b = bO-l e? On. Hi) 2 13 im. 211). 2 ire. 2IH <> <L· re. ill) ? 5b re.

I Hl. s I 84 ra, Hl) MS 182 s MH ).

Example I Pa : N-<2-t i lebex-lroux teate trooth.M»lx nr-.-mec

Prepared as mF wimple la Pram d-ummoess obex-l-enccarbomirilc (Example

10b) and benzoyl i,.idih>ra antae .r a white s<>hd MS 2x0 (Mil· ).

Example I Ob 2-Anronoey ek-hre.- I -cnccuibonm de \ .'bued miu-ire el l.“-beptancdmfhilc (21 44 g. 0.2 mol) .rod ;-Bw »K <22.44 g. 0.2 moi) was healed al 80 3' lot 3 b under nitrogen. Die mixture was then cooled down io room lempes taut. and stored a; iKii tempo' taa;e re. ci'.ngh’. Ire i. sidae w I routed w Ph w aiei, are r\Uacted w hh t.the? 12?<j The combined organic layers were washed with brine, dried over NaaSCh, filtered and concentrated. The residue was pmi-lcd hs reersstalhzation from McOH te gsxc rbc titk setapeiind a - a white sehd px2 g. 5 ’ ra 11 NMR (400 MIL·. ( IX'1A0 I 58 I .1 (m, 4H).2.U-2.20 (m_? 4H), 4.23 (hs. 2.H). MS 123 (MET).

Example 11; 4-Amiso-6-melbyIthienoj2,3-d|p>4'iw idin-2( 11! h»ne

N H.

€9

Prepared as in Example I Hom N-(3-evauol.b.iv|'he:'i-.?.-yicarb;i!Boyi)ben/:m-ii.k^> fl s ample 11.0 ⁵ll NMR {ipp ΜΗ , ΙΙΜχΟ-,Μ <1 o ' N. ? '< ’’ lie Illg ' M (d ./ MIL· lll) i>0<s ?H). 11 kX'.hs III! Ms ϋ mMH )

Example 11« N -(3< \ anothipphen-S-ylearbanioyIJbenzamide

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Piepau'd as iu I sample la 6. in 2-umnmhi. piaitc-Le.t>ίν·>al; ,k ais.l bcuo x isocyanate as j w •kite solid. Ή NMR (400 MHz. DM\« U.i 4 ' 23-' .A (m. 2H). 7 55 (t,./ - x.O 11/ HhM.0-RNiPim.2H). Il o2 <jre Hl·. 12 k-< w. Hh MS 2~2 <MH 1.

Example E2: 4»Amineq«uazofc-2(IITmmc

H

Ύ13

N

NH_?

U§

Piepafcd as m Vxami'lc I i-<mi \ {2 >.xanopbenxlearba Th y )l m /amide l’Example 12a) us a white solid (156 mg. 41%). Ή NMR (4(10 MHz, DMSCMN) b 7.12-7.20 (m, 210, 7 ?o 7 f>3 im ΠΟ,ΜΟν.,ν HMd, IHi n o<l _kb. 2H2 (h Π0 ' NMR 0>MSA ./,) > 103.72. s A.9n 122.32, 125.M, 13.V>n. ,42.4(.. Ι54ΛΚ, lf-3.51 Ms HC(MH ).

t sample 12a: N- {2-Cy anophciix tearbaraoy Idvm amide hcpiiu a.ir*\.Hxk I ί acre 2 .rem's heare-m lcand I . me.'isv?., 1 m. .b , M'.-.-wmjcf IMO rag. - ’<-) ^!H NMR {400 V Hz, HMM) </ )a~ 2⁷ 7 2Mf HI), M ~ _N. _ir. Hi;-, e4 .“4 {ί·;, 2Hi, 7 32 7 M {dd, HI). < .02 N.tM sra. 210, 3.22 5 24 tJ, Hi; XIS2pp (MH i

Examplr 13: 4“Amino~^medioxy-5-mtthy ifhieno|2.3-d|py rimidiif-2(I H)-nne

MM

Pix'pafcd as h. F\.u*mk' I n-,m

N-{3-cx ane- '-mtobaxx -4-inetiiyhhi·iplk'h-2-yk-Ofhasnoxl/benzaai-i-.k' (Example 13a). ^!H NMR.

(-106 Mllz. DMSO-ώ,Μ' 2 19 M ,00. 3.78 (s, Oh. 2.“-l (s. 210. MS 212 I MH 1

I xampk- 13^ \q^?>-( \3no-5.p\-ihoss-4-uiedsx lhamheu 2 y ca- xtirmObencenudc. Prepared as Hi F xamplc la t'rem

2~amme-5-meihoxy-4-niethyithiophene-3-earbeuiinfe (example 13b) midi benzoyl isocyanate as uumi-nlmcse Id H NMR (4fo) MIL·. DMSra J.hMOMn. Ί0, 3fto(s. HO, 54 μ, 7 7 2

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H/.2HN ~.6~-ίΐΜ “Mb. IH). 8.01-4.()3 (d. 7 j4H/. 2Ηι. 4.<-0ο. ΙΙΓΡ 12 03 re, IIP? MS Mo (MH >

Vs.siiipie 13b:2-Amin0-5-.mefh0xv-4-niethvithiopheiie-3-carbonitrfle

Prepared a- in psanspk 5n from l-n»cihoxy psopan^ronc maloncnurik'. aid sullut .o a brow i -.•id Mb e’MMH >

Exampk- M: 4-^inino-(k-meihGquinaz»ha-2UH)-out‘

NH_S

161

Prepared a' in I'xatupk' I than \'i2reyan>-4-ni;ihyIphcuxk’aibaitiaxubeu/ar.u.L (b'sinnpk I 4c- as a w hii< s-ohd *,259 nig. 57 *'«I. H NMR (444 MID. PMSO-hp. p 2 20 ss. 3H). 0.00-7.05(01. IH >. 7.5-5.-,re id. IH). 7,~2 (b. 2H). ?.~» Mil 4).55 iro. IH1. MS ITt-iMH ).

I sainplc Pa \ {2 C'auo 4 mcdp Iph.ax IcaiI jheuzajmdc

Prenncua.-. in bxacnnk la iron: 2-.»nsii· ·? nicinvΓκ-’u o\li led xauiplc 141 ) as is -xbile pevwki (724 sng. 4o' ₍-i Mx 2so {MH 1.

I sample 14b 2 -Amoi<?--siicihx Ibeiuouiu de

5-Meihyl~2~?dtrobenzo?dtrile (1,92 g,. Γ1.84 mmol) was added in portions to ai -tisred sMuuunof x-v Ί { Ή 22 u. 54,2 m eons Hi h 12 nsL) -,a.dMOH J 2 nd l, 1 nt reaction tcnipcralure was nudotansod at 20-30 A' using an sec baih. fhc reaction ini.xui-c then stirred at room tempmture for 1 b and poured into an ice cold aqueous solntioa of WOH (ί·\. anp 30 r..i 1 to neiuiob/c pH f:-c p- >'.f'et xxas asts.-ctcd inio I iPM. x-<a.> icd xxuh brine, dried over MgSO* and concentrated to provide the title product (1.56 g, 99 H) as a yellow-brown solid. ^SH NMR (400 MHz, DMSO-rO 4 2 21 (s. 3H> 5.79 (bs, 2H), Oh<71 (d, IH;· ” in M (>1>2 IIP-. / I: <<, IIP- ⁵'C NMR iDMMraA) -I .M IS ^!3 00 I |ρ_ΐΛ ps ‘H.

12: M, rod 32. 13? 76 ?()M.MS 33 iMH s

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Example 15: 4-Amino-8-metliyIq ahuuulm-2{l th-cae

NHz

1®§

Prepared as -in Example I from N-td-eyan wh-methylpbcnylcarbajuoyi Ibcnzarmde fFs.unple 15aΐ a-. a v nite <<>0 mg. x> <! H \MR (-100 8 HL· DMSO-,/,.-, 6 j 2« <> 'Hk 6.96-7.00 (t, I Hk 7.37-7.38 id. IH). 7.70-Λ72 φ. 2Hl, 7.80-7.82 (d. tH)„ 9 87 ibs, IH) MS 176 (MH ).

FN»SWAfe.LS.a'. N-(2-Cyanp-6-melhyIpheny1cafbam.oyl)hinzam'ide

Prepared as in Example la from S-amitm-d-meiio Hvnzordtrile (Example J. 5b) <rad ben.'·.-) I i^teyanate a- a 'ahitc p<radei {I8u m-, u~ %) MS 280 tMH ).

Lfodill e 15b 2- \in:H<<'.'-n:c{hslbcnzmiii· de !<» a solution <8 2-brorno-6-merhykmiiinc (Ϊ 26 pl.. 1 mmolι in dry NMP (3 ml.) was added Cu< ’N s OF ntg, 2 2 mmol). The rni.xture was irradiated irt a micrc-'xine at 220 ’Τ' ibr 40 minutes, cooled to room. temperature and poured into a mixture of ammonia 150 A u.x. 10 nd ; >ei>l ία 1 >k r.-M.. c -^fr ed fol fo'mr and l is* pu'dccl ?>.w eVtaekd -aitk dichl> >r< >mcihane (A 20 ml. 1 The organic layers were combined, u ashed with waler and brine, dried over MgS<h und concentrated. The crude material was purified on Mbea ρίΟ % EtOAc'hexancsi ic· yield a brown oil that crystallized on stand my t i 28 r<· T-l ^l.H NMR (400 MHz. DMSOmV) 0 2.Ch is. .>«). 5.68 lbs. 2H), 6.51-6.55 (t, I Hl 7.17-7,14 1H),

7.22-7.24 tdd. IH). MS 153 (MH).

Example 16:4-Ammopyri.mido|4,5“d|pyrimidin-2(lH)mae

NHz

181

Prepared, as in Example I from s-^-e av-l * du Ire nr., k .ul ,, io- )ocr in I (I xn?' Ί» JOaj Ml \VR ' +00 \l,'?

HMStVi i.>8 95 m ilh,.' i.'to Hh.fo6 'll) (h llh MS if l₍\lll }

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Example Ina: N-{2'-Cyano-4.5-dun£ihyHuran-5'-yicarbamovl)bcnzamide

Prepared a- in Example la num 4-ammepy innidHic-5-cs· fenitriic and benzoyl >sf v analc a,' an < -H-w hik p<n\ des MS 2ux {Ml 1 ι

Example 17: 4»Ammo“7-metbyIqmnazeline'-2(lH)Ahs«me

nh₂

167

Picpared a- m example I born

N-(2-eyuno·5- mcthylpbemlearbamothioyDbenzamide (Example 17ar ‘H NMR {4-00 MHz.

DMSCM,'..id 2.35 {s. 3H), *\0x {J,d ^:: x 'HU. IH), 7.1 3 (-. UH '6 (d..M 8.0 H>\ IHj x .:1 (*, 61).8.24^, HI). l.W III). MS IA iMH } .ES.^::U.l?i?.Lsl...l7.ir· N-(2-Cyano-5-mcthylpheuylcarbamoihk.>vl}bcnzamidc

Prepared as in Example la fem 2-am inn-4-m·. myIhavomtrile and benzoyl tsorhiotvar.ueaeapdle-wd.'tt p-mder H \MR {-+00 MH? HMM’-./jn ; <' pl J ^: 8.0 Elz. IH) M- \x(m,5ib.7W'Η J - 7 8 Hz iH). 7.7X {d. J - x.O Hz. Ilfs. 7?)x-x 01 (m

88 <>. IHr. Id -W (-, I Hl MS (MH )

Example 18; 4--Ammo^>dime|iwIft«^l.-2s3’d]|>yrimidi&’'2(l.H)-i>ne

Prepared a-in Example I fens

N (Ax-re 1/ dtr'ctwPum ('Jcfe-mw mem air i J. (IN a'W. Ix<; ^lH NMR . u>0 MH?,

DMSQ-4H 2.11 (N 3H), 2.20 fe 3H). MS I SO ι .ΜΙΓι.

Example 18,c \; .1 ('yano 4.5-dime?hyifuran 3-ylc;:-bam»:y Ijhenzamide

Prepared in a similar m-mner (<· Example la fem

2-aminc>-4,5 dimc'dr'.lkmm-3-carbom?rik' and benzoyl isocyanate as an ofewhitc solid. .MS 284 (MH ).

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Example 10: 4re\mmo-7-methylumnazolin 2(1 Rhone

NH₍>

183

Prepared as m txample I bom \ -(2-cxano·5-inetitx Ipbem kanbans > Ob---n.xmjiJe ihu.ir^'bU ‘HWlWfodiW.· 5Ηι ⁷/lxlH) ⁷49id.</ ~ 2 Hr.

IH). ?.2I id, 7 7 2 He. IH). MS 17(. (MH i.

f:\ampte 19u; A a 2·< '\ ano Mncibx Iphem kasb.'.nno l'>ben'unude

Piepared as tn rxumplc la. bum 2 ·αι·)ΐηο·4- :net;jx lben?> n tnh· ,uid ber.w f Aoexareiteas a whiiesmid. H WIP (400 MHz. DM^V‘ > J i? ' l^i! i '(m. IH) 7 54 (t. J S Hz 2H). '766 {f. J ·;>Η/.ΙΗ· /’MJ Μ s.OH.·. IHl a 024.04 ου. 211) sOMs. ΗΠ H 52 iS, HI). I i.44(+.. Hi). MS ?MMMH ).

Example 2ft: 4~Amiws- l-benzx l4,6~(fi?iiHhylOik'iio|2.3~d|pjriiimlime-St IHMhione

127

Prepared as in Example 1. from

N+(bcBzyl(.hcyano-4.5-dHncihylthic-phcn->2-yl)carb3moibioyl)benzaniidc (Example 20a ?. MS 502 (MH').

Example 20a: !^<>(Beuxyl(3-<yanQ-4_>5'-4ime^:thylthiophen~3'‘yi)carbmnothiox4)’benzaim.idb.,

Prepared as in Example la from2~(bcn.'\'kinnu<N“4₅5--difiicth5’hhk’>plr7ne4~curbfi:nitriIe (Example 20b) and benzoyl Aralnoexaiiate Ms 40^ (MH ).

I xampfo 20b: 2-(Bpra:yiwinp)-4_s5dimgMiyHhiophen'et3“Cutbonitrile lo a selmion <0 foamin' uMdimuKWroi'IjCiv· '-cutbeimH e {,5, ;·ιζ 1,0 nuuei) +ud bencu.ldehv.de fj(fo nig. Iminc.i m .15 mb of 4 %,acene aeul in Jiehlmoefoane wa··. added sdiea supported c van eboron ydriee (2.0 g. 2.0 nnnofi, The reaction 'xat· placed m a microwave reactor for 5 minutes st 135 *C. Silica supported eyuimhw'hydriJe was removed by

166

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2017200704 02 Feb 2017 filtration. and the product v< j- purified by prep H'PLC using acetonitrile./water as solvent. MS

243 (MH ).

Example 21: 4-Ammo-lethyl·?,(udimeihyUhieaop,3-d|pyrlmidia-2( I H)-oue

Prepared as in Promote I from

V(('~ro m«>-d,5-dim<Jhskhiepbcn-2-χh(eflnHe ^nmno'Uheu.'aniiile (lAampl·· 2> at MS 22 I (MIL).

Example 21a; N-{{3-Cyano-4.5'dimeihyltbiopbcn'2'Vb(cfnvl)carbamoyhbcnzamidc. Prepared hi a -itHiiar manner to Example Lt from

2-(ctbylannne)-4,5.dimethykhiophcne-3-carbonurile t Example 2 ib) and ben.ro I isocyanate. MS 328 (MH ).

Vrompte 2 lb 2-(1 ’dulames·»-4 5-Jimefoxk licpLuje-ro\-.rh>-mi:d>.

To a mixture of 2~(ben2y1amirip)-4,S~dimethyIihiopIiene-3-carbomtrile ¢3()2 mg, 2.0 m.rnoli peiaxdmn carbonate <2,7b my, 2 0 mmol) and a i aulvur atnoam of poiaromrn b\kde m .«ectomi-sle 11 ml I w ' 20 ml· nnmonaxc vial uro added cdsxl ied’ce (3 J· ri.'. 2.0 ntmel) Fbc ivaefion \ ial uu _t Ltud m a microwave reactor for 15 minutes at: of V I he reaction routine w -s drexohv I 1 .reeute and w ashed v< itb wate: and bsme 1 he cilw -.icelulc n<.mon was dried «<.? s-edtma mlfule and rob. cm was evaporated mdc’ reduced picroure. and the product was purified by prep HPLC using «eekuiUriie-watcr as solvent. MS 181 (MH' I. Example 22: 4-Amimi-I,5.6-'trimethyUhIeao|2 3 d|pynmidHi-2(l!l)-one

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Prepared as m I winpie I hum

N-113-cx ano-4.5-dnnetlix-hhiaphen-2-s 1 huietUy 1 karbanmx I)ben/uimde (F wangle 22al. MS 210 (MM i.

Exauipte 22,i Ns ί nt % ano- 4.5-Jnnethx -dm -p'ret-2--)-hi methyl )earbarnoy Ipbenzumklc. Pizparcd ,n m F\.miplc la n--m

4/' dm>cil x > ’ {{..ci! x»^fm> r nepbcnc ' x ,tb<n.n de d \e iq fc ~2li a id I vcM s<>ex.? ttc MS 314 (MH).

Kamp i h 4,5.Omicthy I 2 t metnx Icrniexohu -pt-cm.·- 3 c,u h -mts ile

Pivpurcd as m Example 21 b from 2-amhh>--4,5-dimc-by l?biopljenc-3-eurbmjitrjlc and methyl hrnidc.

Example 23: Hi-Benzo|c|| 1,2.6hhiadiazi»-4-amine-2,2-dioxide o-f

N nh₂

159

A stirred. mixture of 2-eywomiline 1236 mg, 2.0 mmol), sulfemide (Γ92 mg, 2.0 mmol) and DBU (304 mg, 2,0 mmol) was heated at 160^1>C under nitrogen for 3 days. After cooling to room temperature, the reaction mixture was diluted with wafer and extracted three mmv with EtOAc. I he ague-:-0,- lay er x-, u<, --cm-.-x cd under \-aeuum ansi the residue u m- purified >\ <.hi> r'3t< w ιρΗ o s I u eel e u tic wu Id < Me-hl m e J< oi ^sme l< w to ₍„n h ml compound -a- a tx.de yellow solid. ^;H NMR ¢40(1 MHz. DMSO-fo,) <) 7.93 (dd, </ fox. x 0 Hs. HO 2 12 {dt ./== OS S.oH?, 111),7/0(..0,./ = O.x. x.O Η/., I Hl, “ S3 (dd../== 0.x xOll.'.Hl;MS (XIIT).

Example 24: S-Methy M H~bouze|eH1 2,6|Otiadiazin~4mmine~2 ^-dioxide

MT

16S

-X s dwb.'i of N ¢2 cyano 3 mJhy'.pher.yl)i,.il\mifdc (bxamp'.e 2-a'i t211 mg. 1.0 mnb.-i) in LtOH na- treated v,mi \,n?H ο N. I 0 ml... 2.0 mmefl and tlie rostilumt .toUmon was

WO 21WEU221

2017200704 02 Feb 2017 heated to 100 ^<;C and stirred at that temperature for 0.5 h. After cooling to room temperature, the ekar imiclion Ohuim* was Hhxwc aid Pie nlimBoa 'xa.sc.;:dd x neuroio/cd wifn 10 XcOH while with r igorous stirring at 0 ^C'C, Jhe resultant precipitate was collected by filtration, washed wPb trains wale* .»*<.· 20 A, En Ή ro wai. i m give Uie oil·.' pow.ei

5-Methyl-1 H-bcnzo|’c|[1.2.6lthiadiazirs-4-amine“2,2-dioxide as an off-white solid. Ή NMR

1400 MH,\ DMSO-AM y-te o 8<o s7 J. J 8 4 1.U IH'n 6.92-^,.94(0../ 7 2 H \ HE. 24(s. Hi) 7 3 (l../ 7.0 He. HE. S.24 *s. HE. I0~o(s. HE MS2i2*MHi.

Example 2-ki Ν-{2·('χ<im*'.>-nvd y Iphctw fisiilftrinde .A sobifism *.-f 2-annik'-0-metliyH>civ.*nitrik' f 1 32 g. JO num>E aid suhkmde (4 31 g. 5{? inmoli in dry k4-dis'x:me {50 mL; wis- reilnxi.si unde*· nil***gcu foi 3 days, xfte* the rcacii*.-ii mixnm.· was «tended dsawn to r>mro lempemture. the precipitate wa- fibcred and washed wnb dioxauc '1 he i'du ate w _o ^oneeurrutc-J under unissued piessiiu., and foe *<. ml*sc was purified lw s.In>·ι,\η*‘g'apl x o : s.l'ea eel esiitine w^h Et* J 'xe b^xane.. {’ ~H. e < ic tstk e* 'tsp uid as a pale-white solid. Ή NMR (400 MHz, DMS0-<M <> 2.44 (s, 3Hk 7 J 9-7.21 {in. 3H), 7.39-7.41 (d,,./=== 8.4 HzJ0),7.53(t_s./- 8.0Hz, 1H)₅,9.41 (s, 1H).

Example 25: 5,6-Dimethy l2(meihyhhi0)Hiiene[2,3dh>yrimidin~4-anune

109

Te> a suspension of

V{ kes .su>--4.5-du* tefiw luii-ephs.n-2-x leaskrnnei liny fbencaunde ¢1 \amele I al {. 4 22 mmol) m ctlmuol (25 mL) was added Na*. tH (2.0 N. 5 .8 mt) at room temperature under nitrogen. After stirring at 109 ^<!C under nitrogen for 0.5 h, the reaction mixture was cooled in an ice barb ami Mel 10.8 mL) was added drbpwise. After stirting fbr another 0.5 h, the rcsuhmg precipitate was collected by filtration, rinsed with wat·..···. 20 % EtOH/HyO, and dried under vacuum to give the title compound (840 mg.. 89 %). Ή NMR (400 MHz, DMSOMd d 2.32 (s, 3H *. 2.34 (s, 3Hj. .' 1. (s, 3H). 6.93 (bs. 2H). MS 226 (MH ).

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Example 26: 2-Meth0.\v-5,6-dsmethylthkim|2 3-d|py rmmim-4-amme

nh₂

IM '’iCpiiKi. in.· i»^! i s n'i'Ci *o »· x mi d

N-i3-e}.in>--4.5-dnn<.tb\hhic>phcu-2-ylcrah;;-no\hnenzani:dc {Exunipk 4;.p and intahyl raJide ra ?o ‘ <, \ icld. ^lH NMR (406- Ml V. CO( =, j <) 2 35 (x. 31b. 2» ra. 31b. <55 is. 31b. b,C> ib<, 2H< MS NO {MN )

Example 27: 5.6-Dime(liyE2~(meibylthiG)i'urp|23-d|pynmj(lin~4-amine

113

Pr.-p.iied .re in Fxampk 2* from

N -{2-crano- L5-dimeUp., lturan-5-r k'.urh.mimte-.-'A)ben, ara.de il· w.mpk 2~.il ‘11 NMR (400 MHz, DMS0-<’,i 3 2 16 <x> 31 h. 2 23 (x. Ml), 2 - I ra. 3Hi, 6.'C ra. 2H). MS 2i0 (MH).

N-(2-( y an· (-4,5-4- metbx 1 furan-3-ylcarbanmthfoybbcnzamidc h\.'paiCil .re m Example la from 2''tanino-4_>S'‘dimcrliylfumn-3-carbonitrdc anil benzoyl ispihiocyanate, MS 300 (MH ).

Example 28: 7~Methyl-2VnictWUhi0kpfinazoIiire4-amine

Nig

171

Prepared as in Example 25 from

N-s2~ra a ί-v-'u.. refi .rare < . um .m.w 'leer, arid·. AN . np<c , a) Ή WE (t-OOMll·

DMSra-./ id 2 4<j(x. MH, 2 Η(χ MH. “ Γ i Jd. A 2 0 8 X Hz. Illi. 7 '·2 ξ.χ. Hh. 7 7i φ 2H).

8.01 (d, J ----- 8.4 Hz. H I). MS 206 (MH ).

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Example 29: 5-Methyl-2-(mt'thylthiok{ai»azalm-4-amjae

173 bTcp.ired ,t- in Example 25 from

N-{ 2-exan- -3-m-jhx ipncny tearhnmerbi-wbKrvan'iiJe d -ample .·> ,> ^{ll NMR {400 MHz ί tMSO-fo s 0 7 -h> ί-, 5II ? 2 5 Η, 3H >. 7.11 id../ - 7.2 Hz. 1H). 7.33 id. 7 2 Hz IH i. 9 i (dd J -0.8 7 .; Hz. HO Ms ?0o<;MH 1

Exampk· Ito: 5,6~l>imefityithieno|2,3~dipyHmidiu€~2_!4~diamtae

NH_?

Λ Hxixtme w 2-ammo--L5-;dimcthvkhiophene-3-carbonmile (500 mg. 3 2° mnrolk exanoguarndme (27o ding. 3.2° mmeb and HCI (2 N, 1.5 mL) in water { U? mL) was refluxed ui-dei nuuigcn for 2 b. fiw ieacdoi: mixture xx.i* cooled io r.wm temperaUne. and ba.-ukd ?- uh fokued \.z *H anneou'- -ok;Uen t<- PH s. ΛΙki ex.meraueu el wtoet. the icxJuc wa<- purukd bx prepurutix c IΠΊ t' ekniug w ith acetonitrile and w ater to give the title compound (33 mg, 5 %) ‘H NMR (400 MHz. HMS-M-fo 0 2.22 p. 3lb. 2.2 (-. MH. 55 fS. 2H'>. o 2'MK 2H) MS 195 (MHfo.

Example 31: 2,5.d-TrimethyIthieno[2,3>d|pynmidmM»amme

M5

A imxt'uvo; 2 .anno 4.5-.hmctbx h u.'pLuiC-'-c.ub-'mU.k (200 me. 1 32 mn.ol).

<imne-nm «.uctutc 12(4 nig, 2 o4 nnuoll. and tHetbx I --rtboacetatk. (2.0 nd.) wa- -med n. a -cak'J tube at 120 ^Λ0 overnight. .After the reaction mixture: was c-ephng down to room temperature, the U'ccmitaic -xa- uedccied bx leu mo.t. un-ec x-rb Eb » \c asul fo'ed m the .m \> gnv t-de

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2017200704 02 Feb 2017 eeinpouml {'^x2 mg. 60 ·! :re a xelkm M<hd ^!H NMR (4()() MIL·. <' T>CL·) ·? 2.41 {< HI). 2.45 (,,.

HI:·, 2 te (s, 3Hs. 5 23 <K 21 b. MS 194 (MH ).

Example 32: 5.6-OimefhyIthiemp2.3-djpy rimidi»«4«aim»e

nh₂

117

Prepared a·, in Example 31 item ?-<ιηΐ:·ν-4 e-J-m-.ibylihiophene-Reirbo-u'uik' and n->ethyl wte.>P>rmare Tl NMK i-Ms) MIL·. I JMSOrfA 0 2.3«· re 3H). 2.39 Η 3H). 6.Ν- tbs .210.8.14 <s. IH). MS ISOiMHs.

Exampk· 33: 2-ΕΟΐ}·1-5.ι'>-Οέηκ⁴Η(νΟΙιΰ^!ϊΗΐ|2.3-(Ι|pyrimidm-4-mmne

119

Prepared as in Exasnple 31 item ?-<ιηΐ:·ν-4 e-d-ni'.iby bhmphene-Re wterate'ilc tmd. triethyl >rahopr;'p;reile. Ή NMR (4(M MHz. HMSO-te) r) 1.19 it,../ - 7.6 Hz. 3H), 2 rets 3H;-. 2.3- <.s, 3H), 2.M (q. <7 - ?,(< Hz, JH's. 6.74 (Μ, 2H). M.S 268 (MH > Example 34; p.d-OimelhyOS^pheayhhienep^l’dipyrimicymd-imsuie

121

A mixture of 2-amino~4,5-dl:n.ethyltb.iophene-3-carhonitriL· (152 mg, 1.0 mmol),, ammonia 001-(,.60 (>6.8 '» mg, 4 (i minoO and (rede I reiiv-Kii/oaU- (2 P rd.) ni a reeled ;nhe was pi·:) ma interim.ore .0 200'7' f.-· 26 nim Aites the r.-aemm miwire was eooled (a scorn . 1' res to isi.. ,r ·'> odi.led \>slb I is.' V.'xasbee x-reb s,n. rak· l\aHCO and Η Ο Γ.ί. soke P xvas removed by vacuum and the res-idtie. was purified by preparative HPLC ekmag xx ith axrein/nk. and v<alc) io go v. the tn e reuipresm (nO mg. M ’ .>1 iIXMR (46s) MHz. ('(> '1 1.4 2.45 (s. 3H1, 2.48 (s, 3Hi, 5.34 (bs, 2Ηι. 7.46-Λ4? (m. ,>H). 8.4-8 .M (m. 2ID MS 250 (MH ).

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Example 35: 5.6-Oim£thyi-2prop) hhte^!no[2.3“dft>w mridmMmmine

123

Prepared as m Example 34 ticm J-amhmM.o-dimcihMtbtopbenc 3 cMv.nt'jk and iiicfhx I >-nlk'>l>iiranate. H AMR /460 MHz, DMSO··./,) 0 0.x ft. J I.g Hz, ©Hi. ί .721 67 (nt, 2.H). 2.33(x. 3M.r, 2.36 (s, 3H(, 2.5 7 (/.,..’ ~ 7 .:. Hz. 2H}. <>.73 (hx. Mil MS 222 (,MH ) Example 36: 5,6M.)imethyE2-4metbyhulfm»ybthieno|2.3“d|pynniidin~4-amiBe

MH 2

125 be a xmpxiwkat of x 6d’:BR-':hxl-2-(:neibyhhio)rbR'n-'[2 3d]f>jrinu-jin-4amine

H 'ample I) (200 mg. 0.K9 mmol} in DCM <25 mb) was added .'tt'ChJoroperoxyhcnzote add. (767 mg, 4.44 mmol). After stirring at room tcmperamre overnight, the reaction mixture was diluted with EtOAc, 'washedwith· water and brino^ dried over N&3SO4, filtered and. evaporated.. The residue wax pnrified by preparative HPLC eluting with acetonitrile and water to give the title compound /4-5 mg.. 20 %i. ^lH AMR /460 MHz, DMSOM.0 <>' 2.42 (s, 6H1.3.27 (s, 3H). MS 258 (MM A

Example 37: Ethyl 5.6~dimethvl-2~ihiexe~l ,2~dihy drmhwrm|2 3-d|pyrimidm-4~x IcarbamaH*

Q

133

Tp_: a snxpenxion c>f 4amino“5,6~dlmcthylthieno[2,3“d]pyiimidme-2( 1 HMhion.e (211 mg I mmj'i w DMI /> ml 1 was .nx\M I nA /6 21 nd ? mme 1 and eihsl ©hlrnm-fumne (0.143 ml·. 1.5 mmd) The reocuon mature wr- snrred at :>»>m wmnemime exetntgn: then mhned wnh 11*.'> \e, '.wished web v ater m<l hune, dried ·η ·. =' Α.',Μ 1 her·, d >md ewip-sr Axl

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Tbc w/sLhic was pnfeed eii Bmiage Sl‘-I ckamg with InOAc bexant t.· gi-e the title e<«upvtmd (154 mg. 54 %). 41 NMR (400 MHz. DMS(feL) 0 1.22 ((,../ - 7.2 Hz, 3H i. 2.38 (-. 3111. 2 3'» (-. 3IH 4 25 «|. / 2 EL.2HL fe'A~fe _im. 2H) 56 2x4 {MH }

Example 38: 2-<diIor<xpdaazalin-4-amhie

NH₂

18S

L> a o >6 of.' 4-dn.hf i- qmiu.fe n·. p f> g IP rnrfe) :n I'HI (10 ml ) waadded ammonia < dsfei m vvan-r, 18 mL} Πκ reactl.m mixture wns -mired .it r,mrn temperature overnight rhe reaction mixture was diluted with EtOAc. washed with saturated NallCO . waie and Orme dn-J ever Na SO., fihered .uni evaporated. The ιesahinn xm'd waufen'd with I itiAc n> gbe rite uric compound {i > g. 72 %) H NMR s Rip MIL'.. DMSLLd.·,'’ 0 52-7 18 {tn, IH) .<>-7 58 (sn IH'i.LS-⁷ Ytm Hi). 8 22-8 2') fm ^; Hi. 8 -2 (Us 2Ht Example 30: S-Chiortr-N-methyklitisazoIin-d-asniae

NHMs

1ST

Prepajed a.- ii; Example '-s Ifom d.-l-dichloioqumazelmi.· xud nuthv lamine, H

NMR (400 MHz, DMSO-^) <) 2.98 (d, J 4.4 Hz. 3H). 7.53-7 49 (m, 1H). 7.61-7.58 (m,. 1H). 7.79-7.75 (m, IM), 88.19-8.17 (m._t 111),.78 (bs, 1H).

Example 49: S-f/IHoro-N.N-dimethyloumazulhi-d-smine

189

Prepared a- in Exampl·.- 6 fem ?, l-d’chlorotpi ω feme and d(methylamine. ^!H

NMRt-00 MH,, fe)( M.'>fe'{- ('Hfe ''-fe9_rn IH /fem. Hl) , (r ,

HO x 03-8 p; im. Hl) MS .W (MH I

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Example 41: N2,N2,N4,N4-Tetramethylqahiazalme-2.4-diamdofe

191

Prepared as io Example 38 from 2,4-dichlorixium.iZoimc and dimefhylamine. *H fe MR t-tOt;ϊ MHz, CiX'hi .·> j.2 A.). 23 i-n. ; 2H L 7 Ol -<> 4 (m, IH) \M~' i7or...'H) ⁷ Ate ’ > rm.I Hl. MS 217 {MH }.

Example 42i 2~HydrazinyIqηΐnazelhi-lmmme

NHNH

NH₂

193

A re rm re. .- 2-ehletee.um ./oL-t-4- amp? ff \ .'nple >Sl (JOO-ng. 0.5o rnmo'.i are uydnizme tp 60 ml , 2 o pen.':) io etbanel {? pd l reas healed ir a w dee At be <r 30 'C oxetntgto Λfie> the reaction mixture was cooled down., the result?m? precipitate was collected by fibration, rnsed with ethanol and dried tn the air tu give the title compound (84 mg, 86 %}. ^fH XMRrtJOMH I ’ ,bs. Ml) Ioffe Hit , fill >' IH} ’Hd f

0 Hr. H'j / +3 to Π Π oi t-· iH). to uU ’Ml? Ilh

Example 43: 2~iHydrexyaminoH|ulnazaltn-4-amhie

NH,

195

Prepared as in Example 42 from. 2chlordqmnazolln~4-amine_: (Example 38) and

Uydm-tohHjtoie. NMR MOP MH'. HMSC-fe) d 7 44-7 35 (p„ 2H1. 78Λ7~ (P., 2H).

η 24-8.22 (tt., IH).s /hi ΜΧΙ7ΉΜΗ I.

Γ75

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Example 44: 2-(Methoxyaauno)qumnzoIi«~4«a£nine row ^N^NHOMe fT V hh₂

197

Prepared us m F rainple 42 Hutu 2“ehforoquiiuuo '.nV-arnme (Frainplc 18) and oicthovdamine. Ή NMR (400 MHz. DM<< >-.V <> 3.79 (s. ?lh, 7 4s- 4- (us. ΙΗι/ tfo-7.80 (m. 2Ht. S2“id,./ /.(Hl·. 110.800-s. HIV,» IV HI). 12 >0- 2i'>Stri. Hi) MS Pl (MH).

Example 45: N'-(4-An»io{iqusnazuhn-2-xhacetohydrazide „row W ^NHNHAc

NH₂

198

Prepared ro is: I xamnle 4.' fioir. ?W*oqim:a e.m-*-.i:nu:e (I xanrore M '> and :ncra<>M lam x Ή NMR <400 MH.. DyN Htb)! m^s. 3H) / no (p / ,'ΗΙ.,ιΗ) } ₍\\

J S 4 HzHHi. 7 54-7,44 im. 3H). 8.04-7.99 (in 2H). ‘».63 {s III). Ms 21MMH ).

Exampte 46r 4(Methytamiao)qpma2eiin82(IHHhione

H GU

HHMe

175

A mixi.urfc of 2>chlorG-N>meihylq«iniiz0lin-4-amine (Example 39) (i.OO mg.. 0.52 rnnV), thiourea (47,5 mg, 0,62 mmol.) and formic acid(0.0.2 ml.. 0.52 mmel) in ethanol (5 mt.) was ref! ro ed fur I 5 h Mier cooling .to room ten^emtore, foe rcaoifonjwxture wa neutralized with dsluted bra< 41 aqueous sehstirm The solvent w:p removed nnder vacuum and the residue was profiled H preparative HPl (' ch Ring xx uh aeeroncrd·.. and water to give, the title compound (l>'oi··. i.x%i ^!HXMR(400MiL. l)MS0V.V2 0'Md. / 4 8 Hz Hi}. 7 2 - (\ / 7oH/ 111)./^617 8011/. !Hi. WH (m. Jh 8use..< 8.0 H . 1 Hi <s /0 id, / afot, 1H)_? 12.32 V I H i. MS N2s MH i.

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Example 47: 4-{I)imeih> hammolqumazofioe-fo I HHhione

H

NMe₂

177

Prepared as -in. Example 46 from 2~chloro-H«N-dimefeyIqui.nazoh'n~4-amin0· «Example 40) and thiourea ⁵H NMR (400 MHz. DMSC.W <> 131 (<, <»H) 7.2.4-7. <9 sm. 1H). 7.40-7.3* im.. I.H), 7.55./.¢.: (re. His. 8.60 (c../ -- x.O Hz. His. 12 35(s. 1 H>. MS .20«· iMH }. Example 48: 5.6..7.8~Tetrahydrmpnnisz.oR»e~2.4(IH.3H s-drene

263 \ s.'knu s <4 k' < lebe-rove .^.ηιηιΕ <M 5 mg i 0 remob an-l urea {Ν·0 mg. ;3o,'r?h )h >\|jr m E>' *H <20 ml. s w;h rellnxed ovcj night .Ahcf it was cook'd dox->’> -o 0 '6 Hv preciperme x^as eel J hs fik'atem washed x\ th btOH r\( \ arm <ή m under xaamm <w erniglu. to give the product as a white solid Ή NMR (400 MHz, CD-ODld l Ο M 80(m IHk ¹ ,:Hi. ’ 12 (re 'Hi Ms (6/(MH )

Example 4T S -Oihydrothiem.d3-4~dfpyHmidim.^!-2,4(1 H 3H j-dioae

H

20S

Prepared as m Example 48 from 4~oxotefrahydrmhi0phen.e~3~carbonilrile as a

Meusoid HNMRforOMH OMSO- 7 ) R: _f. ./ Ms Η/ 2H» rohre,. / M'Hz 211), 11.06(8, IHk H.21 (8, IH).MS 171 (MH^:).

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Example 50: 5.6-Oimethyi-2-thiaxa-2..3dihydrmhieaop.3-d|pynmtdim4t 1Η)-(Ηκ·

H

P

To a suspension of ethyl 4.5-dina'tb'N2'ikje»ra\fn\n>piR/e-.Ncarhox\ kite (Example SOa) (37 mg. 0.I7 mmol) in dry E(GH i 10 mL) wax a.l.ke xoe.um hydroxide (21 mg. 0.52 mniob. Ihe reacurui mixture \ra-s then •'tilled at r>»>ui trmperaltnc for 5 nnnm*.s and rctltixed for 10 minutes. The reacHon nxi\(;ec w.re cixdcd *o tooni temperature. neiarah/cd with 10% Ae()H and then concentrated to dryness, Πιο residue was purified by chromatography on x..ica eel A vadici’.t Ο x) NI *0 \c rc Hcxuii.-‘) to _;j\c fee t.'<c vompeufki (> me) ie. 24 % weld ^lH\MR (iOOMKe. DVS(> )?2 Ntxtih. 12 24 tx. IH). M2' (χ H) \b 202 {MH ').

I xa np\ ^tv I ‘fo 4 >-dimeti x ί 2 thr i icidothb p’v i Nvikwl.k'

Γο s’. -ratf<·η ofcfoxl 2 '-'•thioey.’.r.-tto V-dnretfo jtl'.opher.c-o-ea boxxLitc f Example 5ob) {1.21 g, 5 2 mmol) ns dichtercracdsanc f lu ml) raw .iddcd stmmomst t M m Mra Ή .12 ml, 7/H mmol) at F?I'be. reaction mixture w;re' then Me red a^f room tcmpuiatuie h'i 3 h, quenched wdh raaei and extracted rath diehb-'ν'lu:h..i(' Xi, The corihp.cd organic layers were washed with brine, dried over MgSCU, filtered and concentrated. The dark, orange residue wax purified by chronWbgraphy on silica gel (Gradient 0-50: % EtOAc in Hexanes) to gne :he rate comp> r.mi re ’ reg.o',1 H\MK MOO Λ) 0 I 3.Mt. 3li. / ” I

Hz). 2.18 (s. 3HI. 2.W is, 3I< 4 30 (q. 2H_S J~ 7,1 Hz), 8.43 K 2H), 11.38 ix IH) \b '54 (Mil·).

Example 5t’b I tfol 2 woiba ex eras’ 4 ? dur.ytl'x kh'Ophcre 3 cait.'xylare

To a mixture of thinphosgene (5.10 niL_x 7.64 mmol) and calcium carbonate (1.05 g, 10.54 mmol) in CHC h/EfiG (1/2 by volume, 6 mL) was added dfopw^g a solution of ethyl 2-amino-4,5-dim.etbylthioph©ne~3~e«rboxylals (1,05 g, 5,27 mnTOl.) lii ('HCh(7 ml)at 0 ^eC »>vcr a period of I h. The reaction mixture was the stirred for 2.5 h :w 0 ^CC xx aslu-d w ith water i 3 X). fbe οι game lux ·. r w<ix-drred-ovei· MgSO<, filtered and concern rates i to gixe rhe nile compound fl H g 3)0 w.t ^JH NMRffooMH , EAlraWA d ί 3 It, ' i ? lUfs.oll), 2 .% A,

311),428(9,2^:,./=7.1 Hr).

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Example 51: ^Elhyl-SMdimeihvkhk’nolJ^-dlpyrimidiiKfo 1 1 1 i-onc

to

135

To a solution of 1 -(4,5-dintcthyl-3-propiony Itbiophen-fo-ylptrea (Example 31 a) s 15.4 mg, o.OinS mmol) in diy EtOH (Id ml.} was a J Jed ,++1 aim m drox ide (S.4 mg 0 20 mm·') >. The reaction mixnire u.s iben stirred at R ΐ nr 30 niinnres under nitrogen. i It·., reaction mixture w I.' rtoulbiliz. J a uh : 0 “ > Ac? ;l | c_:vd then e>-n.'.m+iicd to c.+ ++. I Ire esMue v.us eutif+.J hs clu- mak'gj.q'hy on silica gel O nad-ent iM*J % Met q j <r ciJ-.oromerbanei io >,1x0 *be *uie compound (2 7 mg, 1⁰ M H,\MP. (400 MH? (ΙΧΉΟΙ 12 (i ,/ oil', ?ii 2 jits, ?Hl 2 33 is, 3Π + Woiq.J 7 (> Hz, 2H). MS 20MM11 i

Exampk 5 s a +i ES-DmjcthM-c-poiptiniyhhi-iphen-z-yhur.a

To a solution of tr-pho-'-gsis? (ES mg 0 224 mni<>1) m dr. dn hloiomcfnane (2 mi ) +:+ added dropw+e a mixtureef l-(2-;<min+- l..Miimerlwdhmphcure-wliprop,mM-ob.' tl'xamph' I o) (IM mg 0 nOS mm,4) and DIE A (O?l ml I 34 I mmol'» in drx dmbiosomtob.'He ( 3 5 nd ' over a period of ’ 0 nmmiex After the rem tier mixtii’· 4n-i: h y ηυτ,ιΐοχ, a imxttire of ammonia Μ M in Xk'DH 0 0<fo ml , 0 o(m mmol) ,md Dll A (0 ’’ 1 nd ,BH nwiol; n dry dichloroiitclhane (2ml.) was added hi one portion. Tbs rcaeiioti mn.tuic was then sluied al room temperature for 1. h under nitrogen. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc (50 rnhJ and.then washed with 10 % N;dlSO_:, 5 « XaHl O' and brine, The organic I nrr was dik'd >wer MgSOj. filtered and voiteemraled. The xellow +++111. +>λλ p’Wk',1 bx e a-tmaiem„u'ln eti sib.'a ο,ΰ Aj+tJ’enl O-'O · < f ,O Xi in licxcne-t to go eihe title compound OS i mg. Vs toi ^lH\MR (l(H> MH< DChidl Istr.JdLJ “2 11/1 2.25 (s, 3H), 2.30 (s, 3H), 2.87 (q, 2H../ 7.2 11/), 4.77 is. 2H), 1.L99 (s. 1H). MS 227 (MH').

Γ .ample 5lb I-{2-Ammo-4,5-d':metbx lihiopltcii-3’X Dpr/pan-i-one

Hi,: sebiPon o! .>--.'s>'p+uianeu';iiie plI me. Omsneb tr ώχ I tOH ^00 nd I was added sulfur (2.57 g, 10 mmol), buianouc (0 vi mL, 10‘mmol) and morpholine (0.88 mL. 10 mmol) to ?<mm icinpciarurc under nitrogen. I lie ieuetiou iinxlure then refluxed at ^0 ( fm G aue then Ρ.,.ν <' i iin.;'.,+ iceir \'r,p.i,_siiii. .mdes +tlio.’,eu Γ t« et. i_ <· hum» iedc.ii>’, 'iis\n,+ x > one.'in,+.:, ΓΙ+ esidn. eJ+te. x.i'h ?. ,u> i ,+O s M,a.\'d w/b t »V (2\j

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ΤΙκ <„0{j'h:ucil otean x lax v>ek' o as kJ <a u i bure diicJ tner MgSlk Tkted ..nJ conccniialcd. The ronlne was purified twice: ihst by chromatogiaplty on sikcii gel (Gradient

Π-25 te- fb ⁵ \e in L^ancsT and then bx Pun I IP! ¹ ’ <fW... eetoint'be ir x-ctei) to mxx tte. ink emi:p<>:mdd25 mg. 7 ted. M \MR (400 MHr.l D<'i-)0 J.l7fl, ΠΙ,./ 7 2 I L'i. 2.1 is. 3Π).

2.24 (s, 3H>. 2 ~8 (q. 2H, J =- 7.2 Hz). 6.81 is, 2H). MS 184 (MH ).

Example 52: 4-Ethyl~5.6-dimethylihieuu|2.3-d|pyrimidhi~2(lH)-*me

183

To a solution of niethyiniagncsium bromide {3.0 M in ether, 4 ¢) mL. 12.0 mmoll in dry ether ¢5 ml > was added drop'-' ire a s>.>hm-m of 2miijinoben/<?niliifo ( 72? mg. o ^:? mmol) in dry ether (5 ml,) at RT under .nitrogen. defter it was refluxed for 2 h under nitrogen, the : e.:et!< -n imViae xsas cook'd Joxxn to 0 '3 auJ mcilwl ehkim.nmaic b'l “ ink. 9 ¢) mnnfo was added drnpxxtse, Ihy THF (5 mL) was add-Τ. to dissolve the resultant precipitate. Pic reaction rmxttii c w .;s then i: 'tie xexl ox ?! n ighi n odes ir j cue't Hie : cwt .-m in. sb ,i c ά as -.u ids bed x- uh I \ Ik I and then ueutrali/ed with 5% NaHCOi aquemis sokttion. The water mixture was washed xxnh LtO'W and the water laxe? xxas corn'entraicd The residue w.n purified b- f'tep ΗΓΊ ( ((il-xhl 'h- .a etouiitik· in xxuterl to eise the tide eompouii-l {15 2 me) ^lH \MR t-RKi MH?, (0-0-0)0 2/9(-.111).^1114,./ I Hz 10), l-l (t../ .I 11/ 111). 7/5 {id. J 12./8

Ik. 10),5.01 { dd ./ I 2 SC: Hz, Π0 MS loMMH k

Example 53: 4>amitt»pyrido[2 j“i/|pyrimidi3t“2(l//)~mte

Nite

174

Λ sokniou ».'.V(3-cx unopyrixitn-2-x tcarbam>>xl)benzainide sexample 53a> (346 mg, 1.35 mmol) and NaOlT(27N, l.85mL) in EtOH (5mL) was stirred at 100 °C uiteief nitrogen lo, tail an hem Vm w-< h m. te υ e u umpe al. i tnee.a ' ~eu on mhilsou w as , Me- <„2 awl the filtrate xvas carefully neutralized with 10 % AeOH with vigorous stirring at 0 Χ'. The

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2017200704 02 Feb 2017 rc-mlianl prccipitale w.kenlkcted by t'ilmnk·*:, and cashed with v.arm 20 'L. Γ tOH in watct to give the Im J pjoJact 4-,>.inmeps iido|2,3-Jlpy tnnidni2( I H i-<»ne-1120nig. 55 %i as a white scud. ⁵H \Mk (400 MHz. DMSG-dO ? 7.22 sdd, /==== 4.4 Hz, 4.8 Hz, JH). 7.29 (dd,/ === 4.8 Hz,

HE. 8 24 (dJ,./ 2 11/. Lb Hz. Η E. 8 5‘,’<dd. ! 2 Hz. l.niL. 11118 00-8,7] tm. 21P>. 8 70 (J, .1 1.2 Hz. IH) MS 162 (MH L f- samp . Lt \ 11 e^i <»ήh I _u 2 x icai bame s .Ibei /an.j 1

To u soknion of 2-umiiK>-3~cyunopyndiae (300mg. 2.5 mmol) in 1,4-dio.xane i5 nl ; «:t·- added ben my I i.-ocy aiteie i3“0 mg. 2 5 mmol s i'be ivaetion mixime v then stated at ;><>:·! kinpcMturo uudei nitn>gvn s^eimgh- I'he pieeipitatio.j was <.. ilccrec :>x fiki.’.ncn. washed with EtOAc/Hcxaaes (1:4), and dried under vacuum to give N43-cyanopyndin-2y i-.afbamoylibcnzmnide as a. 'white solid i3’>0mg. 5-*%) MS 2oo <MH I

Example 54: 5J-dimeUiylqumuzniine--2,4(I//,3/fj~dteae

172

Prepared as in Example 53 from iV-(2-cyano-3.4· duncthy ipljcnxkaibanu'yIdteoz-srokk'H xantpe 54a) ·.·..·.: wlnt^ sojJ {^Oriy tm’A ^!H NMR i4(»0 MHz. DMSO-</>) 0 2,24 ro, Ml), 2 54 w. 3ϋ). o 87 id. I e 4 Hz. J HL ,32 (e. I 8 4 Hz. M 10.51 (s, 1H).MS 189 (MET).

I xwim e %a \ {2 cxero ^J 4 .Innetnxh lum Lad .\nnxb κ tzam de

Prepared as in Example 53a frum 6 a.miBO-2.3 dfiuelhylhzuzotntrik’ and benzoyl isocyanate a off-white solid (2l0mg, 72%). ^lH NMR (4(10 MHz, DMSOsfd 0 2,27 (s, 3H), .' .43 (s. 3Hj. 7,48 (d, J === 6.4 Hz. 2.Hx 7.53 (t, J - 8 Hz, 7.6 Hz,2Hi. 7 05 (L J 7.2 Hz. IH), 7.94 (d, J ::· 8 Hz. iH), 8,03 <d. J ·== 7.0 Hz. .:H). 11..:9 (,-. IH). 11.3“ (s. Nil. MS 293 (MH ? Example 55: 4~amiae~7-meth«ixyqm0azeIm~2(WHene

1.81.

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Prepared as in example 53 from Ara 2-eyanoS:iKtho>xpb> :K kai fam-re bb>-'iteannde {I xan.pk· 55.6 as a white solid i2 hug. U° 0 H \MR. (400 MHz, DMSO-te- 3.79 u. 3H I, 6.63 (d. J 4 Hz. I Hi. 6.67 (dd, .1 - 2.4 Hz. 2.8 Hz, J Hi, 7.67 (br. 21b. ~.MtedJ S.S Hz, Mb, 10.61 (s, I Hi. MS 191 (MH ).

l:\rnank 55a: 3 -t 2 ey an<=-5 -mc-hoxx pbem barbam· y 1 Ibcfizairadc.

Prepaivd -is in Esanink 53a front 2-antm><-4· uvihovbc izonnu . and nenzoyl. ;s<-q Rials' .re v,ime s.>l.d Ot'hre, 45*\n H \MR (466 MID, teMSO .06 χ ra. p,. 3H). o ^x «dd. J - 2.5 Hz. 2.4 Hz. 1H), 7.54 it, J - <s Hz. 2H), 7.66 (1, J - 1.2 Hz, iH), 7.77 (<]. J ~ 2 Hz, IH). T.sOulJ MHz. IH). N.OSidJ 2> Hz.2Ht. 11.35 re, ΙΗι. π .52 re, HI). MS 295 I MH ).

Example 5o: 4~amino-5-meihnxyq«inazo8n-2( 12Z)~o«e

i7Q

1'rcp.ifed as in example fram \~( Rcy.raui-Sri> ihpxxpbe w I, arbam.Abhenzum-de ί ί xample 56a) as a I* j r x ellow solid (35mg, 513«}. ^lH nMSrarfj.M ')te MO M<0.kU - lb xllk .-ra ’ --ra. 3 0 Hz.

111). '-<b HO, 7.93-7.97 tbr. lib, 10 totesjΠ) MS ll fMH )

Hampi> ra ,r \-(2~cy.;ni>-3-nv:h>-\spbem9carbu sex kvr.'arr I

Prepared as in Example 53a irem 2-an'nno-o- no It ι\χ h i 'emn e. nd b./n ό\ I isocyanjiic as light orange radid (; tomg 'll NMR (400 MHz. DM$0-4$P 3.94 (s, 3H), 6 98(d_; I - SH.-'. IHi 7 Μ ί i, J 8 hz, 2H), /.(do. I - 8.4 Hz. 2H}, 7.83 (d. J - 8 4 Hz. IH}. 8.01-.1 .1 == 5.6 IE/ 2H). 1 : .35 (s. 01). UM (s III) MS 295 (MH ).

Example 57: 4~amiH(re5-hydroxy<psifmzGhu-2( l/brame

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Prepared a- Hie-an-ple 53 torn: Y-ι 2w'ya’i<'-.-h-Ju>-x piLarbam**- iRteu/aande {Γ- anepk 57a) ..,- a gte-m -olid t50mg ' ’%) ’I I NMR (4O0MII/ DMSO-d ) to-tmid J 5 nt -MMHk'5'k. s VMi/

HI;·. 9.Γ (,-, ΠI). 0.68 (.-, I Η i. H .84 (-, 1 Hl. MS 177 (MH ).

b-ampk 5'a \i2e-an<’-3h--h-'X'Phcn-karba u- - )l'vnzun'.dc

Prepared as in Example 53a from 2-amino-6~hydroxybeazonitri,te and benzoyl -Μ·-.) anaic a.- 30 oil white -olid i lomns. -to%i H NMR 140*1 MH,\ OMSO ,63 _{16 <· id, I 8.4 Hz. IHl. 7.4n η, J :: x Hz. I Hl 7,54 h. J x Hz. 2Hl 7w>-7.~3 (m. 2Hl 9.04-8 (*o (d. J x Hz. 2H>, 11.24(.-. HO. H 30 (x. IP). H 42 *x, IH) MS 2m (MH i

Example 58: d-amitoi-'Mn.droxyquinazolm~7(l/Z)~o»e

Prepared a·* in example 53 from ;V-(2-_Cyano-5pdfovpl'- t-kaib.. Hex Oaen.’am.de ir xani.dc 5aa) m a L·:. v mev -**hc (hUnig41* <>i H

NMR MO0 MR \ DMSO-i/R J o,5l to. 2H), 6.52 id. J ^:: 2,4 Hr. IMP ~ (br. Hh. ^.82 (d. J - 9.2 1¾ 2H)_? 10,57 (br, 1M MS 177 (MH k

Example 58 a; M(2--eyano~5“hydroxyphsnylearbamoyl)ben.zamide:

Fiepcicd a- m P '-ample 53a. bm ivf.w-cd .n acetone *rste:.u of I J-d’Oxanc, l-mu

2-am*^!a<.>-4-h\d**?xxbemoen.* *lc ano benzo^--1 i-ce-mi'-te a- a x ERx*. -obd (-'^ihg, °4’ fo. Ms 2X1 (MH ),

Example 59: d-smim^'-met hoxyq uimiznli41-2(I I7)»-dne

NH₂

182

Piepared a* in example 53 from N-(2-cxano-6roedi*f\yphe*edcmb onoxllben.'amak (Example '*?.** a- ad.uk x-hde *olid FV.,1 ⁵H

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NMR {400ΜΗ/.Γ>Μ1ηλιο3 86 6.3Ηι. 7.02(1. J 8.4 Η/. 111), 7.1 hl, I T2HzJH). “.58 ul. J “6 Hz. HO. “ 85 ibr, 210.0.71-,. HI) MS ΠΗ ₍\1H ).

(Xauiplc •'Ή Vi 2-e>./;<-medio\-phonyIcarbarnoyi}bcnzarn-de:

Piepared a- m I'xampk 53a uom 2-animi-3-'iiclhox.'l\i.'’·. wifi c . nd nciizov I isocyanate as a light orange solid (2x0mg. 95% t Ή NMR (400 MHz. HMSO-fej 0 3.89 (s, 3H), 7.42 it, i - 3.2 Hz. 2H) 4o (d. .1 3.n Hz. ' Hl, 7.54 (t, J - 8 Hz. 2H), 7.66 (t. J - 7.6 Hz, IH), x 05 <d. J SnHr. 2H|, 10 55 (s. HO. Il 32 (s. Hi? MS 2’6 <X1H 1

Example 60: S-amiHO-l l.3|tlioxolo|45-)>|<}»imizoha6(5W)”One

NH₂

184

Prepared as in example 53 fem ;V-(6’Cyauobtnzo^/][ I ,3]dk>\ *r ^sylcarbamoyObenzamidc (Example 60a) as a light yellow solid tSOmg.. 77?·«). H NMR (400 MHz. DMSO-kH 0 6.24 is, ,?IH 6 '4 is, IH). 7.75 is. IH). 9.36 id, J - j 0.4 Hz. IH). 9.80 id. J 7 2 11/, H). .2 0t(-. JO MS 2*J5 {MH >

Example 66 .\-t6-cyanohen ο I,.)|Jic-xol-5-skarbamoxhbcozamide:

Prepared a- in EXamnL- *3a from η-,η^ΐηοΟοπ/οΙJlH 3 ldioxolc-5-carbomtrile and hemoyl isocyanate as ayellow solid (157mg, 8236), ΉNMR (400 MHz, DMSO~ds) d 6,19 (s, .310 7 42 6, Hl). 7.54 (t, J - 8 Hz, 211), 7 66 (t. J - 7.6 Hz, 1H}, 7.7-1 (s. IH), 8.03 (d, i -9.2 Hz 2H), 1132 {d, J - 12.8 Hz, 2H). MS 309 (MH ).

Example 61: 4-(M_;et.h0xysmiii0)qui0azi.iHn”2(ll/)”One

146

To a suspension of 2 4 Idiloroquinazoiinc (995 mg, 5.0 mmol) in dry EtQH (3 00 mL), were added methoxyamine hydrochloride (569 mg. 5.5 mmol) artd NaOH (227 mg, 5.5 mmol) in one portion at 0 ^fiC. The reaction mixture was stirred at 0 °C for 1 hoiir, then placed in a refrigerator at 4 °C’ for 72 h. 'Upon completion, the reaction wa- emKcmr ^ted, and the residue

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2017200704 02 Feb 2017 \sw ib-sobcd m I lOAi. ami -wr-kiM wuh -.i.iitteec Aalk ¹ Mlxi©nd brne (l Ό I'tu ©'y iiPe phase was dried over MgSCu. filtered and concentrated. The crude product was purified by piqsiialwc HIM t {10-90 % ί H%A m H id t>. provide 4-imeMk'X'. am.'imqun.iuv>lm-2( 1/Λ-οπ© f?-o mg. .%%> ©s ,_;{! ©n-vvin© s<4ie *H AMR /400 Mil·. ΓΑΝ ι0 3 08 (s, 3Hi 7 02 (k / 4 H/ >Md 7 7 9 Hz Hh. *2 <ddd../ M '0.1 Mb.llIV'AlU \I4 IL·. Hb. 10.15 (hr .< UH. 10 /1« _x IH'r.MS 192.2/MH i.

Example 62: 4-Ethox>qmmszoIm~2f l//i~one

H

Ϊ68

Puritkatem by preparative HPLC (10-90% CH ;CM in H?0)ofthc crude reaction of example 61 also pint hied 4-ethox}qitm.izolin-2f I π’ι-ο-tc (90 rng. (bio) as an offtwhite s.did. ’HXMFliOOMHz IHN'-J >31 %'(>.,/ OH? Mb. '· 11 (q. / ?0Hz 210.7 M ©LM ,/ X I/O. 1 211·. HO 46 iJJ../ 5 2 HO H./. Hi} ? M (Odd. / 8/ ' 0, I 2 Hz Kb. 8.01 idd. ’ l ΉλΙΗΙ I? \%brs K> Mb H ' (MIH

I· sample 63: 4~Amiim-5~meth_svl-2-o\u~l 2-dihydrethiem>P.3~<f]|p rimiiHnC6~earb<m lie acid

H

T6 a solution offert-butyl d-ainino-S-tnieihyl-d-oxo-HS-dihydrbthienofiJi/]pyrimid,ine“6--carbo.xybite /example 64k) (10:7 g, 38.03 mmol) in CTfeCl·? (25mL), was added iTiflum’oacetie acid (25 ml 324.3 mmol). The reaction mixture was stirred at rt overnight The precipitated solid was collected by filtration, and washed with CH?O > to yield 4- \mmo-3rnedwb'.A'Oxo-H.bdihydio'd·:' n©[ ’,3-'f -wurvdi w-n-, aib©' ylic acid (5.98 g. x2 %} as a light brown solid. Ή NMR (400 ΜΗ \ ΗΜΜ'.Μ/Α? 2 ? ,χ. 311,> MS 226.0(MHJ.

Example 64: hvr-Rmyl 4~ammo~5inetbyl~2~oxo-l ,2~dihxdrmhicno|2 3-d|pjriimdmm6 earboxytaie

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To .·: -u.-peusren of a iz-butx I 5~{3'-bciwreUncufo)Mredno- Lmubx llim-phcne-?' caibexsbite {csatnpL 04-0 is 8 g <>0 52 mmol) m Fo »11 {266 ml ι a.is added Xm »11 (“5 ml 2N;. Fhc suspense-u became Jem. and the imxlmv a as heated to reflux f<« 30 mm, Mier cooling t>- ti. the fcueUem «as filtered, .and the filtrate was coded to 0 °C in an ice/watcr bath., i he -Mudon s_A rv.uu>thA.-d a 10 % acetic add. The precipitated solid was collected by f-bratdn ,_And hc.iicd ;n I- lull m 39 'Ό under N; for 20 min. After cooling to rt., the product was collected by rikration and washed with 10 % FtOH in H?O ro yield Arzr-Buiyl 4-armno-5-metbyl2-oxo-l ^-diiiydrothiesK'p.S-d^pyrhntdt-K-n-catbexylate {10.“' g, <>3 %} as a bi-mn sobd. ‘11 VMR i W MHz. DMfo >M ; 3 1 51 fo. Uh, 2 73 (s, 3H,g 3 J b (s, 211} MS 282.2 {.MH ).

Example 64a: re?.’-bun I Mdrbema-' un-uku-4-eyiUh»-3-meth) hmophene-2-rarboxylate

To a solution ol mn'-batys S-armno-4-cyario-3-methylimGphene-2“Carbo.xvlate (es.anple 6-lb) (O' g, <Ί 1 I nanol) -n dioxane i 260 ml ι, άas added Kiizox I 'socxar-ak' (16 g, 67. I I mmol). The reaction mix tars was stirred at rt overnight, and upon completion was diluted n uh EtQAc, washed with NaHCCfi, water, brine, dried over MgSCq, filtered and concentrated to yield .m/7-butyl 5-(3-beriz.oylurcido}-4-cyano-3-methykhiophene-2-carboxyiate (21.78 g. 881 %) as a brown solid. ^;H NMR (400 MHz, DMSO-<M -i i .34 is...911.),3.58 (s. 3H), Trk (t. / ’ Hz.

2H)77l(i,/ ^511/, HI} 7 zb m r MH.JI1) tobu! d 7 MV. 21 Π, i 2 2'< (to-_s, Ji)

Example 64b: zm-butvl 5-animo-4-cyano-3~metbx khiu-Htcne~2~earboxvbte

To a solution of tert-butyl 3-oxobutanoaie (30 mL, 183.94 mmol) tu dry EtOH f?o0 mi ). v,a. added Jenum-d snltut 15 “0 g, 183 94 rime », m.d.'U>?n'Ude (12 io a. 181 94 mut»' ) a*d .ficdtCairmc ¢25 6 ml . 18 <94 ruu> I lire teaeimn ne\6ac was Ijeatoe. 80 l'. and stored ? a 2 h Adci coolmg to it, the mixiuic rxas concentrated under reduced pressure th. resakiug ι.-’due wes d’-'svhed tn I lOAt.. vashed with SaKCiM, wafer brine, dried ·,>νοι· MgSOw filtered and concentrated. The crude residuerw» purified by flash chromatography mi silica· gel (20 % EtOAcin hexane) to yield fc^febutyi SmmiwMreyanoM-methylthioifireneM* c irb> xMce { w ' g. > 5) a- e ’> ή - w n

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Example 65: 4-Armaftqmaolm-2(

NH₂

1S6 \f'un> .’ <»ι<< '.,2 Jshvdux u:nel iu 3 cain, xyhc ac.d tb vtmp'.c oh (Ο <60 g.

(*.15 mmol) wro boated u-i-at at 2'^!5'c f_or p) intnuus.then cooled to jr-om tempo:mure to gov 4· aminoqitinolin-21 lH)«one (0.023 g, 99‘M as a light ycilow solid. Μ,ρ.; ·> 250 C. Ή NMR (400

Miiz ΙΛΝΗμΛΜ.'ρ IHVte'P 2II>. ’P p. >’ HH/ lll'>. i IW Mill/ ilh,

4.' <: J ' H.' ,Hi '>rfd / f Η,,ΗΙ; ΐΟ,ΉχΙΐη \blil₍\Ui)

Examph· 66: 4-AmiBoC~0xoM,2~dibydrm|mm4me~3~emhovfie acid

o nh₂

196

Benzyl 4·-αιηίηο·-2·-οχο·-1 ..2>>l»bydroqnmoline-3-carhQ.\ylate (Example ami) (O.h g,

MM mo'ob w ,s j'xro v J . OMt (S rd ) sad i.-.v dm 0 i \noe: ο o li> gz i tv'loon ’ t the presence of 10% Pd/C (0.15g) for I hour, The Pd/C was filtered out and washed w itb dichioromethane and the solvents were removed under vacuum, The residue was d -sehed sobpended m Nm »11 CM. ad ml ». sjr'cd ..teeem tempemture Im 30 nuuutes uud the soNn’01 was tec wr ! disc ^c -j -j .eth m. t h. ropieoto 'm. was c»Med to Rv m.' amcik’d t> pH i \%:tb 2M 11* Ί Tbe resultant puronhate was cdiecteu and w ask'd w Jb euddoromethane to give d-ammo-Z-Oxo·' l,2-dihydroqui.iwlme-3-eatboxyllc acid (0.050 g, 12%) as a light yellow solid. M.p.i > 25(FC. ^{H NMR (400 MH?. DMSO-d 10 T.C im. 1H), 739 (d, J- 7,6 Hz, 1«),

NM pro Hit.7 Nil, <’ S Hl/ IHk.'RUs IH),%V (s Hy '3 (s Jis MV M-mMH

Example.66m Benzyl d-amino-J.-oxa-f TMihxd’oqmnoiineM-carboxylate

Benzyl 4<.hb?ro-2-uxo-1. x-dihv dn><]uiuo'· is·ο-3-, a?baxylaio (Example 66b) (0.55 g, 1.75 mmol) was dissolved, in DMF (8 mL) and 4-methoxybenzyiamme (6.56 mL. 4.31 mmol) was added., The reaction was heated at .1.1.5°C ibr 30 minutes , then cooled to room temperature and poured into ice water. The resultant precipitate was dissolved In: H) mE TFA and stirred at

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2017200704 02 Feb 2017 !<.'<>ns tempex-jiurc for 15 minutes. (hen ihe iiuxline w-.i- poured mlo ke xwHei. The rcsidmm nicexpiiate w.i-Ovlk-W diss<>lxcd hs d.dsloiomefocne ds.c.l roe' M;folU. fkcivA- and exoperated !>> gtre ( w reudc ben/y I d-ainimVroxo-l ,2-d< o diaqmn<']me-3-cark's,x late <ni;(l mgs xxhiuh used ;w Un- wdhom furlnei purification 5N 205 (MH I.

bxuiiipk bob. Bvsw?I ^·οΠΙ»>:<’··2·οχο· I .2-dihydu-qyhiohne--dcaiboxx iak'

Diben/x ImaloiXite (7,75 mL. 31,6 nnnoli was added sloxx h i<< j suspension of 60% sodium hydride in i-mieral od s I 41 g. --5.3 mmol) hi imhydious DMF {100 uitj al -20 C undo mHegun \he> vtuhu·; al loom loaewra.me le: 30 >m.n ιχ. satox i.n wdn<k (5 p> g, xp 7 mmol) was added, and ihe reaction was heated at 120 'ι' f<« 1 hour. The reaetidn was then rook'd le -50 t <hsJ oxalx > chloride f Id. ml , 127 irm-sh o.ro s on lx fokl The reaction mixture xv3* stirred at room temperature for 2 hours then poured, into aqueous \a(. 1(10’’SO ml.;- at 00and rhe w.<Hhas-s precipitate was filtered out fhc preeip:la 1-..- was fosxeAed :n dichloromcitianc, dried over MgSfU. f?tiered ami evaporated under reduced pressure. Diethyl c:hex v a- added io the is^,'-'duc. ansi ibe tesuh mr solid w..-- eolieered to zsxc berex l 0-<.Μθ!θ-2oxo-1,2'dihx droqofn<,line-.'-c;nboxx hue (3.5? g. 7~% <sJd) xxhicb was used xxstboul forthcr ρ·ΐϊ!ΐη'·.:ίΐοπ. M's 314 (MH s.

Example 67: Ethyl 4~hydroxy~2“nxml,‘2-dih¥drm|uinelini‘-'3-ca.rhqxylate

r-.cd'x'uu.iku'aN 111 4 nsl . ⁷5 1 u'mol} added - oxi lx i>- a suspension of o0% s>>dmm In d ide iu m-uesal oil (3.09 g. 77.3 mmol) in asihydsous DMF (100 ml) si -· (0^;C under nitrogen Aik-r stirring at room leinphnittire for 30 minutes, isaioic anhydride {12.0 g, 73..6 nn-eli xva-J added. .V -he -eaLifou was heated at 115 C for 2,5 houre The reaction xvns cooled to room tempcratarc, then poured into iee water (1,4 L) and acidified to pH 4 with 2.M HC1, The resultant precipitate was collected, then dissoix-od suspendod in diehlc-romethar-c (450 niL). The dkhloronlethanc sMuties- was filtered out then evaporated ω provide a residue that w:w< vigorously triturated with diethyl ether (1 50 mL} for I hour. The solid -aas c u e^ec ^Te jixe gthvl 4“hydn'-xy~2~oxo-i.2“dihydroqu.ino!i.nC“3“CarboxyLue (3 63 g, 2Poi js a xvh’te^<hd M.ps

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HOC. 41 NMR (400 Mik. DMSO-Λ).> I O {?. / = 7.2 11/, 310. 4 3'7 Iq. ./ ~ 2 Ik. 2H). 7.21 rn. 10} 2” (0../ 8.0 ii'. HO ~ K ;m Hi).’ 9-· {>10 >^f 0 3, 8 Hk IH), ί t iil· U ik 13.40 k, HO Μ8 234(ΜΗδ.

Example 68: Methyl 4-amino~2~oxo-l .l-dihydroquinnljms-.^-earboxylate x ^H &O, A.

δ NHg

Mcthx : 4-=,4-5 nd hewben. x amm. ) 2-=<Ko-l,2-.hhxdieqmrolf!te-5._vafbas\'l<ite (Example 68a) (0,841 g, 2.4'9 jnmol) was dissolved m I FA (5 rnL) and xuned at ίoom mrnpcmw; Io; 3='l m.nmk.s. The TFA was ;emoxcd under lednced picture, and the residue xxas disseised ;n dtehtob-mHinme. then pmmpmited · nr nx adu.nc •.•xcc.'adscrh’-l etlic;. 1 lie u'sukxm s>.!;d xx.¢.- colketed b’s bInate·η, sums’mkd m d:ehk>irmo^fli,md, and wnJied Μ i emicenn-ncd sodium bicarbonate. I !te s.>hd was collected to give methyl 4--amino-2~oxo<4,2dihxd?>->inmehm 3 caiboYxls’.f^ (0 230g. Ί2'’·1a xs.nte ><’hu M p 2o< 1 ^!H NMR (400 MHz, DMS(W0<>· <73 to. 311). 7.12 {Ld 8.0 Hz, HI). ~ 17 (J../ 3.0 Ik., Hl). “52. 0..Z 8.0 Ik. IΠ). S.Ox (J. J 3.0 Ik. IH), 8 38 tbs. 2H). iOAx fox. III). VIS 219 ΛΙΗ ).

Ϊ sa'np’e 684: mtehyl 4-(4-methQxyben2yhrnirm)-2-oxo-l .2-dibyJroquinoUne-3>·· cm hexsi de \k*hx 4-„hlo o-2-.'χ.'- 2~e .isdroct'm >1 οο-Ι-ι. al ov km· (1\ arnk ¢01)(0 *28 «, 3.91. mrnol) was dissolved in DMF (6 rn.L). and 4-rncthoxyberizyfcnnine ί 1.14 ml.., 8, 78 η,ηηοΠ \su.s added i'hc wacoem was beaten at ’>0'C for 30 unnuts'-, tber cuetod to ’>?>>'» tempo'.utaic and poured into a stirred mixture of 50 ml, hexanes and 100 ml ice w ater. I i-e resuluit precipd.ue xx.ts coiketed by uhm-m? and umh' r cmcmategmplr-d e.n -shea gel (0° > to 20%. \kw'n{ m dichton-methan,') ;>> g;\c medrw In +-n^-imln'\s\^>n xkrntino»-' -ί>\·ί-= dihydt^oquinpline-S-e^ifepxylak as. an off white solid (0.841 g, 61%). MS 3 29 (Mil ) Example 6¾ Methyl 4~cMaro-2-axa~l J-dihydruqitiapEne-3-eurbexytete

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H

Ns.

MeCc,

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Dmielbx lmai<>nau· (2 2 nJ . 4 2 miroli w <s aeeed Newb. x> a stispor.s'on >; {<’% sod. am Kendo in ir ntr.d ,l {r x c. 20 3 nnawl) m mb' 0' <= re 1 ΊΜί iH’l’nl i;.^A 0' C lira. er nitrogen. A tier stirring at room rentperamre for SO maintes, isah ·:»: a-ifo di tdc 3 U g I s 4 mm>. >1) was added, and the reaction mixture was boated at 115''C for 2.5 hours The reaction was then eo-’-lcd to -40 R and oxalyl chloride th ml, 68,x mraob w:re dowiy added. I lie teucu-n w.re sljtet', al b'ooi temp, tat .> ret ’«» eisi tees see was 'ben -mim, „ik <_s , ,'p > \,u , a, (r C Hie :esultaitt preut'Kalc was e-'dcctedlw -isiiation \> grer einde mctK I 4-vblofO'2rexol^-dihydiOquiii'-iine-S-earboxykue (I 40 g. nM-.t, v, 1=:.,.0 ?. as «sod without fonher purlfieatn’-n. ^fH NMR (400 MIL·. DMS<K0i <> 3 87 μ, 3Hi ,fo(m 2Hk 7.70 _υη. IH) °.; id.,/ -8.4 Hz. IHJ, =? 4«<s, Hl} M\ ?M<MH )

Example 70: Meihx 14-hydroxy-2~oxo~l .2-dHiydroq»jnolise-3-earboxylate

H

192

Dimethyi.matoate (2 2 .mL, 19,2 mmol) was .aided slowly to a suspensem of60% sodwim LxdnJe m m-neiai aS <0 Si g 20 > mm-Ό :ii ,mhsd;ous DMF UO ml ) a; -10 C imdci nitrogen. After stirring at room temperature for 30 minutes, isatoic anhydride (3,0 g, 18,4 mmol) re λ aJdeo, and Me te,i»'icr wa- boated re 11 e'%; for 2.5 hours. The reaction was cooled to room tcmpei.mise. then Homed mm watui (rafo »:( _s .,--,0 acidilied m pH 2 win, 2M HC TL. resultant piecipitak was collected by hitration to give erode methyl 4-’hydroxy-2-oxo··1,2-i h\di>> > ivlne '-raiboxx -w 1' te* «I winch w re used v π tout fo'die* ρ.ι» ewar ^!H NMR (400 MHz, DMSO-&) 3 3,86 (s, SH). 7.23 lira 2H). 7.63 (m, 1H), 7.94 (dd, J - 0:8, 8,0 Hz, 1H), 11.55 (s, 1H), 13.33: (s, IM). MS 220 (MH).

Exsmpte/71:H“Amhor2-owl_sMihy4tw^^»«We~3^ari>0nHrfk

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4-cbforo-2~oxoI,2»dihydr0^atnoliner3~carboriitri1e(example N) (Ο.<·<· g, 3.23 mm-ii was χπ.ψοη·.Ε3 m HMb (’ ml » and-Mm-'ih-!\ybcr-..'y lam· tc ({= ^4 m). ’ mmol) wax added The react ion --01-. healed at H)0°C for I hour and the DM.F was icmoxyd tinder sanai’i)

The residue was dissolved in ΠΜ. (6 mt) and stirred at room temperature for 30 minutes and dichloromethane {10 mL) was added. I he sUid po-duct that formed tu» coih'Ctvd. -i-spuided in w.u - an J ihc sUui;· 11 -t.ucv. cxcintp 1 ic sold u.s eclkc'.c !w fiki^is η (<* -.ixo 4 amni· 2 <·\<· I 2 Jihxdivqmf'olmc 0 caibonihix fo :59-. 25%) ax 1 while xolu. Mp 2^0'C H

NMR (400 MHz, DMSO-fo) n 7.19 (m, 2H), 7.57 (m, .1H), 7.88 (bs, 2¾ 8.12 (d, J^:::: 7.6 Hz, IH), H .23(0. IH). MS 180 (MH ),

Example 72: 4-ehforo-2-oxo-1,2-dibydrpquiHoRne-3“Carh»»it:tOe

198

2J-dk-hfonk:UPi>>hne- wcailhmmilc ihNxmipk 2:t? (0 °x g. 4 2e mine! 1 and ammonium acetate (0.3(< g, 4.67 mmol) were hcrm-l in acetic acid (20 mL) <ii 14(FC for 4 hours, then cooled to room temperature. The reaction was poured i-ite ieev-a'ci (409 nil 1 -ir.d rhe 'esuham. precipitate was collected by tlitrarion ω give 4-chiiiro-2-e-xo-f .?.li1wG:o>.piino.in/-0earbonurile (0.668 g. 77%) as a light yellow solid. M.p : '·' 250 C. H \MF « 101’ MH ' DMSO-;!) 0 7.42 (m, 2H), 7.79 (m, iH). 7.96(d,/- 8.4 Hz.. 1H). 12.72 (0, 1H). MS 205 (MR )

Example 72a: 2,4--dichloroquinoiine'3'CaTb0nitriIe \ cyeiohexy: I hydioxy ? oxo L2 di.iydtoqum» hi'/ caik>\.roiidc <1 \ample 3) ( LI h g, 4. i 2 mmol) was dissolved m phO'-phoras oxy chloride (15 ml) -md irn?thy Lnnine (1- ,72: mL, 12.4 mmol) was slowly added. The reaerien was heated at I20°C for 7 hadrs, then cook'd (> tooin tcnnkraime and poimd catehifo nsto tee watet {.Ό·Οml,) 1 he icsuhaut

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2017200704 02 Feb 2017 precipitate raw uNlccied bx llhitaien n> gixc 2.4-diehl<<fcqum.>linc-3-caibeiiii· sic (0 Six g.

92%). which wax -ixed without Further purilR’alton. Mx 223 {MH ).

Example ^?3: N-cs clnhexyl-4-lsyd roxx-2-oxo-1,2-dshχ droqahiullae-S-emlroxumhie

194

Methyl 4-hydroxy-2-oxO I ^-dihydroqmholine-Scarboxylate (Example 70) (2 ,.70 g Hl 3 ιηην>1) tx.w suspended m toluene i.'T· ml?, and eyeh'-hexs lamin·..- (I 4Ag. J-1.1 mni->l> raw adl.d I h *c o . w <w herace <r. '.. *> (. fo> co lici ceel.J .<> looir \'rip.iaUnc Ρι;’ υ I cthvi (5(} jn| j wa- .idde-J, and the w'xuham precg'iiatc w.i.-·. emk-eted by hitraum· io gixe V cyclohcxSs-4· h) di>-y ·2 ·ο\ο· ι .2 -d;hx dr- ·ψιι·κ>1ιι·<· 5· _vajboxamide 1..22 g, 35'· M j- _1{r₅ off white solid Vp 2 21 χ' H NM‘< (4ud Xllk’, IAISO ./?> 3 3 iru 4H). 1 5^ {_{;_k | H j l^ini 211), I sd (m. 2IU, ' >'6 (m UH, 2x0../ s 0 IL', HI). 7 3o id,./ s p Hz. jll). ox <t.,/ 7.0 Hz, i H). 7.05 (d,./ - -8.0 Hz. IH). 10.35 (d. 7 - 7 b Hz. I Η ι, 11 ,K3 (bx. IH). MS 287 (MH ) Example 74: 4~ami0fw2-fix»-l ,2~di.lwilrmjum0liue~3~carhoxamide

H ϊί o nh₂

202

V-pj’!pi-H<_t;ih<'Xsbenz'.Ylk':-{.i-'n,'Ui.)s.\be'i'\lanmtoN2’.'X.'-l .2dihydroqtiinoi.in.e--3~earboxamide (Example 74a) (2.0 g, 3.55 mmol) was dissolved in TFA (15 mL)· and the sohrii0.ii wax stirred at room temperature for 6 hours. The TEA was removed tinder vacuum, and the resultant solid was stirred in water overnight, then, collected by filtration to give I x grouw efciU’.k InsM pi-.MuU, H \.MR (400 Mlh\ DMv< > a<a _f.> .18 (uj, 2Hi. 7 25 id../ ~.2 H'. HU 7,56(1../ s jAHz. Il U 8 (M (d. 7 t> Hz. 21U A83 fd. 7 4.8 11/. I H)ra 0 85 ύχ. Hl;·. Il 12 <„x. Hh MS 204iMH').

ΕχηηηC 'C: MAM>is(4”.inethoxybcnzyl)~4(4-methoxylroniwlaniino)-2~oxo-l,2d i hydrot; ui no I me-3 -ca rbox ami de

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4-Jilm<> V 61--6-0101=10 v-beu/x Π-2-ολυ-1 ,2'ds = pJjoqmm Jme- fead υχαίηΜο (Example ~4b) (4,2S g, 9.18 mmol? was dissolved in DMF {20 nit), and 4-mctboxybcnzylanimc ¢2.68 mt. 20 o mm--l) was added. 1 he seuemm λ a- heated ai l(i(i C for l .5 hcm-c then cooled to room temperature and poured into ice water (300 mL). The resultant ppecipitete was collected ?Ji a n, r . nJ ,»ur ·. J, > net \ s .p .,d on sitica ”c 0‘ to 20 < \k< >H n e Jj oromethanel \> -’J'., crude \ \-I >wM-methods ben'x =)-1-( t-ireihoxvheivxI'.mii'ni-d-ese-i.dddifeseqirnfeme'Neurhi=xam:de i V'5g. 71'Ή winch was if^vd wii=i<uir further pimucaUeii. MS 5t4tMIi }

I xamp=e 4b. 4-chioro-.V_t.-V-bi.s(4-niethoxybcnzyi)-2-oxo- l,2-dibydroquinolinc-3carboxamide

Tiieihx knmic {5 “3 mt. 41.2 rnniM) wa- added to plix.-plhnus oxxehhmde (*Ό ml 1. folh-xxed bx 4-lpdfx'x\-V ν·ρ^(4·ηκΊηοχχΙ·υη/>1)-2-<'\-)-1.2-.1=ηχ dreqimmlmc-5curboxanudc {Ex.im?ilir 74c) ¢0 11 e, Id. mmob I he teactfon x^.s, 1 scabs.) at ¢-5 i' tea 4 hours, then cooled L? room tempcraum. and ean*fu=b· poured into ice water {1200 ml,). The solution was extracted diehh>ru=net=umc {2x200 ml The ogana l.wesc ue>c e«>mbmcd und waxbed with water, dried oxer MgS* is, Biiered md evaporated Thr «esttbu was JtssoKed m d’chfeonvihan. 8 ml ? and p,-nre-l ims> 200 ns I ,-=' 30^l'.> hex.mes m Jieshx 1 zibet Ebe ;e-s'jbant p-'ec=pit,isc χν,ι-, >·ο11,νιν<1 m fihr„=mm is' <fxe ·. rude )-. Mere-\, \-hi-q Inet.->xsl· JUfexrw 2-c h\>b pi .4 ν-ν-κυιΚa n\ i-, 4''g 6 ’ι,Ιη-ιι, i was used without further purification. MS 463 (MH ),

Lx§.Q.lglc.2:l?.· d-Hydroxy-VA'-bisid-methoxybenz\d)-2~oxo-iJ-dihYdroquinoline-3carboxamide

Etlix i 4-hydiOxy-2-οχθ-i.2-dihx>beqtmiohnc- t-earbexx mu· (Example. o7) (3..5x :.\.

I ‘74 nu-'/d; an·I bist-’-methoxxhen/x hamire a I m e, I t> mmol't were suspended m miu.mc (3o ml ) and boated at 11 xt' j<a 5 hcut^, then coded te ’><> m Ampe- .=tu:c, I hctlwI et icr w.w ,idded (50 mL), and theresultant precipitate was collected by Oration to give ·- rm io l-hydn sx-V.Abis(4~metboxvbcnzsl)-2-0xo-I3“dib.ydroqumoline-3^Ciirboxamide (6.45 g, °5%ι which xxas used without further purifieuiiom.

Example 75 : 4-.5mino-6,7~dihydrO”I H~cy0iopenia[d|pyHffiidiii-2(5H)-0tie

WO 2(W1M221 .PCWS29Wt)Oi58

2017200704 02 Feb 2017 \ - -Ιιηι> -n of\-t2c’-a:teQvlopcrd· l-·;ηχ leuibamoxb benzamide rex-auplo 5a) (500 ma. I.96 mmoli and NaOH (2 X, 2 ml) in IROH (20 mi.t -nrrcd .n 100 ^CC undo: mrrog.cn ior 2 hours, Xfler cooinig ι-.= Γι>ο·η teniperalure Oar Hc'n rc'u Ρ<-·ι -<-hiti-m w t,- filr.ned and the tUlratc was carefully neutralized with 10 % AcOH with vigorous stirring at 0 C. The resultant precipitate was euilevied by tiitratioik washed with warm water and then 2‘J btOH in water to gwe the final pn-ducr 4-amino-6.7-d:iv.-lj->-Hl-eyelopcnixfd]nyrimidi-i--.:(5ilDonc 1200 mg. 69 '>> a- tot hue *,-l-d H XMR (-100 MlD. |)W,<9 ipR” (brs llil. m’M Rns. HR, 6 65 (brs, HD. 2.56 It J 7.2 Hz, 2H). 2 43 (i,.f 7.6 Hz. 2Ht j .96-1 e° pn, 2H). MS 152 (MH).

1..8.9(1.989..LDf- N-{2-cyan-ocyck>:Kut-1 -ens teatbana-x bbcnz.an.ide

To a solution of S-uminocyelopent-i -eneearbonitrile (400 mg, 3,⁷ mmol) re I 1 ώον,κίΨ ί! Mr-JI «νι w, _K\ ma .. p D _ I γ·> xo’’» fbo v. <J 01 m'xtnre was then stirred at room, temperature under nitrogen ox cmight. The precipitate was collected fey filtration, washed with 1.4-dtexane, and dried to gne N 12-cxan KxclqxmM-smMearhmtnyD benzanree f t -oU H \MR U00 Mite OK 1 ) ? '1 ί I <s, HI), 11 ’ ih?s. HD ^,,Μ- '.·)··{ηι,.:ΐΓ) ” u”-? _jiru hD 7 5D” 51 ( η ?H) X b 1-* 0 (m ?H), ? 1-2 r (in. 211 i i .95- ΐ bi) fjn 2H) Ms 2 v< {MH >

Example 76: 4~a»dno~6,7,8,9~teirahydr«”lH^e¥<duheplujdlpynmidia~2(5H)^oue

NHs

298

Prepared as in example 75 from (Z)-H-(2-cy8noeycli3heppd -euylcarbamoyi) vn.a.n'de(Om'rokH,.i* Ή\MK (-100 MID, RMS0 <A) d 10 NJi,- IH),n Kfh.- ?H), 2.49-2 4i-2 39-2 3Om. 2H) I ?,?-1 ,οη pn, JR). 1.5)-1 48 (m, ?H) 1.M-1.36 {m. 2ID MS 180(MH )

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Example 76a. f Z ι-X -t 2 -e> a>i< >ux ul.ihept-1 -enx L'arbamm15 x it/ann de Pmpaue a- in ps.rn.pk 5a .scri fZ)-2mmi:w\cl. hte'.- -ov-u. fh-umril© and benzoyl isocyanate as a white solid. MS 284 (MB ),

Example 77: 6-Ruoro-IH-benzo|.cHL2,6|lhiadiazin-4-anitnc-2x2-dioxide

500

A solution of N( 2 ex auo-4·tluoropbcn- i>sulf.mjide t Example 77a) (211 mg, 1.0 mmols in EtOH {I mid wo- beaie-J with NaOH (2,(1 N. 1.0 mL. 2,6 tnm> I). and the- u-si-ik.m solution was heated to 100 ‘V tor 0.5 h After it was cooled down to room tempemlme the > ο. ο i oa- aeei'.iL eon .H '0% Xi«>11 the e-ulhmt ρ t © plate w a- < © lec.eu t> u © .% s' xvMied v. ilh Water to gr.c ο-fl-tor©-11 l-bcr-zokH 1,2.6]-'hiadiazm-4-timine4-2,2-dioxide .is an oil - % hit© solid ‘11 MIR t -109 MH/. PMSO-md <> / 01 0- {©.©.,./ X.8i tz. - 211.\ Hl) , 4©- ? im Kb, <’ SO l x? i'UU, <’ 9,eH/.,.,-IPL. t Ml, x ,D >_xs. His, II 9© (s. IH)

Example 77a: Ν·{2 <νιιη<»·4· fb©oroplwyl)sulfamide

A solution of S-amino-S-fluorobcnwutfile (136 mg, I mtns I) and sulfamoyl chloride (114 mg, 1 mmol) m DM A 12 ml I wa.- .-tn ted ./. n » m temperature fi»r 2 hi-ars. I he reactionxt a-purified by Marian HPl >'' (Iteh. \e,-ionnri<e Watei) to giw.- \'i2-<'y,mo-l.lhioj...phenxb»u;famidz ©s a ptec-wlus... .sold. 1,1 AMR (lv(> Ml I ' DMV )-,' ) 7 I x /m. Ή; 7..56-7.60 {J J ./ == X S 15z ’’ M te .Ί I) 9 14 t-, 11 Pi

Example 78: 6<.'hta/(>lH-lteazo(cHl,2,6'|thiadi<ixia4-ami»e-2,2-dio,xide

NH_a

S01

Prepared as m Example 77 from N-(2-cyano~4~ehfompheilyrisulfemi.de (Example

78a). Ή NMR /400 MH.\DMSO-.E)/ 7 06-7.03 (d, 8.8¾ .10)/759-~62uid. 7-OHz,

MI.. HE. x iH-X 06 (o. » 2 40 HI'. © 2“~X M {.1,,/ 2'11/.th l^c’(s .H>

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Example Sa \-{2-ι+ anm-t-ehL-mp t'aru.k ‘urarcd as in Example 7?a from 2-amiuo-5-cbioraben2onitrite ami sulfamoyl ride .de ^!H \MK (drR MIL, HMSCM/d 7 rex -Η» Md-M'(<‘ > 9 2 It UH 7L ? (dd ../- 8.4Hz, 2 Hz. IH), 9.67 (s, ill).

Example 79: 5-(?hloro-lH-beaze{cjn .2,bltbiadiazin-4-amiac-2.2-dioxide

Ml· Cl w

I'ie-uircd a.·. ?n Example 77 fu>m 5 -ohlom-il' \A j.jo-3·cbl<uopbe’is M.dMnidc (Example 79,+. ^!H AMR 1400 MHz. I AIM 7 7 0(1-7,03 (mJH), 7,20-7.23 (dd, J------ 8.4¾

I.ML-'. UH. .4S-^;.52 (m. i Hi. 7. -5 m MH S.e-1 m.iHk I I D. IH)

I: sample 'fo: 9-{2-Cy;;m>-3-».hlOiophen}lhulfamide

Prepared as in Example.....a from ..'-aminc-t-ehlorobcnzonih'ik: and siufatnoyl chloride,

EAampk· 80; S-Fluoro-l H~i)e«zo(c|11.2.0|thiadiazia-4-a«mie~2.2-dioxkk’

NH- P §03

Prepared as in Example 77 from ’A-(2~:Cyang-3-frii0rophenyl)srdfaub<le (Example y'Oal ^!H\MR<-h30MH7. lAISO-J,) <> b.x 1-0 9'lm, ,'H), HtASAn; 111),-,59(,. Hi) X ' (xJH), 11.29(8.. IH}.

Hamp - SR. M'-i ,aeoA-^.miepber»}..I - rev

Rrepared as m Lxample 'rem .'-ammo-o-Oiiorebe w. r mt-and sulvm-fsi chloride

I· xample 81: 6.“-Himethoxy~nLheuroleH L2,bUbiadiazin~4~amiBe~2,2-dinxide

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Prepared m Exainplc hem X ?2 Cron· -k5 Jinretbcxxpheny'.ibuliaiiiiJc if ro 81.Λ ^SH NMP i -60 MIL. DMom J i<)3 5 5 > bl / M 4j>Hi.b4b IH). ' 3>

(b. I H:·. 7.89 (b.I H). 8.04 ib.l H). 0.04 re. 1H?.

Lxampic >k. N4 2< vaDem..b-,j:incth--\yprreinIditbsiedc

Prepared as ii: E xaiireL' a h> in 2 ci'aino -15 diircilb-xy κίι/ο.ηιίΕ anu suifamovl chk-iidc 'H \MR (400 MHz. MNUM 3 77-3 *0 rel·/- 14.8.6H? 7.05 re., 1 Hi.

IH'i. TdOLJHkbJM.w nil.

Example 82: 7-TrifhunmnethyLIH-henznlc|| 1 <2,6hhsadiazm~4-mmne~2,2-dioxide

SOS

Prepared re re l'\airl' ⁷/ 7>,>π' X i? <.\aao ? '.it: (i.'iaurethy pltery flsai'.a'UlCC (Example i>2a) ^!H NMR (400 MB/. PMS(W,) 0 “ 28 (s, IH), 7.43-7.45 (dd,./ - OHX 1 nl 1/ IHj b I LS Ibid../-- /*>11’ Ή) 8 i're .'Mb Ήι. h :o H>

Example ;C.y Ν-(2-Ε\,υι·:-5-ί·Ό1ί·<>?<>ηι·.-·8χ'phen'· iMrdfanude

Prepared as iu Example 77a: froin 2->amino-4“h«fiu0romethylbenz«>nit0U and udfanroJ K-derde H MIR (400 ΜΗ/ ΠΜ8Ο-M o' Mk.IH}, / L ' T (d <’ b Hl/ HH 8.01.-8.03(44/-8.411¾ l.oHz, IH), 8.23 (sJH), 10 HMb. IB).

Example 83: 6-PheayL 1 H-bem»[e| i L2,6)(Inadiazhi-4-amine~2,2-dioxhle

SOS

Prepared a- in Example from N-(2-Cy an-j-Lphcnylphtnv IKiManudc (i w/il S'.;· ’ll X'MP. v +00 MHz O\Li »-a i <> <> “2-b 70(/ ¹ χΗΉΗ eM-Tp^n JB

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08-~.l 2 (m. 211t. 7.3-1-7.'0 pn,2H), 53 s dd, .’ 8 -HL·,. <'>11/. Π Π. 7.SI {lx III). 7 87 i no n-n.

fsampk 8¾¾ \-{ 2-(X nno-t. ρΡ,.ηχ Ipbere I hre'dareule in a 2nd mreboxaxe + :<tk phenyl boronie aeid {·’ njg. O.u snmob X-t2-ey an<»-4bromophtnx'Osuifamide (Example SSb) {137 mg. 0.5 mmoi). and potassium carbonate (400 mg, 1.5 mmol} were dissnh cd m DME Water mixuue ί i .5 mt. PME Wa-ej 4' 11. Tnc soreboix u as deg.;-sed bx nabbing X- yas nno tbe reachon solunon i»-i 5 mruics .red 1'aliadre n terrasis itfphcirx Iphospisi·..· (25 reg. 0 62? inm<’l| xx:?'·' added Pre jcacPor was p .reed re. a m.Cb-'xaxe react-a for 5 -nsnates at 15ΟΪ'. The crude rcacU<’a xxre; dissobred in vreier and xsushed with ethyl a<„reare lire aquc>-ns sob-trere was exapoiated undo? xa<j:v.ni t>· e.xe X (2 Cyare a. pitenyipheny I isulfimiide;

Exampie 83b Ν·ι2· v\;mo- 4-bremolphreo k-Hhanndc

Prepared as in Example 7 7a fre-m J-an'dno-S-bromobcnznrJtrik’ and sulfamoyl enbre.k ^!ll XMRJ'-PP MH . HMMre/ } d ” 3lto 21 It. 7 lx- / ?0 (J.,/ HI? . I i) '' z-- / 88 t_xdd../ === 6.3Hz I 2Hz. HI). S.03-8 iihtd / == 2.4Hz III). 9.67 (s Jilt.

Example 84: 6-(E)^rop~l~enyl~iH~ben£iHcH L2,6bbradiazhi-4-'amhre~2,2-dioxide

(b\.;mple 8 kp ^JH \MR (100 MHz, DMSO-.</M <) I 83-1 82(8,,7 5 Oil.- 3H). 6.29-6 25 (m. -’HM-Se-nd/pl ./ sdll/ HU 7.5-7'53 {dd. J - 8.-111/ I Ml? 1 H). 7..86 (s.l H). 7.96 (h. 2li). IfiO'x.h t H)

Kampii 8 be X-( )-Cxano--bli??-prop-i -enylphe-iyllsnilandd-..Prcpateeas re = x.»r.pk' < < > n m \-i'- x a w<- l-bie 'mlpre αΙΜι,Ιλγτ I (Examgk· S3b) and (/”)-{>u,q?-.l-tmxdb0ro.n.ie_: add.

I· xample 85: 6~{ 2-methx Iprop- I-rny 1)-1 H-htnzold (I

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NH508 ^Prep.ilcd a.- m b'xjmpl·..- Pom \ i2 i'xano 4 i2 .ncmx Ipreu 1 ·απ.ι 'Worn : Wi'Vc i Example I ^fH \ MR t-Ψ0 MIL. I AIS<> di 5 I 8 1 Smuu. > 72 -Hz.

I 2H/.8H).n %ls. s MU IHi ⁷.M ,3'< pc. 7 \ 1 HI. 7 m- ts.

HI;. ·χ<ηΊΓί O'NnJk fix ample 85;.ϊ: bH .kCyano-M .'.’-mcihylprop-l-enyO phenx iixuifamide

Prepared as in Example 7’-^;a wm \-i.?-ex ano--Hbromelpl-enylM,! faiwidc (Example X3h} .red c-inodwip-Op-l-e-niboremc acid.

Example &>: O-'EnlhKiromethylMIHbenzolcllE2,6UMadiazinM-amirw«-2,2~diexide

Prepared as in Example· 77 from K-(2*eyimo-4Hrffiiinr «phenylHillfamute HrempleSw.; ’H \MR MCM MHzJMfotW, id' I l·/ % M, / %l) IHg ,- >' ss ( M / \/H,J6ll 411^-/0..1/ QnlLJIh Ή> ll>MH) fsanipk Sr\-C-i''\_i;no-'-Ei:h.;r'<'Hje;hs'p v.nx Wrvde

Prepared as in Example 77a from 2~amw>-5“(tri{hi'franieihy\l)berjz,o.nifrile (Example 86b) and suframoyichhw.ite. ‘.H NMR..(400.MHz, DMSO-JM 6 7.53(s, 2H), 7,74-7.76 id, 7 - K.4 l-U 1H), 8,01-8.03 (dd, 7 === S.4Hz. 1.6Hz, IH), 8,23-8.233 id. 7 === J .2Hz. HI). 16.16 (b. Hl).

2-An:iino-5-(iriffuoromethyl)benzijnitfi!e^

In a 20mL micro wave vial, 2-bn3nxf>-4-(tridiioronxethyl’iauiIine (238 mg, 1 mmol) and copper < sanak (V me, I mmol) xsew d;sxc sed re VmJbx lpw'ebd«cu‘ (\MF) {10 nd i The reaction was placed hi a inic-Owave ivackir for 5 rnirnnta at 2004 ' Ebe crude xvus dissolved in eihyl acetate and the precipitate was removed by fihraiion. The clear spluifou was washed with water. The organic layer was colleeted, dried over sodium sulfrle, and evaporated under

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2017200704 02 Feb 2017 aciium 1 be rexidne w as pm died by V.iua ΗΓΙ C >J(1% teto<<mtek sx..:a ) a; gue ire tele compound.

Example 8^: n-Ixopropy MH-ben/o|<jl L2.6|disadia/iH-4-atnim'-2.2-di»\itk

510

Pscparcd as m Example item N (2-ex,me-4 isupb-p? phun Iteika.muo si x,- vk' Ι'-' ’Η WIR {40-0 Mik, EMM»,/ _b> | ίχ i gpl, >' η 4Hx ton g x> ₍m. Ho.

<H ··<> Ή {d j X NHz UH .4?-'45<dJ../ '' e.silz 2Hz IH). 7.7<A-·' 73 id.,/-3 Hz. I H). e 13 <h .?H) id.x Ο IH)

1·.ϊί01?.Ε1»:...8..7.;.0 VuM.ynxv kispptepx ipbcmbxuHamide

Prepared a< in Example ⁷⁷a fo-m NAnnno-toisopr^x ibenz-'nhrile {PNampk 87b) and snifam<»yl ehknde.

Example 8 b: 2-Aniido-S-is-opropylbeuzonitrile

I'sep-ited-w in Example sub frmn .? •b(omo-4“i$opropykniHne:.

Example 88: 6M8obutyElH~beazaten72₅6]thiadiazi8»4’amine“2,2“dwxide

511

Ptepaiee as tn ? x.u'.plc - - non' \-(2->.x mo-fos »hte Iphcw lte.dk tree (l.s.mH. XX.· ^}H \'MR MHz OMM’-j »<>Ι2λη°Η» o f/ ’ 8 Hfo HI) ~\s'tote ₍jj ,/ g.xH/ 24H-Ilk,/xKxHJ, / gdlk, ΗΓε 8 00 Hh. x V>₍h. HI) 10.8 (s, IH).

( sample 5-(2-4 >an·»-1-:sehuo ipbi nxI'js». fan'J,'

Prepared ax m Example a t'rmn 2~ \nir.s= >-5-5.α.»|χ«ρ,Ibeu/amUfe (Fx.urek xSb) and snlfamcfyl chloride.

Exgwpfe.§8h: 2-Am.iite~5'is0butylbe0xon.iiH.1e

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Prepared as hi I x ti->le sol· bom 2-broniO'4-reobulxLimlmc.

Example 89: 6-Methyl·1 H-beazn| t. 1| 1.2,6)thiadίaz.m-4rambie-l^-dioxide

m·:

512 hcwiKi ί·- it't xu 0 ti nr \ t2 erei > 4 n 'K ''X up <' > fit'ij np\

X9m. MS2I2{MH ).

Hdflipie x9:,t; N ?2 c> an + e_ut wIpke λ KnHan’

Prepared a< in Example 7?a m-m c-atnino-S-rnethylbcrtzonitrik.· (Example 14b) and sulfamoyl chloride.

Exampledfh NMsnprnpyl-H i-bmiznl eh 1,2,61 thiadiazint-4,5-diamiae~2,2~dioxide

513

A v.'lmmu ofz-ammo-e-t,xopro|'X lammolberz'-nmile sakramoe U xamp-e 48’») ¢0.14 g_? 0.54 mmoi) and NaOH (2 N. 0.54 ml..) m EtOH (3 ml..) was stirred al 90 ^VC under mtn-srer) nit 0 ·' ternr. The reaction mixture was cooled io room temuerahire, ami eoncenirated makt vacuum 1I A) (I ml > wax added and the reaction mtsiure w as neutralized to pl I - 5 wuh !0'\ AeOH The ivsultam precipitate wa- extracted wuh flOAc, and alter oapondion of solvents the residue was perilled by preparative thin layer ehmnnaography using a ΓΧ'.Μ/EtOAc tj ’ i-.ίΙίΖιοη ,re elua.r, t > \ -re >ri,'px'-Hl~nen <· 2 t'^biailta/i’ i - x-dmn’,'i.-2 2ilioxide lh.02 g). ^SH NMR. (400 MIfe, DMSQ-fo) 4 1.1,1 (d, J === 6.4¾ 6H), I dfo tbs. JU 5.24 tbs.MH.622m Hteni 2H, \H). “ 0^ il <’ 8 0 H ·, Hl).“.48{B- 21 Π. MS 2x5 {Ml I )

I \a m\x Xk 2 . mine ' υχ ί <> p' iarnm Λ norm k ra *ap, ,L

To a solution of 2-aininO'6-ii.xopropylamino)bcnzonitrilc (Example 90b) (0.09 g. 0.54 ntinoll ut DMA {3 mL;· w;,·- added sulfatiyoI chloride lOJ g, I,o2 mmol), liie reacihm mixture was stirred al room tempe-ature under nitrogen fo; 2 limits, dilated with ILO (5 mL) and extracted withEtQAc. Solvents of the cumbmed organic phases were evaporated and: the residue

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2017200704 02 Feb 2017 was purified bx prepariup. e thin k:\et cbu>mat-.:grapbx using a Hexane Ftti Ac {3.2} solution as Jn.U)i (<· <;hc2-aimik'-+-0s<'pmpM<mmimbc?.A'imn e - dfaniulc (0 14 g) MS 255 (MH )

ExampA *Ob 2--a un >---+-(h<mutp'. lauuaolheu+'WJ: c f<.> '-•Julfou of 2'<i'piopykanine)'6-nUi>4K'{t?onU>ile t1 xample 9tk) (0 2! g.

I R2 minoll m McOH <0 nil) uas .Jdcde- ·ιχνηΐ:,ικ\1 H( 112 nd '· I her. K-(0 1~ g. 1 R .ηηηΉ was added peitiv+eA isc. .-.nd (he reuewm mrvinc a as re^uxed at 90'3' for 15 mimiM. After evhng to < < <m teinpcKtnm.. ddiition u nb H '< '»t5ri ml) and exit act ou «. id: I >CM. (3x Ml ml 1. she eemhmcd mgume ph» χν.-rc x'-.+hed unh hmc. dned oxet MgS< h and (be ,<Φ.-.:+ uete c'repoiak-J t>-gne d-emuk» + 0-.·ρι>·:ρ l.nnm.-meii/<>:mnle id P g. 1RR p ,_ic, j ημ.^ι. <-H uhreli uns t+cd m ihc next step without ;mv irn ther pmiheation. MS I7+ i MH ).

V sample 'Tc 2 iisupiupx iammot n niuobci'.o.moi e ⁵ u a -4-1(1.-:1 of 2/>-di:niu-heiizoiutriic (9.5+ g, 3.00 nanoh in LAll· ((> mL) vres addec +op+-ps :air.-n>. (R Me l 2 00 rrn.'h and Pie loa-.u/n riixi'.i:·. uas sij;-.,J a* 'Ό C tn.i.ci mhogeu ri'i Kit paintles M\.: w.'lin; to '<«.'u tctnpci u.ne. ddutum wab H+ »end ,\.fu t.<«i urih Lili Ac, unis <u (be eotubmcJ utea'iu p^-ta<« ueu· mepouiK'd cud the residue +<+ pt-rifled by flush ebt'omatogijphx (Bs-tagc -wtocm. 80 g siheagd column) using a Hexane I K).\u <3 2; s.-umon as cu.ant, v aoc 2-t+on;opx ki'inro)-6-iiit'obcitoeuiUilc (0.22 g, 35 %). H AMR tdfifi MH/. PMSO-aM 0 t 20 td.7 - 6.4 Hz, 6H1 3.85-3.80 (m. IH), 5M4 (d. J8.0 Hz. AH)_? 7.2+ UM'- 9.0¾ Hit 42 id..? - 9.0 Hz. IH). 7.60 (t, J - 8.8 Hz, 1H).

Example 91: b-meihyb.ni-thisuofS^-clIl^sbhfr^^^^^-d-andne-^^-dipxide

1¾

514 .X solutkm of 3-ain.ino-5._r._dph_s lihmpbenc-2-earb.mupi.: 1250 nig I 0 eq , i 8i rirnuR .ml sidfatuoy 1 euk'rde (2 ~t mm/'. I ^,ς eq AHng) m DM X (' ml '> was sitm-d .4 + >< >m temperature overmglu. Water (30 mL) and NaOH (1. .5 eq., 10 N, 2 ~! mmol, 271 pl.) were added ami the mixture was frozen iu a dry ice/acctouc bath and the \Otatiics were removed on the PeplduA'i The resulting solid uas uasked wlie u .iter and then -mspended in Γ,ιΟΙI 125 ml,, 2R0 pi+otl, 1+ dus suspension +as ad.kd AaOH 11 A. 2 5 eq . 4 52 mirok 4 52 .nl ) and fne

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2017200704 02 Feb 2017 mixime hcat/J to *U1ua fos 45 minutes the tcactom uuOme was cc.-led to '.<»mu icmpeiaturc and quenched w ah Hl I <J N. 2.5 eq . 4.52 nnnol. 4 52 nd ). The pH was adjusted to - 1--2 wi-h 1 \ Hl I and the \>>:aklcs rcmo\eJ ms - totmy mapmato: Fhe icsuhmg s. hd w.o -mspended in w;ne> s Hi nil·), stirred. zihemd oil. and washed with wares. 1 m emde product was dived m a vacuum oven to give b-metnyl- I H--fnicnv[3.2C]( 1 ,2.b]thiadiazin-4--amine-22-dioxide {257 mg) as an off-white powder Ή NMR (400 MHz. DMSO-rM ή'2.46 (d../=== 0..8 Hz. 3HI. 6,53 (q../^::: OX Ha 1HL““s{br s. 2Hk ΐ I 34 (s. Hh ^;H NMR (400 MHe CD ^! 9)) 0'2 52 id. / 0 x He. 311;. mfo (q. ./ == 0 Mlz. Hit. MS 218 (MH ).

Exampk- 92: S-iwclupropyMH-benzolcHLS^tbiadiazin-d-armne-l.l-djoxide

515

A 'kJutje-n «..f 2-anduo-6-csefopiepy Ibi-nzomh'ile fF< unplo ‘Hal i I 0 eq. tdfo proof 99 mg; and sulfamoyl chloride (1.5 cq„ 039 μπιοί, 109 mg) in DMA (Ί ml..) was stirred in a scintillation vial, at room temperature. .After 2: hours, NaOH (1.5 cq., 939 pmol IN, 939 pl.) and wutet {.5 ml.;· w_v.e sCued .mu dm \s Itmg ; uespmmd w <*JuM x.nw.4 ove”jght at -0/-0 tctnpvraiuse The precipitate was tumred off .mJ washed with w,itet {3 λ ? ml I, The wet pwmpitaic was dissolved m EtOH (5 nil·. 209 proof) and Nel Π1 i2m eq.. I5tm pmwk IN. i χό pL) was added. The reaction was heated to 80 * C with stirring overnight. The reaction mixture v, w cooled ie- room tempoudme ano HCl {2 5 eq , 15«<8 pn'i-d, IN, 1 Nm pl ) w a-· eddeJ to -he miction wsl, Fbe „.h<n*>-l and m-wt -eft te wetei w,> mnse> k.,1 -m the totem mapomtet. ] nc resukmg precipitate was suspended m wates (5 mL). stirred, tilteied off. and washed with water (20 mL). The product: was dried in a vacuum oven, to give 5-eyetopropy L IH~ ben. oicHx.d.wjtlnadtazn. u dm/tc-2.2 eweide (a' me. 28°<,; .s au m.-w bne sold 1 ί NMR (400 MHz, DMSOuO ft'0.71 ('m, 2H), MH pn. ?Hl 2 401 _f:it. H), 6,85 (d, J == 8 Hz, 2'H), 7.37 (1 * br. s, 4==== 8 Hz, 2H), 8,40 (br s. IH). 10 >0 ί_Λχ Hl) Ίΐ NMR.(400 MHz, CD₃QD) A0.89 (m, ,?H). 1 15 (m,.?H), 2 35 {m. Hl), b/fo id../ X H . Hl) o^-.'J J === 8 Hz. iH), 7.4) (t,./-X H/. HI). MS 238 (MH k

Exarnple 92a: 2-mnino-6--cycl0pr0pyi:benzoh.itrile

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Λ 2-5 ml. mimroxave x ud e-,nstasuing 2'ansino-6-broinoben/.>aiitiik' {1.0 cc.. 1.0 cunei, 19? mgs i,\dopiemll'oses'u ati- *J 3 e.j J 3 rm?.» I, .. 12 rt;„) and HdX>j (I eq, ,> 5 nstnel 74'- jnql -,xas Ib.-hed anh tCisege*’. Fe -In- -sal \-;.s add.'x' toluene(- ral . Xura-Scab Ante-· (200 μΐ -. niesdobcxxlphosphine rO.OIs eq.. |s,l pmol. 88'’- pew, 20\> m hexanes. 32 μϊ.ί, and pal lad turn ill) acetate ί (»,05 eq. Pd?' trimcr. 0.()167 mmol. 12 mg», all taulcr· nitrogen. The reaction vial was flushed with nitrogen, utpped xxnb a crimp-top septum, and mix'roxxavcd for 30 ininiites at 130 ° C The reaction mixtaro was eoolcxl to room temperature. partitioned between l:t ).Ae v- m* ) and aatcr (I ml > I bo ktyei - xxe>e scoarnee. Or., natcr ,.q a* >wuacted EtOAc (2 X 3 mL), the combined organic layers dried cn er sodiunt sulfate The EtOAc was bin-red through a 0 % urn P*TT pp ?<> tenvAe fmclx «hxtee-Ιrobd- an-l coree’Jrai<\ler a hLiu ex apoiab-t 1 he crude product x-ros preulcd on mhca eel uro b.dh .\> sbe ca ttrekc. <>tads,re elution irons ΗΛ HoAc hcx.-.ncw.c 4t'\> (tOAc nesaac-, Im-.ded . t .«-Ιιη.οη m I I hex,me- IX'Mt The I'tacoem con.tamng ptodtui 'act·.; emh-enuated <>n a rousts cxap<-r.ttor t-> give 2-'mnino-'6-£yeL -pt opx lheuzoni»rilc r 99 mg, 62.7%) as a waxy yellow solid. *H NMR (400 MHz l)M$C)-rot <>0 668 (m, .:11). 0.9‘N t m. 211). 1.9 % (m. I II). 5.882 i br. s. .2 IM. ο. I 2s <d../ == fife ill), 6.546 rd../ === 8 Hz. 1 Ph. 7.12*> (t. ./==== 8 Hz. lib.

Example 93: 5,6-44,5Miihydronaphthc[,r,2Xb]]-.lH4h:ic-no[2 De\ l 2,η|0ιχιο,αζηϊ-·4-·ίηύίηο-2.2dioxide

NH_a

516

A sohi.b'U ol'2-sal· ettoxlunr'm>-4.5-J. txdron a⁴ i*b.'| ,,2-b tire-'* tctu-3cat!·< , U.k (1 xeetpk t t?^s'> are. I 11 nured' a Et* Ή {5 ml ) rowwah X .01 (2 0 X, I. I ml·, 2.22 mmol), add the resultant volution was healed to 100 'V and stirred at that temper mure fm 1.5 Is Aitcr st ά as coeA'd do'an to room temper.mire, the clear rob.mcn v-as 1'lu.tcd. and the Muate c .uftrl·- ren ι-a t. v.d s-.tl. 10 ’, AM1I wink st o.as wgrero.-b, stirred at 0 ^C'C, The resultsmt precipitate xtas collected by filtration, washed \x ith warm water, and i> I tOll at v.ak'r te g-xe 105 nt? ,-f the ills. ps-'Juet as an .-••-txbUk -al··.! in ab'e xteld. Ή

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NMR URO MHz. DMfo fo\t re 2 38 (nt. 411). 5 70 2H). tUM 89 id. / 7 o It -. HI). o 90 ti.

IHh 7.06-7.10{m,2Hs MS 106 (MH I.

Example *Ha 2-x»lfan;>>x hm(u-.'-4.5-dih'divnaphih«<| ί fo-bjtmophe’K-3-cailx-ηnfilc !'<.» a radium otA-,umno--E5-<bhx«h«n.aphtl'o 1,2-hfo aupi^re- 1-ead . m.ti c (Example °3b) ί 250 ntg, I 11 nmols in dimethyiacetaruidc (5 ink) was added sulfamoyl ebb-:uk {.A? uie. 3.33 mmra). I'he ι-χκηοη nnxture ra*'- xR -ed a' rermi te upviaintc under nitrogen for about I In, then it wax diluted with water and extracted with EtQAc, the organic layer wax uaxhed unh brute, dried overNu'SO,. filtered and evaporated tn give the crude n;<'duct which was canted ! for next step·.

bxanipte 93b 2-.«nnno-4,5-dih> >.h<’naphth^ 1,2b|inj>p-hcuv3-etel’-«-njtrJ^f.A --lur(> n of <4 ,hisxd’«.mapbrba cn 2( Hitrate (2 2 <>, 1 5 05 ,ηη'.«·1|, muiononiude {994 oty. i5.05 nimu).suhui Ur 2 ntj., 15 05 ntrnoi). ,-.n«.i tried)\utminc11 52 g, 15 «95 mnv>l) hi 1:.(<)H (100 ml.) w.re rctli-xed for ? bi' under mm-gen. The sc-lvm raw then cntrae-l under n.dttceJ prectne and the residue w.re eixxt.’Jh/\d Oom I K'tAe Hexan-.-' to >.sxe 2 Ή g -n'she Idle pradiwi ax .i bsoran xUsd m 8(- x w d 11 NMR (40() ΜΗ.' ΠΜ<< )-J t > ? 'O Η. 2H}, 2 x6 ((, 21 Η. 63»4 {J. IH) ”03 re IHl. ‘ 11- l«>ren 2H7.4x (χ. 2H ?.

Example 94: 5.6-tdihydro-4 H-cxcbspeuta-1Ή)rhter(o|2.3-cli 1.4,6|thiadiazia-4-amiite-2.2·· dioxide

517

Prepared ax re Example °3 fiom fartoyLmire-'·’ ^--.68)0-^-1-11i'ta|h (iioplune-4-ς , _lt> st le <J χ? >η h-'HO ’ll \\’K(f00MHz IAN’-?) > ‘>

ρη ΊΗ 2 o3 ire ?Hs, 68 (m, HH ·> 39 {χ. Ί1) MS ’ 11 (MH 1 foantp> ra. ’-mi lan'i'isi. .tip’-«>-hhx, >Olll-x\> open a(b’tex phe t -l-eirhci' He

Prepared ax »' Example °'a treri ?-jrimo-',(’~dih' er«'- llli,xel'>rx'Pta|b ttuapbi ne-'-e re »>'01'J. «JAcsph °4bl H MIR UtU MH , CHCI,s <'> 2 -H (nt. 211),2.82 On, 2H}. 2.89 (m, 20), 5.46 ¾ 1H).

ifo.0njl3lg.94b ^: 2-am.im)~5,«S-dihydro-4H~eyc!<ypenla[b]th.i0phene-3-carb.on.iiri.le

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Prepared a- in Example 03b from cyclopenlanonc. Tl NMR (400 MHz. DMS0-«6,) 3 2.23 (rn,

2H:·. 2 '3 (m. 211). 2 ©3 <,m. 21 h. ~ 09 2H3

Example 95: 5~e{hyi-6-me(hjl-l H-ilrieao|2,3-e}| L2.6|thiadia/jn-4-amiae-2>2-dioxs(k

S18

Prepared as in Example 93 u©m 2--nifanmy’lamirm~4-ethy l-.%nmihykhiopboue-3carlx'mlrdcH - ample AO ⁵K AMR (400 MHz, l)MSO-</.i<i I 0l (f. 3H) ? O<> (-. Ml) 2 ©3 (q. ..Ή), NK-, 2Hj MS .Hi'fXIH )

I -amp.e a'-a ?-<η Rm© -1 j-ηη* - 4-ed y E'-mc >l y ah <>rh· r.e-⁵--ea: ι·>η,nd>:

Prepared as in Example 93a from ..'-amme-4-erby l-A-Btethy iih:oph,r.e-5earbouilrileiExample<)5b). ^!.H NMR (400 MHz. CDCI.9 3 1.17 0., 3H). 2 31 (s. 3Hj. 2 59 (q. 2H), 5 45(-.210

Example 95 b: 2-;mmm-4-ctby l-Smetbykhmphcne 3 earbsttitrile

I rep.ued a- in Exan'M.· 92b umr -v)if.>n-voi'c H AMR ί 199 MH/, DMSOM ) .3 1.01 (t, 3H), 2.06(.-. 3H; 2 33 tq 211),o.81 (s. 2H). MS 167 (MH';,

Example 96© 5^di»icthyblHMhie»n|23“CHl>2,i|Wsdi»4B”4*8mi»^2^“di»3dde

67?

Pupated a- m Puiwk'M I'<>m2 -u fan.<O.\nn.>' d.S-Ju'ied'-kl.'epIkne· E ead-wt U;k s I -ample 'U-e) ^!H A MR (©06 MH ·, PMSO-uM a 2 64 p.. <H), 2J0 (s. -Η), 5.4© 2H). MS 232 fMH ).

Example 96a: 2--$ulfanaoy^,kmdnO”4,5’dim;efhylthiopheiie’3--carbo«itrile

To a solution of z-aminrs-T.S-dimetbylihiopheae-S-earbonitrile (Example 4b) (1.0 g, 6.57 mmob in l,4Mioxann (50 ml.) was added solfemide (3,87 g, 49.30 mmol). The reaction mixture was heated to reflux for 24 hr, after eooled to roam temperature, the solvent 'was

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2017200704 02 Feb 2017 removed under reduced pressure and rhe residue was p-Mfied l>\ cinematography cm silica gel eluting '«'Uh Et‘ ¹ \c Hexanes (2:3t m give 3ΟΠ mg , ’'pioeuct as a dt.'x ted ,l H NMk Mud MHz. DMSOfe) <> 2.99 (3, 3H1. 2.2b (s, 3H 1. 7.32 (_s, 2H?. 10.17 (s. IH).

Example 97: ¢/7)-5-4 3-Methoxx prop-l-emly-l H-beft/.n|c|{ L2,6)ilihidia/.iu-4“iU«iRe-2.2» dioxide

A a-luriaH »>f (A i^-suifamox lan'dne-o-VfeKilvsSpron-1 -ensHKrnmnuHle i I vample A (139 mg, 9 nm-olt m I tOH xr <u· u rated vs nn NaxHI ν' Ο N, G s ml I 0 sum·>1 and the resuit.m· femiosi was heated m· 190 f ;md s'mn.d ar that temperamre lot 4 h. After ir was cooled down u· room temper mue tru. clear seacts-m <>>lutbm xsa- fthcred and the fitrratc xvas carefully neutralized with 10 % AcOH while it was vigorously, stirred at 0 °C. The resultant piceipitaic was e-afeted hy futradem walked with warm urn·.-:-, and 3’ % EF >H m xxa?cr to give the title product _;(£}-5-(3-M:ctitoxyprQp-1 - em 1i -11 l·benzol c ]H ,2 .Mdnadmzn i -4 -am me-2,2 dwxtdc {Ub mg. N 'fe as a w bile s_Okd ^:H NMR (499 MHz. DMS<fed d 3,29 (_V 3H). 4,fe idd. >’ -fe j 2 Ha. 2111,0.20 (dg 9. 2, 5 9 Hz. HH. 6fe -o ini, 2HI, M7 (0s. IHfe Io (d../ .J Hz. I Hi. '^T -M {¢../ S.OHz. IH|, 0.31 (s. IH). 10fe (s. IH? ^fX \MR (DMSOfei 9 55.4. 72.5, 1 M.6, 117.0, 122.4. 129.9, 132.?. 134 0. 13s I, 143 Ind3 MS ..fe tMH ).

Example 'fe: ic i-2 s'aifaam>j. iamino-6 {3 mc(hoxyprop· I -enyl.ihenzeEiiirilc

To a s.- utio'i of{0; ? ammo 6 13 rietbo'xpiup kuayljbenzunimic (Example feb'ul.-M _tr.g. 1/1 mmol) >n DM \ was added NH-feO {34“ :ag 3 9 mtn>a) at 0‘V under nitrogen. The rcacnoii mixEre wa* then strned a* toom x'inp.-falurc for 6 Iua dikticd will: Ft<i.Ae, washed wab o= m. (5X'> and di ed >sc’ Na.x'g I h.· solvent was exuporated under reduced pressure to giv e lb» .' sulfamox hunt no ♦> \3 metliov p!qp-4-enyi)beazonitrile as ,a paleyellow soda, xxhwli ua- us>. d m the ao-d step· wnbout fuHv' pmit'e.tb s'

Example 97h: (E>2~amino~6~(3-methoxyprup- l-enyl)benz0nitrile

To a solution ofS-artiioo-e-broniohen'/onitrilc (1.0 g. 5.0 mmol\ (^1-2-(3m.eihoxyprupenyl)-4_;4,5,5~tetra.tuethyl-(l,3,2}~dsi?'xab'..>nxine (1.2 g, 9 0 nimol). and K.<COs (I -38

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g. 10 0 n;UR>P> m DME ΙΗψ.Ι, 20 nd ) was added Pdf PPIun <2*9 ing) at <>·ηι leinp^aUite imdes irjoaen Ihe react'en n Mure v.a- wanned to *5 A and shned a* l lai fancies. mre «. rdes ndi-ogen ex eringht. Mier U a re c<« ded d< >w n ie s oom Jcmpci'amre, the reaction solution was. diluted x\idi Vw > \e washed xxOb bane (2.\f, and daed <<rer VS⁽h- Atk rcri<»' -J <4 the sekcim the residue w ;re pinilied b\ chi'-mang-ap-liy on silica gel eluting w 1th 30 % EH >.Ae in iiexansA to g<xc rhe tide compound us a p.de-sdhr.x .solid. Η XMP <400 MHz. ( IX'M p 3 40 is, 3H).-M2<dd,J >·.(». I.* Hz, 2H). 4.42 re. 2H'>. e.42 alt../ lob. 5 * Hz. Hb. 0 m (J. / *.0 Hz. I Hi. 6.85 kb J 16.0 Hz. i Η). u53 alM *.0 Hr. IH). 7.26 (t,./ - 8.0 Hz, IH). 4 NMR « H< '1 ) 0 5χ 7, ?7 . ‘<5 4. H ^J< 0. 115 1 in.o. 2(- >. 130 A 133 4. 140 h i 50 '. MS i.vi iMH )

Example 98:

PiOpared its in Example 97 from 2aminO”6-(3-nictbylbui-2~eii“2-yl)buuzonitrile (Evier'ko* Ι.χ,αηιΐκ x>L· H\MAiA»PMlk HK'k-'.’H. k’l , S(i(s >H; . an <s. Ί1;·.η “O(dd../ 2,10 Hz. Hl.0 82 pJll ·.<''/? (dd. J 7 2 J 0 Hz. 1H. 7.-0(0/ 2 Hz. IH}. 8.28 IH). 10.98 (¾ 1H). ^s CNMR {DMSO : )020.8, 21.4. 22.6, 109.4, 116.8. 12Ί.4. : 2'V, 132.(0 1/4.3. M4 L 144 n, 10.2 1. MS did. iMH )

Example 9s,.; 2 Χιυήκζ 6 (3 nietbxlbm ? en y V,>dni:onif:ile

Prepared as in Example 1 a from d-amina-O-bronwbeuzonitrile and /'Mcthyi-'S'bniM· 2-ylbciimie acki as an /-rang·..· <?d. MS 1*7 (MH ).

Exiimpte3)9: 5-Bromo-l H»beftzo|cHl,2,6jthiiidiaziii»4’iimigie“2,2Aiioxide

9x ,fi

OS' Nf o

N.:x

NH₂ Br

521

Prepared a-ί in Example 97 fr<)m.2-ainiTif>6-breni0b£mZo.n.rtrik' as a Mate solid.

H NMR.(400 MHz. DM$<.W..} <7 7 (07 07 (m, IH), 7.37-7.42 (m. 2H.i, 7.05 (s. Uh. 8.60 (s.

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I Hl. > I W {-. Hi). ' XMKiHMS< M <3, I IS 0. 121 0, : 29 0 135.0. 145.5. 161.3, MS 275.2~7 (Mil ).

Esample 100: 411-N^;aphiho| 2, 1 -cH I,2.nj thiadiazin-1 -amiae-2.2-dnmde

522

Prepared a< in Example W- from 2remhw-l-n.mi'itboiy:iriie as a v.rule solid ^:H NMR (400 MHz. DM$O-mi 3 7.17 (d, J = 8 0 Hz. i Hi, 7.48 (di, J === 1.2. 8.0 Hz. I1H. /0-3 idi ./ - I .:. x'.O Hz. I H). .90 is, 1 Hk 7.93 (dd, J == > 2. 8.0 Hz. IHL 8.24 re H i) 8.39 id. 8 o Hz 1H‘, 1 I 4.1 <s, Hlj Ύ’ XMP in\N’).₍/.|,i I Ou < I >3.2. 12-1.4 Mr 4. 12« 2. >2v.s (30 0, H0.2 133/-1, >43 ' 163.2 Mb 2-18 {MH )

Example 101: 5,6,7,8-T\'ttahydrO“lH~bi^!»zi>lcHl,2.6bhiadiazi»“4»amine-3,2~diexide

523

Prepared as in Example 97 trona 2-amin0cycl<?hcx-l-cuccarbonitrile (Example lfM>as„pak xdlo'A wbd ’ll sMR ν*Ο0ΜΗζ.ΠΜΜί-.Ζ p. I M-. Mire Mil. 2 08(1, / '9 11/. 21 n. 2 20 (i,,/ 5 6 Η/ 2H1,6 9-I (s, IH?, 7 -I I _Vs. 11 h, 10.53 (s_f 1H). ⁱ³C NMR (DMSO-i/3 2 21 n, 22 ή 2S 5 9 <\ 1 so Μ I MS 21'2 (MH ?

E vasnpk 102: H l~py rido| 23-e|| 1th la diazi a-l~a min e~2 J-di ox ide

NH_S

524

A stirred mixture of d-aminomcetinomnsle {238 mg. ..'.0 mmol), sulfiimide: i 192 mg, 2,0 mmol), and 1 mL of DBH was heated at 160 T under nitrogen overnight. After it was cooled down to room temperature, tbe reaction mixture was diluted with water, and extracted three times with EtOAc. The aqueous layer was dried dawnrender vacuum, and' the residue was

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7.95 (brs. 2H; -8.22 (d../ - 5.2 Hz. IH). 8.39-S 3“ ym, IH), J2.58 (bm, IH). MS 199 (MH). Example 103; 6-Bromei“lH“hedzu|cHI_s2,6|thiadiazhi »4-amine

nh₂

025 ^5>fcp ned s.s m Example 97 tfoir g-amux» b=o='i=’bc;'.A>n;Uiic H NMR t4;;i;

MHz. IAIN ;-.x Hz. IH: 7.73 Λ70 (m. I Hl. 8.Γ td.3 l.o Hz. I Hl. 8.28 ibis. 2H), I IO ts. IH). Ms 25. 277 = MH }.

Example 104: 5-)Methy hhmh1 Hhauo|e|| I,2,6hhtadmm-4~amifte“2.2~dmidt

HH₂ SMs

528

Prepared as in Example 97 from 2~suifamnx9amin&-6-(niefeltbio)bcrize=niiril.e (Example I94 <O *H NMR («99 MHz. DMSO-A) d 2.39 k. 311). 6.38-6.36 (m. 1 HE 6.47-6 45 (m._f IH), 6,59 (brs. 2Hk 6 97-6.93 (m, IH) MS 244 (MH ).

I sample 10 la *-te fam'-ylamm, -(-= m· thy lihio >benzc-r>)r le

1ί. jxued as so (Nannie J ft-ms 2~a'U'no-6-{iref=.x Hl·. >:6. = ./0050:=0 0 χαη=ρ o Nd auds;thl»nw>: ehlo-ide Ή NMR H00 MH , DMSO-,A) ) 2 K 'HE 73 S ί J.,/ 8 -1 Hz HI) 726(s,21H. 7 V, (J J .siMiz 111:.^59(1,/ x O) H.< 1 H° M (s. ΠΗ &ample,104fc 2-amina-6~(nlethyⁱiihii>)bcnzonitriIe

I-; ;= .tebmon ='= 2-lineikx Him-:-==-,61:06000-mituh (Example 10-le: {(5^7 nnuol) iu EtOH (150 snl)/THF^? «50 mb FtO \c(50mh acdeJ 200 mg-of W % Pd/C/The XAlo' 'mxjijs sXus he o-oerNoo =-\ oasts .ales <,xmuo.p. Μιοϊ the 119:,= aou. ihc. Izkuco solution was dried down under yacuum, and the residue was nunu&J by chrom'Uagraphx on μ sea nN chiunc v<dh Elt >Ae I kxere to g=xe tbe nt e souipoerd =.79 %i H NMR (4*10 MHz. CDOb) ¢52,51 (s, 3H), 4,47 (&, 2H), 6 J3-6.5I (m, IH), 6.58 (d, J^:::: 8,0 Hz. IH), 7.27-7.21 (m, IH).

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Example 104c: 2«(n tefn v I th io )-6- ei trobenzoui Ink

To a «-! of 2,i'-dn»H'<':\'jfZ0uU'jlc (5 0 e. 25 so ίηροΙΊ ic 100 tnl of <iulr, MeOH c w u'.dcd Xa>Me {2.0 g in U)0 nd of\k·' ?H) Em.-pw-se through luklna-H funnel under nitrogen at 0 ‘C. Mier the eonipkliou ,n oddniost, the reaction ini\l>nc was sirred at O d' !>·; 1 hr, I hen 250 rot. 4 wutei uns added to the reaction nuxu-ie, the resultant :>i'cc>s'ii..ite a, as collected by fiitrun>?n und di led in the air to gn c tire title product us a yellow sehd i’-B Vi Ή XMR (4ϋ() MHzd'DCIdd 2.04 {s.3HhT_C0.7.5 un. IH), 7.7(i(t,J-8.4Hz, HivOl-Wm. IHi.

Example 105: 5,6-(IM'^’.T-telrahvdrw2h2M-foytenedfoMde-benzo>M iMhieaopje] [ 14,6) thmdmzm~4-wwme“24’dtadde

52?

het'areda' in I'sampk 07 from d-aiPuio··⁵,' d'bxdic-Mlsp 'omen/of'ltb'.ophere ί\2'·| < .3kb.'s>- ano'- '-resbremri e {I ren.pk lOfol H kMR <400

MH \ DMSO-u,,)d 1 n0H\2H).2reM^2H'>.2~4ft,,/ Mill/. 2Hi, vteTM {m.

4Π1, - OOtbte. 2H) MS dlbfMH ),

I xartmte Η?5α: 2-utnot<<-5,7- ,I<hx dro-M1 -spirojbenzei bltbiophenc-V- [ i ,3] dioxolancj-

3- carbOirifrile \ -oh Per <d I 4 j_f> savin.Ή ocvao 1 ,'ie ι^ς 0 z '2 0 ,n no’) ip, lot, . tr,k (111;, >2 Ol mm>·:), vdtus r s .03 g. 32,0 i-nnob, and u rahy hnmne (4 5 nil , 32 6 mirol) m E1()H (.100 inL) was stirred at i'oom. temperature for I h under nitrogen. The solvent was then removed, under red need, pressure and the residue was treated with EtOAc, The resultant precipitate was collected by filtration and dried in tlte air to give the title product as a light green solid (44 W- ^SH NMR ¢40() MHz, DMSCMd 6 1,77 (t, J - 6.8 Hz, 2H), 2.43 ((t, J-= 6.4 Hz, 2Hp 2.57 (s, 2H), 3.88 (s, 4H), 6,99 (s. 2H). MS 237 (MH ).

Example 10P: 5,M,lk2’«V.4'-tehahydi'O2'~o\ide“beazot~lH-4htenol2,3*e|| thiadia/ia-

4- ami w2,2~dioxide

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Λ slmcd mixture >>f I ^:.2'« f.-b-ren.mydf<=-2',2UOMcncdkxxidc-KnzM’11Idneirapra-el; L2.o| fraadia,mi-d-;nmne-2.2'd:0Xfd-..' lE.sanipk^- U)·') 1130 mg, 0 41 mmol), 5 ral to IHh and I ml ei'2 X was refluxed under mtrugen f>e 2 lira. ‘Vter '4 wre-cook'd down sroom temperature. the resuhani precipitate' was collected by filtration and dried in the air to give the title product as a pink sold ^}II \MR (400 MHz. DMSG-te) 0 2.57 (t,..7^:::: 6.8 Hz, 2H k 3.10 t- ./ e4H/.2lb. 3.50 ra,2lb.6.9Mhra, Hl). 7.8s ibw H I). 11 Xl {hra. Hi). MS 272 (MH k Example 107: 1 x5,bx7-tetrahydroey clopen tafo)) 1.2.6) fbiadiazin -4-aittioe-2.2-d inside

Ni-b

529

A .Ohmen ol 2-snlram0\luimnocs Jopc-u 1 -Cxucail = it ut. (Exanpk· 107,6 (I Or mg, 0.57 mmol) in EtOH was treated With NaOH (2.0 N. 0.5 ndJ. and the resultant solation was hc.itcd to 100 *'<' and fitted at mat tempei.mue tes 4 h. Mur st was cue cd .kwsn to ream k'mperauire, tite reaenon solution was carefully ne-UraltzeJ with 2X Η* '1 white ii was vigo.o.n'x surred .at 0 ^C'C, The reaction solution was dried down under vacuum, and the residue wax pmificd K chroraati'j-mplo an .Mica gd cHUmp wUh te °<, MoOB in il'.ehb'nmi.'ih'cu tn give th.' title loii'pocnd llXMk(-inOMIL.l)MS0..7b>a . «4-1 M t m 2lh. 2 2 il / 7 ο II, 211) 2 Ml.

8 11/. 21 b. 5 i2(s. 21 b MS 188 (MH 1

Exauipfe s OXi: 2--siiifarn0ylaminocycl/^e.nt~l~e0eca.rboniirile

To a solutitm of l-anrinijcyclopent-l-e.iiecai'bonitrlle (440 nig, 4.07 rnmol) In 10 ml >4 DMA was .teded sullam.w t Udo· ide ted) ' mg. 6.15 im'i<*lk and iL· te.-ultari .mxUtu was stirred at rooottemperature under nitrogen tor 2 h. Then it was diluted with EtOAe, the < x.a»:C kraei w«s wesluo w thbt ra. a .1 d-ieddown uu.k.' e.t.ht' id Ore resie.e w -pii'tici by chromatography on silica gel eluting with Et‘ ‘Ac Hexane to give tire tide reinposnd. TI NMR.(4W MHz, CDCl/)d 2-04-1.97 (m, 2H). 2.ot -2.57>m. 21112 9< (nt. 2H)_? 5..66 (s,2H)_? 8.04 is, IH).

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Example 108: 5-(Pheaylthio)-JH-beiizo(e||1,2,6|lhiadiazin-4-anitne-2.2-dioxide

Ihcpawd as m Exanipk 9 kern 2—mhanov kmiinpO-f pbcnvlthiolbcnzotimik (E-amuk IOx.) 'll AMR {%<>\H t . DMSO-JM Po I l-o-tl tri. HI), ©o-w Ctm 1H), 6.75 fbrs. 2H\ “ 01-6px IH). ~ 22-~.l5 ipi. 3H). ~3-~ 2t- tm. 2H). MS 3(M {MH )

E-ampA Prj 2--u Rm <>y krm >-<>-< ph©in ’.hm: χίιλίιιι*H©

Pteparad a- m i -ample 104a Item 2-amti > ->-<,p i<a\ thmi wh/oml'it© {Example 108b). Ή AMR ί 400 MIL· J >MSOM?_; Λ u85-n .< (m. IH), 7.32 <s. 2H), 7.47-7.42 (m. OH). 7.53 (u <7 8.0 Ha IH).'^! <·3 ι-, 1H)

E-ample l08l> 2 aaUib· (< t mem ltb.<Obcr.A>rm de

Prepaud ;.t.- in Example 104E frmn 2-ntrm-6-(phuny’lihk'ibvnzoiiitrilc «Example |0\©p H AMP v*00 MHz. DM'.O J, hit· Jipbr-. 2Hi 6 .<- <>30(m, 1 Hi 6 <>9·© r>7 pin ;H). 7.19 (1, J^::: 8.0 Hz, IH), 7.4-734 (m, 5H).

Example IO8e 2 -n m-> - η -p a way t duoybenzoniirile

To a mixture >»f 2.0-dmitmbeiiZQiutrile (2.0 g, 10.36 mmol) and K?CCb (1.43 g,

Η) 3o iiiinoll -u 5 ml mAamydmu- DM1 added Ph>ll 11.14 ml m 5 nd ci DM!) dr-am-tse under nitrogen at 0 ^!‘C. After the. cpmpletu'm of addilmm the reaction mixture was stirred at 0 *'C for 0.5 hr. Then the reaction mixture was poured into 50 mL of water, the resultant precipitation w © col <\‘ed h\ f'lt'.m m, ν.Μιοο «νΊι η.'*,ϊ mJ du-’J tr 'he <m m j.ix© die' He pi Jin.’

Example 109:5-(MethyIsuIfi»y4)~lH’heimn[eHi3,61fh.tadiazin’4-’amiae-2_i2’€li»xide

ΝΗχ SOM®

551

I'iCpan..® a.-m l.xaa il IO' ; m -_ultjO'« k mi iP (m>'ibH-ulllm If» n/o urd© 3 -^mp’e ΟΈΗ II AMR (100 MHz I >M${ >-<7 ; \\t. ilh

I / - ?Hi, ·> /8-6 t i o Ihji iH'i'f,) H; ' ’19 (m, H1 > XP- Ή,’ (XP’ 4

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Example Ui’ki 2-+;fam< +km+n>-+-++/(1+ ksti'Jnr. )ben/+'imik

The nnxunc et 2-sutfainos kmnno-o-une'lA l;h+ 'Hw+ze+m rle fI x ample 104a) (4s rng, 0.2 mmol i and MCPBA (+9 nig. 0.4 mmol) in Jichloronictbane i 10 ml) u as heated rcfhixcd overnight. After cooling down, the precipitation was collected by filtration, rinsed with d+hlor+mctham', »J= re J +t the an ?· e+c Ilia tale ere+i’+n+O. Ή AMP (400 MHz. t)M+* '> rt i 0 2.83 (s. 3H), 7.35 .¾. „Ή), ''.~2-e.+9 +a. 2HI. ? >>2 +, + 0 Hz. 1H). 9.:^ ihs. sHl.

Example ] ](»: 5-(MethxIsaltmnIl-Ill-besi/G|eHL2,6hbiadiazm-4-amlnc-2»2-diO.xide

532

Prepared as ni F cample lit? tram 2-sn]tam0ylammo-«6s 'Kfbx Isuho rehhen '>-i 'If + HAarti'k' I 1+..) Π AMR (4(8) Mik. DM8< xR, j,,- 3 ifi^s. 31b 6.95-6.93 -tm, IH), 7.01 tbs, 2Hh 7.17-7.Π ++, I HL ~.24-7 M (m, IH) MS 2“c (MH') f· samp , fh aiII nrox I. mine _r ^nct+x bnifreix |'>bcn+ nit I

Prepared as m Example 10~a fi+ni 2-amino-e-iinednb-itlf'+nx Itberronhnle (Example 109b) NMR <460 MHz, DMSO-.Λ)0 3 ,Γ is. 3H1. 7.46 (s, 2Hk +5-7.83 (m, 1H), 7.93-7.91 ·ϊη. 2H).. 9.92 (s, 1H).

Example 1 IQb:: 2-am.ino~6~(mefhy I sulfopy ^benzonitrile

Prepared as in Example 107b bx)m2-(methylsulib+y|)--6-mtrobeimonitrile it S '.iple I IPe' Ml A HR (400 ΜΗ , Γ-ΜΜ) </,.) ' ? 2+ {. χ}|), o + 1 {bi - 2H;, ~ ~ 0<> ar

2H}_:. 7 51-7,47 (in. HTi.

Example 1 Kk ^> (mthyhulfbm b r« ititrobenzonitrile

Prepared as in Example I»f o rem 2«(mefhyltliio)-6-m trebenzoni (rile (Eximlple.

EHel H AMIMWMlh DMs-O <<-+< ' kp. 310 + ' I id 9 i 6 IL ’rii λΠ S 1+if

HL 8 +6 +.+4 (m. I Hl

Example 111; 4-Ammo~>(propytoxy>lff-beuzn|el 11,2«6 Hhbdmzme-S^-'dioxide

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To a suspension of 2-sulfamoyiamino-6-proTX)xybcnzonitriie (Example 1 I la) (4 3 * 9.53 mm-a) m ethanol {«-5 ml ). x-as addre- aqike-re Na* Ή C\ 9 «- rtl. 3 On mmol) t he resulting dear solution xva? rcflnxcd for 3 hours under nitrogen. A dvr cooling to remit temperate!/. the *v-;tltrng -ohman xx*..- tlltctcxl. the ftltmte -.xa- coded to 0'?' a*-d uetUutlt vd xxnh i ir\> acelic aetd. Hto i/seltmg preJpttaie v,a-/· JL'/k'd l x tiitration. ^nspcudeJ st 5o m m ethanol xxatvr (I I) and xx-amed to 40 (' f--r 2b nan Ihc -ohd colk-cicd ox nlUiiiEon to ρο-x ide 4- λοίΗ;*>-5-{pojpx b,re pl //-6·,'ηζ>φ'|{ 1,2.'>]th:a-hazm<.'-2,2-di-!\nl<‘ ( i g, 55«) a- ·. pair -dhux po-xAu M p 2242)()( Ή\Mk JOO Mil·. HMSO- A) 0 0 9(. _G, .7 THMii I 81 tsexl .? 7.3 11/. 2HJ 4 Pot .( - ο ^? H/. 21 It <· (^((/...7 9.(. H,... Hi) t- /.·> (0 J 8 t. Hz Hi), ?-1-1.:,.( 9<>H' Hi %t (0 - Rik^R'! - HR Hi'Mik - H>'(\MR(*00 MH/. HMSO-teiP | | <)' .?.? 18. 71 -H 100.93. ί(Η 64, HO 21. 135 51. i .1-. |(. ire 4’ R.l lo MS 254 (MH).

I -ample Illa 2-Sni fan ·<\- lamh-o-o-ptepoxx ben An, tn I·.

Η, a roimion ->f .'-.-n'dno-('--p:'op->xxbereon:^!}s:e H xantpk' 11 In) ί I 23 g,1 Of mmoD in d.mothx iac/treude«.'0 sol s imdes v\a- added -nk'amoyi ehfondo i? 5p g 48 (?.’.' mro t Ike ? eer on r.>te e xta- then <. e l -·ί tootr νη.ρ- t/mre under ' is< pen \n i ’· eu Upon eompk'Ekm, the reae-i-n· \-,a< quenched bx addition < e xx.uer (250 nd j J re- resi.-kmg proc ipilatt' \x re -el b.-eted bx 01 tr.;r ton t in.-ex,'-'- uh \x .Uer and d? ί/d tor i el il 2--ui fam. >yiarni.uo-5piopoxxbe v--nnti-e {i ' c. '/*'<,) .- a pale χe ioxt >-d'd H \Mk ί IkO Mil/, OMSO-,re) > ί (M id,- ⁷ 2 Η?. 3H). I ‘6 (se-(,.(' 2 Hz 21 b, LOs (r. ,7 o s Hz. 2H) 6 -h< (d, /=85 H?_. | H). 7.15 it .7 9.5 11/, iH). 7 2;< ibis 2H<j y 8 5 H/. ) H s. 4 i ?t _s ?0S2%(MHj.

h9.itI.^!.lpte...L.L.Lb. 2-Annr!O-6~pro|O9X hftjzonttrik'

2-k:iiO-6-propoxyber.iZ-eiiii-i'iie (Example 111c) (4.95 g. 24.01 mmol) was ihss-'b. cd si ΓίΟΙ i (5p -_:n| ) _iJ5JJ ΠΙΕ (Mini) 10^c,, Pd ( (255 mg 2 -I mme ) xx a- odiicd, arethe :e«u'Uon >x> romoi'emued nsmg a Pre appa''.tla- fe: 12 bouo- at l(t p-i I pen co-ip-derOu the reaction--was fiiiered fiirough celite ami the filtrate cp.neentrated tv provide 2-nitre~6WO 2IW1S4221

2017200704 02 Feb 2017 pn.pncy Iweiiiinie {4.1 g. 100' >.i a bpm bsow u gj. H W1R t4o0 XI Hz. F|’( hoi I .(H (d../ 410.310. 1.85 ise\-.7 ~d Hz. 210. 3.W> (t ./ -.010.210.4 <bi ·,. 2 10. 6 2b (d../ > 5 Me. :0),0.28 {t. ! 8 · He. IH). .Wrek / 8 5 He. IH).

Example 111c 2 Amo>6-prorxzxy benzonitrile lo ;; solum»:! <9 2.6-dimfrobemmr.m.0 (6 x, 3 kb' r.i.noO in diy iAlF nd ) .n 0A'. wax added .-. - :; M! of sodium re 15 mg. 35.42 mm->l; m n-ptOpaao) s 23 5 ml ) drepw fsc ον er 30 minutes. After compete addition, the reaction mixtore: was warmed to room tempcratuto and <nred u·? 2 5 isnure I he reuct-ou was poured mu anwewatc .revure-(250 rm ; and the p:evspifate wax <.>akxtod by 0Ifeauo· j and Js:e I u = y sc-d 2-nri· <> ρ<·ρ<>vben/·>mu f te 4.·^ g, 7^ <9 as ., ngl.: rewn s<»lm H \ΜΚ(·+ι^ΜΗ; ( l>'! )₍H h (j.,/ ^ς Hz, 3iO, 43 u.\·. --5H.'.2H).4J4{t..'^! 7.0 Hz.’2Hh .3 ltd../ 8 o Hz. IH), ,6·» tkft 8,v Hz. IH·. .82 (d, J-- 8.6 Hz. 1H).

Example H2: 4-An««O5-(peatoxy)~l//~be»zo|i Hh2,(>|thiadiazine-2.2~dioxide

H

N -x ,..A red

T. T

534

Ηορ.»>Λ. .b re 1 xarmt 111 trere ''-μ. laruwk m< <>-<·>-ρ ^,iu'\bere re »u (Example 11,2a) to provide d-armno->~i pontoxyj-l/Abenzx^i'lf 1.2.r^.ra'adiaxifie“2,2-dioxide (59 ng 'VO; ^!H \MK fobd M1W p\lv Μ, ΐοΟχχΐρ / Hz 310 4-, _Cft wj 80 hnnm ./ 68H ’d)JHi' e 1 H - )H),» - 0·',./ 8 2 HIHi, t,/? (d / e-f Η, HO /44 (t, J ^::: 8.5 Hz, IH). 7.8; (br s HO 8 1 i (h: s, HI), IO 92 hr x Ml) Xfo 28 1 iMIl 1

I x.imjde 11 ’-Sn fairnyl. nire-o- κηη>χχ i\ ivrenre'e

Prepared as m Example la .fi'0:m. 2-'amino~6~pentoxyben:zoniin.ie to provide 2sidfamoylaminO'-b-'peutoxybenzDnirrile.

r.8‘d’?pk.U.2b 2’Armno-0Mp.'n.y b>v, »hs.i:/omink' lb epared as in Example. 11 ib from 2-mtro~6-(pemy1.oxy )be0ZOniirile to provide 2Ammo-Mpimts-toxy. iK'-reouiiok', MS 2”5 (MH ),

Example 112c: 2-Nitre-0-{ | >cnts H xy )be- crore tri ie

Prepared as us bxarepk- Hie from d.O-dinUb-ixmzonmile and peutau'd re prox ide 2-niteo~6“(pentyIpxy)benzonifnte.

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Example 113: 4-An«ao-5-(pheaoxy)-l//4benzo|H(t,2..6|ihhidia/.itm-2J-dioxlde

535 LiJ

Prepared as in Example 111 fmm 2-suifamoylamino~o-pher.oxybcr._!'r0nin'ile (Fxaraple 11 -/.) -o pn-\;de 4-Ainino-5-lpheno.\S·)- l/Lbcnzop-li I 2 «>phiad:.xzine·2,2~drcd·,- (29 mg. 59%). ^!H NMR (400 MHz.. MeOD) 3 6.3v (Rd ./ = 8.3, 0 > Hz. j H), s> (Jd,./ -= x 2 1 I Hz. Hlk'\l8{m. 2H) 7.30 (m. IHk 7.400.,/ == 8.5 11/ IH). Ax im. 2H) Mb 2‘XHMH !

Fxampk ( > 'a 2-Svdiamovktrmne-6-pfo'r>'>\'.ben <>'Ut;iL·

Prepared a< in FxampL· 11 la hem 2-amhuM,-.phe’u>YYbm)Zommle (Fxinnple 113m ic |>·'!Λ ij,> 2-ssif anox lammo-p-phcnoxxbenz-mmiw (250 mg. i (>{?%'> ’ll \MR (100 MH·, McOn-.lpi.Otd,./exp Hz HI), 7 Π M / x 011/. Jib .> ((, / ? > Hz. IHk ” M id, ί X 7 Hz Illi, 7.45 {η;, 2H1 50 u ./ x <. H \ dll MS 2'M (MH )

Example 113b: d-Ammo-o-phe-ioxx beirzoisiuiie j tsti<> ’ ->f 2-ηΓ’'>-ί·<-(ρΙ\’η> y then on'ink' (I xariplc H3· > (I ^<! 1 g x 08 mmol) in MeOH (164 mL) wax slowly added concentrated HCI (7,23 mL) folloxved by iron powder (1.58 g, 28.3 mmol). The' reaction was refluxed, for 30 mm and concentrated m vacuo. The residue xxas dissolved in EtOAc.and washed with IN NaOH, water and brine. The organic layervva« dried <wet MgS* h ilhered. conecuhau?d ami punliedbx ri.rek ehtonadoxuephy I I Flexane:EtOAc to yield 2-antin0-6-phe’.ioxybeuzonibiJe (384 mg, 22.6%). ^:H. NMR (’400 MHz, MeODM 5,97 (d, J - 8.3 Hz, IB), 6.50 (d, J --- 8..6 Hz, IH), 7.06 (m, 2H), 7.18 (m. 2Hk 7.40 (m, 2H) MS 2(0 (MH )

Fxamp\ (( w 2-Nuh'-(<-pKm',y.he'i .'in.nle

A solution of 2,6-dinitrobepzonitrllc (2.0 g, 10.5 mmol), phenol (1,42 g, .15.1 mneli and K.tTn (1,45 g. I0.5rnmol) in DMl· ¢2() ml·) was stirred ..it’t unde’ S' for 4,5 hears I 'pen eonmku-.'ii. the uacnen was folmed our ( ifo.Xc (100 ml i. tx .islrec \x/h HO, Jt icd o^· w MgSi'E ,. te cd and eeswxutiate'J Inc icuac xx ueres. Jl.o bom Hc.xam I tO.Xc te pieck 2-mtro-6~phcnoyzbcriZomt:ile ί 1.94 g, 77%). ^:H NMR (400 MHz. MH 4)10 7 20 sm. 2H), .28

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Example 114: 4-4nna»-344-metho\sbc8Mlo\v i-lZ/-benzn(e||L2toHbiadiazine-2.2diuxidv

OMs

Prepared as η. I sample 1.Π from 2~xuitamoylatnm0-6-(4-methoxybenzyfoxy) benzoiiinile (Example 114a) =u provide 4-amino-5-(4-mcthoxy bouzytoxy)-1//iieuzo:· ]| = d.elihjadLi/me-z.d-diexi-le (12 mg. lo%i Ή LMR (199 MI 1/. Γ»\ΙΜ ME) 0 3 ~b (s, 3llk 6.72 <d,./ === 8.4, IH). 6.80 {d.d == 8.1, 111),6.95 (m, 2H). 7.48 {m 3H), 10.89 (br^.. IH), 11.0 (br =< IH). MS 334 =,MH l.

Example 114a; 2'Siiitamoylaniirio-h-(4-meihexybcn7Yloxy i hc’i-'.oreuile !-> a 'Cmhon <-f eh're->s.d:.'ns' isoesanak' id' 2 rm = 50rime ) m t 11=6=-(0 55 ml..) at 0 ^cC, was added formic acid (0.575 .mi.) under N?. The reaction was stirred for 30 min, and ,i sukmon of 2- emne-tm l-mefij.'SA knzd-w· i ber/’-mPtia· iFxairple 11 lb) U mg. 0 M 'in H i' v* ml ) « - aeee-l .-. = H\ - I m „i, % I I \ f9 i 2” irl + '{= ,ί η Ή XPe, min, rhe *cacifou v.as earieemrated..in vacuo arid diluted w dk waier. The -d I adfoMcd to 7 <\*ih co Hweiaud H? , and pi.'Hled K kx phase HPl 4' (:0-99% a>.i‘ien.*ri\'m e.aleri ;e sd. 2--.4 .mor i-eii^e-bH-'-u'eMu-xx Knz-- hres) hrezonilrde (I '0 mg. 52'7-1 Ί I \MR. (400 MHz, MeGD- 3 5 so (_Sa η h. 5 i 5 is. 2H), 6(d, ./==== 6.1 Hz I El), 6J4 (m, 2H), 7.40 (m, 2H), 7 4b(t./ 8 ~Ηλ UH. 7^1=40. ' 8 b. 6 8 H,\ IH)

Example I Up 2 - Aumι<i-6 -(4 -methoxybenzyioxy) benzonitrile

Pu.xuedas m Fwurnle I ΐ?b fo?m2-.nu>- 8y4-n.Mhowben, slow)ben '< wli.L s I- wnigle 114c 1 to puu ide 2-annnw6-(4-mcthc>xybcmzyloxy) benzonitrile (451 mg, 22%). ^SH \MP (400'MHz. M-.x >1H 0 3 fol re. 3H), 5.06 is. 2H), 6.33 (dd. 7==== <8.3, 0.8 Hz, IH), 6.38 (m, IHy (. *’3 {m, ?H). 7 19 <t,./ a ?. IV. = H), 7.38 (m, 2H).

Eomuled 14c: 2-Niko>6-(4-m<4boxybcazyl0xy) benzonitrile

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Prepared ax m I sample = 12e fr-.-ιη 2.n-diniti>>beii/onmde and d-mcdmmlxm/xi alcohol to provide 2'nitro-M4-inetho.xybcnzyioxy} benzonitrile (2.40 g. M’ »i Ή NMR (40(1 ΜΗ/. ί Tx'lHd 3-82 (a 'dh, 5.2o 6 2HI, w-M im. 21b. “.35 fdd.J 8m 0 ~ lb. IHi. 7.38 yn. 2H:·. ~ o5 0. J J Hl. 7 8 '< rid, .1 8 2, 0 x 11/. ΠΠ.

Example J15: 4-4mimx-5-nxxueOic acHMZZ-besuohH L2^thiadia/.ine-2.2-dioxide

Prepared in a similar manner as Exanipte IΠ from ethyl 2«(2-cyano-3i'-nTmmULamnmphab-y. Rucuac ip sample 115a? to ptox ide -i-Ammo-Voxx .icrire -uJ· I //· hcivok Π = ,2.3|thr.tui.’-’ino 2.2 du'xidc t4 9 mg, i5%) .ts ., ab.i. xobd 'Η NMR (400 MH/, DMS< W 0 4.88 (χ. 2H). 6m5 (JJ. J 83. 0.8 Hz. I H). M>9 (dd. J - 8.5. 9 ~ Ha. IΗ I, 7.46 (t, J x 3 Hz. I Hi, 8.-12 {hi IHI. 8.53 ibr x. Hi) I 1.02 (Hr v Hit. 13.40 tbrs, JH) MS 2~2 (MH j bxampk 11 5a: Etbx I.'.'-(.'.'->.x ano-34-m i fanruylamino)phenoxy)ace.tate

Prepared in a similar manner as Example Illa from ethyl 2-(3-antino-2csan».<nheri·.*x\ laeeone (Example ?Vn : ptox -do mhy ? (.1 e\am> 3 (sulfemoylamino)phcaoxy)acetatc (567 mg, 79%) as a light yellow solid. ^lH NMR (400 MHz, DMSO-tfrid 1.22 0../-fed Hz, 3HI. 4.19 !<{..% ?.O Hz. 2H). 5.01 m. 2H). 6.X7 = d, J == a 6 Hz. IH\7?0td. s 3 Hz. IH). % 6 ?H). 56 (t. ’ 8 _v Hz IH).‘>5 < = h x.'.Hi

Example 115b. EthyI 2-(3-amino 2-cyanephenoxyiacetate

Prepared, in a similar manner ax Example 11 l b from, ethyl 2-(3-amino~2~ nitruphenoxylacemte (Example 115c) to provide eilly12-(3~amino-2-cyanupbe t »\x |\( elate (539 rts '-i'¹’ 0 ax ,m off-xsh w - =d H\MR = 100 ΜΗ/ ΠΜ80- k> 4 21 rd ο Η ' ΜΗ,Ίΐ st, t ?6 Hz .'IE, 1 x^=x .'lH,i>00(h x ?}-n 6'Oi/, t-80 rto IHUMl <’ x m =) x Hz IH), 7.17 (t, J™ 8,4 Hz_s 1H).

E\2'hph:'...Ll?e: F-hx = 2-(d-aioino-z-inntaihcnoxylacemJ·,.·

I'o .; xoknnm of.?-hynrc-xsto-miml··. nromnile (fe s nple 1 led* ((06 mg, 1 % mix ΐηνΚνΟ ( >x ng ''0 mm i m acetone (8 nil l wax mt e J mxlbomx <, Lire (0 0 e il ^x 20 iLmol) Γ’κ rem'iR'i wax reflux.d >mde' V io. 4 ' hems 1'p m .wrnph L<> i rhe

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2017200704 02 Feb 2017 reaction was fihcred, and the filtrate was concentrated urtd dried to yield ethyl 2-(3-nrnino-2xib-’>:_lU)?yd ^!Π NMR (HIP MHz D'NsmA I 2? <r. / Oih.dn · 2<Ηψ > H 2Π). ' 19 is. 2H). ~ 09? x.n.O.s Ik. IH). 89ft,./ x 4 Hz, liu. ”.9? fdd, 7

Hz, IH), bsainnk H 5d 2 ikdioxx-o ndw-Vuzomu le ' ·,> <’. -mtn·η of 2,*> dreiti»-heu<.oniti.lc tid 0 c, 523 mineb re MeOH ?2 < 5 rehk was added. a soiulion of Na ( 132 g, 57.5 mmol) in MeOH (23.3 rah j. The reaction wax reduxcd uisdu V t'·.; 2 5 hotire, v-med to :t and the preeipibtfe w-fs vo'dccted b>- 'Uia'.tre·. 1 he sesultin<> residue λ as e- -mbincd w;th py.idine bydp-chlorwie H 5.1 g. 130 mmol). and tbe -<ilids were owned at 200 ”(' n-r i 8 Imres. t ^;p> ή eonipk-t i-m. the reaction a as cooled to rt, washed with brine fl x <00 ml 1 ;red cMtactcd with En He ;2 x 500 nd t, I'he mgauic ksyei., were c/nibmed. di red over MgSO,·.. filtered and concentrated to provide 2-hydroxy--6--nitrobcrizfmknlc (0.70 g, 87%).

^!H NMR (400 MHz. MeODlO 3-tdd../== 83. 0.8 Hz. Hl). 7.0” ft, J - 8..? 11.'. Hl) Ν'(dd ./ - 8.2 1 I Hz Hi)

Example 116:4mAmiiHN5~(fe0propoxy)”lff“be0z0|c] 11,2,6] thiadiazme~2_?2dioxlde

Ο: H

g.,.-bW reZw, w τη

NH₂ £k/

S38 1

Prepared in a seimUr mamier as Example 111 from 2-sid&wyl.amini>6~ wopropo\\ bonzemtrik (h'xinnnle 116<i) io provide 4-amin<>>{isopropoxvLl .Nΐχ-ηζορ |p 2.t-iiiu.khazine-2.2’dioxide('0 nig. l~l^!'m. H NMR f400 MHz, DMSO-./.) d 138 (0./ 5 8 H -, Μ I), 434 (sept,/ 8,0 U_A H l)_? 6.59 id, J ? ~ Hz, 1H), 6(77 (d,,/ - 8.7 Hz, HI) 'MlMd.,/ ο “ Π/. un. “8: tbrs, Uli 8 32 ibt s, Hlk 1094 thr -. HI), MS 250 ίΜΗ 1 <hxapp?1e..I16a: 2-Sal1hmoylarmno~6~ixopropoxyben.z<mitrile

Prepared in a xlreilar manner'm Example Illa from 2-amim>-6isopropoxybcnzonltrilc (Ex.anplc Oh) to piox ide 2’'.ηΙί35ΐι·ίΥ13ΓηΓ:ΐ<>-ο-Η/ριηριΑχ ben/oiihtde (21 mg, 8%). ^fH NMR.(400 MHz. Met >D) d I 5 (4.3 5 ο Η · 0H). 4 07 (wpt J o,0 Hz. iH) 6,29 (d, J -- 8.2 Hz, IH), 636 (dd, J- 8,.1 , (0 ¾ IH), 7 0“ < 0,/ == X.2 Hz, IH).

Example 116b· 2”A?mno-'6-ixopmpoxybefrzomMl e

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2017200704 02 Feb 2017 pjcpaicd :n a smnlar manner as i'xaniplc 113b frem 2-mtr0-Oispp-e-'exx buijconduk' ¢( sample 1 l6e'· io prwhJc 2-amm0-o-te.>pi.'p>-vi beu/omO'k ί201 na.·, 0’ mas .= telkw oil ^}H NMR (WMlk.MeHD'.p ^J date. / b OH,. <M Ik 4 <4 (-^ t / ^fnl Hz, IH), 6.25 (d../ === 8.1 Hz. IHi, 6.34 (dd.../ === 8.2. 0.8 Hz, 1H), 7.18 (t, </ ==== 8.3 Hz, 1H).

Exuinpk Hee: 2 N: >^fo 6 ssopropoxy I =enzont?rik

Prepared in a similar manner us Example 115c from 2-hydroxy-6·· nitmtaz»«0hsk (Example 115d) uud isopropyl Pr-mide to provide 2-ndro-o· teV'.up xMvu.erai >c f 324 nig. i-4%> 11\VR topn Mik. \k=»lM Λ I 43 td, / n 2 Hz. 6H'·, 4 _Vxcpt../ 6.2 Ηz, IH k 7.61 (dd. / 8.0. 1.0 Hz, I H k 7.80 (t,./ s.2 Hz. IH), 7.85 tdd../ 1-.2. I 2 Hz. IH).

Example 117:4-Amhi0-5-(benzyi*nyHl//”benz0|i’H ldJ,6Khmdmzi»e-2,2-dioxide

Prepared as in Example 111 from d-snltameylattuno-O-fbonzyloxyObenzonitrik (Example 117a) to provide 4~amino~5“(benayl0xy)-136-be}W[ei[L3,6]thiadiazihe-2,2-dioxide (4? mg. ΊΊ NMR (400 MH.:, X1c(d)>o 5.32 (s. 210.^f· o5 (dd.,/ 8 3 I...' H.r. Hi), 6.85 (dd. · 8 6. · p Hz. IH) / 3«<- / '’’ ·,m. nH) MR 301 (Ml I ·

I sample 11 a~ 2-Snifamndumine.*6-(ben/y loxx >bentef:itr:k

Prepared as in Example 11 la from 2-amlr:O“6“(benzyiox.y}benzonurile (Example 117b) r.o provide 2*sulfamaylamino-6-(benzyloxy)benzonitriio (74 mg. 30%). ^lH NMR (400 MHz.. MeOD)6 5.22 (s,2H), 6.94(0../-8.5 Hz, 111). 7 2=5 (J_;./ 3.2 Hz. lH).7.32(m. HI), ' 33 Ο,./' - 7'.: Hz. 2H). ? |7 (d. ./=== /.4 Hz. 210, ’ s) p ./=== x..2 Hz. =H}

Kampb H 'h =00-6-(be vslusy jtvivomi)i e

Prepared as in Example 113b iron· .g-mtte-O-ibenzYJosyJih O/oniirile (I sampk 117c) η- moxk'c 2-.mmn>-6-( Ru/\k's>)hcn e'oli.k' (21^ me. o2^c _v) H NMR (400 Mil, Mte’I'Ho 5 :5(s. 2H} r Cid. / S2H\lIKo^HJ Z 2 11,. ) H). 7.20 it. · .UH, IH). 7.38 (L. J - 7.6 Hx, 2H)₅ 7.46 (d_? J - 7.4 Hz, 2H). MS 225 (MH),

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Example ϊ ΐ e 2-\i:jmu-iben. \ os\ llrarn'ern'tifo

To a '>-nm<>n of 24pdtex<,-o-mn<»bciizomo tie (I xampk- 118J11.0 g. 6.04 mmoli and CssCQ? (2.16 g, 6.64 mmol) in acetone (14 ml.) was added Benzyl bromide- (1.16 g, 6.76 rnm»i) Che reacti<m '/a- refluxed ursdet N. for ΐ 5 hoists. 16/0 fthered and the filtrate' concentrated. The residue was purified by Hash chromatography 3:2 HexaaeEtOAc m provide 2 .nt.<» ’ ;bcr.zx lexx KMitenmik pt)0 reg. 5.7 <6. Il \MR (40(¹ MH/. MJ OH 0 ' 4«i (s, 2H?

34--.45 (w.3lb. 7 53tm. Jh.'PWJ sv'iMb, lH1.7s2tr.J < 4 H/, IHl 7M it J - 8.2. 0.8 Hz, 1H).

Example Π8: 4-An««o-5~(ethoxy)~lZ/~benzok n H2,6|ihiadiazine-2,3-diuxide

nh, O.

Ί

548 ‘

Prepared os nt Example 111 from 2 --n farnwhunnu'-o cmvxx P/nzonttnle iExansple 1183} pro\ -de 4-ammo-5-i.-ihex} tef hcnecfoll Uwjilnad-az-uc 2.2 dioxide t M0 mg. 511%-. *H NMR(400 MHz, DMS0A0) 3 1.37 (0,/- 6.9 Hz, 3H), 4.18 >^! e 9 Hz, 2H), o<M(d.7 8 8 11/.111).^6(4.7 0 5 11/.311.^2-53.^210.-5-(1,2 χ 4.He 1.0.9.44 (br A ΓΗ). MS 242 (Mlf).

E.xampkH im, 2-Sudhtu<?x kminb--’''-etho,xx benz<>nitrilc

Pizpused tn a smbfor maimer a.-1 xumplc 11 la item 2-.imiuo--0·ethoxybenzomti de (Example 8b) to prox ide 2-8υ0ηηΜχ1·(Πΐίι·ι.ο»6-ούΐ0χγ^ηζοπιίΓ1^ (161 mg, 67%). MS 242 (MH*).

I sample 2 Mamo 6 ethoxx Kcvem'nle

Prepared in a similar manner as Example 11 lb from 2-nitro-6-erhc-XYbenzouitriic (Example 8c) to -provide 2-amiuo--6“ethoxybenzo.ni:tnle (162 tug, 100%). MS 163 (MH*).

Example 118c: 2 Ni rro 6 eth- - xs'henzon itrile

Prepared in a similar manner as Example I I5e frunx 2-hydroxy-6uitrobenznmtnlc (Example 115d) and ethyl bromideto ptm-idc 2-mtro~6Cthoxybenzohitrile (192 mg, 5054).

Example 119:4~Ami»@-S-(b.utoy>1>-WBz0^ | l,i,6jthhdfozme~20~dioxide

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Prepared in a similar manner as Example 111 imm 2-sudamox lammombutexy bcnz©nitnle (Example 119a) m prm, :d·.. •tocmino-Mwtexs -1 /Z-ben.tob ][ I .1 /]<·hladi ©:inc? ’-.liev-dcf sO“,₅ ^fH \MR(-W\IH,. DMSxMx) 0 0 9© (l ,'4 H HO ’ 4 I (sexi ./- ' MH, ?H). I XI mmm../ 9(0.:,210 Η ’ a 6’11 ΊΟ < M (d / 8^11/,111)

76 id.,/ - 8.2 Hz. IH). 7 4<> {{ ./ - 8.2 Ik. IH). ? 82 (br © 1H). 8.35 {hr s. I HI. 10.96 ibr s.

HO MS MnMH ) xampe . .°a ’'-ΜΜ.ηηχ l.’mro-m-lnm x-ben ©mode

Pr. pased m a ©mnl a* m-inrws I xan.ple H la ucri 2-arim.'-6bemxy beu/omurie H ©ample m p>'Ale 2-MjUaimw Limmo-c-bmoxyben/i'muile MS 270 (MH).

Example 119b: 2-.Mnmo-x-biw.'S.y Kitzotmrilc ί ie^aseu .n < s mf.ai r.mrei a- f \,i np e 11 > I <> r ' m -t ~ix<x --Seme ©tr le (Example 9c) to provide 2-aminp~6~butoxybenzunitril.c (190 mg, 71%), MS 191 (MH ). Example 11.9c: S-nitro-b-buWybenzonilrile

Prepared irr a similar manner as Example 1.1.Sc from.' J-hydrexy-bnitrebenzonitrile (Example 115d) and butyl bromide to provide 2miiro-6-batoxx benzonitrile.

Example 120: d-AmrauM-methy 1- ///'”pyrazal0{iC| [1,2<6]thmdmzHm~2 J-dhuide

nh₂

542

Prepared in a similar maimer as Example 111 fiw 5-sul&wylaminc)-1 -methyl«' //p\ mz.'L - Wearhonit.i'ile (Example 120a) to provide 4-Amino-1-mA by I- /M* pvazol·’|>-IH.2 '>hbiadiazm©-2,2.~dicxide (100 mg; 507¾}. ’H blMR. (400 MHz, GMSO-toj 4 3.76 is, 310 ·' S3 is, 310, ‘to' (s, HH 9 84 (-, HE

Hamp ?0i «‘lamM^,<x’r^,.mo-j-‘'nethxl-/«7-ns bo’e- l-s uti I©

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Prepared m + sarnlar mmnct I sample I1 la .rent 5-arun. -Imrei + 1-¾ pyrazolc-4 -carbvtmrth h? proc ide ' + J fan a >> lamn :+-1 -methyl- / /7-pyrazolc-4 -earb< >t til rik. Example 121: 4*Amian-2IZ»pyrazeMt'l [1^^Ithiadiazhie-Sri-dioxkh

NH_a

543

Prepared in. a similar.manner as Example j j I irom '..sitUbnix,' lummo-ZH~ pymzole-4-em'boniitile (Example I l;O +> proxJe l-amme-'Ai+raA’Iok H l-LMbhiad+iziBC·?.?· mexide Alum. 48L-) Ή NMR (4t'P ΜΗ\ 1AHO \b' ο 9“ is. 2H'>. r 4¾ ΙΗΕΟ'Ί (,. IH). 13.36 Μ I H r.

Example 12 hr 3-Suliarnoylamino-7r/-py;azolc-4-caiboniir;le

Prepared in a s-miiai manner as Example 11 la frem 3 -.nnin> --,7V p\iaz.me-4·

Cfih'.tflr pre, de I -u fan > w .num Ή p, a + „ a cad-'m I

Example 122: 4-Aml«0-7-mei:hoxy -ZZZ-betuekH 1,2,6|thladliuine-2,2di(ixidt·

Nib

544

Prepared, in a Similar manner as Example: 111 from. 2~sulfimoyl.annno-4me(h< rxyheivonitTile {Example 122a) tn provide 4-^kimm'Q~7~meth.bx.yrfJZhenzt'b'IU 6]tbiadia/hje-2.2-dh'xidc (49 mg, 65%). Ή NMR (400 MHz, DMSO-cL) 6 3.81 (s, 311} o 5+ id.,/ 2.1 11/. IIH. b %(dd,,E^l;2.7H^^^^^ 10),10.85 (hr

s. i H) 10 90 f br s. ΗI s MS 228 (Ml t r

E)rnmpleJ72a: 2-SulEmi0ylamiu0-4-methoxybenxo:miri.1e

I'a'au. e nr >., vm as marre, as 1 xan'pk 11 la *i?i i 2- e ι+χ'-1meri<>x>be\A'»'as e 11 xampsc .Izzos to ρυη ule 2-A:l{m~uuLrmro- 1-ΒΧ'0η+\ίί<'ηζοη4'Ιο as olmecAA^m n g,-bl%l ’HMIR'iWMlb \kRD)3¹SH' 'll) o («. 2 8

H.\ IH>. “.54 (d. ’ 9,(! Hz, IH). 7.+4 pi,./ - 2,4 Hz. HE MS 228 (MH ).

Example 122b: 2-Ammo~4-methoxytatzomtrile

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Prepared in a snrsilar mariner as Example I1 lb from 2-nitro-4mefnoxybenzonitrile io provide 2-amsno-4-Tneihox.vbenzonitrik' (910 mg, 78%>· Ή XMR (400 ΜΙΗ%Τη'Μη3 7^re.3HVP~Mb_r.. 2Hko20iin. (Ilk Ml <ne liu. 7.30 id. / 8.7 H/. IH).

Example 123: Ethyl d-ammo-A-methy 1-2-oxo-l,2-dihydruthseooIrΊ113,61thiadiazlne-2,2dioxfik'-w-earbaxyhtie

MU

545

Prepared in a sun-lar marmei ,w Example 111 ftom ethyl •'-sultamrolamm-'~4cyano-3-methy l'_sbb-.nhx'iK'-2-earbox3kto{i xarnple 123 0 t·· provide ethyl 4-aminO’5-methyh2Jn'sdiO'J> nef I \Pfou-rea/me-y - fo'x.de (-en\>\xL· {' ’ ’ e 23) ’t\MR (400 MH/. OMSO-J j .4 1.26 ((. 7 == t-Miz tHy .? 73 re. 31 Ik 4 j 7 pi ./ == 7 0 Hz. 21 i } MS 2%i {MH).

Example 123a: Ethyl fosifltamoylamm·>-4-vyan<»-3’mefhx 1th cpheue-2-e.n k«\s -ate

Prepared in a similar maimer as Example I I4.i front eon I y-.tmir.o- l -es >ιη·ί-3m>. thy liitiophene-2*carbosx kn>. /-χ,πνρΡ. < ,2?h> to prm ul>- etbx'. y-^jPamoyhim'.no- l-eyane-?~ methylthlophen. - ’-carbo.xylate (1.73 g, 80%). Ή NMR (400 MHz, DMSO-nM d 1.28 (t. J- 7 0 Ηζ3Η), 2.> re 3Hy 4 2 : (fo J- 7.1 Hz, 2H).

(xan-pb I idyl 'rep-n'·-so- Hex.im--3-melhydHm^Mvne-2-carboxx'ak' <o . xeknmt <Μ\ IMI 3~οχοπη·οηο.ηο <3.6 ml 2 V8 rmuM) mal-mmwnl·,· (I yy g 23/ mmol) and wl:nn ,y3 mg, 23 y mmel's re I'HHl {34 ml ) was added I't (3 28 ml. 2? ? mmol). Theoe^. hmi w.n reftasd;under N> for 3 tours, then directly purified by flash, chromtograpbx Η H T/k:EiOA.c) to provide ethyl S-antinoM-eyanrj-d-t'neihyltb.iophene-d·cmtoxxkte. (2 lee. ΙΓ<) Ή\MR <400 MIL·. DM/t Mrel ₍>M 21 {\,/ 7 u 11/ IH), 2 Are 311),4.15 ^,/====7.2 ½. 2H).

Example 124: d-Amiuo-T-methy'l-IH-henznleSf l,2.6phiuduuiue”2,2^dtoxide

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Prepared in a sinnkir manner a- Example 111 from 2-smkano’. kmnno-4~ mcthylbenzoi -bi . {Example 124a;- io pro'< ide e-amm<'-7-mc;hy 1-Z/7-benz<>ii'J| 1,2,6]thiadiaztnc2.2-dw\-de (Η) reg. 59%; ’ll AMR (400 MIL·. Ak-< >D1 d 249 re. 310. o 92 re.. 110. “ 03 fm.

I H . 7.70 (<±./ - 8.2 Hz. 111 i. MS 212 (MH ).

Example 124a: 2«Suifamoylamirio-4-mcihylbenzonilrilc

Prepared in a similar manner ax Example 11 4a from.2-arnino~4mcthylhvnzomink {Example 14b) to provide 2-svdf:nnoylarma<’-44uethy Urenzomude (20’5 mg. 32%). Ή NMR (406 MHz. ( DCI 1 4 2.35 is. 3HL b.88 ire. |Hi. ? 33 (d. / Hz. lib. 7 2 (bi s. IH). 7.9- <s, I HR ‘5 w {.-. IH}.. MS 212 (MH i.

Exampk I24e 2-Ain_:no-4-mvth\ iben/oimnie

A soluin-n of dduom-'-dmicih-llwiiZomude t2 0 0’ 7 mmoil .nre CuCA (I 92 g, 21.4 mmol; inNMP (IV ml ) wax reacted ni a insuewve l<c 2(1 mm at 2(K) V. Lpon completion tbe reaction v- ax cooled to 0 and 15'* .> aqueous A Η A^l I r 2 i > ml I u a,·. &k>u ly added. The mixture wa* stiaed at a fm 30 min. then extracted w id; CH -Cl - Fbe vigame biy-n vrew washed w ith H/.t. brine, dried O'-er McMC. tiker-zd and conecmrreed I he residue wore purified by Sash chromatography (3:1 Hex»ne:En>Ae) to provide S'-amho^in^thylbcnzonitriic 0 24 g xx'-'- Hi NMR {MM MHz. C1X I id I 4.Ms.Mb > V>!i-i HI), ox-{re. HO C 41 u </ ::: 8.0 HZ. I Hi

Example 125:4~ Xnn«n4l-methyl-W“henzti|t’|{ t,2.6Uhmdiazi8t-2JI~dioxide

NH₂

547

Prepared in a similar owner as Example 111 from S-suifamoylamino-Smethylbunzonitrile (Example I25a) to prox4de4Mmmo»8methyi”Zbr.benz0U'][1._?2_x6]thiadiazine*

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2.2-dre\:de (’> am. 8%). Ή \MR (400 MIL·. Mre HR o 2.3⁷ _b, 3Ht 7.09 it.../ = 7 “ IL·. 1 H), “48 rd. / Hr, Hl). S 04 fd. / 7. II.·. UH .MS 212 AHI }

Example ϊ 25a. 2-Smfant< a l:<mt?s > -3-nta'dp 1=κn/omtr le

Prepared ns a auifb manner as Example I 1 4a from z-amino-dmedp·Ibumemnde t Example 15b) 8- provide 2-sulfumox·lumiao-3-melhylbenzomtnle ί 115 rag.

4tw<p Η \MK t4OO \|Ηλ 5k.OO) A 2.34 (s. 3H). “.31 (t. / ~.5 Η/. I lit 7 5⁷ (m. 2H> MS 212 (MH ).

Example 126:4-Amtno7“cyano-I/f-bejruo|cni_s2_$6]thisdiazi»^2_?2«dfoxide

348

Prepared in a similar manner as Example 114a from z-aminoterephtbalonitrilc (b\ unple 12-ίχΑ ρη,χ Α kuHw-Nwu-H/R·)-. ^'^l,2.6|rh9kbazeu.’-2,2-ei-i<ud>· (46 mg K-’m H \MP UOOMH.'.r>MSOJ,)p~37(d.d i 5 Hz. Hit 7 57 (dd../ 8.2. I oil·. HI), a 12 (d. / 3.5 Hz. ! II). 8 51 (br s. 21H. Il 51 (s. HL· MS 223<MH },

E5.‘9.Upte...L“i:.9_:' 2-A.n-inmmephih donmile

Prepared hi a similar manner as Example 124b from. 24*$bFomoam1.ine to provide 2-aminffterephthaiomirile fl .14 g, 100%). Tl NMR! (400 MHz, MeOD) ¢) 6.91 (dd, J 8,2,1.6 Hz. HI), 7.12 (d,./ 1.6 Hz,.IH), 7.51 (d,,./ -8.0 Hz J H}.

Example 127: 4~AinhH>8-HK4lrox>~///-henzo|<'|| E2.6|tlumHa/iue-2,2-dioxide

NH₂

549

Prepared in a ximdar -nannet as Example 11 I from d-smianuo lammoMmet.h<re-bcu/mnuile (Example 127a) h> proxaic -l-amina-e-metlbtsy-Z//ben ’Me Πi,2.Jtlaadk,.'nk-2.2 db-xak 111 urn. ΐ'%) Ii NMR (409 MHz. Xle(%r <> 3 (s.

3HL 7.14 (t../- 7.9Hz, ΓΗ1 7.22 (dd,/- 7.R 1.2 Hz, IH), 7.72 (0,/- 8.2, i .2 Hz, 1H). MS 228 (MH ).

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Example ϊ 2?q 2-Sti’fan.<-y lamn.»- '-iifdhowki \ ii’Ji e

Prepared in a sinnkn· manner as Example 114a. from 2-amino~3~ niethoxybenzonitrUe (Example .127b) to provide 2-salfamoylamino~3-.methuxy benzonitrile (113 mg ^!l)\MR{4ito\HL HMSOMH p ? x~< re 3H). ~ 2^ {re. Hl) 7.39(44./ ~7 η Ho I Hk~ SMdd../ ~9. k” Hz. IH). I x7<... IM). '> 09 (h _v IH). MS 22a (MH ).

Exan-pk 12η 2 Am mo-3 n -ethoxy t»en c< Mih de

Ihenoiod m -mtnibi mannet as I xantpk 111”» from 3- «ethoxy 2Udo oeroeadt le »o pt- s-dc 2 nun »o nicthoxvoenzo nn.b.- (346 n'g. n»r <) H NMR (466

MHz. MH )H) 3 3.87 re. 3H). e/-5 re J 7.7 Hz, Hi). 6.45 kid. 7 i.2 Hz. IHj. 7 00 (dd. <7 8.2. 1.2 Hz. Hi). MS 149 {MH ).

Example 128: 4-Amhto7~hydr(>xy///-be«zo|<i(i,2,6|thiaditszine~2,2-dioxide

NH_S

5S9

Prepared io ,t xtmdar manner as Example 1 11 from. 2~sulfamoyIaminO4~ hyMroxy benzonitrile (Example I28a) to provide 4amino· 7 hydroxy- 7/7benzop JIJ ,2,6]thiadiszinc-2.2dioxide i? mg. 1 V η Ή NMR 1400 MHz. MeOD) s'¹' o 50 (d. /“ 2..0 Hz. 1H). 6.65 idd.d - 9.0, 2.4 Hz, IH). 7.8.: (J A 8 s Hz. IH). MS 2 M (MH )

Example 128a: 2~Snifamovlaotino--4~hvdroxvbenzonitrite

Prepared in a similar maimer as Example 114a. front 2--aniinP«4->

hydroxy bcnzonhnft· (Example 18b) -o pros ide 2-xulfamoyiamino.-4*hy»lrvxs benzouitrdo 151 mg, ’“’’οι Η NM8 i 100 MH ' μ. ΠΙΑ?!. s<mdd Ο ? I Η ' H) ? l')(d ./ 8<H,,H1) 'o8_vd J ' ? H,, Hl) MS Η 1 _VMH ) lAi)lllllk...L28b.'. 2.-Am!no-4*hydr<'.xybenz0bitdte·

Prepared in asm-rear man-w’' ex Exairph· IIP' Iren·¹ ImsdroxyMmtiohen o’vtrdo (Example 128;.) ts provide 2~ Ammo-1 -hydroxy benzo nitrile (286 mg,. 100%).. 'll MIR 6*9p Mill-., MeOH) 0 6 15 idd,7- 8 ' 2 8 h,\ 111)..6.20 (d_:..M 1.9 Hz, IH). 7.18 id,.7' ~= 8.0 Hz, 1H).

.ko.ai.l.U.isl.k~.'2e.^:. 4-Hy ds ex\ -2-rnt> >het;ronttri ie

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A n=jxtu=e m'dmtcfno.x'.-d-mmd'en'mnuPc (820 am. / u rm=>-i) -.=5==1 puidr-κ he droehlmid·· {7'*-5 n=g, 4.0 _!Πΐ[<ι|) <=;;·. heated at 200 ’(' under Ν'? tor 16 bouts. I non completion, the reaction. was cooled to room temperature, washed with brine and extracted with HO \e {2 x 100 ml..i. The organic layers were combined, dried over MgSOj. filtered and wikcntKitcd 1 he residue purified hs Hash chromatography ί i :1 He-xanc EtOAc) t- provide 4 b\divx> 2 r. ticbcnA κ tid. (200 mg. 2t'‘\o h NMR (400 MHz MeOl>>? 24 (dd.7 < (-.

4 Hz. 1H). VO id../ 2.4 Hz. IHi. 7.83 (d.7 8A Hz. IB)

Example .129: 4-Ami»m5~(2-methylprop-l-t‘»ylMR-benzo{c| [.1.2,31 thhidmz.ine--2,2-dioxide

651 I

To it stirred solution of 2-sul farnoy lmuino-6-f 2-i no thy I prop-1 -coy I Ibcnzonittik (Example 129m (i .69 g. 6.73 mmol) in EiOil Ά-’.Ο mlJ. under a nitrogen atmosphere, an aque=-ns wlanon ot Nak’H =,2 PM (·, % nd . I 5.4·' mmoli ua- added al tooin tenipcmtufe fhe i«Hamed nwstuie was heated at reflux ‘or h. cooled to room temperature and neutralized with 10% d.eOH (pH -'· t.O Fhc neniruli we mixmw kept m an ice bath for 30 min. The obtained pwemflal.· vas filtered. washednuh ce-l-l wale* and dried, to g-\e 1.49 g (8s%i -ft the title compound as a white solid. The product was purified by crystanization fiMm cthanol. imp,: > 260 Τ,^!H-NMB(400 MHz. DMS=M 1 ΑΡΉ ibroac .-.'H), 8.30 (broads, IH), 746(1, J - 8.00 Η,, ΗΓ> 6 °=> tbioec a. HI), => )2 (-1 J 8 ' Η/, ι H). 6 >A =d. I '211/ ' t =) ή +< fb:=.>ad s l Η) 1,80-1.87 (nt, 3H \ I 1 0.3 (n =. 7H). ^! 9 '-N MR <_x 100 MHz, DMSO-r/.) Λ162.1 Al, 138.8.137.6,132.9, 124 A 123.3, US,?, 110.7, 25.8 and 19,2. MS 252 (MH ).

Example 129a: 2-S:ulfiim:oybrnino-6»(2-metliyiprop- l-enyi)bonzamtrilc \ x'let. r of ' m -no e i? menu Ιρ=ορ I eny menzmm' i.e J Nir.’> c ’O-nj g; 7.23 mrnoli in NA dimcthybecr.mudc (DM.A) {20.0 ml.), under a nittogCii mmi-sphew', was n-.-3=-.4 w - th sulfatm-yl ehUmde =. I 6' g. 14,4> mr-wll at u om icmpc'-it.uc f ie obunred nuxu-se

a. too r temp ai s'*0i ' mJlefeui» r= u queue. > u v n v< itct t46 tri > f’-e mixture' wa* extracted with EtOAc (4 x 80 ml.-), the combined extract was War he'd with water (2 x 20 mL) and brine, and dried v ith MgSO.-i. The filtrate was evaporated and the residue was pnrihed by enromutogr.mhy >>n Ah» a <·, 1 usmg gr.=du-:v (Hcveu -< ) tOM Ό t-_t Ί) te g'.xe ' f-9

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2017200704 02 Feb 2017 g > s Ml λ l'l\ c<mtpimi:il as a xxlme solid H-HMR i400 MIL’ DMS1 *</..; A9 42 «b-m·.·.! s. III·'.',!,;! hPHz.lHj. ll(d. J s 0 IL· (til. ~ 2 I thr-ads, 211} 7 -9 id .1 Sfllk IHI, 6.3? (bread χ. I HL 1.92-1.9? (m, 3H). 1.76-1.79 pu, 3H).

xan-pk '29? ?-Am'no~n-i.'>u\'Ho. :piep-l-. nxllben exm Jo

Ho .(cpj .ted H( ,. s nd s wa- aeee l -ι.-xxb . i ? -.-1 mer <9

;.neiuyΙροφ-.Ι-on Hbesi/mut'il»· (b'\.»mpk Udes {2 00 <.«, 9 ,·;·; mmol) m P< »111120 2 ml) 4 oo.n tcnipcrtnuxv. Then, the obi-ained miUhn' xx as ircaie·.! xxiih iter powder -5.52 g, 9x,9t mine; s. .uldcd ni -analI parisi-if al the -.uric iemp-cranne. the iruxturc was μητζΟ a? π·<«υ temperature for 15 min. and then heated at reflux for 30 min. The mixture was cooled to room temperature, EtOH was evapomted and the pH was adjusted to pH-10 with aqueous NaOH s2 0M). the basi-k'd nnxtine wa- exirevtcd with I iO Ac (lx; 00 nd 1 and ilu c.-mbined exinu.1 was J»led xxsd) M ix drees MgSl)< I he iihiate was exaporalcd and die rewiduc xxa- purified lw ehremalegmphx >>): -dn.a gu u-mg g;adfcul l.cxancx V hesaues I itLXe (X 2), to at'fi ).1 s .32 g ί 77%) Mrhc Tide -„0:000000 as xcKre od ^SH XMR {400 MHz. d } O'⁷. -,.7 > _υπ, _s πρ 6.62 (d, J S 111- Hh. 0 to pi, J - 7.2 Hz, IH). 6.23 {broad s. IH), 5.91 (broad s, 2H), 1.86i .88 in·. 3H b I ,~2-1 4 ί m AI * i χampi> > 29c ?-\nn-w-(2~m<.tbxiprop~I-eny*)b^!.mzonitrile

A '-H-qxmsion of .2«cyano“3“nitrophenyl trirluormneihauewifonaK' (l-\ampk>

I^XM) (4,80 g, I·» 2i mmol), 2~metby-l>propeny1boronic acid (2.43 g; .24.32 mmvl).

. takiHi-pbo w Iplu sph -eg-a L. Ina x'R {' 0 0. i n2 1 mu re, scdiur. e .-<«> wt, ί, χ9 << p much and xsaim (33 0 mid m qimcihox>eflMne ίΠΜΓ) {132.0 ml.) was iicaicd ai rellux lot 4 b. under a nhiogen atmosphere The roatlion imxmre was e<>._fh-d io mom temp.'ianire and dihree with water (.100 ml..) and EtOAe (250 mL) Fne organic phase x% ,- -~o,na.« J . id the aqueous phase exuacted with ElOAc (3 x 100 ml ) The combine^ extract was washed with brine ami dried xx sth .miix drous MgSO.i. The hl.trafe was evaporated and the residue was purified by chromatography on silica gel using gradient hexanes to hcxanes/EtOAe (7:3). to give 2.(.0. g (61%) of the title compound as a yellow sohd, Ή-NMR (400 MHz. DMSO-Jo) ^8.19-8.23 (m. IHj '80-' A p-;, H I) 0 4o (brood s llh, I 'M-l -Μ m -.11)% 9 ft) 5H)

Example 1 ,p>d: 2-Cyanu-3-nitrophcs\xI i?:ni;mi>moih.moe;d:Oi).i:·.·

To a solution of 24iydrox¥-6-nitrobcni'nnitrik- (Example 129s.) (2.90 g, 17.67 mmoi'i m Clip 'ΐ ΓΗ» 0 ml s at 0''C and unde^:'.) min-pe . π nosphere tr tmlamire ί -< >8 g. 1 91

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2017200704 02 Feb 2017 = ι I 35 '4 nrniol? -xa- added. f>>dowcd hy dix-p wise .idditi-,-=i of trinuonmicllianC'tilfomi. anhvdfidc (“ 4S g, 4.40 nil . 26,51 t=i=nel; Hie ie icluin ιη·θ'Λ wax xurrrd -.tt 0 ‘i' -bt 30 >ιιη· and the ieaetum wax que=ich>.d -silk wnmmed aqueou- Na J ’* 6 -.-=01(-·=ιt100 nd ), The nrg.mie tax ζι ά as sey.a aicd and the aquem;\ phase w as e\t= amen -x ilh ( 'i I -t 1-(3 x 1 00 nd ), The combined exh act was dued v, =rh unnydr·-u.- \ip^<! L. f= licivd and cvap-iaicd The = c^iduc w ax _>.> i ied b- >nix-. „i ,,=.6 oil -i v. me ,χ neat-die = Hcm u-t<= u'<me- 9V.it'4> t altord 5,23 g t IG'T’«) of the title coiiipotmd a.- a hn.-w si solid, H-NMR (400 MH/, OMSO /.,· 0' 8 49-8.5' {i(=. lib 8.25-8 27 {m, lib. s. = 3-S I’feu, ΗΠ

Examp’e 129c: 2-Hydix>xy-6-nikobcnzonitrile

2-Mcliiexx~P-nm<'iwitzonm de U sample 129f= i j{i 75 g, w).2 mitiob and py = u’mc hxdioehmndz < 16.0 g, = W mmms were mixed together a.- mhdx under mitogen -.-.= 1=1 ihe=i heated pi a p=chcatod m = = =ath al 200 < ’ pdo non Aitzi <>'>=mg to joom leinpetaiure. -sale’ f 200 nd ) and 1200 ml i xs^re added and xiui-.d v^.'-ncaxls 0-=' I =mm Then, me precipitated product vxax ed=eetcd =iy filtraikm and reery s-teh/eC f='<-m water, io ghe 8 2 g (8Τ',) <>f 2hydi‘oxx-6-iJ=irobe=izoriiink ax a brown solid. Ή-NMR. (400 MHz. DM$O-a>} 3 = 2 id (broad s„ Hi =, =->8-“ > {tn, „^!lb to⁵-·’ .1 a pig lb) kxampto 12^1-'f d-Mcfnosy-h-nitrobetiznnitrile

A solution of sodium methoxide, obtained by adding sodium (1,68 g, 73.1 mmol) to anhydrous MeOH s “3 mi,), xvn,- added to d.b-dimimhmwmtrile (l 3.20 g, 68.4 mmol) m dry Mi.<>H (,?84 ml > under nitrogen at room tempemiure oxer = 0 ==iin The rrac?io(= w as refluxed u-r 1 =wim :md then MeOH wa- tern-wed tmde=' xac=a=am Ihchlotonicfmme. b'10 ml) wax added, and the isixoluble xuhdx we=e fdte=ed om, I he νίζζζ ax e' x-ms x-< »tJ:ed w η i mice s, 100 md i, di -cd w ilh MgkO„ and remoxed under vacuum to give 11 4> g (9 I” d < f ?~methoxy-6 mftoltonznmtriU x-Jwh wax nxed \%about fmtber p.infie.d=«> i HAMR. (400 MHz. DMSG-3 ; ' 7.87-7.94 (m,2H), 7.68-7.75 (m, 1H), 4,01 (K 3H),

Example 13(h 4-Amiiirn-5“((Z;bprop-l-eayl)-l H-be»zo|c] i L23Hhiadiaziae-23dtoxhte

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I<< a stsrred solution ol un^-^Mfamfglammf^Apiep-J-emhK'mor.tnL' (Example 130a) (0.82 g, 3.45 nmi-ei ) in Et< >H (18 0 mL). unde: < nZt.'gcn .-.km,sphere ·.·.!. reps-core soiuuvn of NaOH ¢2.0 M. 3.-15 mL , 6.90 inmoti was added at room temperature. The obtained reiximc Α3» Ire st,d al redux her 4 h. Tbe tmxuue was e<'<dcdre mom kmiperatnie amt neutralized spH - 6) wf? j ^: 0% AcOH. i'he nemrahzed irexturc was kept in an kc hath f>-i 30 .,in* t a., >re,..aed pies jit ,k' w w fdkicd wasucq w.<tu tre> C.ie> e ffo d 0 'Ό g Μ s’ ''.o cd the uric compound. Ί he product was punlivd by crystallization from ethanol. ni.p.: > 260 C. ^!H-NMR {400 MHz. DMSO-M) 41(1.90 (broad s, IH). 8.32 (broad ΜΗ), 7.45 (t, J === 7.6 Hz, Hh.7H(dJ 7Mh. Hit. o9-rehi<uJs. Uli. .Ml id J ~ 2 Hz. Hb <> 75 tddM 1 5.0 Hz. J I 2 it IH). o 2 < (dq. J i 5 c it J * 8 Ik 111 >. 1 x%dd. J rSik.J .HL <111 ^s?C-NMR(100Mlk. DMSO-M 0162.2, 142.9. t >fg 3. pm 2. tM 2. i2c x 12i.7. 115.8. 110.4, and 18.7. MS 238 (MH ).

Example t30a: (/:. i-2-8ult'reno\ :.ιηυη.'-{'-{ρπΊ'<-1-«·»χ 'sbcP/'<>nii;ik

A solution of fEi-2-annn<v6-tprop-l-em llbcn amt de (Example iSObi (0 nti *2 imnoll ·η N VeiH,ciK’.<kei.'m.«^!.s (DM 3) (I^s- < retd, unde; a ndtog.m nm-is/bc)/ uax treated with sulfamoyl chloride (0.88 g, 7.63 mmol) at. room temperature. The obtained, mixture „rei re, a see 1 empe m e os 2 b ind t re’ s,m t >n . quo Ή e<t v it ” w ι.^ν( 0 ir 'i Γ 0 mixture was extracted % 4·ι I tOA>‘ (A x0 mt.) me e> mmtwd ^x,r'a,' w a wrened web w.uer ·, x ”0 nt ) asm br 1 and-hied η η , ΧΕΆΤ I v t It ate Are e'>k’I. ed dm eOJuewa-s purified by chromatography on silica gel. using gradient hexanes to hexanesStOAc (1:1) to give 0.83 g (928:..) of the title compound ax a white sol id. .H-NMR (400 MHz. DMSO-M) ¢$9..39 (broad. §, IH). 7.48-7.00 im, 2H), 7.38-743 (m, IH), 7.21 (broad a, 2H), 01-6.65 (m, 2H), l.i> 1 91 (m, 311).

fsmyp'.> <0n U *-?- \minew-f n.op- -c wlike ,.o>'une

Coneensmted KCI (3 I 0 mL) was added slowly to a solution of (E)-2~nitro6(possp-l-..rex s)ben/>>ni:isi'.. {Example 2e) fi)9x g, 5.21 mnmh in Ett'JH (63.8 ·ηΙ.> at room iwpetuture I hen, the ΠΌη,χΙ nuxmro w.ss tsetsed w oh sum powd·. r 13 Ή g 5?. 68 smnui >, added in small portse-ns at iiv..· mme tomp-eiatuk’ The mixtute v, re wstted .u room temperature for 1 - s-mw and then hoaied .4 sefiux mr 3(; min. I'he mremr·, a as rerekM to r, om temperature 1 10( I v.as es.ip'>r.;ted .red the pl 1 w rs adinsted to pH-: 8* w uh .maeere sobstieu us'VPdH f”OM) I he n i^s sod i” xte c u c\i k' . os Η O X>, (t s'00 nl ) .red s’v ouibire I ex J w

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2017200704 02 Feb 2017 was ifoed with radix dreus MgS()< 1 he Eh rate was e\ aporated and the residue was purilk.il lw ehiomategraphs >-i: Oisa gi.1 ituim gradient l-cxanes re hesanes I iOAc (5 2), to atK i J 0 g k1%) of the title compound us. w ' to solid. Ή-NMR (400 MHz. DMSO·^) -/7.16-7.23 (tn. lin O 7-8 <J. J -.211/. IHs c-56-<>(>l (m, HF> 6 35-<> 53 (re, 2H). 5M2 (bread s. 21H, I S?I 86 (m, 3H.·.

Exampi-. t %ι<- (/ ι-2-Χire >-<>-(pn?p- j -en> 1 jbenzosi hrile \ -espemion <n 2-iodo-0-mifubei./i>mtfi e (ΐ xump c I3<\li s j >2 g, 5 '3 ηιιηοΐι. teUakMtiphenslpit>'sphme;palladium(O) {t?.c4 g. 0,55 minelk ?‘(Wx-l-p-<ipcn-l > H.-.-rra-re aem s0 °5 g, !! Or nnnel i. sodium era h<male 0’ or g. 08 minoh and w .tier (=0 0 ml ) tn dtmcthoxycihane tDME» (4O.0 mL» was heated at reflux for 15 h, under a nitrogen. atmosphere. I he ieacttoii mixture was cra.'led to ><,<.?« temperature and diluted Mill ware;· (20 ml ) mid EtuAe (>00 rnl.3 I he otgamc phase w<ra separated and l le a< j iccira phare was <. stra<,teJ w ah I tOAe {3 x 50 ml J the eommiicd extract was washed wrb btme anil dtted w'tb unhxdi.-U' MgSt.L, Hie tihrate was (.'.operated and the sex.due w..-- p<j ukd lw unomiA'i.!. pm on nika gel U'urg paihert besane- in l.es/res Et< > \e Μ D. ra gwe 0 g t^{,} l}%) <0 the .He eemy<iund as a white'--hd H-XMR i40tl MH.n DMM '> /.-) ps H>-8 24 fir, 2H) ⁷ .*? Λν» (in. ΙΗι 6.Π n 5 I tm, 'Ή; i 60-·’ 0? on, 3H) .E8..6p.fok...l30d: ^.-kHki-d-artirolx'nzonurile

2~.AminQ-6~nitrobenzonit.n.k’ (F s>. ople i ?0e» 11 '2 g 2<- 3 mm.pl)· was added in simih pratrotis m a suspension <( redinm nitrite (2,16 H mniM) m concent rated H,SO. (43 ml..} and acetic acid (43 mL) at 45^fiC. The reaciicm w as heated at 45°C for I h and then added in small portions: to a solution of potassium iodidef? .4* g, 43.0 mmol) inH?SCU(t M- 43 nil). After stirring at room temperature for 1 5 h. Iced water w ns added to the reaction, and the pivctpitmed prra.li.ict w as xotleeted bx OUrm-on. The product wras punik-d by ·,.*ΒΐΌί·ηη{>>g:apbx rai silnra gel eh.iti.ng with CH.-CL n> give ^-irak'-h-nitrobenzooitrik' (3 86 g. ??''>} as a yr'.lcw sol d 'll-WIR {100 MHz i p'8 T-< ^2 ι η H) S ii-i k;ni IH) raw , (rjfh

Exampie 130e l-Aininb-h-nitrobouzonitrile:

O’oneentutcd ΙΚΊ (3° ml i was added te a solut'ou of .’.v ο.ίΐίη-.Ψοΐ'.ΌίΐίηΐΛ’ (11,3 g. 58.5 mmd) tn MeOH {233 nil) and 1,4-diox me.-(143 mL) at. 7O''C, External heating was :CUh>\cd. and men pewdc? (I I 46 p, 20^ impel) rare acccd -dcwh in pedi-ips .a rare wr.>..b maintained a temperature of 70°C. After the addition of Iron was complete, the reaction was

WO 20(18/154221 .P:CT/l.sS2(lW065058

2017200704 02 Feb 2017 heakd at icHux set a kushcs 30 mm. llwu e>><>kd m team se-up/raoa>_ ami pouted nno I sOAe i 400 mL> and u ater t 4l»*J mH. The s<-hjs w ate Oik ted . u.t <mJ extracted +, ice + ch bot'mc

EtOAc (300 mL). The combined organic extract was dried with MgSCtp filtered and. evaporated + giw 2-3mn:>>-b-nit:Oben. <>HHfik' <o,5 g i-X''-<) <+ j red wltd, Much was used w ttlmut Luther p-niiieati-m. ^!H\MR (400 MHn PMSO-«M A 4s-’.54 tm. HH/U + 745 _un. ΠΉ, 7 18-722 im. IH) t< 7-1 (broad s, 2H).

F sample 131: 4-Amiiio-5-v,Z)-prop~ 1 -r«yi)~ 1 H-brnzofcli 1,2,3Jtbiadiuzsne-2.2~iHoxide

553

Prepared as in Example 129 from iZ)-2-svdfamojlarmno-6-(prop· I coHbcn'x xtt.k (Example I ' X + \n..n + ((/'> piOp I an’.i <H benzolc]|1,2,3ishiadi.e'inc-..\2-Jso\a.k t_e'x ..' mg 91’00 k a sH-Ue s-'iid ^lH NMR -400 MHz. p\bs a 3 lu ?,' {bn ,ul s, IH) x 30 H'teae. <, Μ1 ' l-L bltrn H D. + 9()-/00 im 2H) r>+3-689(m IHL οΐιχ.ρ 73tm. IH). b SS-5 99 rm = Hl, 1,+((-1 ontm.dH).

Example 13la: (Zl-S’Sdfemnylamino-b^iprop·· 1 -myljbenzmiitritePrepared a., io Example- 129a from (Z}-2amino+-tprop-l-znyljbenzonitttie (Example 3b) in amount of 32 ~ mg {X'fid ax a white solid, ^!H NMR (400 MHz, DMSO-ds) 9 9.45 (br-'ud x. IH), 7.?9-“.65 tm. IH? v-T (d. ) - ?.+ Hz. IH). ~ 18-'-'.2s _{m. 3K). 0.50-+.M (m. IH), 5 99-6.00 tm I Η). 1.74- i 79 tm 3H) χ<?η'χΰ> '> (Z)-’ - smt υί-ο-pm p- > -enxt) <_tm?<mm'l (\> vemr.Rxl HC'H >4 nd ) s\.+ aece-l tc a xaspcmXm cl (/n'-n ’rc-b-(nrop-l enyl)benzomtrile (Example:3c) (035 g, l.M mmol) m MsOH (30 ml.) and 1 M-dioxane (15 mL) ,U ream temporanc'c mH,-wed bs port +? λ+c xddo >m o-'rrei ond-, r{0 /3 g I ' 0 nnu-X> The obtained -m'-umc was heated at rcthtxM let 2 ' it. corned to 0u ' 'U;d the pH. was adjusted to pH-10 w uh .tm.:com> 5(r'e solmi- -n of NaOH. fhe mixture was extracted wuh EtOAc t3 x 50 mL). the combined extract wax dried with MgSO₄. filtered and concentrated. The residue was purified by chromatography on silica gel during with gradientO% to 100% DCM m hexaaes, to give 0.24 g (80%) of (Z)--2-am.ino-6-(prop-1 -myObenzomtrile as a yellow oil. Ή NMR (400

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MH/.O Mm ./ml 7.24-730{!u. HH. 6.083d. I M Hz. Ill· <'-· 55 (J. J 2il·. Mil/' 42o 48 un Ml·'. 5 ‘to (hnud -, 2H). ' 89-5.9? (ns. UFs, 1 74-1,?8 (ηι. 3H) MS 159 (Mil ).

Example Hie: (Zb2A0tro-x-{pr>'p-l <sn ^;)hcn, <«imilc

Prepared as in Example 129c from x-cyano-3-nProphenyl

Ustluomn'wllxme.-nl Innate Example (1294s and cl·· 1 -pr-apen· l-y Ibomnic acid. fhe crude product was pu-iffcd by cisiom.-,f gwphy on Alwa ad du’.mg w-:h .-oh cut gs.tdse u 0''»-- (0(Η·, IP M m hexui'.cx, to g-©c 9.89 g «“Ή of {Z}-2-nirro-u-iprop· l-cny uhcnzo-judlc /'’Au a.- a yedou -©lid ’H \MR t too MHz. nvso ./ ) p i Μ X .9' IB' Hl·. “ 9(i ' 48 (m ?HR* 25 e ”61 n .Hp 6.17-n.2x on. Hl·. I/8-1.82 (m. 3Hs.

Example 132: 4,54>iamhmlH4nmzo|clU,2,3hhh«liuzhiC2,2-dioxiije

554

Prepared a- in I.©ample l.M from 2-sulfamoylam.mO’b’amsnobcBZc»nnrile (Example 13...:9 in amount of 953 mg (x-l‘l··) ©s a brown solid. ^νΗ NMR (400 MHz, DMSOwE) 0 10.55 (broad a 111·. ^91/1.:^3.210/3^-7.16(1.,1 -8.0 Hz. I HR 6.42 (d J - 8.4 Hz, IHk o.'.'ul, J 8-I lb© I Hl ? 9 flcoad .-. ?lh b-ample 132a: 2 SuIfamoyla:·-6 armnobenzormnIe

Prepared ax in Example 129a from ? toJummoben/<-m-ni·' (Example 132 b) hi amonm : I ^Vi I mg (i>0.,4 a- a brows? ΉχΙ H \Mk (100 Mil;, DMS0-..M ,0 9 00 (b'Oad IH;,. 7 18 (t, j ^:: Holl?, Ml·, 7 Ox < br·.»:; J -, 211-3· mAx 6 7 I m, Hl), ί» Ι°-< > 5 ; (m. Hl· 5.95 (I - 211)

I ' omple. 132b: 23-Dlamonobcnzmutnle t\»:W0:4:j Bed HCI (11 3 ml ) w.s- a>:de-l m a solmson >· /-.:imitobom··mmile (1.2.9 g. 67.1 mmol) in MeOH (269 ml.) and .l.,4Mioxane (1.66 ml.) at 70^/. External healing was removed, and iron powder (13,1 ,g, 235 mmol) was added slowly in portions at a rate which maintained a tesuperato-e of 70' C. XOer t-v aedipon »' mw was t err33e m- reaenon was Iwaicd a? icfhix for ;s iuidwr 30 uust. ikcu c>><<kc to icert .empAaltm. .mil ρο.κcd mie EtOAc (400 mL) arid water (400 mL)· Tb® solids were filtered out and extracted twice with boiling EtOAc (300 mL)_:. The organic layers were combined, dried with MgSCU, filtered and

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2017200704 02 Feb 2017 <.-oucenlraied The crude product was purified by ie-cree phase ebrosnatf-graphy (OH 0=3 % = Ί BCA re H.-ι»? m give the mle compmmd {I O g 11' ,·). w hieh wa- ured w idi<un fm die= prjjtieatKm MS ide (MH )

Example 133: 4-Aminii-5-x BbMH-i>enzo|cH L2.3Bid3diazme-2,2-dioxnk

Mu %

555

Prepared aw in Example 129 from 2-sull-noox lamreo-6-vinylbeuzormriie U.sampk HL; re am*>nm of 30 0 mg t l/<,) .,> a whik so’JJ Ή \MR <400 MHz. OM\! >-J g 3 h»98u'roads MB. 3 -'· (hod-. ΗΠ 7 tS_u s x 0 Hz HI). ι x (d J 7 6 Hz HI.09 uld, J 17 o. t(i X H . HO r °0“<»'Μ (ni. zlik ' ?x (dd. t I7< ' 6 Hz MB, 5 17-44 t 11.2, 1.2 Hz. IH).

Example 133a; 2-$ui tamoyhmmo-6-vmyIbenzonltrilc

Prepared as in Example 129a rrom 2-ammO“6-vmyrocnzorutrilc (Example i ?>3b) re amount ι-Jot 0 mg pM' ,-i. a- a wbue sei id ΗI AMR (400 MIL, DMv ?-d i 0 9 4o ^bi-iad x. IH), 7.59-7.67 (m, 2H), 7.46-7.52 (m. IH). 7.23 (broad s, 2H). 6.93 (dd. J - i 7.2. 10.8 Hz. IH), 6.08(=1..1 H2IL· iH).5?0(il.J ll.2Hz.HB.

Fxamffb.I33b; 2.-Amm0-6-vrnyiI>enzunltrifc fa. oared as ns Fxamole 2^i}b r-m. 2~ rm < n.x llvr, - am: sb lExairpk 11 'es =r amount of 123.9 mg (71%). as a white solid. Ή NMR (4(M MHz. DMS« W>) 4 7.25 (i, J^:::: 8.0 Hz, IM). 6.87 -:d. J - 7.2 Hz. 1H), 6.80 (dd, J - 17.2, 11.6 1 Iz. MB. <‘- (W (d. = 8.4 Ife, Hi;-. H00 (broad s. 2H). 5.92 (d, J - 17.2 Hz. IM). 5.44 {< J - H18 ife, IH).

Example 1.3.3c: 2-Nid'o-6- vmyIbcuzonkrite

Psciuuda-m I xamnk 12% nori d-ewmo-'i-n-A.'i-Lur-l ynluosom^d'asKaulh-natc I xamp e {.29% m amount ofo o= g {86%) as a - Jlo-x -.'Rd H AMR (400 MHz. DMSO-%} 4 8.26-8.34 (m. 2H), 7.90-7.98 (m, IH), 7.09 (dd, J - 17.6,. 11.2 Hz, 1¾ (- ?*> (d I 1 7.o Hz. IHi, s 80 (d J 11 o Hz. H)

Example 134: 4-AmhKMr~Raoro-5-(2-methylprop-4-e«yI)-1H-benzolc]11.,2,31 thiadiazhw-

2,2-dioxide

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Piqmied as in Example 129 final 3fluoro-2t2ine?hxIpiop· 1 .nxRo· '-Hifanres I i:nin<>:wnzO.nt detLxeup-c unt of 123 0 nre (W'’·) ns a x. we ><’hu re p ''259 C Ή \MR regm Mik. HMSO Λ)<> I Μ K 5H). I re. λΗι. v T re, MR ’ dd tm, HR “ Id tbie.re x HI). ~ A (m. HR * '5 fbtoad .-. Til. ’.0 ‘A < m <J., JI) MS 276 (MH 1

I xantp e 13-Μ 3-1 m<<Hi-2-(2-meih\lprep- I -end ι-9-sull-.imox iaminoi'cn/<'umik Prepared as in Example %'^?a from 6-amino-3-lluore-2-i2-mcthylprop-leny hiKm?oniirilc (Example 134b) in amount of 156.0 mg 188%). as a white solid. MS 270 (MH i.

I sample 13-m mAmmo)- I<·< >w-2-(2-r ictbx Iptop-1 -em l )n>.m/orin'le

Prepared ax m I sample ΐ 2Ά bote E))uoio-2-f2-metbx Ipiop-l-erxh-cniir>'Oeu/_x'nnr'le f I sample 15-%) ns .marem 9 A c, {54’ _t>> .re ,t wIme ..'iid MS EH (MH > Esample 134c 3-biikxro-2-{2-metip lpn-p-l cnxRo-mvoOemAmtedc

R<’m.' 3 fuel.' e nnieben > reluk (Exampk 1 MJi (0o2 2 53 neu.M.2 niCiu’Hpp-p-l -vox footome aeiJ (0 50 g. 5 uundk palRhamUl) aeesuc (0 623 g. 6 162 mmol), IfoPCfr (1-61 g, 2-58 minol), mid dicyelohexyl(2\6Miniethpxybiphenyl--2-yR')hoephme (0 <383 g. 0 202 mm>-0 wete -usf'endec n arbcdiotre MH f Io nd '> unde' mw-gcu and heated at 70°C for 4.5 h. Solvent was removed under vacuum,, and the product was purified by ehromatography on silica gel elming with gradient 0% to 100% ethyl acetate in hexanes, io gi ve .>-nii0ro-2-(2-reeihyinr<>p-l-ei:x H-n-unnd'en/ouitTiie H.44 g (~x%) a·^ a yidhox solid. MS 221 (MH').

Fxampk Mid IsHronux-l-rkoio-P-remn'vu anntn e

Tneibx kmnne ι2 M wl.. Id 2 mm-»h wax added to a saxpension.of2-bron)0-3h n uoben _rfjiA\ (I x tii'ole ce» (- rO g,«' 98 πηοο' ι n P^{f S}C - _v % u'l t . id the mremu reax Lx. ted at 5 'C ιοί 1 5 η I la. mixture was eaufullx pom-A into a nexline of ice and >,xutei f U\i mt.) and exUxu'U'd uwee woh <ΊL< E t hz combined extmel xxas rexon MgSO_s ‘iile:vd and concentrated under vacuum. The residue was purified by chromatography άπ silica, gel eluting

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2017200704 02 Feb 2017 with xohenl gradient 0% to 199% Fl< k\c in itexunex. to ghe 2-Ι«<«ιι·.:-3-ί!ΐΐιΊΧ>-6nmci’en/emtrde 0 9«, ax a yellow xukd

INatnpk i 34e. 2 - Β t on re 3 - II· ,< n<»- u - n are I »c nzami de ^-IhmtkwMhi.mA'-reUohc'iU --re aetd fl sample 134ft (24 S3 g, 94 1)) mmol (mixture of'two te£tofs..imctre wa,-, -Jrewb cd tn anhydroux Ί Hl·' COO ml '· nudes a ritw.geu auwospnau at lempctatutv. ftmip do-ax PME (0 ^7-:: nd I wax added and toe fOtemeu mixture wax ».ouied to 9 t' < hrevl ehl·-ode (12 3 ml, 14! mmol) wax xk-wte ^Jded and to-„ :eacif<>»i -nsxnm· wax stirred at 9 s. }<<,< |(t η-ίη, and at r>><>m tempo»alate for a forthes 2 h. 1 he reaction wax evaporated te dp; to-, ^expended nr <mbydr>>us I HI s 199 ml } and added -to>wiy l·concentrates! animonium bvdo>X’.le (35») ml t at 9C -Mier xttosng for 45 tsunntex al 0'C the mixture was extracted with d i Ml· re x 100 ml to and rue mgutnc cxu.ku»-ns wete then dixemded \t thL· p--re; the -.(. re red t-.gioixomet cxtxied as an ii'totto c ptecsp- a lite a-p-ce-re saver, which was collected tw ftltiait--n to J’re 19.-. g 142''·») <4'2- In,-tm>-3-iluoro-nnitrobenzamidcwhich wax used without further purification. ^lH NMR (400 MHz, DMSO-<fo) rl •x 2 i (dd. I == s.8. 4.4 Hz, 1 H). 8.10 (broad x. Hit. · 4'5 (broad re 1 H) M- (sld J === 9.6. 7.6 Hz.

Hi)

Example 134f: 2-Bromo o fiuoto o mrebertzoic acid .to a IL, three ne% re Ikwk ή‘ted w-ith a dropping funnel and a thermometer wore charged z-bromo-o-fluorobeMOs». u»d M xasnpte 134g) (28.23 g, 0.13 mol) and eonceotoUed IhSOj (200 mL). After cooling to 9 { . H\vh {'0%, 16.9 mL) ww) added dropwdse over 39 min. keeping the temperature betwe·..»' 9 '.9 ϊ Alter 1 h. the -ο.ιΠΗ.-η nu.xtnre wax pc-ured turn the crushed »ee keeping, the temperature below 20 ⁰C. 'The mixture w ax ext’acted w (th EtOAc (2 x 299 mL) the c mbined > w a, s wax w.ssaed wito btire anuc.t.J wnh Mg% Fbe I'ih? i\> v .tivapomted to give 27 .? 7 g (777(,) of a m store «sf ?>bron'a~3o*6-nii*s>l·· n :oie acid and 2~ bromo-3-flu0ri.>-5-'nitrobenzQsc acid (1:0.4) as a 'mow n x si d Η NMK ί 1 fif) MHz, DMSO-;./#) 9 833 (dd, J 9.6,4,8 Hz, IH), 7 21 {dd, J === .10.9, 8.0 Hz, IH).

Exaniple 134g 12 - B ro mo~ 3 - fl om=obenzoic acid

In a I L, three necked flask .fitted, with a dropping found .md thennomerct were charged ^.-ammo-S-lhiorobettzc’e acid (20.0 g. O.t 3 mol) and acefomtriie Io0 ml..). After cooL\. to ο -. Hli sj ⁰ ,oO ul 'Λ.'χ si! (.’d <>'w wove I Oren 11' the wwli tig wlst’ion txohitom o^'N.'Nf J'('9{’ ; 0 1 1 nx'lt »' w -to s ^!0 >.» nft) w w ssa.ed Inpw-eoser.z M’er

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2017200704 02 Feb 2017 addiu>>u. the rcaedei- nsixtree stirred at O'C i'o? 5 mm. ami euppepb Itresmdc ¢22 0 g. 0.1 5 mid· was added portf>>u\x:s^'oxer 30 nun, xurmg ^v-as c>nmm;cd re 7(i { ma an ml hath fra 1 h Mier Grading g.- ()'’('. 700 ml of txaicr w as added auil the ptecn>i^!.ate xsa- fibrecd. o ashed xxJi cold waler and dried under vacuum to gtvc 28.23 g (100%) of the tide compound as a white solid. The crude product was used in the next step without purification.

Example 135: 4- 1Μί»ο-5-^>€ΐορκ«ίκη-ί-ν1ΡΐΗ-Π<ηζο|χ’Π l,2x3}thiadiftziut‘-2,2 dioxide

557

Prepared as in Exantplc 129 f_rOin 2-redfatno- la-nino-6-(excfopenkm-lvttbenzoiut.uk (Exampk ι - Mi m ameere ?'8e o m”. {33^l\o as ₍ Mak sand H b<Vfk i lp(<

MHz, DMSO-i/J <) I -97 -;m. 2H;, 2.4s (m. 2Hl 2 58 (tn. 2Hi, .8,94 (rn. tilt. ¢-.83 (broad s, IH).

92 (m, 2H1. 7.46 (m iH), 8 2'(hn.,id s, Hj m u2 fbioad s If) Mk?u4{MH )

Example 135a: 2--Sali.amovhunino-o-reydopet)iou- l-yhbcnzomtrik,'

Prepared as in Example f 2Ή frt>-n 2-imnno~6~(cyeIopenie!Sl -yl)benzon:iiriIe (Example f 35b) in amount of 156.p me {88^c.,j. as a -xhitc s.did

Example s ^5b~ 2-,-knn’no-64 ex eftί <enle- ¢-1 -yf (benzonitrile

Prepared a» in Example 129ρ from 2-(cx cl-rpcntcn-l -sdl-h-mtrobunzonitrilc (Example 138/; in am-rent of 9.-I-I (X4’’-d as a white ^-did. MS 185 tMil ).

fe.9W!g:1135gh 2-(Cyclopente.n-1 -x Pi-d-mirobeuzomirile

Prepared as in. Example i 29e from. 2-eyano-3-mirophenyI η iduot-.'inethauesulfonau.' (Example = 2‘kt) m mmmst <>l 0,o2 g (84'' <) us a x-hPc ;mrd,

Example 136:

W k

Ί

558 ^!

Prepared as m Example f 29 -ntm ^-suttUmoyUrntpo^-^rOpylbetigopitdle (Example 136a) in. amouut of 144,3 mg (66%):as a white solid, ’ll NMR (400 MHz, DMSO-/J

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Ο i 0.73 s bread s, 1H 1. 8 J 4 (broad s, 1H), ~.44 (broad s, 1H), 7.38 (t. J ^::: 8.0 Hz. J H j, 6.97 i d, 1 ^::: ox Hz. Uh. 6.80 id J 8 OIL·.. I Hi. 2.97((, J 7.u 11/. 211). I 51 (hux J ~ <- IL·. 211 i. 0.81 p. J >il·. 3H)

Example 13% 2-Smi-.m=ox L;mtoo-o-«-pi\.>px lben/<>mlnk'

1'irp-arcd j- in Example 12% hs-m 2-.-nnno-o·?.·piwpyIbene--nih Jr (Example ^l,x ) h: aiiii,ιχ\>’. Hiij. 3 ' \ ax a w hue x-akd H NMR (499 MIL·, HMSO-A) O') 3 ib:mkK HU. 7.55(-. J 8 4 Hr. iHt,7.V>- 44(m, IH). 7 Γ·7,2.ν (m. 3H). 2 ⁷1 (tJ 8.6Hz,

H). 1.60 (hex. J 7.o He. 2H).0.90it. I

Exampk I3ol> 2- .Anime-n- < p-(>-pyIbcneomtuie (/1 2 Xip no ο ίριορ I cih.iXii/iMii 5 e -U 'amp e υ ρ» 45 ~ 2 82 mmc.) nud H3% l’j (.'<<'}.(' g;. u-.-ic .-tn-ed m En >H {15 ml I trndes a Ip d-oeen atmospka: l<= 4 h. Ike catalyst \ub filtered *ut. and rise organic lay er was c-:mce«lratcd under vacuum to give 0,43 g (96%) or .I-amiuo-n-o prr-pylbcnzonfrrik' as yellow ,·=!. w meh w as used without further purification. MS 161 (MH )

Example 137: 4-Aminn-5-mrthoxy-1Ii-beazo|cn L3m I thhu.liazine-2,2-dioxide

NHa OMe.

5S9

Frepared as in Example 129 from 2-sulfitmoylamin66-meflinxybenzonitrilo (Example 137a; in amount of 13-8,9 _tng {9/%) a.--wbitr solid, 'll NMR i 40b MHz, DMSO-rM u 10 09 (broad s, IH). 8 ?8 tbroad s -H>, ^.()3 (broad s, IH), *.44. ft ,1 s.O Hr. IH). »'.*0 (d J 8.4 Hz. 1H). 6.58 (d. J - 8,0 Hz. 1H). 3 89 _u 3H)

Example 137;;: 2-$ulfamox lammo- o- methoxy benzonitrile

Pivpateuax (nl x..implo 1,.% (n-m 2 mmro 6 me'huxxhcoeotn'ple (bx-implc

I ' '·'») ir ani/f'i'· o’*' »' rq $8 'A ', ax a w hue x-;l d H NMk i 109 Ml 1/ DMSO-.A) <)’* + + ίηο.Η- ’Hl x; p I \ I H' IH). •'(hr- (4-.211) , ' Mu I 8 0 Η,, Η1), 6 % I d ,* 8'8 11/, UH 4 87 M 3in.

I x.impic I MH 2-Amin-.>-6-moil:Oxybenz.m6triie

A solution of 2-methuxy-6-n itrobenzon itrile (1,01 g. 5,69 mmol), cyclubeximc (2.84 g. 3.51 ml-, 3-1 58 mmol) and 10% Ed-'C (0..58 g) in EtOH (25 mL) w as refluxed for 1.5 b.

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The mixture was cooled to room icrnpemiure, fihuted and exaporaud. io ato-rd tnc title compound (L83 g ¢/%%). the crude product was used at the next step without fujdu-r = =wto_C ,i_Wf! b\MK<4rr\?H'Jl\iSC-Md 17 ft I \')lk Hh (·'!·<'· >5{ni Hl\t>l7 o2i tm. on.5<r {bm.=d-.dm. vTi-./in

Example J38: 4-Anmm-5-(prnp-1 -en-2-yl)-l 1 Ebeazo[c]11 X^hladiaziae-2,2-dmxide

500

Prepared m m I .xampic I/° from 2-sulf.xmoxl.tm»-0-(=-(prop-.l-en-2yObc-w η-’ΐικ {Exempt-. = <M) m <mu r; of ¢=3 e ng (5'^iV »> ax .i whn·. xol.-l 11 \M8 ( UK* MKz.DMoi)-% )<> H Ootbroads HI), r. V tbrotox. IBs 44 - ;'.52{m. HI}, <>.%i-'.OO tm. .IHk o >M-o 30 sou Hl).6-82 (broads. Ilh.S 16-5 = 9fm. Bh. 5 3t-5 <5 Pm IH). 2.00 (x. 3H). fAampleJ.38a: 2-$ulfamoylrtmine--6-(prop-i-cn-2-yl)bejrzordlTtlc

Prepared as in Example I 2% frvtn 2-amino-e-i prop-J -on-2-χ h benzonitrile (Example 138b) in amountof 80.5 mg {i(>()%) as a \dloo \oiid Ί1 NMK I hv MB \ DMSO=>' Ί !0 =%= A-,'61 (m, IH), 48-' >' pr. IΠ) / A (broad - .'Hl. ' 1 s-/2 4 i m

IH), 5.34-5,40 (m_s IH), 5.W-5.14 (m, Hip 2. = () (s. 311),

E40.uiP.k.l.38b: 2-zM.nino-6-(prop-l-en-2-y!)beuzonitrilc

Prepared as in ..Example 129b from 2--d(ro~6~(prop-l -en-2-yl)benzonitfile (LsanipL* 178,.) in .midimi of 303.4 mg (83%), as a yellow solid., ^!H NMR (400 MHz, DMSO7>) d 7 16-7 25 (nj, IH). 6.67-6.72 (m, IH). 6.47-6.51 (m, IH). 5.97 (brnad s. 2H}. 5.24-5.27 (m. Hl) ^ζ 07-x j o (p., 1H). 2.03-2.P6 pm 3H) tipple 135m 2 - Mil ro-b-fprop-l -eB;-2-yI)benzon:ltnle

Λ xu-p-.i^nO of 2-cvano-.'t-miiophenyl triOueu'nx'tljanesultbnak' (Exampk·

129d) (0 % «, ί 1' nm =- ), poLixxwm ndO-m'ipmeM-en-2-Ojp a Λ' ii) Ό _ 4 71 nenol) Ochsm? id'-bustdiph0=ulpli>-sphei'nk-n>-cere p.dk=cmndlb ib 2(= g. 0 ^?>2 mmols vk»mr carl»mule (3.08 g, 9 4-~ mmoll and water (5.6 mL) m TH) 156 mL) wax heated at reflux for 25 miiu under a nitrogen atm»wpbere. The. reaction mixture was cooled to room temperator® and dilutee upb v.3tot ( H)() ml 1 and Eh ¹ \c -,100 nd.). The -mgumc ohcxe was .cwimied and the mpicou- phase waa extracted w=(h l’t(>Ac (3 x 109 nsl 1 The combined extinct uu» washed uh

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2017200704 02 Feb 2017 dimed H< '1 (1,5M s. bin:c a?;d d; red n ith anbx drotK MgM)i. The ftfe.ite wa- e* repeated and = % residue x'.as pm u ted b> chtmnal-.'graphy on sdica gei using gradient herein,.⁴- ΐ<» b^xanc,' Ei(»?ke (7 %, {0 gn c 0 30 g %4%; ofth- fide cempotmd to a x J'.mx scad ^!H \MP (460 MHz. DMv ·>kA 0 8.24-8.29 (m, 1H)?,7.86-7.95 (m, 2H). 5.47-5.52 (m, 1H), 5.20-5.23 (m_# 1:H), 2/12-2.15 :(m, 3H).

Example 139: 4-Aini»o-5-e(hxl-1H-beazo|cH L2Jfrhiadmzini’-2,2-dioxlde

561

Prepared a< in L.xample 129 from .l-sulfamoxlnmmo-b-x inslIre’n.’Omirile s Example 139% in amount of 84.2 mg (80%) us a white solid. ^lH N.MR (400 MHz. DMSO-J3 0 I0 74 (breads, HIM Ι(><ΛμΛ. IH>, ”/4- , <(n: ?llV>'^!'fid J ? Hz ΙΙΙΜ»Μφ« s re. i H). 3.00 (q. .I == 7 ή Hz. .:11). 1.12 % J == ’.u Hz, 311 >

Exinn,gte.l39a/2-SuIfe:moxdumino~6-¥inyIbgnzonitrile

Prepared as in Example 129a from 2-affiino-6~ethylbenz0nitrile (Example 139b) in amount of 280.3 mg (98%), as 'a. White solid, ^JH NMR (400 MHz, DMSO-rfr) 9 9.36 (broad s, lH),7.52-~.60(t. J == 8.4 Hz, 1.H), 7.38-7,43 (m, IH), 7 19 7.24 (m, 1H). 7.19 (broad s. 2H),2.75 (q, J == 8.0, 2.H). 1.18 ft. J = 7,6 Hz, 3H).

Η.ιηφΙ> non re a mmo-bre; hy Ibemre-r 4r= bPrepared.as in Example I .?°h fsom ihd-n-nmvdxmzoH.U'-le (Fs.mmle 139c) in aiuenn: ofO )6 g ί 74%) ,ι- a oemge solid Ml NMR flOO MHz, ) <> “ Is (), .1--R 0 Hz,

IH),n ·)<.. I .1 SGlKfihM idj M He IH) S X'Woad ' ?Hk ·Μ){,%ψ.ί- TH/, ’Hg Iler. .) t 6 Hz,'ll)

Example 139o; 2-Eth¥l-6-niRx)benzoni.trite

A. suspension of 2 ethyl-6-mtroaniline (Example 1.39d) (1.96 g, 11.80 mmol) in a xoluuon of Hi Ί { 3 0X1, 2 I 5 mL) was stirred at room temperature for 20 min After cooling to 05 ”(', a 'ωΐιιΐκ'η M NaM)? (1.63 g, 23.6 mmol) in water (12,25 rot) was added over a period of 1.0 min. The obtained mixture was stirred at 0-5 °C for 30 min, and the obtained homogeneous .Solution was transferred to a solution of CuCN (2.63 g, 29.S mmol) and KCN (5.On g. 77.8 nm:i>n iu ixa-c” t,o*J ml·) and th? 41 ( Π 0 n.Lh T'K-t.'su th y nuMum \ias Άπί.'ο xmotm^jx <0

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2017200704 02 Feb 2017 ifi'U) tcmpciJutc f>'< ?0 nnn, and then Leak'd t.t ”0 ‘Τ' ιοί anolbcs 30 nan b· eetuplctc UK iCueitoit, 1 h> seid mixtnse was tikese<l and cxlsacled a uh En (Ac (L\ 100 mi ) I he eombnrd cxtstK't a as a ashed w sth Nat Hl f'd '<M) and bme. ami dreed am. anhxdfei.s MgSO The riki.m was e'- jpmaied anti the residue was pre ssed bx cimmsmogsaph'· an silica cel during aith )()% EH has m ht\3;K.- b- at'toi d 0 on g; 3,0011 of Hu fiik cempout'i' re an , xobd. H \MR (400 MHz. DMSO-Λ) d 8.18-8 24 sm, i H). -085-7.97 (m. ..'He 2 93 up J - 7.2 Hz. 2H), 1.24 (t_{ J - 7.2 11:.-,311).

L\<W.Is 1390.. 2 L-M-b rnmremmw'

Λ s-riution of N-(2-elhsd-6-nitrophenybuclamide (Example 139c) (0.62. g, 2.98 mm>d) m I (OH <,2; mi 1 .usd e»-ju.abated HOI ί ^s3 -υί. '> was efltued 6 i 2J b EKsH are ex apo-ated. the undue a as diluted a uh wa-ei t10 ul > and me pH a as ac UA.C. :> pH - n a ch >M {2 (Λ1 aqae> us .mimics') I he .scamd./-.C sc'.at mi was c\f;acke a rh bni \c to \ >0’ ixil I, the cmrsbmed extrnct xres wrehed with xx;der and hrm·.. and discd aub .uilixdrccs MgbO I he fibrate was essm· mik'd and the residue are puistled en HP1 C to g-xe 0.3? g (64%) -it 2-ethxl-<>nitroaniline as an orangs' solid. H N.\IR (466 MHz PMSO-,/.', 3 .s?-7 8; im 1 H'>. 7 2.7-7 3.2 im. iH). 7. i 6 (broad <, .ΪΗ). h.55-(U'2 im, IH). 2.55 ₍q. J - /.? lb; ..ΊΗ. i 13 it I ” 2 Hr. MH

Example 139e: N-(2-gthvb6-nitropheayl)aeetemide \ sdbmee <?t mires ac.6 f4 ? ml I m gkiccd a.cct..c ack <_ν· 2 ml ) I a,is added dtep a s? v sole ior <4 k-s '-et \ pbe alia cs wwk (1 x -mple I '<Ή { y 6 ’ 3 trere 4' n XU ΗI (22 ml 1 and aeeue anhydride (In ml) at 0 ''C. The reaction xxas stirred at 0 ^<;C for 1 h, dik-ted A\h xx des {‘Όί'.Ι I.... I nes'd'a’i cd am. Xa,x OnpH n> Ih, tens al \v irx nre a,\ cMtacsed :tb b'rM Ac v 3 x ''0 ml }. the csnnhined· extraet was washed with water and brine, and dried With ,tnhx dams Mg.aO_; I hi- ill-tab a as ,-x apora'e„ .mH tne tos'deo xxa- parried s>a Hb'kt te g x f)o? _s. t, lb'h ) et the ribs' eompei'i'si as a xx'tsy - , hd H \MR 1166 MH/ 1 ΑΡΜ-,,ν η 'i si (broad ’: H) s<8-7,73 im > H) , s - ' n~ ur i H'. ’> <9 k J n 0 H , HI) 2 n 1 (s] I x 6 Hz. 2Hh 2 06 is, 3H) 1 16 H, j = 8 0 Hz, 3H).

( xausjpre' ΐ'mf X-MethMpl.cnx Ibw.-t'arnee

2-ΓΗ ' er h m t'/ 'Og, xO<! m k>1) x> ·, asidek> < rnMare' ef e„ kt \eOH t '0 ml..) and aetic anhydride (20 mL), andthe resulting mixture was rgfheced at i 20 X ’ for ?>h. The reaction niixime was then cooled, to room temperature and poured into a boiling snixinre of water a id I x)ll t20'»1 i.re'u Γ s n xtt se xta- ''me I .u u f>n I ί at'd ken i Ox^kd L<-< A i ume,b.

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ElOH was evaporated and the remainder of the mixture w as diluted w uh w,ner (100 ml ) The. obtained mixture was neutralized w ith Na.-CO? and extracted with EtOAc. The eombined extract w as washed with brine, dried with anhydrous MgSt're. filtered and evaporated. The residue was plunk'd bv Juwmatograpby on stHcagei dating with 5‘\> Me' til in ( IH Ί re ailord 5 50 e (42%! of tnc title e»> up· uim as a pn:k ·-> id Ή MIRt4-i'i» Mlv. IJM^O ,\i e ” tbi·s,

I Hr 05--.40 tin, 4H?. 2.55 (q. 1 = 7.6 Hz. 2H). 2.02. (s. Mi). I p, j ?._υ Ha 3H)

Example 140:4>An»iao-5-hydroAi -llbbeuzoicH k23|thmdfezme“2,2-dmxide

Ni-h OH

562

Prepared as in Example 1.29 from 2~sultli.moyIammG-6-hydruxybenxoilitrile (F\ .rede I loal re .-nounl «>f '0 <> mg 170'x ; as . mown m- ic ΊI XMR ₍'·0{> MHliMSOm'·.) 0 11.00 (broad s. IH). 0.24 thread s. IH). 37 (i. J - 8.0 11 \ HIE 7.18 (broad s, 2.H 1. 6/)7 (d. J 8 4 Η/. I Hi. 6 id. 1 84Hz.IHi

Example MOa 2-Su fan < w rei.<'-<'>%< beys Km ret Ode

Piepiued a* m Example I2°a trem ^-amiire-A-m·,Β·i\vK:i.',>imiiie ilb,,meplc

140 b) in amount of 0.25 g (99%), as a brown solid. ’.H NMR. (400 MHz, DMSO-if,) 6 1.1.01 (bread < nn.%2M breads. IH i. 7 57 (c J 8.0 H/. 11H.7 1 8 ₅bn>ad s. 2H). OM5-6M0 <·η. ill). 6.69-6.74 (m, 1H).

f ran p:e ΐ->0^!ι 2- \m rerai-hAUAXsben/e'm ih

A solution of2-mcihoxy-6-nitrobcnzonitrilc (Example 129f) (El I g. 0.% mmol) η I OH t 20 ml...) was hydrogenated over a catalytic amount of 10?·« Pd.-‘C (0.15 g) at room temperature undef hydrogen (1 atm). Alter 2 h, the mixture was filtered and the catalyst was washed w uh I (GAe {150 ml ; Thr combined e\naei was es ated. ti· give I Π gpOO^e.O <4 0k title compound as a brown solid. The crude prodiict was u,-ed tn the next step without further purifieatirm. ^SH NMR (400 MHz, DMS0<) 4 1039 (broad s, HI), 7.00 (t, I - 8.0 Hz, IHk 6.12-6.17 {m. I Hi. 6.01-6.05 (so. IH), 5.77 (broads, 2H).

Example Ml: 4-Amim>-5-“phenyi«I H-benzn[e] [1,2,3hhiadiaxi»e»2,2-->dioxide

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Prepared as m Example 129 from 2-sulfamoylammo-6-pheuyIbenzomtrik' (E -.anple I Ha} m ©mmml <>f Hl mg C?0“..} a- , vJihe -did Ή NMR {Old MHz, D\|S(kM v i; 12 (broad s ill). 8.04 (broad s. IHj.. 7 52-7.58 (m. IHj.. 7 39-7.50 (m, 3H}, 7.32-7.38 (m, 2Hk 7.03-7.07 {m. 1 IO, 6/7-7.0i (is. I Hi, 5 61 (bread < Hl}.

Example UH· 2-Sii=fam«>©’lamm«>-«>-ph<ij\benzonitrile

Prepared as in Γ ©ample 129;' -roni .Kmmhdnphe.ml-2-earbmmnle iE-ample

141 bs in ameum <>' ^;42 3 my _a whsto sohd. ^:H NMR {400 Ml 1/. 1)MnO-©\| ·> 9,4>

ί broad s, I1 h, 7 r8-7.74 (?», ΐ Η I. ~ ^0--.62 urn lib 44-7,55( Η 7.3// Π (m, 1 Hi, ,2^C< /road-. 21 b.

Example 14lb, 3'Ammobiphenyl-2-earbonitnic

Prepared as in Example 129b &om 3-nilrobiphenyb2~carbonilrde (Example 14Im as amount of 11 7.il my (80°<0, a- a v. hii© -mid MS 19© i MH }

Example s4se --Nmohm’um\l~2~carixmi.tale

Prepared a- in '3 ample 129c from 2-e.yano-3-mtrophcftyl triEuoiomethanesuIfbnate Π xunplc 129J) and phcnilboronic add .

Example 142:4~ Ami m>5-ssaprnpy I~ 1 H-bcmw (e] f 1,2,3} thiadi adaa~2,2-dioxide

NH^k._x

564

Prepared a- in LxampR' 12° Oom .?-«;nifam<p. hmmm-tM.-epropy ibenz- >nh^f He

H - a ©ml© I 12. i a ΊίιηΚ <>( -3 / my ί 19\) v k n© s's J ^!H\MR(100M / HMSi ,> lOHlbso.w- ΙΗ\<- I9< ' , a,- JO * H ^? MJIO J HI H'orrjxb HO 07-· /X (m. i Hi. <«.83-6.88 (m, j Hp 3 71 (hep. .1 ^:: 6/ Hz, lib. Ok (d. J ^::: 6.8 Hz. 6H).

( ,awp e b?2a 2-Smnimosl emn'~o~»-opiop'Jben '«''til'ile

Γη, paied a- n F-arwIc I? >a t'lisn 2- amre-e~i-ops,'px ©em«miluk J -aa?pb

I -CM is; amman «>; H 2 0 mg t⁰’’.·) as a txhiu· -olul ΊI NMR (400 Ml 1/. i>MS< //J 3 0 35

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2017200704 02 Feb 2017 (bred v inr.Mlt·. J x.-l 1 h. UR, 7.-R id. J S ((I Ια Η I). 7.2'{.U %H;. IHL720 (broad ,. 2HL 3.20 {hep. J 0 S I Iz. III). i 23 t d. J + s I1/. MH.

(Arn+pk -2b 2- kn .+>-+-+ >p!> p>H^C/+nnuk

Prepared a- in Example 13+6 ficin 2- \mti.>-prep- -c'l-d-dmen/smi+'-k' (Fxmnpk I 'SM ns ajnount I 112 0 me (0‘'->i ,+ j + h.\· sold.. H AMP (466 MIL-. DMsO·· <A? o ~.21 st. i +.6Ha Hb, + +0(d..l +.4 Ph. i H). o 52 (d. J .2 Ph. I Hp 5.s”^: (bread χ. 2H), 3.03(h-rp.,1 6.SIL. Hb. I I8(d. f 6 8 Ha MM.

Example 143:4~ AmmmSHsahutyM H-ben«»| e| 11,2,3 |t hiadiazine“2,2“dmxkie

NH₂

565 !

Prepared a.·, i+ Example I?') n->m 2-xidfamt>ylamitt+-s>-i-s,hij+Jben7,'nPnu.(.Exam+le 1.43 ai m amount +f ^J2 x mg (+3' < s a\ . nt ue χ+ Μ 'll AMR i HO Mli . ί >Mi+ Mi, I b lo <j<hr>-.idχ, lib x 08 «bread < 1H?. .o? tbreauχ. IH< ’ 3+(( J 8 6 Hz IH} + xO-o.94 (m, HR. + +4 ¢- 88 (m, IH). 2.87 td. J ~ +.+ Hz. 21 Η. I.+9-+8.1 tm, IH). Ο.72 (d. J ~· +.+ Hz, +H +

Example 143+. d-Sulfatnoylamitio-b-isobu^lbonzopitdle

Prepared ax tr. Example I2^ua re m ?-am?++ + ireburC.berexOi+tie d xampi·..

113b) m am,-rm? of >..’ 0 mg (°i¹ I. ax ,t v. hit< v.>hd H AMP t i(f» MHz. 1 >MSO re) p > ,·>+ (broad s, IH), 7.55 (t, J - + (( Hz. 1H). 7,41 0, J = S.P Hz, IH). '.21 (bre>.d x. 2H), 7.16 <.3n.x Ha HR 2 +2 (j, J t H , HR I 8'-l (6 (η. HH 6+8 (J J Μ’η,ΗΓ»

x.mtph I s Ih 2- \m ·?.,-<>-!+ htityibemAaMnlz .Prepared »u in Example- 136b fr+m 2~Atvtno-t(~(2~nkMrylpR^--lren^:y.l)ben.'onitrilc tFx > nple 1 ?^-’M t asm,', ms et ,+ I ngs^S'¹»? a, a sell+c cd Ή AMR ( H10 Milz RM'+CH+’i 3 ,1 <‘J SOH lib o+Oid 1 xili' Rj << ' * (c I Ml- flh. x xx (bread x. ill s|7 (d. I ^::: /.+ II' 2'b., 1.78-1.92 (m. IHJ, 0 8+ (d I ό -1 Hz. 6Hp

Example 144: 4- Mmm+S-trifiimnmrethH-l H-lHmA>|£hk2,3|Hdailia/hie-2.2~drexide

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Ik- Λ τ X

Nhg Cl· g

566

Prepared as in Example 129 from z-salfuinoykuumo-P*u:’d<w<in:c'dwpK'j^omn de >J xamp e la4a) n. am>·’.!.* e: 114 x mg (*\''' <) a-a Mute rend ll NMR {400 M Hz. DM.SO-/0 «5 11,41 (broad s,1H), 7.64-7.72 (m, 1.H), 7.5(): (4 J^:::: 2.2 Hi, IH), 7 38-~.6X{ broads. HH.7.M J. J xa Hz. ill). 3.10-3m0 (broad s. HI).

Example 144a: ^-Salfamoylamino-lMnfhmromcthyibenzonitruc

Prepared as m F cample 12*Μ from 2remino'e-uifl.uoromethylbenzomtrile sb cample I44b) m anbmnt of 138 5 mg (82%). as a w hne solid. H XMR s 400 Ml k, DMSOreM 6 9.91 ibtoad s. Hl). 7.84-7.92 <m. 210. “ 6“·'' 76 <m. IH). 7 42 (broac s, 2H'·

Example.! M > 2 Are. io 6 a fiuo.o:ieiv<' ut.:k ¢4 Mrehoxxbuv’d.mmb-i-O (n flaorometbxHbc v> iir.fi > (Exanmb- 144c) s? 49 g. 11.4 mmol) was treated w ids MfkioroacJK' a/id (fk.M (38 ml r at 0 C. and then smred at room temperature for 20 mm. The TEA Wits i emoted under roiruuin. and the residue w<b disseked in i ΊΙ4 b (1.% ml.) and washed with IM NaOH. The organic layer was dried .with· M.gSCL·, filtered and removed under vacuum., The erode product was purified by chromatography re; sibui gd . hmm* *a it.^f IHCH m cue 2 12 g (99%) 2-amhr-0-(100notomedn llben/o-iitdk.· а, a Mme sei -I H AMP (10’4 MHz. HMSf)-.( l P 7 a? _(r,. ijn. 7.07 _{5a. j H t. <> 9b (η.. I II).

б. 60 (hr s, 2H).

Example 144c: 2-(4-Me?bt>xx huuzx Lmimokt-prOluoroineilo Dbonz-jnPnk

I 6 its id !<'<<*n^.hxb Kis/omt'de ,2·+·* g. .2 '' nrnob ord 1 mefro.xx i .avslaumk (7 09 e, 51 7 mornl) wme .msperced m 1,4-diexane (10 ml ^x> and honk'd in a uucrew^c at I XO'<'-m 30 mm fur 1,4-dtexajk' w..s remevM andes xaun.m, ard the erndu material s pr 'ified bx ehromaiogiuphs -η Όη/α gd detiisg wuh r 'H.Cb-o give 3.71 g of2-(4tnefho.>.yL*z) LmunohO-ltntlnoreuk'firJ»ben.'<n Jnle CU’M as an ofi'wbui solid. Ή NMR. (400 MH;.-. DMSOM,) ·: 3 ’’ s b 31H. a.42 (d. >' 3 6 Hz 2H). Ns9 (m, 211L o 97 ί in 211). ~ 2<> (m, SHI. 7.4X {m. I H t.

Example 145: 4-Amino-8-hjdnm-I I I-benzuiej 11.23fihiadiazine-2.2-droxide

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2017200704 02 Feb 2017 hcp.iredu.' in Fxampl.' 12° fretr 2 su'.lhram lamiin>-3-hxdb vhcnzci'-.b Ic (Example I 45% in amount of 53.9 nig tbo%) ax a white solid. 'H NMR (400 MHz. DMSCMd 3 lo 14 (hb-ads. 2H) -^{x f}M < broad $ ?H>. /.31- 59 {n\ HI) 6 °'’-7.O3 (m, I Hi. 0.88 tr. J <'> Hz. Hi).

E.xnmple.].:i5a:. 2-.Si.ilfatr:eyla’mine-3-hydtOYybonzonitrilc

Prepared as tn Exampte }.%, ;_}, _n-_t ?-,iciino-3-;w4>-\sIv.vomtii.o H xamnie I45bi in ammmi of xS.5 mg (39%}. as a white solid ^:H NMR. (466 >y|Hz, BMSO%<; 3 10.23 (broad w 1H) S.m-threads. I Hi. 7.1-1-7.2” (re. Hil ο Π (broad2H).

Example ΐ4?ο: 2-A?mno-3-bvdroxYucnzoniirde

To a solution of 2-arnine-3-metboxybonzonitrile (Example 127b) (0.98 g, 6 59 mmol) in CiTCb (25.0 mL), a solution of BBn in (I 0M, 19.8 mL. J 9.77 mmol) was added drop w ise at -7:8 X under a nitrogen, atmosphere: The ohxrned mixture was:stirred, at, -78 '‘C for 30 min, and then at room temperature overnight. The reaction was quenched with wnter_s ha-iOcd w itn sotitnA'd aqueous \alfi Ό, $pH -M . U e-j-act- J with . H-Ci? The comb n--d extract was d^;'iod unh Mgb<\ tikes ed and exanot.Ued Ί he U'de e_vmp· amd was obtained in areenn· >'> ·) 80 g (91⁰.>i .w orooge >'·did and was used in fl·-, nrx· .-icp w hi-oiit further puiiticatbin Ή NMR <9p{> MH., DMSO-J.) 0 9 86 (broad < I Hl. h.x2~0 s7 (m. 211). 6.46 (). J ^::: 8.0 Hz, IH), 5.34 (broad s(2H)<

Example 146; 4-Anii»o-5,(b(S’_i7*~<tihy(icU”4ⁱH~[2’3*m]pyrnno)thieui.i|23~d]~pyrimidine” :2(1H)-<me

568

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2017200704 02 Feb 2017 \ seitan8: of Vf3-ey,m<'-5.Mdile,d:o-4H-dncne|2..3-i. ]px rer-2-χ IcarL.mrreb ben .simds (I sample 146,9 i '00 m^, I '1 ίηροΙι .-no \aOH (2 \ 2 1 ml ) m i ;OH t40 nd ) \-,:.;.s '-lined al I00 V muki nitu-geu o\e= night. -Mie? coolhtg u> room tempore¹, are. rhe dour reaction selnnon w ax Lucre J. and th. fdoalox' recarefn^;ly iicaiialreeJ with Hi ‘·. -\<ϋΗ'.ηΐ·ι x igoreu- '.:L^:':'mg ;n 0 ' <d. 1 ho resultant prceintlak· wax ceHcxied bx filuation, washed with wr-er and then 20 % InOl I in xs.m'r U> giv e the final product i 289 mg 8.2 %) ax an e-ll-whue solid which xs.js dr-c-l under x.wuuih overnight M.p : '· 269//. JI \MR (-400 MHz l).\1$O-<( i 6 2>3 th./ 5 8 Hz, 2K). 3.μ·η../ ?.p Hz. 2Hv 4 58 is. 2H>. 7.23 tbre. 2H). tI .5«. tbrs. HR MS 224 (MH i.

Hamp , \6j \ cs m> ~ gjIuuiO 4H dacioj' > > pxiar 2 ι..μρ.<Ή) benzamide ⁵ U .= _uf > .'.ΚΗΠΟ-5. ddo »!!>' 4H i Ηχ'.ίθ[2,'< C py -8: 5 XJfbCi'.U Ή (Example I 46b) {499 mg. 2 22 mm>-I) n¹ I 4-di·Are. (39 ml ) was added benzol isocyaiKiic t327 mg. 2.22 mmol). I'he reaction mixture was then xfr·-cd a' roori :e upctautie undes aiimgen overnight. The precipitate was collected by filtration, washed with1.4~disxteie. and dried in. the air io give the title compound {577 mg. 80 %) as a light yellow solid. Ή WIR <400 Ml 1/., H-MSO </,),; 2 red./ y 2 Hz, ?Hl 3 X'M:../ ? 2 Hz. .H). 4 nJ re, „’H) ~ yu ” 53 <_xm. -’HE ·/ <E 7 85 (tn I Hi. 8.04 .\ R (m 211).11.60 (hrs IH). 12 13 (bre. IΗ i

Example 146b: 2amino-5,7'-dihvdrc>-4H-thicno[2,3--clpvran-3warb&nitrilc l\> a tereni’c > < 6’hydto ?H pymn 4(3H) cncf< _’O irg. s W mmol), i'l.ilon-.'rtmde (541 mg, 8.19 imnol 1 and sulfur (263 mg, 8, M mmol) in Ethanol i 50 mL) was added tricthybrnine (1.14 mL, 8.19 mmol). The reaction mixture was then reSuxed under nitrogen overnight. After cooling lo room temperature, the precipitate was co'looted hx nltra'ton. vv rehed X',ith e-b.tem .md diied in ihe aa to <yxe ibe title comp.-imc 11 I ^s ’s'Ln.re x igb- v-nxe-sobd ^!H NMR 6199 MH.?, DMSO-L) 0 2. 43-2.40 (m, 2ΙΓ» 3 /Ml ,/ == s η H , ’’H) I 40 (I / 2 0 H ' 2IH. M^re.JH) MS 94 (MH )

Example 147: iE)-4~amiiKi5-(3-nu’thoxyprop-l-t»yl)q»i»3zolin-2(1H)~oae

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Prepared as in Example 146 from (E)-2-;rmino-6d3'inerboxyp:Op-lerp Dbenzcmrr’de(Example 9/ai ax a v hue ¢->hd ^:H N\IK NOG \IH;· DM8O-./ ; J 1 ?8 t-' SH) -I 0? <dd <’ t % I 2 Hz, HD 6 1 - (d: J In o H . IHl ’ Or (d / h Ο H/, IH) ^!. 3 id. J == x G Hz. IΗ }. 7.52 (L ·.’ === 8.() Hz. IH). ?.s0 (d ./ == 16 O Hz. 1 Η), II.9 (χ. 1 H) 11J 3 (χ. I Hl.

¹ C NMR (1 )Μχ)->Λ) d % 0, 7? to ll I -I l?l‘i.l.‘<»·) 3 2 Ρ··Γ\ UO 2. HL. ⁷ I SH·, 164.1.

Example 148: 4-Aniim>-5,642’.3'-dihydr0- ldl-cyclqKxVa[bj)-thicno[2,3-d]pyrimidin-2( IH )one-2,2-dioxidc

nh₂ §70

Prs.-pate<a ax in r x.tmple 4 Isom N{3mano-5.(>dfhy>Jn»-4H· cyck'>pem.i[hphiephen-.kxkaibam>whb-.-nzamide U. '«.ample 148:0. Ή NMR (400 MHz. O.MSO<0 0 2.33 (m, 2H), 2.76 (t, 2H). 2.87 (=. 2H), 7.51 (br-s, 2H), i i .56 tbr-s, I H). MS 2.08 (MH0,

Example 148a : N-{ 3-cyatio-5.6-dihynrn-4H-eyel«>pema| hjlhiopben 2

- \ mbamoyHbenzsmkie .Prepared a- ir> l-urwlz la fiosn S-armnc-'' η-d’hynre 1H-

e. > ’opcFh^b'thu'pK’ i -^-Ce no-η ,1/0 x^nple I *8b> H NMR ( +00 MJ/ Ρ\Ν(\„),ι ’ M (m. 2Hi 2.72 p. Ml) 2 82 J 2H), 7.M p, ,?H), ‘ η.χ a, ι M). 8 0) M, 210 11 5t· (- 1 Hl. 2 Of. (111}

Example 148b : 2-am.m0~5,6-di.hydrQ-4H~Gyslepenm^bJtbr .phen·.-S-t'ark'nrtrile

Prep.ucd a-< in kxar;:;R' >·; fiorn me «>ρ· man- re Η NMP (100 MH ' HMSO-tZ< 0 2.23 (m.. 211), 2.53 (m. 2H), ? 6 > (m. .HD 700(- 2H) H NMk MOO MH/ DMSO-./pd 2.23 f, m2H) 2 5%( 21 h, 2 62 ((,211) “00 k 2H)

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Example 149: 4-arnimi-5.0-( I 22\.<4‘-icuuhydfobett?o|bj Hmcrnd 2.3-d]pyrimidiri-2{ I H)mne2.4-dio.x-de

571

Prepared ax η- ΐ xampb 4 ftom N-( '-cyat’o- L¹ *> Mcnanydtobcr./-^'VKiopbea,'-y lea-uimovboejre am -1·. t! xampk' ^lHNMR (400 MHz HMM M/ t 3 I ’ Mm 4Ht

57 (t. 2Hk 2.72 (t. 2Hs. MS 222 (MH).

Example 149a: N-(3-cyanc-4.5,6.7-tctrahydrobenzo[b|tlu!.>phen-2ylcarbamoyl)benzam.ide

Prepared as in Example -la from: 2-aminb~4,S_>6._<7-tdtrahydrGbdi»o[.b]thidphbne-3earbouitnle (Example 5b). ^!H NMR (400 MHz, DMSO-fo) 9 1 % (m„ 4H), 2.5! (t, 2H)„ 2.60 (t„ 2H), 7 54 ίι„ 2H). 7.66 (t. lHj„ 8.02 (d. 2H). 11.57 (x. i H), 12 06 re. Hi}.

Example 150: 4^s-Aiai®©~5~(2~methy^rop^:-l-€»yl)qninazoii»-2( I /7)-one

H

•rexpenxion <>| V-12re\ano- M2~melb\ Ip, opH -er» 0 rhcml caih.tmoxl) to-uzamreie Ikxampk' 159_a) (0 13 ' g. *J.4H< mmd t in ΠΟίI (I ml > wa^ Seated wid; a xMuli-m of NaOH (2 M, 0.41.6 ml.._s 0.832 mmol} at room temperature. The obtained mixture was heated at ’)(» C for 30 nun, Auk-d to mom temperature auit neunab/ed w.tb »(>“·< -\cOH The precipitated prrebaet wax rolf'ca-d by fihr.eti· -n to give 6° 0 mg ( 7a, immf:'u>-S-(2-meihs Iprep-1 e it Ik’em'/'4 η* Ή </»->>» »a^ a w mt xok I Π NMR (109 MH HMM t-o }. 60(.. J i2 H/\ SH} I (d.,7 1 2 11/ SH) 6 >8 re ' H) 6 u Cm>aJ χ H) t· » (m » Η), 9? (m ί H), 7.48 (m_s 1H), 7.93 (hr.mJ x. IH)_S 10.72 (broad s_s IH). MS 216 (ΜΗ^?).

Exempt ^Oa \-t2~m . < - %'2~h . Ore ^χ r <p-' ' hpki m ^atL m ret rearer Jc rktszrol re re san.oe the I roe. i) r0 mmeb w/re aeded le a xolmrem ol (2-umnh s M-u \ fret, rut 11 _vl rem pre 120?) <_x”8 2 η _ 0*'η no9 to mo are I

WO 20(18/154221 .P:CWS2(H)8/065050

2017200704 02 Feb 2017 'hexane ttmkr ntoogen. and wa- A--ed at ro-.-tn tciupcnitmc for 12 b i'ne mtxims v.aOfUKcmtabA under >atwi), ano panned In dmmutogsap n on xf.wa gel· ehzmg Ά/h xe gradient 0% to 1 5% McGH m CINCH. to give 125JI nig (86%) of .Wi2-cyuno-3-(2-metit I-enyhpiieux le.e hamoOlwn/amnlc as a wink send. Ή NMR (400 MHz. DMx< Mi- » <> 1 ^:- I 2 Hz. 3H). I. Ή {d, J t 2 Hz. 3Hk n.401 - I Hk “J9 tnx Hi). 7,55 (m, 2Hk ~ 6? (» 8.03 On. 2Hk 5 13 (m. l Η). I i .33 m. I Hk 11.48 to. I Hk

Example 151: 4Amiuo-5-vi«yiqaiaazulm-2(l Z/)-oae

H

0^-fi-x -Xto.

%7\% nh₂

573

Prepared ax nt P <ampk 150 hnnt N'-{2Cyano~3vinylphcnykarbixmoyl)bcnzamidc (Example 151 a) in amount of 20.0 nig t 33%), as a wh= ’ll NMR (460 MHz. DMm >-%.}<) 5 53 (nt, HI). * <'4nn. HI), f-GO<k..=J (ID. c 9,x _u “ OS un, HI). 7.37 vu, 1R). 7.50 tm. IH), 8 Od«<>ad χ, lilt. 10T5 thtoad -. 1 Hk MN lx'

Ex.jmpk = ' = 3 \-(2-= sane-T\uidy’u'm e aiMmoUlhen'ariiJ.

I'iepaicd .ί* m Example 150a -rent 2-;mihn>-0-\inx iben/'-nittik (Example in amount of 99,3 mg (83%), as a white solid.

-Reni yiprop.80 < d. J

t. 2Hh ite solid.

n. -Hk >:MH ).

lb)

Example 152:4~Amiuo-5-(prop-l-em2-yi)i|umazaHu~2(l//)-uite

574

Prepared a- in E.xampse 140 pom N'^2-t wins!-3-(prpp~I--en~2~ yilpbonykarbam-i) htx'uzannde {Example I Va) m amount of 31).0 mg (47%), as a white ^lH NMR (400MHz, DMSO-ik) 0 2 07 (x, 311). 5,14 (m, IH), 5.43 (m, IH), 6,67 (broad s 6,x(Hm. HI) ? ll un HE. ~ %Hw, Hit ‘ 99 tmoad ·= 'Hk 3%i ( roads, Jb MS 2( (MH).

I \a ntxv ^x2a N t2 jo > {)=:> p I ui 2 ' Jh’turx kad’armr 1) « =;za mde solid.

.. i H),

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Picpaied as 11. I raitrele I ^Oa fom' 2-ramroO-f mop- 1 -^n-2-x llbc'i \ >atf Jsi sample i .Mb) ra umoimi of 96.0 reg (”2%). ax a while solid. ^;H NMR 1400 MH.. PMSO-d?? 0

2.15 (s. 3II i 5 23 (ni. I Ml. 5.43 tm. HI), .25 (ns, Hl). 7 55 (m, 211). 7.58 ire. ~i u. 8,0a. un.

211). 8.19 (m. HI). U.35K IH). 11.54 k Hl).

Example 153: 4-An»i»o-5-cycl0peiiieayk)uinaz.olin-2(I/f)-one

575

Prepared as in Example I/O fj-nn Ν-ιΕ'νηηο-οcx\i0pen5>„'nxlpheiiyiearbamoyl)ben7.xraide (l/ramplc i ?3a) in nrooum >(60.0 rag ”5 ’»). as a xxhi*C a did. H NMR (400 MHz. DMSO-%) <> 2.0] (m. 2H). 2 55 (m, 2H). 2.61 (m. 2H). 5. Ή (s, IH), 6.49( bro:ul s. I Hl. o >Ί (m. i HE .08 (ns. IHj. 7 -58 sni, Hi), 7.88 ihroad x. Hi), >076 (s, IHl MS 228 (MH )

Example 153a: N-fC/yano-S-eyck'-pentcny Ipl-any Icarba; noy Obes-zam ide

Prepared as in ExamoL· l*0a fro n ^'miro-h-icb sop? - I -) l)bc iat 'i’i·..· (l'\;reph- I Kb) in amount of 117.0 mg (9358),. as a wb-\- solid H NMR (100 MH.a HMS(.W„) _{·))'ίθ(ηι2Η) 1<·{:·η IH), '8 (su, Hl 6 3? (m Η Π, ' /('(m, Η I), ^r > ' t ra, ?H>, 7 (>s >m, ?H),S06<m. >H).x Mini >H), U U s, HE H 8' k HI)

Example 1541 Α.ηύηθ”5~(ρΓ0ρ~1~β8ΐ)·'1)ί|θϊί3ζοΙίί^2(1.Μ)~ρη€

576 ί

Prepared as in Example 1*0 0m (NCyano~3-(pwp~l“ e tM)j >*re\ aban ,' i’ s' as' de 0 a 'yb IM-Am. w tum <*’ 1 > ” reg s a ’<) .s Rite soln ’H NMR l iOO MHz. p\N<\/ ι ό I 91 <m, Ml), ¢- 0* (ni, ΠΠ, n 10 (·.»>id s. H; a M yn, 2H) _vm Ίί)., h(m Hi ''J reread - Ή) 0 0%JH) MSM)2{MH )

LNamp8:...L5:M;..(2n-8i~{3*Cyano*3*{prop· I -enyllphenylcarban'ioyhbenzamide

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Prepared a- ml wtnpk 159a ib-m {/0-2-<iimno-n-(ptop-] -cm lihctw orjiuiic fl w-upk 139b) m am--mt ol d 22 < > 8SM. 3- a w bite -Mid ^!li NMR {-00 Mil/. HMSO-.A).) ll 50-/3.1./, MIL ii 34-breads. Hi). S 13 (d. J ©4 Hr. ;} 1), 8.02-8 0© {m. 2 H). ” e4-.() int, 2H). 7.52-7.59 (m, 2H), 7.20 (d, J - 8.0 Hz, IH), 5.50-5.18 (a, 2H), 3.55-3.59 (m, 3H).

Example 155: 4-amiao-5-cydftpropylq«l«azoll»-2(lH»-oae

NH₂

577 \ whmer M' 2-am/e-('-i seimr-nw ibanzor./'k’ fl xvnpk' 'CJ s I u . I 0 mmol. I 58 mg) and ix-nzoU an.e'e {60^! w pus©' I 0 eq, 1.6 -nmol i ίΊ·; ml . I <0 Lil ) in dioxane (15 mL) wks-stirred'at room temperature. After 2 hours, the volatiles were removed on a rotary evap-.-r-Uor I he resulting crude N-ben/oyl urea was su-pended in bti>H (10 ml.. .:00 pro-.>f) and SmOH (2.5 eq 2 5 mmJ, I V 2.50 ml < was added. The roa/mn was heated to 75 ' C wfth -tirriug tor ” houo fhe .-oh erU w ore o' .inmate·.! and rhe re-iduo diluted n uh v mes {IO ml ;· i he icmtton mix-ure was ae-duteJ wtm 19'3 mire .,eu. wmet solution .md e.ncful \ titrated to pH 7--8 with saturated NaHCO'i solation. The precmuatsd p-rpduot was collected by vaeuuni filtration, washing with waiter. The residue was suspended in EtOH (3 mL, 200 proof) .and HCI was added (1X1N, 3 mL), The mixture was heated to 99 ° C fbr 1 hour. The reaction mh/re w.^ cooled u· room temp.-nUme ana iblf”-, d w'it water /0 nil ), f here/ ¢0 I^s pm ΓΠ 1' frit), and the filtrate concentrated on. a rotary evaporator. The residue, was further purified by preparative ILC (100(1 gm, 10/90 MeOH/DCM) and trituration with methanol at room teravratme The w a: -m i'uc> 2^ς rm’ {12 1%; -u the {Me eonp mnd a- -m otT-v.hji,' - wJ ^SH NMR (100 MHz. HMM >-<>-u>0 802 sm 2Hh : 0/ rn. ?lh. 2 w. - sri t H), 5 -22 id../ SR·, HI), 7.000-9../- 8 11/, HL N253 (br. s, 11Π .39 p. ,7 - 8 Hz J H), 8.022 (hr x iK; 0.644 G, 1H). MS 202 (MH ).

Example 156: l~ 11Lhcnznlc|JI₅2,6]thiadinziniv4,5~djamiue-2,2-dwxide

254

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1'icpared -ss m Ex.inmk- 90 tune ,?-;tm. io (. imefexkmuno'>bcnc‘· iiti.k sudanu'de f Example 1rc gwc \'-niethxbiHbcnz<?[cH 1J.6jHu3diuzine-4,5.duimme-2.2-diox:dc 127. mg. -M >> ^!H \MR (-I OOM Hz DM^h, . s <> 2..67 (d, J « 2 Hz. 3H I, 5 9{ (bs, NH). 6.21-6.1 7 (m,

MkJUI. M ibs, ?H'>, lOo<K Ml) XIS 22' (MH ) b2iife3pi:_:..3.21.:dl Ikamino-b-Unethx kumimjbcnzonitrik· .sulfamide

Prepared as in Example ^Gib from 2-amino-6-(medwlamiiK.>)b nwimHle (Example iMm {, g-re na-Mmethylaminotoem o '<H*de self.n mk ijm mg, /0 ‘ Μ H MIK. (400X111/. CIX U ·< 2 M (d J 2 Hr .3H), 4.23 (hs. MH. 4.66 ib<, MH). 4.87 (hs. 2H), 6.44 id, 3 === a Hz. I..H), 6.90 {d, 3 ~ 8 Hz. I Hi, 7.39 r. J ~ 8 Hz. i H i. MS 22 / {.MH )

Example 156b: 2-umino-6-(mctbylamino)benz0nitriic br, pared as in Example ^r’0b bmu 2-OK’tbx lamw-b-numben/enmi e {example

I Mb) la gwc 2mmine-6-{ineHiylaniim>ihcnze-nitnk' f0 30 g. 85%? as a hrewu ml whicn was used in the next step without any ibrd-er purifkauo-i. ^?H NMR (400MHz., CDCl.o 6 2.87 (d, J ~ .5 2 Hz. 3H). 4.25 (bs, 2H}, 4.47 (bs, NH). 5.96 id, J = 8.8 Hz, IH). 6.02 id, J == 8.4 Hz, IH). 7 13 (v I s H/. ’111 Ms I IS A1H }

I sample lem· .l-iireaHvlamiim-n-rdtrebcn/unhfde

Prepared as in Example 90e from 2.6-dinitrobe:iizonitri.le and methylamine to give 2-nK'*hx'l'amino-(>.n.Hr©beiizoniOi a IV 12 g, 79· ,.j H NMR t ΙΟίίΜΗ,. DXISO-Ά) c 2 85 (u. J ^::: ^IL'.iHU’MJJ -8 Ha Mh. Ίο{-.ί. 3 > I Ha Hl), 7 15 _it·. j ~ Μ t, I HE “ <4 (i J === 8.4 Hz, HI).

Example 157: 4-anii5it>5-(inethylamiau)quiaaz«liu~2(lH)-0ne

579

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A. xokaktf: of N-ί 2-eyano-3-(nietlr\laimmOphen’- kajhareox Bben/ain.de H 'roreple 1 '“a? {0 B? g. 0. l~ mmol) .sod lAaOll -;2N. 0.1~ mi bul lOH (u nd s w.·.- alined ... '»> > ’ i-'idci nitrogen for half an hour. The reaction mixture was cooled down to room temperature, and eomcutfak-d undei -momre 11 O =J ud i was added and the reaction reixuue was neutralized to pH -I v.im 1=1% Act )H 1 he fcsuV.rer pucipuafkn wax Shored aud dried unde: vacuum. The erode pioduet was punheJ b\ p-epwauxe thin kn-ci cmomatostaph' a.-mg a tX 31 Md iH {9.1 > solutuai ,re -.luanr. *o g:xs, 4 -mnuo 5 roiethx lannnokiianazuhn-2(lHi-one (Is 2 mg. 5a %) Ή NMR j-wxiik. p\N >-Α% 2 dlH.O.HHd. J ⁷ 6 Hz. IH). 6.12 (d. J - 8 Hz. IH), 7.13 (?.J 8 Hz. MH.7 25{hs.\|b. ΗΦ th-. MM 16.M(M.2H|. Mb |H {MH )

H.ampk Izki A 12-cy.nb· 3 (m.-thHainf-vOphcr.) lea IxarmDbo iza.nux

Kn xolutsou of 2 .nnnb> (<-(.mtthylumiao)benzomin:e {example I56bl (0.14 g. t)_;9' itnnnl) :U 1,4 di<’\an·-(3mL l was add i Χ'ϋ-ι>\ h‘ ( er ana' (ΟΓ4 . was l He rtacuun ouvure \%>\- zoned at rm-re icir.peraturc under nitrogen overnight. The obtained prcCipnafc wax fni-,red red dried andei xacmim u? give N-(2-eyano-3(m'..tbyb'.roino)phony karbamtw Bbonzannde ί5 rug, .'.’(V’c). H AMR ί-ΙΟΟΜΗζ DMSO-ha o' <d. J 4.-1 Hz, 3H1. 6.?o (d. J - -1.8 Hz. MB. o -P- <d, J ~ AMlz, HI). -.49- - 43 (m, 2H1. 7.51-7.55 (m, 211). 7.63-7.65 (m. IH), 8,01 id J' - 8.4 Hz, 2H). 11,23 (s. NH), 11.30 % AH). MS

295 (MH ).

Example 158: Α^:5φΐΌρνΙ-!H>benzn|e||L2-6Hhuidiazinv4,5-diannae~2.2-dinxide

580 t’i>-'χηο<: as ir 1 x ir.ple Ms u<nr ⁷ airk> <- {p- m _t .-mn jxivo nti le fan 1 d>

if 'ample 158:0 t>» give N -pr ’pyl~IH?bepZQ(c|(l,2.,6]thi4!di^ziw4-,§^diaininc-2,2«dii.’Xule (183 m< ‘M %) ’H AMR (400MH, JlMSO-%) 6 0.91 (t, I - 7.2 Hz, 3H). 1.57-1.63 (m. 2H). 2 48 nJ ' 'll),',w'^ire.Ml! Μ,Η I '11; Η ί 6 3 ’ i u. .1 rlH.Hl) 21{i I 8 Hz. Π-Β. 7.87 {Μ 2H). 10 (- (bs. NH'i MA 'S5 (MH 1.

Example 158a: 2-am:no~6~(propx * ar, uo)benz©nit.ri.lc sulfanrid.e

Prepared as in .Example 90a from 2~amiiio-6-(pri>pyki.minc>)behzonii.rile (Example

158b) to give 2~an'.n'»-n-(propylaininG)benz.onitrile saifair -tz (2* I mg, 43 %). ^:H NMR

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2017200704 02 Feb 2017 (400MH/.<TK'h) POSM·. j 7,2 Hz. )H). 1.48-1 57 im. 2H). 3.10 <<|. J J 5m2H). 5.86-5.89 (m. NH). 6.49 (d. ,1 - X 4 Hz, 1H), 6.69 (d. J - 7.6 Hz. ί H), 7.13 {.«, 2H). 7.29 p, J === 8 IL·- lΗ). %06 (- Ml) MS 2-- >MH i.

I '.ample 158^ 2-.;nmx'-o-fmupx iammuUrer/miuuk

Picpased as m r xampk' mip Oom 2-piopx kimmr-n-mi obcr./·'imide uxampk

15sc) to. give 2-amiiKi-6-ipropylamiiio)beiizmibrile (0.41 g, 915b) as a brown oil χχ-hich was used m the nest.sicp xxdhoui aux uuOm' pupfic-moa AIS Γ'5ιΜΗ '·

Example I5xc. 2-pi mw Hmm»· <'- nmobcuz<’amilc

Pivpared as m Example 90c fr>>m 2.6-dimip?ber<zomuiIc and pr<mylmnme 2propylamino-6-nifrobenzonitrile tO.53 g. 86%ι, Ή NMR (400MHz. OMSO-e.·.) ·> O.xx ft. J === 7.2 Hz. 3H >, 1.51 · i ,57 im. 2H). 3.22 {q. J 5.6. 1 6.4, 2H), M-O-o r>3 (m. NH), 7,22 (d. J x 8 Hz. IH), 7.40 (d. J - 7.6 Hz. i H), 7,58 (ΐ, J 8.4 Hz. I Hi.

Example 159: 5-(py nfilidin-l-yP-lH-beuzofeH LSHdHriadiazmM-amhie'M-dio.xide

Ο H

O~S W' %

881

PicpUK'd as Hi Example ‘Hi bom 2-UHcm'm {pwrehc.'i-l M) xiizomuric siiifamide. (example I.) .o give 5-{pyrrMmm--l--yli-lH-bcnz>>icj[i ,2.ΜΐΕίΜ1;^ηυ4·-ϊίΐη1:ΐν-·2,2dimti.de (14.2 mg, 11 ·%). ^lH NMR (400 d: 1.88-1.86 (m, 4H), 3,16-3.10 (m, br_f

4H;-.645(d../ 7Mlz. HHJU'Mc.M 3 4 Hz. IH). 7 30 _f., .7 8 9 Hz. UH. KMs, HL NH2). 8.14 (s, IH, ΝΗ2ι, '.0 M >\H). MS 267 (MH ).

Example 159a: 2-amino-6-(pyrrolElm-1 -yl)beozonitrile sulfamido

Pi, <au'< as ir ^τ .u dM’M or ' iruue» e t >x ii >, <im ' )1 ' umiie (Example 159b) lo give 2-amino-6“(py?Tolidin-l-yUbenzonitrile sulf&mide (0.34 g, i 00%). Ή. NMR 1400 MHz, DM SO ms 0 1.94-1.91 (m, 4H), 3.48-3,45 (m, 4H). 6 55 (3,,7-= 7,6 Hz, IH), p8| id. / 80Hz. IH), lk. 2H,KH.O. ’,32<j.</^: 8.0 Hz, 1 H). 8 9 ire INH), MS 267 (MH ), \ample %9^:> 2 amieo ο i m”elidm 1 > liK-mrem/ide

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Prepared as in Example 90b from 2-nitro-6-(pyrroljJin-l -yhbcmmmijiie (example 1 '9ei io an > 2-.amnO'(''(pc-ol:<hn-I '. = ihco. ontolie (0 -'8 g. s5 ’ »s ax a biown oil w i.-eh ;sed in she next -top wid >- a no. fuiibci pimncM»--; ’ll NMR (-00 MH/. E>MM »-ιΛιΟ I 91I >s tin. 4Hk3 43-3 40 (in. 4Hi 5(=1 (s. 2H Ml·), 5 rm (d. 7 8 8 IL·. Η1i (J../ 8.0 H/, IH). 0.99 y.<j Hz, IH). MS i88 (MH ).

Example 159c 2 nstro-o-f pyrrohdinl-y Ol’cnzomtnle

EicpaieH ax m I van.de ‘»9? ')> m >/> dn'=B<= κιην nt tie am p' <'0(96 to .,0,. 2 -_}iii>--i.-(Py riohdin-Ι·χΠΕ0==/··ηηπΕ whtcb wax ux% the next step w=i6oiii am initber pmifieanoB ^lH NMR <4iM Ml V. DM SO- .%> <> I 9. | -to (ni. 4H'>. 3 60- '· 5 in. 4H). 22 M, ./ 7.1)19. IHi 7.4: n.s IV, IM). Nee (t.J x 0 He. IH}. M> 218 (MH I.

Example 160:4”Amitt€A5»ix0butoxy/7f”betu®[i^>l 11 ^^|^adbz!nt-2,2-dioxide

582

Prepared in the same manner as example 11.1 from 2-siil&nmylammo-6.isobutoxybenzonitrile (example 1 <>0ai io provide ^aminp^-SMsobuto^y-./Hbenzofejn,2,6|thiadiazit)^-2y2di0Xidp(65 50’ m. 41 NMR(490 MIL·. DMSO-dg)3 .1.01 (d.

</ ο.” HmH. 2 iV- t-v.pi..7 0 6 11/..11),190(0.7 o 2 Η/. 2H i, 6 do id. 9 83Hz,. IH). 7i5(dd 80Hz H). ⁷ 2⁷ ( r -. 2ΠΝ ⁷ % MM x ” H w . 111 -o t χ. .11) V$ 27'i(V( 1 )

Exampie I Mia; 2-Smiasnoyl a- inno-o- isobimw ben/< == utnlc

Prepared in a smiil.tr mannerexample ΐ I la ucm2-antme-wisobutoxyben/o-iitnle (example 160b) to provide 2-xuha= uey 8iniiiie-o--=x>-h:jvo\ybtowtutriie (130 mg. 50%) Mx MH 5MH -MMSO '=

Ex mw |.e_; 160 b: 2-Am mo-6- bo batox vbenzonifrile

Pn ;>a(0<. a , \ mi b i (rrc> a- .xairple 1) Io f >ia ^s ‘,ηο Ί> \s 6 nitrobenzonitrile (example I60e) to provide 2-0.01=00-=^-isehatoxybeazonitrile. MS 191 (MH'),

Example iotic: 2-i--'ht't.>xy n iiitTobenzonitfile

Prepaid d in a smuln manner % example 160c from 2%-diiiitr0beiizoftifrne: and 'se.%11.m01 to οκη me ' «buio'c ό β.Ύ 'Km/eii/rile, Ή NMR -.400- MHz, HMS(? .,<-.) P i 0:< id.

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2017200704 02 Feb 2017 / + -( IL·. Mb. 2 H (sepi.7 + (ML·. Klfe.fe.l J i-- 11/. 2H). 77-{.Id. / S.O.HH,.

Hb. 7.91 0.../ === 8 2 H . IH), 7.94 (dd. 7 - 8.2. 1.9 Hz. IK).

Example 1 01: 4- Amiaure-.rei'-baloxx~Z//-bv«zo|<'ni,2.b|thiadiazssie-2.2~dmxide

583

Prepared m-a similar manner as example 111 fem .2“Su)fanreylarn.ino~6xw<~ bourex ben 'emu de (> > anpk h>l pre prex rec ·-.«ma.+-5-+ <'-Petrex -;//benzol ]| s 2.r|Mhdiarme-2,2-d?exi4e tmg. Mfe 4l NMR {-M0 Ml 1/. DMSl MM a 0 'M ₅t, ./=== 7.9 Hz. 3H1. 1 28 id../- 5.9 Hz. 3H), 1.+ im../- 7.4 Hz, 2H14.57 (xcxL./=== 5.9 Hz. IH) + 9s(d / s ” Hz Nt}. M(d, / 8 2 |b- Hi), 7.2 (h's. Mb ’ 55 ii / SJH/Hb.^H ix. IH). MS 270 (MH).

Example Id la: 2 - S u i ta moy I ami no-6-scc-butoxy benzonitrile

Prepared in a similar manuei a- example la from 2-.isninore-re- butoxy benzonitrile (example 20b) to provide 2-s-.ilfan.i<\vlaBrii.so-6-siv+b-.stoxybc.BZon.itrile. MS 191 (ΜΗ -ΝΗΝΟ.;}.

2'Amirse~6-xixxbutoxybimzonitrite

Prepared ns + χ·ηυΐ.υ mannes .+ exainpb. I I lb few 2-+; -bai>>x>-++Ί ο\'ΐι <·.ίΙί.1. fe, 'tpk hife.cpire de 2-. m .<-<>-+ - +t·' b ozcw k MS'Ή (MH 1

Examptfeblgi 2-,&?+-Butoxy~6~nifebenzonifee

Prepared m 3 arnnfe manner as example 161c .from 2_:<^dinifebeiizOnifrHe_:.a.nd ssi'-bmmfe to pi ex Me 2-w, -Imi-xy-O-nitrobenzomtrilc. ‘H NMR (.400 MHz. DMS<)fe0 0 0.98 0,,/=:: 7.5 Hz. 3H), 1.33 -td,,/ 5 9 Hz.. 3rh. 1.73 (w. 2H+ 4,~+ i-^\. J - 5.9 Hz, IH), 7.78 (dd, </ :==: 8.8. 2 8 Hz. i 11). ~.MH _?P, 2H ?.

Example 1 (?2: 4^A.mi&o-cyetol>»t(wy-/H4)£»zo[cni_$2_i)6|ihtediaz.me~2,2-dKixide

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Prepared in a ssmikir manner a·, example 1I1 from d-srehanox kmiino-pcyclobuloxybenzonitrilc (example I o2a> to provide 4-amino-cydobmox.V'iH~

K'U/Oj ||' 2,r |imam reme-d.^-diexidc i 19 4 res.. MA ) <, ., wr.k send ’ll AMR (-()() MIL· I)Mx«¹ -42) d 1.65 (in, .1 Η), 1.79 (m, 1H), 2.19 (m, 2H), 2,43 (.m, 2H), .4.82 (m, I fl), 6,52 (d,./^{:::: 11} Hz. i H). n.5x (4../ 8.2 Hz. | H), 7.40 (t J ------ 8.1 Hz, 1H)......9 (bi s, IH). 8 31 (br s. ί H),

10.92 <br s), Ms 2b-x {MH ).

I sample ie2a 2 Sn Omro O.ana- (> eAlobm<»\y bcnA>mi He rcpuicu tn a > m> i tapper w ex i npie H la re 2 mitw o cyelobub-vrMizomi:de tsAample %.>) -e pn vd-„ 2 .sulLtmox kanme-o c-e mmfexxxm’o 'it.sk* <2 H reg, R»(r _e) ,-s a a .are sola H AMR < 4)0 MIL·, I >MS% ./3 6

1.67 (m. 1 Η). I.x2 <m, Hi). 2.03 (ns. 2HL 2.47 i-n. 2H ), 4.33 (pent. ^;' 7,2 Hz, IH). b.”9 {<1,,/ < 2 Ha -.10.7/:5^,./ 9.2 Hz, I Hi. 7.28 (br s. IH), 7,54 (t,./- 8.2 Hz, IH), 9.46 (hr s, ΐ H). MS ?(re (MH >

f'\ampb. )< ?n Z~Amin^“6-cyebbutoxybenz0nhrik·

Prepared in a similar manner as example 1 l ib from. 2.--eyclobm0xy-6~ vtrobenzonilr Jcample H>?>.) u- pint-de 2rem:-'t->-’>-/\ th-hm-Ay hcn.remirjie (s 74 nig 'Ό” >) as white needles, ^!H NMR (400 MHz, DMSO-did d 1.65 (m, 1H), 1.81 (m, 1H), 2,06 (rm 2H), 2.44(m.2H),4 -2 (pent, / 7.3 Hz, I Η). o,00 {hr m ,?H p 6.07(6, J-7.8 Hz, 1H), 6.34 (d< d9/09)0 Ή) Γ > < 1H., Hl) MA MMMR 1

Ham_p> < 2e ?-( si.k'b'ze'x-bre'trehe'i'o'nr le

Prepared re ,u remikir mariner as /sampi·. 1 He free·!.: 6 dinitrebenzenitrik' and cycmhuranol to prm kk· 2-ummo-(>-ey eiobmoxy bce/'snitril.e (298 mg, 34%) as a white solid, ’ll AMRi spuMH. .HMSiWOP 1 m\m, HO, I x~>(re, Hl),2 14 (m 2H) '> < rm. Η; I % (pent,../- 73 Hz, HO 55 (dd.d ^:: 9 .?, I J H/ Hi), 7.9‘ (t.d - 9 Hz, IH}, ^c’2 .dd d ' 1.1 I 3 Hz. i H}.

Example 163:4relnihs(w5-cyel0biR.(wyt|n.h5a2<diri--2( ///Mae

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Prepared in smnkir manner a- example 111 from V-(2-ex; ο 3eyck>btite,x\pbemkurbamox hbenz-mndc rexampk' 16.09 )·.· provide 4-am' re ^cyci0butoxyquinazoiio-2{///)-.-ne 119.4 mg. 76%) as an off-rebite solid. ^!H NMR (40ft MHz, DMSO-.<fr) ft I ,o.< indlU J .M <in. i IR 2 2ft (m. 2Hk 2 4% m. 2H)% .87 (_pcm, J - 7.2 Hz.

IH), 7.52 id. / 7.2 Hz. INkb.M id. ’ 8 2 Hz. Hik 7N2 it 7 8.2 Hz. I Hi, 7.48 (br s. IH), 7.xx i bi \. 1 H i. ft.kny ibr .-. ; H ). My 2 -2 {MH )

Example io3a: λ·-t 2-Cyano·3-cyclobutoxyphenyicarbamoybheneaniidc l\> ., -int-op of 2-.imrno-o cyek'4mmxy I cmremnik' (e.vumpk =n2b) <_ν>0 mg, (i.|6 nunoli m 1.4-dioxane t2 ml/> was added Ηπζον I re-cyamne (23 -ng. 0.16 mni-I). Ebe ivaction v, „.'·'·{ j red <h ii md.. N i<. 19,Penns I pop vo.np:ct.<m. ii'.c react >n was di are v% th FtO-R. washed xvith saturated XuHCO? (2xi. water, bmic, dried MgM % Altered and concentrated io pi-, :de ' {?cy j: so· 3 evcl-J’Ufoxxph.nx L'nibarioy Hnen/amidc {38 rig. '%). ^ιΗΝΜΚ;4%ι MHz. HMSO-wsd I.Mlrn. HI). l.si (m, 2H) 2 R%m HR 2.42 tm 2HI 4 71 (pent../-·/j Hz. IH> 6<)x{d.,/ x Ml. , IHk i 3red / x3H' Hi.? -(<·,? ϋ Mb llh. Ijir.. IH), 7.56<;m, 2H), t 8? (ni, IHk 8.05 (m. i K|. 11 35 (s. Hi?

Ixamph- 164: 4-Ainine-5~t J-nieihylhul-l-eft’S-yr><juinazohn~2( I H)-OHt

5S6 '

Prepared in a similar manner to example 146 tram IN“(2-eyano-3*(3-methylbuts 2>en2yl)plwnylcarhunoyl)berizaniidc {example 164:.9 a.s a white solid. ^!H NMR. (400 MHz, nx'Id.» I lire Ml). I x3 (.- 3H), x»(s 3H).{'o?(dd. / 1 0 H.' iH).6Hh.- ?H).

7.04 (dd, </ - 7.2,1.0 Hz, 1H), 7.48 (t, ,/-= 7,2 Hz, IH). 19.74 (s, 1H), MS 230 (MH ).

Example 164a:_: pheny i ejdvmos ’) ber.x-rede

Prepared in a similar manner to example 146a inym J-amino-MJ-nu'thvIbuHJcn-l-xI'jhenzunitrilo (l ’s,j:nple 98hi as a white solid. ^!H NMR t h)0 MH/ HMSO-.Rln I I is. 311;, I x S re 3) J, | )2 (·. 'Hl, '9 ~ Olin Hi ? ^s I - / '6 im Hj <' n 69 ;m ^ζΗ» x ft I · ?0l<m,2Hj,8 l2reJ5(nn Hl) H 32(-,, ΗΠ H 49(- MH MS33HMH )

Example I i>5: Improved synthesis of 4~AmHr0~§,6”dmiethyithigu0|2,3(i] py nmidi»e~2(1 H)~o«e hydrochloride

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587 i m ex tn p e AxtuKre <m i npiexco roodr d foi p cp a ng s < ,'( L· . t of compound I. Specifically, the improved method involves a particular washing protocol and formation of the HCi salt as the final step. Wbon compared n? the general method for preparing HCi salt this method provides <.ignifie.xmly more pure material vvith improved remihiliiy and ease of handling.

To - M'mtiou of 4- amno-'A-dupeihx hhumei 23-d ip} rwu‘,hue-2(»11 i-rey lExampl,' I <>5a > i 1082 g. 5 54 mM,si in vaterth I Llxxas added an efijanoln.· solation oi HCI (I. .25 N in SOO proofvfnancu The resulting slutry was iieared t<> retlnx for ^; minwr- to afford a <, k' tr x.'iution t to some eases additional I I 11/,⁴ i 25 x l id οι ci-iauoi mtrei be added to obtain a dear soluiiou}. The solution was filtered while hot and the filtrate cooled to 0 °C while stirring. I he resulting precipitate was collected by filtration, and washed with .acetone (3 x 5 4 1) and heptane i3 x 5.4 L). The solids were placed. in drying trays and dried under vacuum, overnight to give 4-.amino-5,6«dimethyithieuo{23-d]pyriMidine-2(l Hfionc hydrochlorides an olTwhire powder (117b g. 02°<. yield) *>9% paw >is determined by HPI ,C. M.p.: >26032,. ’H XMRteOOMit.., DMSO tok'2 fore Mlfio ΜΉ , d9fo(lwiH; I2>?2(ov2lh < \MP M00MHz.T>MS<’-3d 12 2. 13.3. ifio.5, 12x5, 125.7. 146.1. i 54 9 155.3. MS 196,2 Alli ) PiiHtv us determined bv HPI^f', vv,o4'^k.<

Example i65a; 4-anuno-5,6-dimcfhyhhicno{2,3-d]pyrumdinC“2(l H)-onc.

Ethanol was added to a 50 L three neck flask (30.8 L) and stirring was initiated.

A ex n> 4 5 dir ctS.t. χ luo 2 x lead ,nno>b κ uzam de H rear wk I < Abl {9 > > g. ) 12 were w,i‘, added fbih-wod by the addniou of Nat Ή i' X, 4.5 I '· I he toaemm mixture was healed to reflux (- 77 *C) and stirred under nitrogen t<>' ? > hours; The solution was then cooled to 65 °C and treated with charcoal (233 g). After stirring for 30 minutes the hot solution was filtered and du ‘ JLate w^s s,o x k pooled m i> > ; w ppcmf,ae (rec *ftiWc λ.ι'· t uf.db actn al ^dwibN HCI with vigorous stirring, then further cooled, to -5 to 5 The resulting precipitate was .collected by filtration., washed with water (3 x 14 I k IJ Mb il x 18.7 L). acetone (3 x 14 L) and

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2017200704 02 Feb 2017 «ak-r (3 x 14 I ). I he solid·' 'were placed in drying ira\x and dred under vacuum oxernighi to gue 4-an:nR>-5.O'd:rn-,-ihdtlnen<M2..>-J]p\’iir dti,e-2i 1 Hi-tlnono (573 g. 8⁷ '63 .> an otY-whuc '..nd M]· 2οΠ'\' H NMk <460 MIP.IAISO ./0 0 ' 95 ibs.'.HI. 2 25 to. 3H). 2 16 to.

3H}. MS 19NMH i beuity ax deteninned h HOI 0^0

I xangne AM \-=Vmo-1.x-druet-o hhs'prcn-?-’' h. asbamox Ibonz ιη'·.·1ο

b. a tolntom <d 2-and»v- L'-dinv'lhxblaopbone-3-carboniuiie {168(} g, 11.04 m<4; m ϊ .4-di<to..ii:e (42 1 j wax <tddi.d Ux'nrox hsocy.male i Jt>24 a. 1 i .04 κιοί). the reacmmi unxime wa- then xtmed a) sooni lenipcialwe unde> ntoogen atonight. 1 he ictmlting precipitate w.as e^Hcmed by ilhmUon. χχ.·.χΙιο<1 with I 4~dm\an< P> \ J 7 11 and heptane f3xl,“ L). and drwd under xaeiann «ne'imgbl to ci'.c \-f3-t 'xci'O'4.5-elnn.'l ixh}'iopheu-2-xk3iha'n. xi)ben, amide ax av jte''<.hot>00g.84 7^,'tok.kn Π \MR (400 MIL. bM\< to6 ι< 2)0<χ. Hb 2 24 <m 31b 7 52-~,w {ip_A 21b. 7.64-7.n’t Lm I Hi. 84=1-8.03 im, 2Hl. H .57 s brs. ί H). 12.0$ (brs. 1 Η), M..x Η*0{MH ).

Example 166: 4-(2-(4-Amitm-//f-bea/.w|i || L2.6|thliidin/.inv2,2-diaxide-5yloxy jethyOpiperidiftlam chloride

.to:i4“Bvtyl>4-(2-(4-Amin<>//7-b£tiizok?][L2,6]thiadiiizi.ne-2.2-dioxid.e--5·ylow )ethyl)pipcHdinCl -carboxylate (Example 166a) (20 mg, 0,047 mmol) was dissolved in a. so' .ίο > of HCi in HlQH (1 mL, 1.:25 M). The reaction was stirred at reflux under N_;;, Upoa Odmpicttort, the precipitate wax volkXK'd by vacuum deration to pr.j\ ide the desired product«I' rug : Otb.,) a'to vjme Wiiid H NMk 1100 Mlle .DMSO-./,} 0 3s (m ?H) = ,'lp't.Hb I 8: s ώ Tib 's ( π. TH 2 8 i p-η ?Hy 3 2 '· (r„ ΊΙ> I Ί (i / 6 4 6=, ’(1>, f ^f> 1 (J 1 el Hz, IH), 6.78 (d. J-8 3 Hz. IHy 7.47 O.J 8.3 Hz. bl?, 7.81 (hrs. IH). 8.35 (br s, IH). 8.59 (m.

IH) .\<ύ<ηι HI), 1099 = ^, ΗΠ MS L’oAIH ί

I xi-np’e .ma < >-fM Lar' 00-/ = /-60 o(. I blihia .1. mo-' -box do-''x to' x lot by I )pipeHdi n c -. -carbexyHk

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Prepared ax in Example I i I from /wv-butyi 4-(2-(2-cvano-3(suitamoylanunojphcnoxy ic(hyl)piperidine-1-carboxylate (Example lK»'n in 15% Meld a,- ;·, wbKxehd. ^!H NMR (400 MIL·. DMx'>--/,,1 <> I O'⁵ <qd / 12.S. 4 o IL·. 2H). 1.40 (.-. TH k I eb (ηι, ΠΗ, I.%) (rn. 2Hi, 1.79 (q,./^::: 6.7 Hz. 2H), 2 70 un, 2H), 333 (m, 2Hj, 4,21 si,./ r>”IL·. 2H).6.i<2ul,./ 8 I Ha 111).6.% (d../ 8.3 Hr. IHk 46 (k 7 > 3 Ha IHk %\2 {hi -, Hl) c- 34 (b; x. I H i 10.96 ibr x, HH.

hxarnplcH-kh 8 ?/ Bun b442t2-CAm>--3(xuUaiuoylamiijejphcnov) ethyl) piperidine· icaihoxylu-e

Prepared a- m Example Illa fre-u k-A-biux I 4-{ .?{ 3··;.ιΐηίη< i-2 eraiK-Kien· \s K’thybpipeudine I eai boxy late (Example 166c? in 72% yield as a ac,·: syrap Ή NNSRUObMiK J>MS<.’a id I O8im.2H\ I 40 (-. O( Ik I 71 {m. 5H). 2 > (m. ?Hk 3 03 (in. 2H), 4 17 <y,./ <-3Ηα21Η,6%Μ../ 8 6 lb. I H). Io (J. J t 3 Ha 1 Hi. T28ibt s. 2Hk 5/<; ./ \JII/ ;Hi 9 L· (0* s HI).

Kamp;-. H 6e kn-Bu'd M ^!-(3 amev-%·'. anopl’ene\-. '>ediv ipipe.ubr<'- ,-eai he x\ -ale Prepared as in Example 11 lb from /err-butyl 4-(2-(.'-asηη<·-3.'(n >,*eiv mqv-id· re-'-nnbe'-x rate U 8<nrp 'uH n h ..wav. uic mem H NMR (400 MHz. CΙΧΊ.) ₍> i 06 ι ηι. 2H), 1,4b (,>. )Hk I m3 (m, 5H), 2 ~0 ί >n 2H), 333 (m. 2Hk 4,05 (t, J ~ 6,0 Hz, 2H). 5,98 (br 2Hk 6,23 (d,./ ~ 8,4 Ha Hi), 6:34 (<t /- 8.4 Hz. I Hi. 7,(8 (t, J ~ .8 '2 Hz. i l l).

wnrjA (se ^r ·7-Βί»χ >- l-l % \\_ep.'-M nroph,-00x\V(hvl)pij»i'tn' n -1-cat Κχ·. I χι?

H> ; xliSpaiWioU ofk//-bxil> I- 4-(2-l'vdrex\<-i-p. Dp'^cndioe* i-e'J'b>>X', Ια, ί 3-0

Μ 3 x0 inu ) and \ JI ι. IS .up - Ό ηΐϊ’υ' ('{“ >>άήι. r n m ku>d - , I u. d.. ΠΜ1 t' nil.) at 0 'X', wax added a xwkm-.'U ef 2.6-dmuicbenOU’lisle (614 nig, 3 IS ninnA m dr. PMb (4 nil ? I he reacbo;·! wax juried under N, warming i..· rr, Lpon-e>-repletion, rhe le-ictb-n was quenched w iih ΗΌ (50 niLk and (he pteeipiiiite w»u> eolicetcd by vacuum filtration M provide _ty?.n*butyl-4-(2-{2-cyanO3-nitrophe»x7Ky)etbyl)pipcridiuc^J| -ciirboxylate (955 mg. (%%) ax a tan solid ^!H NMR (400 MHz, C DCh) 0 i .09 (m, 2H.k 1.40 (χ, 9H). 1.73 (m, 5H), 2.70 (m, 2H), 334 (m, 2H), 4,32 (t, </ ™ 6_:8 Hz, 2H), 7.75 (m, 1Ή), 7.92 (m_:, 2H),

Example 167: 4-(2>(4’Amiiso-2*0X^l4-difey^'»^«i8sx»n»5-y|0xy) ethyl) piperidmhmt ehimfide

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Prepare a- in I'sampL 166 fieir <\ = /-6..:=-1 -i-t2,4-ammo-2-oxo-1,2(hindb'i :ma <Φ,ν5-χ lexOelkx Opipmidme-<-e ab> v Lie ?_xbx mmle k>~al m °2‘ < ' rel.l as a while solid. ^!bl NMR (400 MHz. DMSO- Λ? 0 I 3m m. 2HI. 1.70 (m. IH). 1.83 re../= 6.5 Hz. 2Π1. lAiai 2lH.2x4(m,2iO 1 2Mm. 2H). e to r, / n 11L 2H), - ^(J 7 x .> Hz -H). 6.99 ul,./=== 8 3 Hz. IH). ~ 7n (l. / 8.-. Hz. I Hl. 8.50 (brx I Hi. 8.74 (brs. = H). 8.98 (hr _s. IH), 9.46 (b? s, HI). 11 (hr s, = Hi. MS 2M (MH )

Exampk 0-7,¾. w.gmy I 4-(2-14-anmm-2a>.xo·· 1,2-dihydroqiιίπaz<dΐn 5 'xyg/rhxl’pqre-.'.diire varboxx .ate brepaied -.w in Example 111 from 'c/v-buixl 4-(2-i.M3l5citzox imcid<0-2exanop'rnnoxx k'll-xbpipcndme-1 -cailx-s' laic ibsample io7% m -1'' > y u-'.J H W1R (4Ί0 MHz, DMSO-%) 6 1.08 tqd.9== 12,8,4% H/.2HI. 1.40 (s, 9H), 1.60 (m, IH), 1,70 (m, 2H), I 7 (q. J e 41L·. 211», 2 t>9 (m, 2H). 3.9: _{5Γ. /Hy 4 23 (_U / ¢. 9 Hz. 211). 6 (m. 2111. 7 47 fi,./ 8.2 IL·. lHi,7.5“(b re HH.7%Mb= w HIE lO7.Mbrs, IH).

Example svb fe’i-Butyl 4-(2--13 -(3--bciszoyk:rddo;--2 -cy;umphenexx )etb 1) piperidme

-cm boxy bie

Picpatexlas ml xample I b>a m-mn -'· huxi 4 {.? {3 ammo 2 cyancphciwxx HthyPipiperidmc-l -carboxylate (Example 167c) m 19084 yield as a:white solid. Ή NMR ι«00 MHz. DMSO-eMO I.OMm. 2¾ 1.40(s, 9H), 1.60 {m, H< 1.71 {m,5H)_?2;71 (m_?

2Hp 3 M (m, 2Hb 4 21 <.t.</ 0 5 IL·. ?H). ,P>1 id. / 8.5 Hz. 1 Hb 7.5(. u. J ~.4 Hz. ..’Hi. '’47{t, .7 χ,/ΗζΗΗΐ,λΝν./ 8 ? Hz_ IH),'768 {tv. </=== 7.3 I.? Hz. Hi), 7.8? (d ./= 8.3 Hz. IH k 8 05 {m. 2 Η ι. 11,35 1 be s II h 1.4=1 (hr s. IH).

Example 168:4~Amino-5-(eyc.teh exy toxy> 1 J-J-beazn | c || 1,2.6)( h lad ί a zine-2.2 -di oxide

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Prepared as m Example 111 frwr- 2-xulfasrioylami:'io~i>-he©yioxybcnZvnitriii; Uwampk /89 m {<»-/© Ud w a wln*c vn-kdlme -MM M p. 2/-2// . Ή AMR /100 MIL·, ΓΛ⁵S(//-) .» I 3d-1 71 sm. Ml). I ^0-i /\ 2 lb. 4,n? ?m. IHL - 60 (Jd, ? ©2, 0,x Iv\ 1 HL o ©2 id,’ 8,2 Hz. I HR 7.-45/,7 .8.3 Hz, ΉΠ, 7 ©3/rd..7 2 0 Hz. I lb. x 49/γ J../ 2.4 Hz, IH), 10.0-5 /j ΗΓί MS .Z’MMH )

E\amp,>. A ©a ?-Au fan /k-mn e-o-i \©l MevHo/b© ven -/.

Prepared a- m ΐ· ©ample 11 la -mm 2-amm>mc>ei<>m.©\ ie©> ben Amir/·..

H ©ample/8|-$ ;n/-,. ©teld u-a whim-el d H AMR (400 ΜΗ/ ΙΛΝΜι.Π L'{m,.>ib

I Μ < m 3Hk I ' 0 <, m 2Hk > 8 © f„m ?H) -I — </n Hi 8 '. Η. , H I) / Al J 8

Hz. I II}. 7.24 ibr- 21H L51 (,, = 8©H' 110//)/111)

Example 1/© 2- \m ’/-{«-». ©tie hex© Io©\^.«zonual-c.

I'i/nmcd as ns Evur-pL-11/ fu>ri' ? N.u>· u e©Mehexs/©©hern’em-r/' io provide 2-amino-(>”Cycionexyloxybenz<;mitrile {420 mg, 2“/.} ms a green syrup. Ή NMR (400 :MH?„ CHC'I ·) ¢) L37 ('m, 3.R), 1.50 (m, 3Hy 1.71 (m, 2H), l.85(m, 2H),4.43(m, 1. H)»©<94(b,r -, 2Hi, ¢- 2o fd ./ - 8.6 Hz, I H}„ 6.31 (d_: J - 8.1 Hz, 1H), 1 (· ft / == 8.1 Hz, IH} MS 215 (MH ).

l/.MOP.k/Li'M > Arro'/eyeh © l«>\© bem mis- be*

Prepar'd a- m Kamo/ u<vd (Mm 2-cb hex\fox\beBzomMale and eyclohexanol in 100°. st·le a- a LJm ‘ar -o\>l H AMR s, 190 MH ' f HCid© I. / /g «Hj, lo0<m, Η/ ) 74 fm ?H), Mh/m Ήι 4 76 in. Ή1 ’9 (m IHp/S/m /H I ©maple H90 -LAnursa-S-i e©ί4ορνΗΐοχν///4η’ηζο|«ΊΠ'fhiudiazim“2,2~dio©ide

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Prepared ax m t «...infer 111 fem 2---+ fari<pldntH.n-<>-pc!.lex'> Irevomtn're (Exainplr fefe in 38% \ real ax uff white ii-.cdk- Μ u '?><'>%'. ^!H AMR (400 MIL·, I'Alre ? fed i <>7fe,4H), I sfenfeH), 1 98 (m, 2H). 5.0.5 (rn. 01).6.61 (d., J - 7.8 Hz, lH),676(d₍J s H,', IH). ⁷ It· {( / 7sH . Hllfe72>.btx Hb,8 35(h_f$ H). J'· 9+ { + _x HH MS 287 (MH '>

Exampk +% 2-Su fan.+x .:οιη'.ο-'>-« x.fev+'ore k nzcm'iiL·

Prepared re in Exantpk Illa from 2-anim>fepcntexxfej/o mink ί P vmupic b'-fei m 100% mcM .+ u light bo-wn -reap 'll AMR fed MH \ HMSO-fe <> ) +1 (tn 2H) I 74un. Ml). I 9?.ju, 2H). 4 9x_fnfelh,fefed ^f -DM 1/. I lb. 7 H (d../ 8 2 Hz. 1111 “.28 (br s. 2H). 7.55 (+./- 8.2 Hz. IH), 9.43 (s. IH).

L xan jy e 169b. 2 -,A m mo fecyc I open toxy bcrrzon i tri le.

Prepared ax Hi t wtrnlc i 1 lb bon. 2-X'fe-o-evAi>pcrrefexi \ n+nlc H 'antnk lobe) in 84% yield ax a green syrup. ‘Η N MR (4()0 MHz. C.DC h ι <> 1.5? (rn. 2Η), ί.71 t m, 411). I.X9 0n. 2Π1. 4 84 (m, i H), 5.94 (brx. 2Hi. 6.2() (d,./ - 8.0 Hz. i lb. <+3i id. / 8.3 Ha IH), 7.17((,,/ -Hz. HI).

b x i an <. 1+% 2 Ar.io 6 cfeopeafexvbew <nni ile

Prepiired as in Example 1 (<(<d from. 2,6“diiH(robcnzGnhrile and eycbpentanol in 7x',. -. rekl ax n Knt tan fe'd 11 A HR (fen MHz, (Ί>< Ί I ? 1,0~ tri. 2H). 1(tr. 41 b, I 97 (m, 2H). 5.14 (ηκ IH), 7,73 (m, IH), 7 xs {m.2lb

Example 170:4--(2 -(4 - Ana m?·· I //-bencx*|+j | l,2,6|thiadiazhie”2,2dmxidC“5yloxy)methyl)pipmdinmm ehtonde

502

Prepared re w bA.wrpk H<6 fem ++7-bred 4-+A(-frenmfe/7vivo . ’ o|tnt .utreire ' .1 OMde “ H-s' > re< +l)p ret <‘fr is χαΗ,\Ή x.i-sple ' ’4 '>

in 89% yield use w hi *e fe J H Ali'.KMMHMWkH., b> pn ‘rb 7%?% re

11/ 21 n. .7..13( m, IH) 2 89 (q. J - 11 ,(> Hz, 2ΠI 3 30 sd, / =· +7.3 Hz, 2 H), 4.09 (hire../' -6.6

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Hz. 2H).(>.65 {..]../ x 2 H/. = H). 6.82 td../ 8.2 IL·.. Hh< ~ 4x (t../ o 2 H/. lib. ~.4tbi o. HE X -. HP?.869{m. Hb,x'%)(m, IH). Π 01 re IH) M<2~2iMH ).

Example J 70a: iml-Biuyl 4-(2-(4-ami»o - 1 ΛΖ- ben zo (·.?] Γ1,2,6] t id a d iazinc-2.2-Jio x idc-5=. to sy % re th ·, l ιρη ren id me-1 -cat bo,> x Lee

Pi vparcd .is m Example I i I from ! re-bmyi 4-((d-cy:.i-sc>--3fsr.=fam<.»Linm<-}plKm>-K> mieihy I mipcndme· I vmbo'.xbtk -I xamp· . '. Ohj in 9'. \> as a xxime sehd ibWOH CiCM-M.

=- an p,. ' 0 > a ; huk 4 {{2 ^x mo 3 ta==^Em mii't 'oxximchx '='>if. =d rec

I -carboxylate hep fist is ip * rear'd Hiatio.ii’<-,i bui'l ! ιΐΐ Jii’<'i> .

cytmopbencoy ?merhy’P?ptpcpdinc· I -carboxylate (Example 170c) in 56% yield as a white solid. ^lH NMR (400 MHz, inwo a ) P ⁵li NMR (400 MHz. HMM? </ ).= I 2(! {are Mb. I 41 (s. Mb.

I 7<> rd. J == 13/7 Hz, .71 b. 1.97 im .:1I),4 00 (m, 411 j 6 96 (d_:,/ - 8.6 Hz, = H) ? 16 (d../ - 8.3 IL.', H b. 7 .7 8 ts, ..¹ 11).Ί.57 {i ./ == 8.3 Hz HIk *·’. -17 is IH).

l..sdmp.Ltl...L..^f.?k·. ·' ’* ’-Bmyi 4-(fJ-aminO'2<x aivphen· >.v, muths dpi pet reline-1 -rearbcxy I de

Prepared as in. Example 1 l ib from .w-butyl 4-((2-cyano~3mttophcBOX'x Imerhyllpiperidine· I -crnboxylmc (Example 170d) in 74% yield as a white solid. ’H NMR (400 MHz l)MSO<A) 3 I IS (qd,d 12 6 3 8 Hz. 2H). 1 41 (χ.9Η). I 74(d,</ == 12.6 11/7.111,195(^,^1)7^00,710,3 0.0 = 4/ 6 6 Η,, Ί b -. «9 tb=’ % J % Hz,?H-, ==.00 = % s, .HO 6 .7= Id.,/ == 8 .7 Hz. lib re 3 1 (d ./ == 8 3 Hz III), -'.lx p, / =- x .7 Hz, HI)

Ι%λ1Η:Ρ.%..ΙΪΙί(:Ε /w/-B«tyl 4-((2>cyano-3-n'urophenoxy}methyl)piperidine-1-carboxylate

Prepared, as jp ΐ xamoL· 11 Ic ri	'em .7. 6-J::iihi>bf;nzonitrile and re.-j'.’	-bmyl 4-
hydroxy merbyOpiperiJinx'- = -carboxy iare.· In 7	3% re a re=.n solid. ’H NMR (400 M	Hz, MoOD) .·>
7 l=qd / l'!.o 14 Hz Hb, i Η (χ,'ΟΗ,	t 78 (br 4,../=== 12 I Hz. 2H).2.,02 (	m, 2.H). 7.77
m 21 n ' 00 lb c / ’ > . 11/ 7lb, 1 |X(d	. ./ == o.3 Hz. 2H). 7.74 (dd,..? === 7.:	5, 1 5 Hr; HI).
f.9| <m.2H),

Example i7i:4~Anri»m5-(Qd6behhu£th«mH/?-heaeolr||L2,6|thiadiaziw-2.2~diaxide

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Pivparexl a* m r\-anplc 111 from 2·<«1Γ.ηη«»\ΙαηΗηο·-6cyclobup Imerhoxx bcnz-mstrik ^Example ί 7i a»in 21 % x iekl .as a yellow solid. ⁵H NMR (400 MHz. b\h< >-.·.> <) I 88 <m. 4H1. 2' Ox (m. 2H). 2.8n (sept. J 7.9 Hz, iHl. 4.16 (d. ./-== 6.9 Hz. 21B. n 02 (dd. J 8 .:. I 2 Hz. UM, ο 77 (dd. / s K 9 Mk\ I Η). Λ-Γ (t. > 8.2 Hz. 11H. 7.76 so: _s. IH\r .Wi s. Hb BP'rOb. ... πη Mp 2x2(011 )

Exampk I hi, 2 -Sud-nnox la anno-o· ey v lobmy Imeth» v heiuosrih: Io

Prepared as in Example 1I la Ip’-m ^-amreo-o-cycloburolmxnboxy'jcnzonin'ile

Η xample ΓΐΜ-η \ icld a hgin yelloxs -mhd. ^lH NMR MOO Ml 1/, | oium

IH}.. l.'pn. ?H) .'cnmcpi < >Hz. iKj, 4.13 (d,./<· 3 Hz .'.IB. '00 (d 9 = 8 4 Hz.

HH, I'M J Hz. HI) /3' (8:^2811.-.00(:../:=5-111/.111^74818:^ =H}V sample rib 2- KamM· -ex clobotylmethoxytozomMlc

Prepared as ifc Example 1 lib from 2-ftitro·o- ex cl» •hutyime'didixybensooitriie· (Example 171C) in 41% yield as a yellow .oil- MS 203 (Μ H '>

Example 171e: 2-Nhro-6-cyclobutyto<ithoxybenzomtn k'

Prepared as in Example 166d from 2.6-dimtrobenzoniirile and t-e Ά'ίΐχ medie'<>1 m nz*,» . · ,0 sp ,.| H AMP f IPO MH ' ’Alsi) ? ' '>; ipi Ml ' '0 (ηι. 2H), 2.79 (m, IH). 4,25 (d.../- 6.3 Hz. 2H), 7.74 (dd, J~ 8.,5, 2.2 Hz. Hl). 7.91 (m. 2H). Example 172: 4-Ainiao~5~(tetr^iiydru”2//-pyranM-yloxy)-1 H-benznir| 11,2.61 thiadiazhse-

2,2-diexide

Prepared as in Example 111 froffiM-suldmioylamino-’d-Cteirabydro-zN'-pymn-dyb*\x -benzonitrile (Example 172a) in 69% yield as a White solid, *Η NMR (400 MHz. IM1 SO-

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2017200704 02 Feb 2017 d, i <'> ' (ns, 2H) 2 05 mi. 21 i ). 3 ' i <M. / 11 o, 2 I 1t\ 2H). 3 8? (dt, f 11 4, 3 9 ί I21 I). 48.Mscpl.d 4 I Hz iHh%'2(d. >^! 8 0 Hz. HR o 88 id. .7 s.4 Ha Uh. 7.m. _(l / 8 2 Hz. HI). 77s ibrx HR. 8.3¹%% -. Hl). 10%<Ν Hl) MS 298 tMH ).

Example 172a: 2-Suiunnox lamino~64lclrahydro-x5/-p$fan-4-yloxyJbcnzonitrilc

Prepared as in Example H la from 2-amino-6-(tctrahydro-2?/“pyrun4·· \loxy fbcnzi<nitr-k (Example 172b) in 5x'^!>- a< a Ugh? orange xc>l<<j, ^!H NMR 1490 MHz. DMSOd- > <) I e>4 <ni. 2H). 1.99 s -n. 2H). 3.53 (ddd../ 117-. 8,3, λ I Hz. 2H). 3.85 <,m. 2H). 4.s0 tsept. J 4.0 Hz, 1H}. 7.07 id, < 8.3 Hz. IH). d6 (d,./ 8 l Hz. IH l, 7.28 (0; a 2H). 7.5(. n, ./

5 Hz. HI). 9.4%% a IH).

Exampte 172b: 2-Amino=-6-(teO'ahy<lro-22/-pyran“4-yloxy)bcnzonrtriie

Psepaicd ax in Example I I lb ficin 2 mno-O-VerralkdfO-d//·pxui.-4 yloxy)benz»-nkrilc {Example I 72c) in 49% as _un orange syrup. MS 219 (MH ).

I sample I 2c: 2-Nirro-o-ik'iraby Jre-2/f-pymn-4-s=<>\\ ihenxomtilie

Prepared as in Esample 166d fi»m 2,6-dimtobepzonitrile and tetrahydro-2/A nsian-i-' I in Iⁱ#r'< y ieid -sa-an sood Ή NMR (400 MHz ΗΜΜΜ/·,*3 I o’Mm .’Hi 2 % tyi .Ή=, 3 ,%<m, ?H;. ^Mm. 211). 4.98 Uepf../== 3.8 Hz )Hl. 7.99 tm Un Example 17 3:4~ Ami« o5-(cydopea tyloxy )q uimmrfi «-2 (1HMme

H

UH.,

5ss

Prepared as in Example 11.1 fMMAX2*cyam>3’ (cycl0peutylc-xy)phenykarbamoyl)bcn2am.i<k' (Example I 73a) in. 45% yield as a wintc solid *H N'MR {4i»0 MH.·, DMSO-i/,) <) J.oSun, Ilh, I s4 «.m, 211), I °°(m 2H). 5 9n(m. HI) 0 70(3..7 5 ML.2H). %’A(x. UH %'=5(t. -^f 8 2 Ha Ilh, 7 .% (h Ή). .0 f Ά 0 χ. IH) ( Nample l~?a \-(2·-' \ace- Meyr lopo'W loss rplum e.e' imriwUhen 'aru.k·

In. xmd ax n Fsamok I 1% On n 2-, mre~t>~exNeper. ιόί\ ’ .. Ink' (1 xamk

3b) m 70% _>icld ax a xellem >olid ^!H NMR (400MHz, DMSO-m) I <73 (in. 2H), I(m. 4H). 1.98 ta_s2Hk 5 03 <m. IH), 6.98 id. J ==== 8.6 Hz, IH). 7,55 (i. ./==== 7.6 Hz, 2H), 7.62 (f,7====

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SolLJHkVlfu/ “4 L2Hz. Hh.7 87<d / x Ο I Η. Η h 9 <> (m, 2H1 11 3~ lr v IHh ll 54 (hr:-. IH).

Example 174: 4- Amia»*5«(teti^,ahydref»raB-3'»ylaxy>4/I~bea2d{ti[1^2,d] thladiazme-2.2diaxide

Prepared as in Example 111 from 2--sulmm0yla:-ninO'64tetmhydrofiimn-3~ yioxx jbenz-nOr-le (bXrennle 17-kH in 55% yield ;.a a a hit·.. s/H.j. H NMR (100 MHz. D.MSU7 >020/<m UR-,.'.' ?6(m HU, ί u (td / 9 4, 4 /Hz (HI UUcb ?Ht 3’^(d ./ HU Ha Hlj.-.Jdlm HO.n.M {-1,./ = s I Hz. IH). <>-3 (X ./-9.4 Hz. IH). 7 45 (t,./ 9 I Hz HR-. Μ (X a IH'>. 9 55 (brs. =H). 10?u φ_;-| H >. MS 284 iMH ).

f.'Xampy..) 7 M ?-suifanmy ίαηΐ5Γ0-·<>--(Χ';ηιί’.χ d-«>fre .inM-x Awy '<be.izen.rnle

I'kMUXd'H ma de 111 j ϊ ί ' 'm o o-ue i J xd <>mi, ' xM\x;ben? 'r.ih.L- H xample I”4h) m mio“ xxhtfe sehJ H \MR <100 MHz.

HMACW rd lOOpr, Hit ? M'im, HR,'i 'Rd,./ 8¾ { Η , I Hj.5 χ_? HR U'_u| - 7 3 Ha lib 3 '12 ijj,./ io 2 ϊ.4 Ha Hb - HMm IHk <>%;! <^! 9 3 H ' Hr ’ I 8 (J. J

3H/ IHk ’ 7Mu ?Hy ' -8(/ > 8 Hz ΙΗ/° !){Ηχ UH bxampleJ 74b.: 2-Amino-6>(tetrahydrof«ran-J-x-ioxyrbenzonitriie

Prepared as In Example 11 lb from 2-nitrO“6~(teimhydrc>fu.mn~3~ x ?'' Ibeo/s r *n (t ear 4 1 k ‘ f ⁰ < . ek > -. a οΜη ’> ox <-< p MR ) MH )

E.S.iin)J>k.L?.4sk 2-Ni:ro-i'-(f.eirahydr<.ii..mn-3-yk>xy jbenzonitrile

Prepared as in Example 166d from 2,6-dinitrobenzormnk' and toimhydrofuran-3ol in 50% yield as a light yello'0 ^did. ’ll NMR (400 M.Hz, DM.SOo.M a 2 04 pi ; Ί t 2.32 (m. Hl) Ϊ 8'1 Rd ./ S3 16 Hz HR. M? (re. 2H)M % old. / 10 g l.R Hz. ' Ht (or HI), 7.75 (dd, J-8.1,13 Hz, i 14),. 7.91 (/./ 8.2 Hz, IH)„ 7.95 (dd,./ 8.2,1.6 Hz, 1H).

Example 175: 4-Amiao~5~( I -ssoprnpylpipendm-dAhny)-1 //-benzo|<’| 11,2.61 ihladiazmt“2,2~ dioxide

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Prs'parod as in Example 111 from 2-suliamoylmnmo~6~( I -isopropy )piperidin-L· y k'xx jKiLzetnlnk'iJ sample !“5b) m 12% χicki a- a xs WCM<hd H \MR {-*99 MlL 43 0 t 24 uk / h“H/.Mlj.2 11 {m,2H> 2.28 (m. 2HE 3 I Μην 411).43^. Ilk e did. <'

Μ>Π; 1Η),(>.8~{4% -S o IL·. Hh. -to p. / S3H/.Hl).“.c'{l'.rs,un.8mlfmreHh10.79 (br re Hl). MS 139 (MH )

F\a npk ~M 2-Su iam<-''amm> <% l-remm'ps4'tpi..»d'i I d> v nusojil’ik Prepared a- in I'sampk Illa from 2-3mmo-6-(l 'isopropylpiperidmMylexx -licii/enunk' (FAantpk I 75b't. I he prednel a.as ^nij mttodk.· s-sxi step wilivmt fmihe> puriilciuiom

Lxampk Π50 2- Amam-n- {Ires· -pn-ny Ipipcndm- 4- y ioxy }l'<i\'omnjle Prepared w- in I'xampk-11 Io from 2-nwo-o-< Iresvp-rcpy )pipcjidin-4yioxy}benzonnrik (F'sample 1⁷5el m dM vxdd a-- a h> asn t-yiup MS 2M'» (,MH' ),

Example 175e: 2-Nkro-{ i-isopropslpipcndjn-byloxykb-bciizondnlc

Punaicd as m Fwu'ok Icm bom dfo-dHmix'be'i \rn4i Jo uud irexpropylpipcridin-d-sxl in 90% x iol-d .re a ?an solid. ^!H NMR (400 MHz, DMSCh/,.) 0 0.99 (d, J 6όΗ/.6Η). L72fim 2lb, I (m, 2H >. 2 M ur.2Hk2 I pm 3Η». 4 59 _(w, Jh.~M (Jd. >^!

8.2, 1.3 IL·. i)h. 7.89 (m, 2H).

Example 176: (R)-4-Ami 110-6-((I -buty rylpyrroIhim-2-s Ibnethov»» IZ/~ bunzufi'l11,2,6] ihhdiaxine^ j-dipxide

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To a solation oftR)-2'amino-6-{{ l -butyrvlpy’rolidin-i-yljmcthoxy Jbcroonitrilo is4 mg,.0 29 mmol) {Example 17=36 m aectonmde (9 -ul ). was added ^=.Ifarmyl cnlonde (70 mg. 0,60 mmol). The tcaelion was slttre·.! at it for 20 b. and upon completion was ccnccnhated in iu< ><(.> The resulting residue was dissolved in EiOH (I mL), and 2hi aqueous NaOH (4 ml.) was iidd-.-d I he mixture was jvfluxed for 2 h, and upon completion w* cooled to rt, neutralized w uh IN HL; and stored at O 'C I M re.Ohing pu'cepdah. was colkY.ed b\ -<aui;.im 'llnatom to pn>\ id, the desired product (38 mg, 35%) as a white solid. ^!H NMR (400 MHz, DMSO-d.-.) <> 089(1.,/ “3 Hz. 5Hj. ι 54 fsext, 7 ~ 3 Hz. 2H ). t .9- t m. 4H). 2,2n {t. / ~ 3 11/. 210. 3 49 Ou, 2111. 4.10 im. 1H), 4,25 {rn. Hh. 4.43 tm, III). o -2 id, J 8 2 1 L·. t H), 6.90 (d ./ S.2 Hz, HI·. ~ 45 (t.J 8.2 He. HI). 8 68 {b= UH. 8 34(6=-x. Hit 16.93 (hi s. Of). Mr {MH )

Examplx ioa i/? = -2 Xmi'1=--6-=3/ -but'Ip' u ==li0.n-2-'' '.ri^'.ho\\)ben \ >.'ude

Prepared as in Example II lb from (/?p2-{{ l-butyryipyrroltdin-2-yl)mcthoxy)-6nthebenzomiak (Example 17ubi m 77'·/ vield. Ms 2~- { xt'H i

RxampiejTbb, (/1)-2-((1 -Buly = y Ipy 11 >>hdu ι-2-χ 1 )n=e^!Jio xy uo-nttrobenzontt-rde

T- a suspension =0 (//=-2-(-,2-^-.ano- Lnitr-.-plienoxx hnetlty =)px rrulidinniin chloride i 140 mg. 0.49 mmol) (Example 176c) in THE i3 mL) were added EuN (143 pL, 1,03 mmol) and butyryl chloride (56 ui, 0.54.mmol). The reaction wxs -uirrod for72 h.'at rt under 3¾. I poo =. -imnetien. Ok teu'n r u.=- Iteiod and ( w 'tlftat. was - .'»χοβ6.οο>. to puw-de (A’) ((I -buty£ylpyaolidiu-2“yl)mcthoxy)-6-nitrobenzoniirilo {1.% mg $2%) as awcllow syrup, MS 318 (MH ),

Example I rye- Hi) 2 (i 2 t yaao-3-mir--ph=moxy jmethy )px rr.-'idmium chlocde

Prepared as in Example 166 from (/()-.^.= 0butyl 2-((2-cy;mo-3·· iiilrnphenoxy imethybpyrrolidinc-l-earboxyUtc (Example l?6d) io 71% yield-as-an off-white xo’i I H NMR < 106 MIE. HM() 3 s -5’’ s _n ?H) Ί1_{ή =b 3 V (m 2B). '· 0<' tm ?H) -1^0(-1-1/ Ί0<\<> ' H/ Ml·, 3 ' '(d-L / 3-. 11/GH.i ' ’ id, ί 8 {.Ή?, IΪΒ, 7 9x (m. 2.H). 9,36 ihr x, IH), 9 74 (br x. 1 Hl.

Example 176d~ (^)4<?fOutyl 2-((2-cyano~3-uitrnphenpxy)methyI)pyn'ulidine-learboxy kite

Prepared as in Fxumnk l('6d from 2,6-ihmfe3benzom'inio and (/?)-i,’.w-butyI 2~ ^hydroxymerbyl)pyrrolklinc-j-carboxylate in 87% yield as a tan solid. ^!K \\IR (400 MHz.

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DMSO-R) ft i .39 Ox 9H}. i -82 Om HR 2.02 (m, 3H), 3.32 On. 2H}. 4 (C <m. UR 4 >2 ('u. 2111 “ 7Rd.·/ S.OH/.. IH), ~.<M On. 2Hi.

Example 1 ’T: (/0-2-::4- Knmm-l /7-hea/.«»|rH L2,6|(hladia/ine-2,2-dloxide-5-yloxy naeihybA-propylpyrrolidiae-l-carboxamide

Prepared as in Example 176 from (<?)-2-((3-amina-2-cyanophenoxy)methyl)-_!V· propylpynohdnic· l-eaibn-xumidc iExample 177a) in 57%yieki as a while sohd. Ή NMP. (400 MH<.. IAIS >·<;. i ft 0 r-3 R f 7 *> Hr. 3H). I -2 (sexi..? ⁷ 3 Η.·. 2H). '.HO (·η, 4H). -'· Ρ·Ρ» in, 2H) 3 20 Ri, UR 3.43 (m. 2Hi. 4 01 (m. 1 Hl. 1.1 ή· ί·υ. iH}. 4.33 (m. I ER 6.27 (rn ί Hi. <«.61 (d../ == s.4 =L\ IH) OeOid.J- 8.3 Hz. HI). 7.43(( ./- S.2 H;.\ Hi) 8 ROnre. HR 8.2 (hr-= IH), =0 91 is. Hi! MS 3x2 >Mli I

E s;miple I'-'a: (-f>-2d(3· Am no 2·cv;m· phennw )nielhyl) \ prepslinrrMidme I carboxamide

Prepared as m Example I UP Oom s 6’1 2 t(2 eyam 3 mi: op her oxy Jmefhy R \ p-opy Ipy nobreue = e.nH-sam.dc il xample 1 ,’R) m M% yidd MR iMH 3

Example 177b· ρ7ί2·ύ.><\;;mv,Pnmophenresy mvihyl)·\•propylpxmxlidme-.lcarbexamide

Prepared.as in Example· i76b from (.6)-2-:: .'bey .md-3~ reirepben ·χχ )m> liydipsrrmijmmpi ebi-MJc-J xamp'r ' ’(-e) .me p'opyi rew .wak- tn '00% yi.-’d .-= .⁵ =igbi yebov. si>=m MS H i (MH )

Exampk 178: (^-^-((d-Aminu-l/MH'n/uh ni,24>|thmilia/iHe~2.2~dioxiile-S-yhreylmethyil/WethylpyrreSdme-I-earboxamide

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Prepared as tn Example l“^f> from (6)-2-ii3-ajmm>-2vyanophea<’Xs)methyri· Vclip ⁵pynnlidme-l-carboxamide (Example 1m e0% y (dd a white M-lid. ^fH NMR 1300 MIE, I >\N »<s ί ό I (C <3, 7 6 8 He. 3P!, I ^,su ( u, 40), 1 Os imam ./ 6 8 He. 2H\ 3 20 (m, 2.HP401 (m. IHb 4.|(<um I He 4 33(%. IH). m2? an, i H), 6%2 (d../ b.4Hz. I Hi, o.f.9 (d,./ = x4H.·'. HI). ” -16((.9 = 8.4 Hz, I Hl. 8.20 (hr <, IH) 8..?'’ibrs. His 1091 re, Hi! MS 168 I MH }.

1...>.·:0ΡΡ.ϊλ)..1....ί.ί?.·.⁵ -l~2-u 1- -\m-no-2-cs an.-phen· > \y jmdhy I i- \-e*hy ley t iobdme-1 carboxamide

Prepared a- tn ΐ.xamnle 11 lb from (60-2-112-%an.'.-i-tmmph-,.r.c'xy )moihyp!-\cihylpyrruHdine-l-carbexamide (Exampi·. ' oh) in (<?^fI - \ x'.d Mb 2x9 (Mlf}.

bsample i >86 {/?> 2 u.. Cyano 2-mrophem xyrneihyb 3 ePreJpy('readme-1 carboxamide

Prepared a-, in Example I 7nh from (6)-24(2-% anc-3~ i-mr.'-phen- % -m>. % slips rr.'lidminm ehxMJe <J > ample = ΟχΊ one eihy i.recy .rule in '>?% y add as a hghl y dims re' sj MR 3 = Ή Ml I 1

Example 179: (&’)-4-Amiire-5-(( i-isuhmyrylpy n-olidiu-2-yl}methuxy)-l/?benzn[e| 11,2,6] tlwadmdne~2j2-di(sxide

SGI

Prepared as in Example 176 from (i?)-2-am:ino~6~((l~isobu!y i\ 1py.reolidm-2slimeil:.'\s')hen/i>niirdo (Example I Mb) -n 100<. yield a, a nbiu solid H \MR < 100 'sill.'.

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DMSO-J,) 4 I .02 id.-/ = 6 3 Hz. Mik 154 pn. -Hit 2.70 (nt 1H). 355 2H). 4 12 (m. 1I Ik

4.24 mi. 1H). 4.43 (m, HU r n2 id, <’ “’>11- ΙΗ}.ο°Ι{.1. 7 'ill·. Hk ~ (A ’ Sill. HI). 8 04(brs. Hit S.3-1 (hr-,, HI), lf”>) <N -,. III) MS 3n7 tMH'k

I \awp e I'M: {Α9··2-Αηηηο-6-⁽,{ ' --b\*xnlox::olidns-2-x ) n^.hexs) K'luon.tr-k' Picpared as m Example 11 lb fiom tZil-2-ίί 1 -tsobutxrx lpsrrobdu'-2-y Dn-ctboxy )

6-nitrobenzonitrile (.Example I79h) in 80% yield ms a clear syrup. Mb 2% (MH ).

Example l?9b: h9> 2 s-J I »cOutyiy lpyii--'id«: 2 'binet ι«»χ\) 6 mm h-.idx'nKuk

Prep-ii cd in Example 176b from (.R|--2 -((2 -cy;reo-3·· :siirepbeno\x)uKfhx l?pxrrolid=MU<m /blonde -aid »subutxrxI ehl<»nd·/ m i()0% yield ,w.: xelk»w <>-Hd. ‘H NMR <,400 MHz. UN 1 SO-JO 4 0.96 sdd. ..<' - n.(x 3.5 Hz, PH), i .43 i m. 4H), 2.1 4 {iu.

IH). 2.66 <.sq4../ n.h Hz. IH). 3.55 ire. I Hi. 4.28 (m. 3H). ~.74 idd.J 7m. i> Hz. Hit 7,84 fm. 2H).

Exa mple 18(h f/£)M~Ammo--5-(( 1 -ph rdm Ipy rreli& - 2 -y I) m et b oxy)- |E?~ henzu E? 111,2.61 diimlhizi ae-2.2 -d ioxide

Prepared as in Example 1⁷6 fiom. iR)-2-a-rnno-6-i (l-piv;doydpyiToHdm--2x hrv I'O'x k’eivnmr'h (Excop'c ISO?: re t P’^xied,' , wbit sohd ^!H AMR {’-()() Mb OMRO..,).» I 18 {.- Mk I -A' (p- Hb 3 05(0'. Hl\ 3 73 un. Hi), 2 I3<m, ' Hk 1 '%:n Hi), 4.48 (re, Hi), 6.62 (d.</- 8.2 Hz. IH), 6.92 id. </ === 8.2 Hz. IH), 7.471(,./=== 8.2 Hz. IH). 7.95 (br s. IHk 8.3 7 (br t, 111). I d 95 hr s. IH). 31S 381 (MH )

Example lSO;t (A’)· 2- .\mmo-^{>- -t I p=x ab?y Ipy n> -hd-n 2 -x Ijmcihoxy )be!'.A>rmrdc

Picp.ued as tn Example 11 lb hem s A’) 2 ii I ok.: oy Ipy ::ohdm 2 y Jmeilvsy ; n ' tn ·ν ί ό ' tide ί I x. 'ile l^ΛΗ-\.\ >(«( = %>< d is : el as sstyp MR »)’ iMH '·

Exztrople 180b: -1.91-2-% I --PivuloylpyiTolidin-i-yljmerboxyl-h-nitrobenzoniirilc

Pie'/ n> ο ί - re t satrn . 1 A- > p m (9) ’ ((' e., ό 3 'diepkeno'x ?ref.' Dpxne id ου?' · h'o.ide mJ p χ,ιί,Λ I > doi'de m '»'»· <- Il AMR (lOd MH '

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DMSO-/) 4 I . I 6 {s. 911}. 1.91 {m. 311 >. 2,13 (nt, 11 IL 3.70 rn. 2 H k 4 35 < m. 311). “ SI i dd. / · “5. 2 I Hz. Oik ~’>2/ι. 2Kl.

Example 181: (/?i-2-tf4-Amiu0-i//-hen/.«»|r||L2,6hhiadiazine-2,2-dio© ide-5-© lox© smeih^b5 -isoprop© Ipyrrolidine-1 -carboxamide

Prepared as in Example 1.76 from (/?)-2-((3~aniino~2-cyanopheuoxy)methy0“0/istipropx Ip©rrolidine-1 -Carboxamide f Γχ.ηηρίο I 8 la} in 23- \ mid a- -m Ml-ν', lute M-bd ’ll \MR (10p MHz D\N ’-</ i 0 I 05 (J J 6 4 H '. Mb, I b~ (El, 411} 3J?{m IHi, 3 7O(m, IHk 3.98 (in. .1H), 4.15 (ni, 111).4.31 frn. IH), 5 38 (d../ - 7.4 Hz, I HL 6.59 (d. J - 8.2 Hz. IH). <8.86 (d. ·/ - 8.5 Hz. IH). 7.43 (R ,/ ^::: 8.2 Hz, 1H), 8.18 (b? s, IH}. 8.23 {br v Hi) ^; O 88 ss, IH) MS 382 (MH).

Hamp ©I i (/?}-'-{(·>-\ η i >-2-k' aneplv now ’wf’» I) m\> t> y' lp« olid t -1ea/oxamlde

Prepared as in Example 11-1 b from (/?l-2~((2-e\^!ano-3-nitr6phenoxy)inetbyl)~;3~ ,-o,uopMps'olitbn,'-l-©','?«'©aij',deil\ znpk'58 bl ηΜΗ s,He a- a ©La, -·>;,m H \MR (400 MH/ DMSOM,'. _; 07/,/ 5 n Hz elH I8‘hm MH 2 I Of,n '} H. '« I o On, , H} I -/ f.m Η Η, Ή8 «in. Hit. 3 Ή (m. Η Π. 4.0b {sm I Hk 4 12 (n, I ll}< ' 88 p|, / 7 “ 11/ 'Hl.bOO (η-n, 211} o Hub./ 8 I lie. Hl),n.U (,1,,/ 8 4 11/. ' Hk * © H. ? © III,,Hl)

Exanmk 18lb, (/?)-2-((2-Cyauo-3-nitropbem©xy)mctbyl)-A-tx0propyipyrrofidiuc-lcarboxamide

Prepared as in Example 176b from (A')-2“((2-xyano-3wlfophene©© )rxdw Opvuehd'.uen eh/n,k UXumple >c> and .see©'.nule m ,90% weld as a yellow solid. ⁵H NMR (400 .MHz, DMM l.0~ (d, J-6.5friz.6H), 1.91 (in, 3H), 2 J3(m. HH. >< I7um Hike 7“<m. ΗΓί.4 19ί·η.21Η.3 Ώ (d,./ 8,8 Hz. I Hk 5 <>! (d. >^f 8 I Ha. IHk 7..'M(m, 3H).

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Example 182: (/O-24i4-Ammrel 7J-ben/j^Hh2.bbhhKiinfere-2,2-dknide-feksxs imeihyhA-fer-huty Ipy reobdine- I~carboxam ide

Prepared as in Example I ’'>> fem (a)-2U3-am::'i->-,?->.X3miphcn<>x}.)merhxib\' /err-biuylpyrrolidme-l-carboxamiJe (Example l< => in 56%ykid .+ an MTreJwe $Mid. ⁽H AMR { MOMfe, DMSO-fep I % re, <)H). I.Sfein HR,32i (m, HH. I 02 (m HR,-I Ifeii, HU I 34 <m HI). 5 Ή (x. HK + fepu. UbfeMni. HR, v.lbfe. HU x 23 fbr x. Hh.X 25 (brx. HR. IO Of {> HR Ms i xampa. 82a (/0-2-((3- 1ir.n<i-2-cxamfemnoxx feed.x I)-\-u .’-hnixipxiu» sd.i-’carboxamide

Prepared re in Example II lb fem (/11-2-((2-ey .«ni'-e-niitophcnow }mefe i)-A,<x'<b’.exlp' mlubne-l-c jreuxanfe.'(Example Ix/blm W< yfed re irex fee > >bd MS H/ t'MH ).

i van ρ e fe » (,0-2-((2-(3 a‘-fen ofemzx A-n.Jbx R-A-¹’H-mm’re u.H.dnn-dcarboxamide

Prepared as in Example 176b from f/?)-2-((2-cyano~3~

'.'ire' xbcii''trIίscli.l'niiir. eh'*>”i.k (Ere npb '7treandn M-mxl j-ereunm m .00% «,e d a-ar f ff-w'-re. read ^!lI A’MR +00 MHz. Γ>Μ\< fe ι a I -.7 fx ^c,l 1). I 8+ (m Hi) 1 °'^ζ (-n 2H), 2J2(fe 'll). 3.18 (w, Hb. 3 37(m 1 H). 4.20 On. IH}. 4 23 (dd. J I P.O, 6.3 Hz, IH),

31 (dd. ,< 9 2 7 H'. i Hl. 5 3+ f'. I Hl. ~ 84fdd. ' ~ 4. 0 <·> 11/, .Hi. 7 9. (η, 2H),

Example 183: 4-Amfefe-(peman-3-xloxxM//~b£.'nzn|<'|n.2,ifehiadiuzfe>-2.2-dhfede

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Prepuiedax nil winpie 11 I Iren: 2—ιϋί4ηι<\χΗηιηι>>-/.-(ρο!^η-1-\k)\y 1 l>enzoriitrilc (Example 183a} in 48.7% yield. ^SH NMR (400 MHz. DMSOM.MO.9l it,./ ===7.6 Hz, 6H), 1.73 (m_? 4H i, 4.54 (m. 111}. 6.59 (dd, 7==== 8.4.1.2 Hz. IH), 6.79 (d,</ - 8.0 Hz. IH), ~45ti../ 8.4 Hz. i Hi “S4fb: d. / 2SIL. Ill) \?.%h .1. ? 1.6 Hr. > Hl. 10 'm <s. HEMS 284 (MH ).

Exampk 183:¾. ? xml-mun iamino·η-tp-mnm-3 -y rnxyiber.zominie.

Prepared a- m Exaiiitde 11 la Irem 2 a nino ’> (pefiran 3 yoy il'-c.izen.Une s Example 1831 I = > »8 I y >dd MS 284 ι ΜΗ i b vtrapk I x3l> 2- Am> m>- «>· (pci min -3 > h xy jbenzonrtnle:

I'fcnui-.d ax m Exampk 111 o fi-,>m imo *> (p.rbin 3 y k>xy il-ca/emmle (Example i.xScon IOG%yield. .Mx2O5iMH i.

E:\ampk 183e 2 Νηι···6 (pcukm-z-yh-x> ibenzemin ilc:

Prepmed a- m Example 11 Ic in-m pentan-a-ol and 2,6-dinitrobcnz<.mitnk^> in *% yield. M NMR (400 MH? HMSO-a J <> 0.94 ((../== 7.6 Hz. 6H). L'-’O (ra. -IHi. 4.62 (m.

HI;. ’ x MO J -I H? Hl). - 8S (ra ?H.i

Example 184: (_kyw4~Amimi~5~(xrr''hat&xy)~U/~ht»z&|{'lU’>2,6hhi;idiazine’2,2~dio\ide ό H

606

Prepared in Example 111 fmm (i$%2xidianieHaminw·'- ’'•^butoxybenzenitide (txj'M ix-H'n K ·\>χ\'3 H NMR ./00 MHz HMM? . ;()91(’J /(<10, Mb . '9 id,/=== 6.4 Hz. ΗΊ), 1.69 (ra. 2H),4 72 (m, 1H). 6.59 uld. 7 8 4. I 2 IK IH), 6.79 id, 7=== 8.0 Hz. IHk -15((.7 8 Hz, HP- 7 x4fh d 7 2 x Hz. IH). x Mbbi 2 / I ·-H.. IH|, 10‘>η

Hl) Mb ' 0(/11 i bxanip'.e OHa i M 2 Si.'.lfat'\wlamei<> 6 t*a'8\y hcnzei'.iiilc

Prepared as in Example 1 I l a from (5)2’amino-6«y<?rebnkxy^;beiwn0rile (Example 184b) in 60.1 % yield. MS 270 (MH )

EN3l)Mdk..I84.b·. (50-2-AniiiK^4wA'<:<:-bu(exybenz.pnifriIe;

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Pupasedax m I s..anple 11 lb bctuf 9)-2-¼. -butcxy-ο-πΠΜκΐηorit>'-L'd sample

Isles m 100’. vd.': MS ^J’NsMH )

Example ϊ 84e ( 9)-2-¼ <. -Bum <y-%mb‘0be0zonmsle:

Prepared as in Example 11 le from (.Sl-bman-2-ol and 2 t>-dsmrrjl.--.mA=iiiUlie in 85.2% yield. Ή NMR (400 MHz, DMn« s s>9 “4 6, J 7 o He. Hi), 1.2'» (d../ 6.4 Hz.,

IH;-. I o9<;m, 2H). 4.7.2 <m. IH). 7.74(33../ (=.N 2 4 Hz. IH), ~.8o (ns. I Hs

Example 185: (A>4-Amino-5-(mefhoxy propoxy i-lf/-benzo(e||1.2mlthiadiarine-2.2-diiixide

N% 0._χ/·_Χχ%λ eg?

Pu'parcd 3' ml· sample 111 from 2---=.-lkiEn<'yl:anmo“6-{3 nerhosy pi--p>% stxmzomts de t 1. sample 185a) m tm.. <> s senl. H NMR (400 MHz, HMSO .% P2.iV(-n. 2H), 3.23k. Uh. 3 50(¼ ? 5 4 Hz. 2H). 4.1 8 0% 5 υ Hz. 2H'>. 0 5s (dd. J -% h.s Hz, Hl).6 'Oijd,,/ = 8 4.0.8 Hz, IH) ”430 J ’ xOH.·. IHs. 7s 22(brs. 114),8.31 (hrs. IH), 10.90 (s. IH). MS 286 I MH ).

I sample 18.% ? Su'damosIs.mmo o so =-ne'h.-\yp'«y'o\yIbe'm rmte e

Prepared ax nr r sample 11 la fmm 2-.mimo-6-(3-sne?hu\ypr>-poxy 'ibenzermn?e H sample 18.%) m =w ^7>· veld MS .%-iMH )

Example 185b: 2--Amis>c»--6--{'3--mcthGxy's)ropo\'y)benzrjrs=trilc:

Prepared as in Example 11 lb from 2-(3-nK-'iio\yE’>E\>pOxy)-6-siirrobesnZi3nitrile (Example 185c) m yield. MS 207 (MH').

Exampig 18 5e < 2-(3-Methe xypropoxy) -6-ndre benzo-ni tnle:

Orejasee ax ns ? san%‘e . 11 o r. %ne bgx\ p wpa-1 -M a d d'iOisNvsxxmsnik’ sn «>3.6% yield ^SH NMR (400 MH?, CDCBl 0 2:.16 {in, .211». 3.3(= (χ 3H), 3 «·>3 (( %^: % Hz. 2h:s 4.20(:,./=-6-4 Hz. 2H). ”.35 (Hd,./ === 8 8 6,8 Hz, IH}, 7.(=9 (I,,/ == 8.8 Hz, Hl) (dd../ -=8 I 0 8 Hz. HO

Example 186: (S)”4Amio0-§~(cy'otoprgipydmetb0xy)~l:jH“besizo[cy l.,2,61thmdiaxiae-2Jdtoxide

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Pr.pajed as m Feampk 111 0am 2~reJtam<a Lrmn'.-n!«x etopfap btvOx-syIbenzimm de I sreampk¹ I xu o m In *‘. x'ebl Μ P 24η-2 ₊ t ‘ll\MR (400 MU/ OMMJM.oM) W(m, JI) M-Olm 2Hk I ^{m. Hl) 4 0.? (J.,/~ ” 2 H/ ,?H). 6.< i) idck / ^: x.-s. O.x H/, II 0.6.3 ? J,,/ 8 -111; IH) ‘ 4r p 5 x 1l;\ lΗ» 7.99 {br d../^:: i .<> Hz IH), 8.41 {hr d,,/= 1.6 Hz HU M Ou (hr \l Η) Mh?i-X{MH 1 l:299?l?h:...lM:.9.: 2-$uifamt>y la num >-<'> -<:.x el->pn-py imcih.\.y )hen..imilr:lc·

Prepared a< in Example H la tn-m d-ammo-x-Gych.'pn.'pylmethexyjbenzor.itrile s Example I8<«h| in 8'\M... y :dd ^{H ^MRi-'-OOMIU DMSCWb)0 0 18 (m. 2H), 0.41 <m. 2H). !07(m HIE 3x0 (4,./ 7 211/. 2to, <, 7o (d ./ x 0 Hz. iH), n 90 id../-7.6 Hz, I HI, 7.09 ibr x, 2H1 ~ 37 (i Milk Hb MS2(>x(MH i

1:_:8.4Π.ψ.Η..Ι<ϊήί?.;. 2“Aminf>“6“(cyclGpr0pylmetl':Gxy)benzonitrile:

Hexad 4'ίηι\<ιη > ΙΗή ev %<.'» «οριορχΊη» Ιχ?χ <,>-<·>.. _f p out Pc f l'\;mpk' I xbZ; ^!o 100<' x re'kl Ή NMR i lOn MH/, DMSO-aM 0 0 3? tn' .Ή), 0 -χχ (η , ”H) I ' 5n(d J re.H/.Ίη ΊΙχΜομ / x 0 H , I fl), s< 3 (dd J 8 x

8 H' HI). ' i (i, 8 8 H/, 00 MS 189 iMH '>

2*(C^s x'hre'i opyhneihoxyj-tS-be-rzonitriie:

Prepared as J r re ar ede J .1 le from 23~dinitrobenznnitnl.e and cyclepropylnieihanol in 908«. 11 NMR: (400 MHz, 14.1180-¾) d β.40 (m, 2H), 0,62 (up 2H), I29_ijn UH. d. I 4(.,1./ “ 2 Hz, 2IH. 171 (dd ,Z “.2. 1,2 Hz. HI',. 7.9(w. 2IH Example 187: 4-ziiBi»o-5-(meibaxyieirahydrn-2/f-pyrsB~4~y0iH“ beuzpjey 1,2,61 llfia diazimre2,2-dinxide

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BPS

Prepared as in Example 111 fr->m 2. reidfamoyHrnim >-(>-(rati diy'di >-.?/A pyran-4y Ubeivonnnie (Example lb'.'aj m 92% weld as u cream xOiorcJ -'olid i NME (-100 MH.' I ) 9 I.% < m, 4H). I.(»3 i m m 41Π. 3.31 (bi m, 2H). 3.86 (hi m ?H>. -I Of (! ./ 6 8 Hz. 2HV> 57(4./ x,4 Hz, IHi a I (e > 6 OIL·. I Hl 7 41 11 J - X 0 Hz. I Hi. ”68 (br. HU x 24 re, Hi), ks%%br. Hl) MS 7} 2 (MH )

I xampk' 187a ,','-8ίΓ3<ιη'<>Η .mmo-o-i tenah>ba>-?7%p r _tre-a-x))berz-mPti/‘ Prepared as hi Example I Ha from 2-amin0~o-f(ien'ahydro~2N-py i m-4y bmc'dx'xx)nen,'<milrd.· (Example I %H m 51 ·. y vhl as .m cranx' satd H NMR t 100 MIL·. l')MSO~/0 <) I 35 (m, 211I o(> (hr 2Ks 2 Ul (br, I Hi, 3 32 (br 2Hl, 3 8 (%' m 2Uk 3 96 El ’ o 4 Hz, 211), 6.92 (d, J - 8,4 Hz, I H)„ 7 12 (d../ - 8.4 Hz, 111). “ I % hr s. 21b 82 (t, / 8 4 IL·, Hl), 9.44 (brs, IH), ( xa.mjpL· MM 2- Xmm-i-o-UUiUahy dio-2/Aprr,m-=-xOmzlboxx llx'r.A'mteik

Prepared as hi. Example 111 b hum 2-pm'<>-6-((icUaliYxlr'f-2/Apymn~4·shn:mhoxy)benzmiit de (Esumph' 18%1 m 80% \ sold re a ydmw solid. *H. NMR (400MHz, HMSO-cAld 1.32 (it 2H-, I ol« m 2H-. I 9“ <;%. HI). 3 31 (m, 2H i. 3 8b (nu 40),5,97 %, 2Hk6.19(d₅,/- 84Hz, ilh u M (d IH),7.150,/-3.4 Hz, IH).

Examp:x t8%' ?-'<:<ie-r-{t(ei”ab\ mO-27/-pc;an-f-ylnm'tbere)hcn, t-wli.L·

To a solution of tcu Jiy dropyrari“4--m.e(hanol ¢782 mg, 6,73 mmol) m THE (25 j! 1. x,_S' added Hoo t I „>8 M ι % |' -:4.,. ?,70mmol) m wx.ine a. 8 \ wreks ncrnm a At one hour a sohmmi of 2,6-dimtrobenzoni|nle (1 00 g, 5,18 mmol) in THE (25 mt ) was: added. The rcaetion was stirred under N= ovcinight at.rt then was qmmched with water f.IOOniL), The Piccipume ere eolkewd b= film··.a-n m pi·,.Me 2-wIki-p f(retainmo-2// py'au 4.

Yhme?li>»xYik'uzom(’ile (1,13g. 8 ί%) as a Imhi brown x>4id ^lH NMR {-M0M1L·, DMx< >„_t/. j;;

I tstm. 211-,2 On (%. H), ,>,M (m, 2Hi%/8 |m%H), 4 1 {,(, > (. (i Hz. 2H), ~,72 (d../ (H’> EL, 10),7,89-7.85 (m,2H),

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Example 188: 4-Aniiau-5-(mt4hoxyU^!iraliydro(araB-3-yj)-lJ/2benzo|<'Ul»2,6|fhiadj3ziae-

2,2-dtexide

Prepared as in I sample 111 Iron· 2-suit ano? laimne-o-ime^boxxteinrhy J>‘oh:rand-yilbenzenitrilc (Example 188a) in 26% yield as a white solid. Ti NMR (400 MHz, DMSOvkl <> I .e-4 (rn, il l), i 99 (m, IHk 3.73 (in. I H k 3.56 (m, 2H). ?·,<> (m IHk 3.7? (nt, I Hl -I 04 (m, 2H). 6 51 (J, J 8.4 Hz, I Hk 6,62 (d, .7- 8.-1 Hz, I Hk 7.34 (t, J - 8.0 Hz, IH), 7,70 {br s, 1H)„ s OMbrs, HR, 10 92 {H -< Hlk MA ?<)s {Μ H )

Example 188a: S-Sulfame-ylrirnine-bHmethoxytetrahyrkofuran-^-ylJbenzonitriic·

Prepared as in Example Illa from x-amino-6-({teirahydrofur'iin-3x Hinehm.xy ibeit/oinMle il xanrpie 1880-re H% y Md as a v-hde rebd- H AMR i-lull MH/, DMA* h/4a l.o2 (m, III). I.Ontm. ΗΠ,2.·Ρ·ρυ, IH),2M (m. 1 Hk 3.48 i;n. ill}. IpOfm.

HI). 71 <m 2Hk.'99<jm 2Hi e90(d. 7 8 8 Hz, Hlk“(N{J. 7 8 011/. !H).,Hr HR, 7,-h>u /- 8,4 Hz, 11:1),9.42 (s, 1H).

Fxatrpk s88b 2-Anrno-64{ten,shxdr/furan-RrMaev·. Ibem'/n/'n',/

Prepared as in Example 1.1 ..1 b from. 2-n:h:ro~(>-f(lerrahyd.rofuran~3~ λ i)medh>\\ HxmzonuMe <Γ\ηηψ\' 18M ) re AA'^!·, y seM as :. golden mown oil MS 21A (MH t

I xampic Ι8χ</ 2 \Pi,' 6 {{te/ubydb fi.wm e x Rnetboxx Ηχο/οη/ίι' 1-.

Prepared as in Example 16bd fiom 2,6--511590606/611-9110 aral 3Iwdroxymethyltetmhydrofuw in 48% yield as an orange-ud solid. Ή NMR (400 IMBz, DMSO-u) 0 1.68 {re, HR, 2.00 (m, IH), 2,70 (re, HR,,’ -4 _vu. 1R), 3.66 (m, HR, 3.76 Ru, 2H), 4 03 (ru, IH), 4,19 (.m, IH), 7.73 (d, J - 7.6 Hz J H k 7>M- 7,95 (m, 2H).

Exaa sple 189:4-Ami m>5((tetmlwdroia ra«62 -yljmet h oxy )q immzelm»2(l j^heae.

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611

Prepared as in Example 11 I from A-^-cvano-S-fftetrahydrofuran·?· yOmctho\y)phcnxlort»amvybhcug.umdc (Example I8%i) m 39% yield. ^:E1 NMR (400 MHz, dΓ«Μ8( n p | ιό -Η m. 1H\ I x? 0« m.2Hk I 99%ι η:. I HP 3 Ί (in. 21% 3 % (m. IH). 3 Ox f-n, HR, i'JO e i.7 un. 2H). .42 % <’ x 0 Hz. IH), ~.o2 (s. HR ,x8 (s. UR R o2 (s, IHi

Example j<x^(>a: A (2-(. s -3 ( (ten al is re <mu.m -.2 -vi)p'cth‘ \S j pheny I caibamoy ilbcn.mmide

Prepared as in ΐ xample 14*>;j In-m 2-amino-o-(Uotrahydr<.>fu).m-2y')me*l:?s'\ iRn/omiMe Rx rmple kmb'- a R'P.y He. re a w line--4:4 H NMR <460 MHz,</OMSO) η 1.98-1.74 (m, 4H), 3.54 (m. IH). 3 69 (m, I H). 4.204.07 (m, 3H), 6.97 (d, J - 8 8 Hz. IH), 7 07-7.51 {ir:.4H>

Example 18¾ 2-Ami00-6-(((cirahydA'iur»m--'-yIkmM'mxy Hxmzomtrile men «>u t.- m t ^x.wr > Μ I^Λ f >«' ' mt 0 0 pjeh P'xds -Hire'' yl)methoxy)benzonitrile (Examp e 89e) in <>2% yield as a light blue clear oil. ^!H NMR (400 MHz. MeOD) -ϊ 1/)7-1.68 (m, 41R 3.75-3.64 (m, IH). 3.80-3.75 {m. I HP 3.98-3.90 (m. 2H), 4..15-4.12 (m. IH), 5.96 (s, EH), 6.18 (¾¾ 8.0 Hz, 1HK6.3I (d,_: J- 8/0 Hz, IH), 7,14.(%¾ 8.4 Hz, HE).

I sample I-/8 ’-'xnro-b-ulemjhx JrotVam'-x ’»m··boxy >bo w, r n%

Prepared as re E'xampl·.- 166d 6-88 2 n-lirmn heri/mmnlc and ieuanirfuryl aieoholek; ^fH\MR Ν·(8> MR, MeOlM 8 ' '0-1 ,M(m. H), Rs~R₍₁R\ HR, 3 ,x0-' ’8 {n= IH), 4 29- = 26:re -·Η), ' ' p\ ./ 6 0%, IH), '»0-' χ ) (n\ ' H) E sample 1^6; 4~Amina-5-(2~mefhexybeu/y levy 1-1 //-himzoUiH -2.61 thiadiazine~2.2-ilsi.ixide

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612 few^{1 P}fepncd a- re Examd.- 111 fieir ?. la im'ren-U n elh*-xy :xnu\ low '· ncmomfee Η%-·.%ρΙο IWM % fe^! > wdd H MIMioo Mik. HMSO-M d > S'. re, 3Hi. - 2: ix.’HfefeL·’ 8> Ha IHfe Mfe,·? χ n Ho. HI), > »n (t, ? '' 2 Ho IH '>, (M ;d, J MJ.Hr HH, ''<’(!, 7 x O Hz HH, 7 46-.4? im. 2H), Ή {χ. HI). 8 M re. Hi! 10 On re. I Hi MS 33·+i MH 1.

1.η.'.0.1}1?.ί.ι)..ΐ.2.^!..Η.'. ?-Sullamcw kimino-b-i2-nieilmxyhenzyloxy) henzoniirile

VunxiiA. .re η I xat' Me 115 Mumi αΏιγ> o-<fe're,'sd atoM'-?

yi)inothwxy}benz‘(>Jiiii ile f I wimple biOhl in 23% yield. ^!H NMR (400 MHz. rf-OMSO) <> 3.s0 (x. MifeSMd./ e -MiA I Hi 6 88(0,./ Μ II; dis (.«t'fj ' ML' Η H. ” 'do id J x0 Hr 211», ’ kHd ,/ x 4 Hr HI) 5Hi. ” -55 id / = Ha Hi) IJ Oh IIH

Example 190b. 2 Ammo-6 (2 methoxybe-nzylwxy > bennsutuL·

Prepared as in Example 11 lb from l“mtn'-o42-m!.tlK>xybcrezylexy) benzonitrile icwimple 190/} in 56% yield. ΪΙ NMR (400MHa MeOlM <> 5 9 is, 3H>, 8.04 (x, oH), 0.300 2» (n' - 7.06-6 °4 ln\ 2H\ / 22-7.28 (m. 31H ' s '. _b Hi).

Iximp 4i\ ?-% ''i-n-(?-r. vbor/Mow 1 ben,οηη i’e

Prepared ax tn I wimple 11 ic fem 2,6-dmitrobenzi>niirilo and 2-mcihoxybenzyl afefem fe< χ de ’li \MR (fed MHz HMSfr) ό 3 x? (x 2111. > 2 i i, ?IH. w-n (t, / '6 11/ IH). 'P.x{ 1, 7 ,\ 4 Η ' H) ? 2; p. ,7- s,i Hr, IH), 7.10(,1 ,.^f- 60H.'. HI) 81 id,./ = 7.6 Hz, 1H), 7,93-7.87 (m, 2H).

Example 191:4~Ami»m§^(melhoxy teh'©hydre&ra»~2-yi)l //-benzoM 114.»$|tftia<Ii«$tte~ 2,2~d.toxide

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Prepared as ip Example 111 fmm. S-xulfemoylaniino-b-Cniefhoxytctrahydrdfhian·· 2 ylH wonmde it xamplc Ρ’ΙΜ ·π ΕΛΗ. veld as a while '-obd. H NMR s hi MH/, HMSO </,?(’ IH;. l.ho (m, IH). i.98(-n. iH), 3m'·¹ vn, IH). <7xim. i lb, e.’K pu. IEH4.25 f :u, IH). 6.M id../ '22 He, 1H). e.74 <d. =’ NO Hz. IH).

Ewimpk I9j,t ?-Sn.f.uro\h.mnn >-<>-<,mem/sw· l*ahsdr> lv.;.in-?-yhxivoliinle

Prepared a- tn Example 11 la In-m 2-anitoo-Mbeti.-bydr>'idi.m-2yOmetbe'X >b-..ozemn'de f_vb’x.rmple I N’b? m sseki ax a light yellow solid ^fH NMR 1400 MH/.HMbO-Atd? O.M 08 (rn. 2H) -<.<-i'«m IH), 3 Μ-3%· im. HH 4 20-4.03 (m. 3lh <·’% id,./ - 8.4 Hz.. IH;. 7.1 2 id../ = 8 4 Hr. UH. ” 23 (s. Hit ? ?3 V > 4 Hz Mb. 9.34 (br<, IH).

Example 19214-Amiito~§~(fiH’an“3’yh»e&»xy>17Abenx»|eyi_i2,bifhhiliiizine’2,2“dioxide

Pu'IMred as mExample 111, from2-suif3moyiaminc-6-(fttmn-3bmuhev )ben. mui! th (Fxatnpk 192a» ttt 45% _{s IC} j _k, off white solid. ^!H NMR {4()0 MHz, HMSO-M) .i 5. II {s, 2H). o.54 {d../ 0.4 Hz. = H). 6.5c (s. Μ I). bMMd. / 8.8 Hz, IH). .39 st,./ 8 411/. Hh. 7o4(x, Hh. 7.4_iv HH. ”,M m. Hh. x 23 is HH. J09f)_{s_x HR MS 294 RIH I.

Example I92;c 2 Sdli-imoyLmiioo n f tyrar 3 y hnctltoxylbcneonitiik'

Po'pme·: ax ir I x tt'.pie 11 la ίΌ'Ή 2 -ma Ό o tt'w.i' 3 y hretboxy )ecii m ut:ik (Example 192b) in 57% yield as an off white solid. Ή NMR 14(81 MHz, </-DMSO) <> $ 04 m.

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2Π). r ©2/. lHLe©SM.J © s Ha Uh, “.15 id. J 8J.0 S Hr, Η b. 7 35 /1. .7 SS||,.

ΙΗ:· 7 A>-~A2 pn. 2Hi. 7(>~/, Hb. 779/, Hb. 7.8© / I ID. ~ 9/ _f., HI). (/)( _is, HT>

I sairpA ^ίΧ2ο 2 Vie u> - Rih >' ’ \ lr Hao©© )l ui/n s

Picpar/I as .n Exanipk 11 lb than 2-niliV'tH furan-A\hitelho©© )ben/<<'iHtilc (PAatapk- 192/ tn 2.1% \ teida Hehl ©chow ml Ή AMR (409 MH/. </ I AISOi 3 4.92 is, 2'lb. h H-6 ?© (m. 2H), n.59 {s. IH), 6.99 0, J ------ 8.4 Hz. I lb. 7.27(/ IH). 7.45(/ IH), 7.6u Is. ;H), “frA HI).

Example 192c: 2-As?rc>-©{l\Bun-3 yhnerboxyshtmzoiiitrilc

Prepared as nt r.©ample 11 ie ln>-u d.i'-dmitifjhenzoijitule and e-RmtninetlumoI m 199' e © (eld Ή AMR <,4(M /IV, d V/S/i ? 5 /, o '-9 > I HR “ 69 ί > HR, 91 / M (fa, 4|b

Examph 193> 4-.Amino-5-13-melhwxyhenz© l«xy)-1 //-hen/njr111,2,6frhiudmzin/'2,2-dio\kte

NH₂

Si5 ^Μ.····^>χνΎ^Χ

Prepared as in Example 111 from 2-sulSimoylamin0--6’(3niethoxybenzyioxy)bttyzonkrile {Example 193a) in 54*/yield. Ή AMR (400 .MHz. J-D.MSO)<;

- 1/ OR, ' A'/ 2H),<>-/(1 ^r Mill· Hl (< (c / x 0 ’><, HR ( ^9 id < < (Mb.

IH) 701(4 <’ ΉΙ/ Η), Ό.Μ© III), Hk ’ ΜΗζΙΗ\Ί2;Η *9 10 Ή), ©9 ib/,ΙΗ) ©3'^!<,bt' Illi. 1096 φ/' > Η) MA33HMH >

I s,inp‘e 97 $ 2/su’l ιηη>\^!,-p,me-r>~t Rme'a, /hen \'o\©)bev, r, r

Prepared as in EAampfe Illa firm 2-amim'·-0~(7~m><box\bcnzsi«rey-heiwndrile (Example 194b) ini Ή yield / a white solid. MS 334 (MH ).

b©.i).ll.lllk...1230: 2’Am:nO’6’{3’n:Clhoxybcuzyloxy}beTizr>:iitiilc

To a mixture of 2-'0itrO''6-'(3-'m.eihekybenzyloxy)be0ZGnftrile (Example 193c) (480?n.g, .1.69 mmol) in 5:1 acetone: water (9 mL) was added zinc (5S2r.ng. 8.44 rnn.iol) and ammonium cblpride (91 ling, 16.9 mmol). The reaction wds stirred at room, temperature for 30 minutes, then, filtered and concentrated. The residue wus'purified by flash chrbmatogrqjhy

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1400 MIL·,./-ΓΑΜΟ) ό )73+, 5IH. -.04+. IK). r2~td. / 8011/ 11 Π. o 31 (d,./ \4IL HI). ffeGT (m. 311;, 7.27 (t.fe 8.0 Hz. UI1. ~ 3·'-+. Uli. .55 (+. IH1.

I xanipte 193c 2-(3- Med ;> -x\ = «cure In \ - be-t-: n > or .is do

Prepared .+ re F\-m;pk' 11 le how 2,felhnm?benzorHiriIc and 3·· nohoxy rerebde+'rel + 8? ’<> \ «eki Hi NMR (400 MHz. ₍Z-DMSO) 3 3.75 is. 3H). 5.3s (s, 2H), o‘>l<d../ 8 0 Hz. Hie 7 04 ui.,/ ~.b Hz, IH). AIM k, 1H). ~.33 (i. J 8.0Hz. 1 li 7.78 _{J,,/ b+Hx 4H;. 7-0 k/infeHl.

Example EM: 4~i2~(4-Amim>//Zheiuo|r|| l,2.6Hhiadiazhire2_<2'-dioxide-5» ylexy)methyl)pyrrniidmmm «blende

Prepare·' ax tr Fx. nrede loo Iren' ·' H rxi 3 ·.' (4 er.,wo ΐ>ί benzol· Η1 ,?.o)ihwdt.u’me 2.2 drext-Jr ? x loss fecMx llpy :fetdme I e,nboxyL:eH xarrple 19 lai w '% y sei Jas a x< hue fe J 11 AMO MHz RMS? ?-</ )3: /2 (n\ 11R 2 0'(m lilfex’RH Ή; ? r 1 t m ' H). 2.91-.2. Ήη.'.. 3H). - 9(m *R> t fed >’ r 9 Hz HR 6 3’ (d„./^::: 8.8 Hz, I H)„ / ·ί9 +«,./^: 8 0 Hr. i Hi 7 31 thr x I IP. 7 9(> (hr e, IH) 9 03 tbr x. (H)

Arrf-Bidy I 3p.?-(4-amin₅- ’/7-bcn7,.|_{ I; 1,2 sdihia>::.jzinc.?.?+dwxi(L-5yloxy Ir+ethyRpyrroHdine-1 -oarboxylaie

Prepared ,+ in Example 111 fem ++'Μ'>ηρ1-2-ρ2+'Χίιπ·'-3txnlfamo^lmefhx Rpbe+>oxy In-efe I) ρχϊ-reHJme-1 -xarboxy lare (i xempie 19 lb) ·η -M \> x reld as a x-,h:\' -s'b'd Ή AMR ₍ :0() Ml Lx OVl'/ )-.4 ) 2 i ⁴ ' +, ->1R, I ·« (bt m, I II), I ^C}' (br m, HI) 2 7y <o; n, IH}. ^γ -18- - 20 (h w UR 4 2 th m 21Π r (Ό to ' 8 0 H , I II) o 74 td 7

-III/, lib. ” ((, / 84 Hz. HR, 7“(i(x Ilh.S V, (_V HR, Ιΰ^ρ. ilh

Exampfe..l94b;. /m-B my 13-((2 -cyano - 3 -(sulEunoy bm jna )phenoxy )methy 1) pyfelidine ~ I -carboxy late

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Picpased ax in I sample I Ha fr>-m χ,”;·1·ιιηΙ 3-((3-<imnm-2eyarmpheuosy nueihybp'. = = <Ή4ΐηο-Ι-·χ;ο0οχλ late (Ex^mpk· HUc) in 4~% χ .ekl a- a win’.' .mbd. ^!H NMR (400 MH/. DMsH-%% I 3(x.9Hi, l.70ih. IH). i 9%br. Hh,2.63(br, Hi).3.472.98 (br tn. 411). 4 Ox th m. 2H). o 94 (d. I s χ Hz. IH). 7j 4 ol ./ s.4 Hz, IMh 7.24 (s, IH). 7.48 (s, 114).^54(0./ Ml, Hb. Us ibis. IH)

H.ampk l^Q-k te>! ΒωΜ ) na-anim· 2 κ\.ηκ'ρηοηο\’ν)<'κΟ'\Ι)ρ’χΓ:θ.Μ·.ιο . can x<.nc PscpafCd ax in l· sans,Ίο 1110 bon· ' nry ( u 2 ey a i<=- -<

mi. iphen-'x'jiUet’wbpy? <=hu’ne 1 caiboxy l.-t. (Fxamb. RMJ) =r ΙΟ;?’, υ.ΊΙόχ.!.'··..·'υΐΙ *Η NMR/dOOMHe HMS()-</.% I 37 m. %l), I (% Η. IH). 1 “n (bi. Hi), 2.59 (br, 1H), 3.07 (br, IH). 3 23 _V%. Hl)..%%%. IH'·. 3 40(%. 1H). 3 %-t.n. 2H). 5J< (χ. 2H). <- 20 <d / MOb. IH\o32(d, <’ 8 (!%’. IH). J-it.,/ 8,4 Hz. IHH.an-pk 1944 a -,- Bur.; $(2 vyano 3-e.i- =pl:cu v )nnu b'lipm.- m. w 1 -carboxy Ian. Prepared a< in Example imsd from 2,6-diniir.ibenz--niir-k’ and ?<-i;-hi,»y I 3(hydr0.xy/mcti':yb|'yrrch.hne-'·-carboxyOne m « 9%yield ax aycOon x*»hd MS 34” i.MH }. Example 195: (RM-Aminm5-((i-acit¥lpyrrolid!n-2-ybmethoxy )-1//benzo | ej 11,2,6] thiadi azl m-2.2-4 inside

( o -^;x i

617 < ^ΧΗ·^\ ihs-xue·: ax sr I s nujle I-> Rom f <”) 2 a-u? -ο o >.('. -ee*y lpy o f>’ u yl)mcthoxy)ben20nitrilc (Example 195a) in 31% y%J a,- a while solid. ^!H NMR. (400 MHz, PMSC%.)d I 90 (m. IH) 2θ0(χ. 3H) 7 2Hy f 09(-M ./ 9 %> i Η/, IH). '· 2 Hdd ?

^r’x ' Ή' -Hi 1 H (u. IH) 6 i-2 / 8 'Hz, HH.oS'ul. ’ 8 ? Hz IH\ ' IP (s, / a 3 H ' : H). 8 i ' (hr -, Hl), 32 (h= χ. 11H 10 °3 (br χ HI) M^v (MH I

Example 195a: (/i)-2-.Aminp-6-(( I -acetylpy rrd id: n-2-yi )rnei.hoxy)benzoaitrile

Prepared as in Example 11 lb from (?\)-2-u I-ac cry I pyrrol I din “2“y l)mc:boxy>6btrebcniio-mrde (Example 195b) in '77^i;y yield, ax a .lea- xy -up Ms .260 (MH r

I -..imp e..195b I - Ac-.-ly lpy rrolidin-2-y l)m-, tnesy )-6-nnrehe:'izon:tril.'

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Prepared ax in Example 1Ton item ( R)-2-((2-ey aim-Snitrophenoxyjmef.' RpvrMid(nhun chloride and acetyl chloride in 100% $ icld as a yellow syrup.. MS 290 (MH 3

Example 196: ^AimnoS-Cmethoxy^-pymlidine-l-propionyl)*!/#· ben mfr-H 1,2,6) th iadmzme-2 JEdio/dc

Prepared a< in Fxaniplt.· 111 from 2-sidf'air)oyi nn xo-f»-({ i-propienylpynoiidin-3χΐ)ιηζ4ρ·ν ivii/onit'de(I xanspk' 19o.0 nt 2'<'^!.. y C.d .;s :.'iott-w itleMid H NMR ( l(>0 MHz. DM\< >-j\i a 0 95 0../ 7.0 He, 311), ; on pu. Hl ι. > ιηι. I Hk i /37 (m. Hli. 2.05 (ni, > Hk 2 21 <<4,./ 8 OH/. 2Ηι. 2M (ni. HI). 2·% {in. IHk 3,03-3.2 3 (m, 4H1. 4 13 (m. 2H).o.n() {d.,./

MH/. 111m. ”5 (J J 6411'. Hi) ~A)(i ./ 8 (3 Hz. Hh. ” 72 κ .Hi.8r-M2<m, HH 10.94 (s, IH).

ί MPO.'.LO. 2-SwktmosI omm'-o-p j -pr.'pmmIpw.obd'.M-x I) 'nedi-reyhc'i mreo-e

Prepared as in Example 111 a from 2-.;:nino~6~((l~pr<>pionylpyrrolidin-3\ imi/iho w )ben, ιοιί; il.· (ΓνοπιρΟ- IM-) m 2'¹ x 'dd as a w Im·, xol.d M?> 3 '3 (Nil I i

Example i96b· 2-'.AndjKi~6--((_:l -propiQnyiiTyn’Ob'diib3-yl)inctbo>;y)bcfizotiitrile::

hc'Miou a-.n i xaneiu . 12 Oren 2 oho 6 >.H in.') ’em Ιρ-,.οΙι,Ηΐ 3 '<Oined.i'xx »xij/ahjicde (I- \ .'ΐη-le Wk) >n 00“ < y wid .. ekaj .Ό M\ 274 MH )

I xamp-e 2 \\m-n-i( s -p.ooierHp-udidir-3-χ Dn.ciboxx IbenconiLik

Prepared 3\ re Fxjirde (obbon.2 <'<->jwHCd.hr-3 Hrixtrore fimvenrask bsdioebbredc (fwinple w3od'> and pwi pa ή-I c'lMrde .w .. xd eu Mie MS 304 (MH 1

Example 196d: 2-ΝΐΙ:Ώ-6-(Ρ3'^ίΤο^41Π”3-νΙίη6ΐΕοχν)Ε«πζοΰΐΐηΙρ hydrpehiende;:

Prepared as in Example 166 iron· se;'i-buryl-((2-eyawo-3·’ nsto-phetiexx'raethx l)pyuol(dsii·.- I earh'-xykae (I xareple I94d) m lOO'’e yidj as a w'drex Mid MS 248 (MH ).

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Example 197: 4- 4n«BO-5-(mt4hoxy-3-pyroMme-1 -baty ry 11-1 Zf-benzo(c|1I >2 ihladlaziee-

2,2-dioxide

619

Prepared a- in I'xanipk 111 from z-sidiamox knnino-o-ilI-bifWrxlpvrrolid’ii-3y s|n\'Hi>'\y \Ίυonitrdc J xamp’c 197.i) m “T* > y >U as .. aL.'tc '-> \i ^JH \MR (400 MHz. DMm >-jM Λ O.ren (l. J 7 (> Hz. W I 48 «q. I ~κΗζ.2Η). I o? (m. Uli I 76(im IH), I 9 (m, i HE 2 1’5 (ni I Hl 2J ~ tt, / ⁷ 2 Η/ 2i IE 2 74 (m. j Ih. 2 x5 (m. I Hl ' 10 mi. HI 1, 3 e>43.23 (m, 4Hk4.12 (m. IH), 6.60 (d,J^::::8.0 Hz, .1H), 6.75 (d. ,./- 8.8 Hz, IH). 7.44 (t, J^:::: 8.4 Hz, 1H), 7.71 is. IH). 8.35-02 (m, 1 Hl 10.94 (s, 1Hl

Example 197a: 2'Suifainovlaniino-6-((l -butyn-lpvrrondin-3-s-hmctnoxvbcnzobKffe

Prepared as in Example I Ha from 2·ίΐϊηίηθ'6-Ο I-butyrylpymlddm-?yQmcihoxyjbenzonmite (Exumpk l'^}7b) in 19% yield as a white solid, ^:H NMR (400 MHz. DMSMH 0.85 %./ - 7.6 Hz. 3H), i .48 (g.- 7.6 Hz, 2H), 2J3-1.64 (m, 2H12.17 fm. 2H), 2.75-2.53 (m, 2H), 3.65-3J8 (m, 4H), 4.09 (m, 2H), 6.94 (m, IH), 7.13 (m, IH), 7.25 (s, IH), 7.54 (m. I Hl'145(01. sH)

I \ample 19-¾ 2-Annno-nM i-lniWry|pyi-Olidhv-3-yi}nicthoxy;bcnzcnlirite

Pu.xucd as as Fxau'pk- I > lb 1mm 2 .Mb 0 OH brnyMpyim Kiel yi)mcihovs)benz«.>nitiik' (Exuinpk' We» m 100% \ iJd as a blown oil. MS 288 (MH 1,

Example 197c; 2^Nitfi6.-6-((l-butyrylpyrro1idin-3-yl)mdflK>xy)berizbmtei1e:

I'lenaizd in ONampk' N'i-b fiurr o tpyn> idir. 3 ybncih<>xy''ibei:7eiuiide hydroehknMe d xampie I9i->.baud huy:y I Cnleftde tr. HWeyieie j^asre range sol d MS 318 (MH }.

Example 198: (EJMI-Ami W)-5-(.I -(prdpylcarbamov 1 jey depropy lot eih oxy)-1H be.irzo | c | (1,2,6| th iadhizl ne-2,2~d (oxide

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Prepared as in Example 111 from I -((2-cyano-3(smbanox la>mno)pbenoxs)=netbx h-X-po-py Lxel>'p><>p,iucemb>-x<tinide H vunple l‘kna) m 94'3.. yield as a while solid. ‘H-NMR (400 MHz, DMSC>-fA.) ΰ 10.95 (broad s. IH). 8.35 (broad s. 1 Hk ' 45 «bread - Uh. > (t. J ' 2 11 '. I Hk 7 .|X _n I xpllz Ull>iW{dJ S.xHz. IH). <S.0l (d. .1 == ?.b Hz. = Hk 4.22 (8.21% 3.01 tqj == M Hz. 2H). 1.40 (hex. J === 0.8 Hz. 2H}. I 12I l%m 2in-J?xx-(M (in 2llk OxOpJ .οΗ-,31)) MS 353 AHI 3

ExampR = Osa; |-o 2-6 yane-3~f·Μ=Η'.υΗ<.>γΙοηυπ>.>>ρΙιο»ί>γνsneihy. I >-\~ propylcyclopropane* jiiv' an ode

Pr. pas ed as in Fxaraole I Ha frrnn )-((3<nu:r>o-2-.'^a:?-ipheu<-sy imMhsn-Apropvlcyclopiopanet.Hbosamkk (Example 19<8b) and .sulfamoyl chloride m 7830 yield as a wh % solid. TbNMR (400 MHz, DMSCM0 ^9.45 (brocui s, 11Ik ~.5l-7 6 I (m. 2H), 7.26 (broad s. 2H;. ~lo{d .1 \0Hz. Uh.n.’H _VIJ x 4 H.\ Ill). -I .% (s ?H). 3 0 Ip J HH.’.'II).

13 ibex. 1 ->tk 'Ilk I Ox I M n- .'Ih.Ox) oxx_rn ?%, 0S?r, = ΜΡ/,3ΐΙ) Example 198 b = -n 3- Amino· 2-ey asm-pl· eno xy jmcihyl i-A oropylcyclooropaner-a: hoxamiJe

A solution of MliytifG^ynie.thy.lj^-p.ropylGycfoprQp.^^arbpx.wide (Example 198c) (0.67 g, 4.25 mmol) in auhytfecals THF (10^:mI->) was treated wthNafl (0.17 g, 4.25 mmol, 60% suspension in mineral oil) at 0 ^!'C, under a nitrogen atmosphere. The obtained mixture was shjr.-d ar 0 »' for 10 smn and at - >'. .-r 30 =m : ΐ hen a seli'.'hre <>f .‘'-jn'in. -u-l π-m hen.emiri'c (f).53 < 3 x6 mmol) in H.ll·' (s f) nd l was ad-l-.-d and me obr-um'd m-xinre was nc;re<' al retle-x .bserriight: The cold mixture xvos cpieuebed wnh saturated aqoeou«- mlmicre ol \^TH;f I (20 ml i and .'vroek'd w nh h'n) \e { % ?{) ml '> 1 he coir.hbvd e % am was -λ asned ?, im bs ire dried nx-r anhwh-'es M-?SO llbesu. are ;\ap- and The tesjeie u <- rnului. m «,bu ’ κ»η> j .p’o on silica gel using gradient hexanes ----- ^!5t\..es E:O.\e (4:6). to give 0.75 g (7 J %) of tbe title uou'poo'd a-a\i I’i-w se'd U-AMR« h'i= MH , HMSO-m'» 0'7 % ll I o 0 11/ nh,7i~p-3

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SOIL·. IH>. 6.34(4, J 8.4 iv. HD.o M-l, J 8.4 Hz, IH), - 07 f bread s. 2H I, - B<s.2Hk M)4u|. J 6.4H/.2H). AM (hex. J 6.8 Hz. 2Hk I 05-1.11 re. 2H), 0 ~9-9.Se (us, 5Hi

Exatnpre Me > a Hy. 4r< >xy nre-ihy 1t-A -ριορχ ley x loptoisreccatbox.remL·

To s-.'iulfou of cthx I 14pr>>py kaib.-inox He?ciupropanecaiboxy kite (Example I9xdt {I /re g, 8 2 mreoR in Efi>H {6 ml ) w.e- added AaBH: (0 9 -, 25 e > rarno'.l ,n it I he obtained Oiixiuse w;e; ^t-ned at ri oxer 2 days, quenched xtiih 15M HCi and em-ec minted under reduced pressure. ⁵ he concentrated mixture was extracted with Et’/Ac (4x70 mL), the combined extinct was washed wiih saturated \aH<'(?, ami hinc, and wre. dried ox er MgS<\. 1 he filtrate χχas ex -pe.atvd -red ihc residue was purdied by vbrotnmog?;g>iiX on silica gel nsree the relx cm giadicut hcx.recs ' Irexaucs EtOAc ί i 9). i>. fu;uixli LR e (8X^,-i>i of ihc 'uoduc' -re a 'xh.tc <iLI ^:ΗΛΜΡ < 400 MHc. OMSM-dm A 7.49 (broads IH). 5.09 . hro.d s. Hl) ^P^.2H) 3o5(qJ 6 ML·. 2th. 1 4s ijrew J ~ ο 11 -. 2H) .0 So-0 91 _Vn, 2H\ 0 x3 t. I “ 2 Hz. ΊΗ 0 55-0 ^h» (re 211?.

Exaippk u'Ss- I ttwl i-ι mepx lc.ithamex' rex Japtcp,i'ic..ajlx'\x bite

T<»'-.'lalK'U of l-telboxx^rebonx Irex^lopsopa'renaflx'Xsbu acid (Wrcc ei. 1 \ , Kay, .1 \ o< m'/s <'<·. era res 1988./MJ.’, 141 H < 52 g. ⁿ o2 iirei-l) cad t'-i'u py.amine (0.63 g, 10.58 rurnol) in anhydrous D.Ml·' (65 raL> at -t. 'acre a.kkd AaH< 3 h (4,04 g, 48.11 rnrnol), Nh(,-Adinre'thylarninopr<>i'y^,ll-'N'--cihylc;uOodiiUiide bydroenkuide (2 21 g. 11.34 rnmol) and .-bxd'c \y ireuzoiiiacere bxc.au (1 j> it 54 mn.>-b unccr ,t u-tiegen .renuephew. Mu; xreg sinuo <6 '* >ne-ught. .he mixture '-ax pmlRrereed Koxecn ware* f Odd nd.)./ u I tCAc f?0(i nd ) I be organic phase w.w sepamud, xta-ticd wren xuitcs .red «nre. ,ree ixcs t - c<. -x x r uuhxdb-n.' Mpx< Tire lilii .4e was vtapoiA'd to go. c 1 .n5 e (86’m of M viudc prerekre xx bred χχas cse<.; re the next step wi(h»-ut pur-tkaiiou H AMR 140*,* MHz, HMSO-d;,) -Ϊ8 33 ibioad s. IH),dOx(qJ <> ,x I L· 2H) ⁴ 0 J 6 IH;· 2H), I M ik χ, I o 4 11 -. 2H} ' M (s, Mli

l.r<i. s 6 4 IL·. 311),0 85 (I, J 2 Hz. Ml).

Example 199:

dioxide

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Prepared as «Π χ,ηηρΚ' 111 Rom 2-^n:fam<\slamjnH-0'(4-mu'thoxxbut-2cnyioxyibcnzomtriic (Example 199a) in 01% y u-kl a xsmtex>>hd ‘H-NMR (400 MHz.

OMv ι A10.94 (broad s. IMP 8. 14 thread s. IH», 7.90 (broad s, 1H), 7.45 tt. J ^::: 8.4 Hz, I Hl, <> '(ft J oil.' HR. {'M id, J /Oil- HI), sSS-rfCfni 2H). I ?^ζΜ3ΐ im 2H). .'.w 3 ‘Rn’ 2Hk 7 22 % -OR M\ 298 iMH j.

ifxampk = 9% 2-¾ tana>\ k:mnto-'>-(d-nje;hevsbm-2-e'ix k\ jbi'urerJrle

Prepared as in I 'ample 11 la hem i/M-2-anjino-6-{ l-methvxyhm-2enx loxs jbemmumik' (Example = 94b) >n 4 M . veld as w hue s,Md H-\MR (466 Ml M

JMSO-r) AW4n lire -ad s. Ilh 7.5b (l J S 4 11/. IH ), 7.26 {broad s. 211). 7. j 5 (d. J - 8.0 Hz,

IHkn9o<d ,1'8x11? MR 5.S4-oil6im, 21H,4 6\~i 'Mb; 2H). 3 X'*-3.93 ir.) 2H) 3 2 3 (x

3H).

Example 199b: ('E)“2-Amino-6-(4-inethoxy but-2-.eiiyloxx ibeneemitfile

To a solution of(Ep2“(4--nu^vthoxybut-2-enyic»xyj o mhobenzonu I (I x npie

199ej (0.23 g, I.00 nnnob in u mixture of AoGH, EtOH and w net (3a mL, 1:1:1)was added iron powder (0.56 g, 10 OR mmol) at rt I he ohureed mixture wre spired at rt. for 20 min, then wax^: heated to 50 { ra turtbei l χ mm red allow j to<x c The wspenxion was coiteemrated ’.-..det rereiucc p' - sjie h. esidire wax t. ated v. nr u oer ι ό re, ) ,ird exlr.u is’ I wnb I :O A (Ixrej jrVt H's’ eerd'ircd .-'tree' a x v.a^bee urb sanrale-l η/,κχ m Nail·. Oi an<' bRne and xs> J '>er e\e: a’-ixdreiis Mjst s. |'h> $ h ate'a.h xa xnated xid 'he-residue wax purified by silica gel flush chromatography using gradient hexanes heXaneM'EtOAe· (1:1). to gix-'e 0J 9 g (8n«_e) of ihe mle compound us a white solid. Ή-NMR (460 MHz, DMSO~%1 7.17 (t, ,1 ~ 8.4 Hz, IH) n 3 I < d ,1 5 8 Hz MR 0 22 id, 3 ; Hl; MH 606(bim>ds 21R, > x2-' 'M (m ?Hi '6-1 i<2 Rm 21R. ' x8-2> 9s Rn. 21 h 123 (s, 311 s frA.?I.nplc..L99cA (i2)-2-M-Metho.xybuR2-cnylo'xy)-6<rdtrobcnzQnMiie· : i e >e .‘ion ί%)-2-ι l~»'xdrexxbnl’2rersl ms ι-t-r Jiebs nzer Ji’k H s rn'k

199d) (0.50 g, 2.13 .mmol) and 2.6-><lt’/eTrtbuiyh4»meihylpyridinc (2.18 g, 10.65 mmol) in

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CH Ί, ί j 5.0 ml ) at rt, was added tremethy kreiium ten ..iduorel-.-^0.0 i 1 58 e, ] O.tre mmol s under a mitogen mm>-sphere' .Auer = h a re. rhe '.ichors was qatiiehcd v-uh water (So ml.) ;md extracted with Et^f >Ae s4==50 ml). I'hc eembmedextrae* wax washed wnb water, I Al HCL ^mutated aqueous NaliCO; and brine, and was dried over anhydrous MgSO.?. The filtrate was evaporated ;md the residue was purified by ehroinatogruphy on silica gei using the sob. cut gradient hexanes - luxancx EtOAc (3:7), to give 0.25 g (72%) of (he title compound as a yellow solid. ^!H-NMP i400 MHz. DMSO-m.) 07,84-7.92 (m, 2H), 7.68-7,73 (m, IH), 5.8.2-6.03 (m. 2111 4 82-4(.(. reu, 2H). 8%3%3 (m, 2Π). 3 21 =,=.. 3H).

bxampie itehl. (7 ι-2-(4-Η\ Jiere 1'ί7-2-οηΗ.οχχ)-η-η.η.4ΆνοηΖηΙχ'

Psepared ax ns F sample lood ream tZ')-bm-2-cuc-J ,4-ds.] (Alfdci, I'. < I , Phs,^

I W„ Sehwurt.'man, I . H. /. (>.',’. to,/,=>. 1^59, %, r=2 _;n 30% ucld <ba xclh-w -ohd. ΙΙ-ΝΜΚ s 400 MIL·. DMSCM.,) 07 83-7/14(6:. 210. 7 <w- % (m. IH). 5ή'^!“-ο.?'Γ sm. IH). 5.78--= x%m. IΗI I xM-80 t m. 7H1,3.0 M 02 {in. 21 h

Example 299: 4-.^119^0-5-(2-(63(^-0^571^01516111510^^-1-11141^1/610111,3.01(91^901/151^-2,2diisxide

HjN θ_νΑ .-OH

622

Prepared as in Example .111 freon 2-((2-cyano-3(sulfam0ylaruinu)phenoxy)methyl)allyl acetate (Example 200a): in 44% yield ss-a-white solid. ΊΙ-ΝΜΚ {4ili> MIL·. HMSO-%) 0HW (bmuJ χ. Ilin S.% (broad s. IH). 5.01 {bn-udx. Hh. ~-I5tt J 8-p Hz. HE. <x'o<.L J x 4 I L·. 1 H). h o hd, J 8.0 11/., IH). \2u Η. IH). 5 20 {a. HI) - l-htM 5 2 Hz Hi). -5 ~x 0 2IH, 4 t% (d I Hz 2H) MS 28UMH )

Ls.w.lT <·' OlOrn 2-((2-Cyam>-d-(sulimno\ kr_:nmo)phenivxy jnuthy l)aii\ I acetate Prepared as n= Fxamplc II la from 2-((%ammo-2-cyanophenoxy)methyl)allyl aeetau (Example 200b) n= 8^c.< y izkl as a white solid. *H-NMR (400 MHz. DMSCi-m.) <>9.50 throa-L· Hl) x'it .1 x I H ' IH), ’ % (bread == 2H) 7 ' Md J 8 0 IL, H l>, (m'>'(d. 1 ^s ? I 11/, MH ibroads IH), 8 33 (broad s HH I His 2H) %·>3(-= 21H .1 05 (=. 3H1.

I x.mspte 'ΌΟ'ί 2%v '--.Ami >w~2-cs,m->phz-u>xx ync'hs Hllvi >u‘o: Je

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Prepared as m Example 1 99b bom 2-u2<sano- 1-n,^Arepl,cuesx lireiie Dalh = uceiuie (Example 200c) in 76’>i:· yield as a yellow oik Ή-NMR (400 MHz, DMSO-Λ? 9'7.1 x (t, J 8 3 ll/JHM- 35 (d 3 8 8 Hz, HI?, 6 21(-.1 J 8 0 Hz i ID. U.iM = ;_X<c.J _s, 2H) %3-|-S ?-S (m. IHr 5.28-5..?·I (τη, IH), 4.61 is, 4H), 2.05 (s, 3H),

I ^^’upje. .2Q.0.O 3-u2-Cyauo-3-·lilix'-p’nene % InicthyI jally I declare lo a. sehem-' <d 2-(2-0/.9<-v.JrMhdbk'V. R=>“'ui,oucn/'<>'imih J s_t>mpk 2(80) our? _g, s .73 innv-D, 4-ibmcthx Μηηυορχ rdme ι0.21 g, 1 7? mmol? and pyijJmc {ikes g x r>4 -modi ip ί Η 8..Ί. { U? 0 ml 1 at 9 ’=' v, a- added Ae-t 1 (0 ·'I g, 5 19 mmol) under a nitn atmosphere .After being 'lined ai 0 '= ’ E-t 10 ηηη, fbe in ixiim,· -aas sin 1 cd at it ,w /might, I'he reaction mixture was diluted with EtOAc ( 100 mL), washed with 1.5M HCI, saturated aqueous N.d ICO and hnic, and was d> led <--,er McSO,. fhe tibrjlc e\apniaied and the 1 csidue was psnjtled bx entomaiogKiph'' on MUt.a gel using ike sobeul giadun, hexanes » hcAducs. LiOAc ί ⁵‘~i. u- tininsh 0 49 g (.x4“..l -,-f the idle e<niip>-niid as a yellow- solid. Ή-NMR (400 MHz, l>MbM-d, ?ff7'kMdd, 1 x4H,\J I 2 Ha I Hi. 7 91 η. J x.4 Hz. IH), 7.74{dd, J 8.4 Hr. J ^:: I 2 He, IH) ·'4lA,p'in.jH). 5 HUioi, HI), =90 0..2H). 4.66 (s, 2H}, 2.05 (s, 3H).

I xanqde 2*8?d 2-{2-iHx Jri-symeth) lAdbHov, )-6-106obci ί-όΟde

Prepared as in t-xamnl·.- loud 9>·πι 2 o-Ihi-m-benromirde and 2ineiuxk-nepi''pa>ic-l,l~dioi m 55% sk^:d <*- a wh-*e .-=0=J HAMR f, l^!J0 MH -. OMSi 1- /.) a* o 1 (dd.J x4lk’.J 0,8 Hz Mil, 7,xdp, j <_<,i Hz, IH) 73 tdd, I 7 6 Hz, i ΟχΗζ,ΐΗ), ? 23 x„9(m ?Hk ?tM{t. I lHu4 8s{v„ib. 4G61JJ > J Ha

2H1 |Πα~Αχ;Ο 009% /ΖΜΓΠΆ Π

Example 291: 4^And&u-e-t4,5>-dihyds'bf0raii-2-y1)~l.H~benzu(€y i>2_it6]tIiiadiuzi«w2_>2-dmxide

Prepared.as ip Example 11 1 font 2-sulMmoylamin0-6-'(4,5-dihydrofUran-2yl)benzuiiiirile (Example 201 a) m 31% yield as a white solid, ^rH N.MR (400 MHz, DMSO-Λ) d 2 5-2,χι {in. 21 h, 4 43 μ,./ 9 2 He. 2Hk 5 35-5 9= {m. Πb, 7 07 ydd. J I 2, ,8 0 He, Mh,

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7.12 (dd.,/ 1.2.7.2 Hz. HI), 750-“ 54 i m. IH).8 2-fetfeadx. lib. ll 09%, Hh MS 2w (MH),

Exatnpk 20la 2-Sidt'ani<'y l.mun>'fe4.5-.hhsd:oturer-2-\ lllvw ίγ;η e

Prepared us in Fxantpk· I Hu fem 2-mnh:>>-<'-(4.5-dibxdtotbran-2-\ nivu/uniude (Example 20: b) :_:S py <. meld ax a w hue v.>hd Ή NMR MOO MH;\ I >MSH-fe 6 2,82 2 8/ (nt, 2H), 4.45 0,./ 9.6 Hr. 2H), 5.89 (?,.? 3,2 Hz. IH), “fe to 2H), ~ 4~ (d../ 7.2 Hz. iHs, · 5b (d../ fe Hz, IH). fe~ (),./ .xilHr.UO.9 42 (χ. IH) MS 2cn (MH »

Example 201 b 2 ..miino·o-14,6 -dd-y d= <4 ntcn 2 -y I )he-;zonre jle 2-A?nino-o-i>reinobcaz--n:tixlc (R 75 m '-.8'· mm,·!). (4,6.dihydiofmxm-2· x fetic'hx aaiiftJxlV re\^s>, I a,rec ,-, \ 1 <>re„ > I λ,ώχχη I d'am, Μ I Y Pa.wuzf. \ 'few <.fe' Z.1994, 35//2». 776“} (H>2 -, 3 .% tr. n >^!'>, and p.dl.uhum renakfM): (phony IphophreM (0 33 λ 0 28 mm- ^;) were rellufe m relm-.sc {',0 (> mt > ur.da nirregen Mr 1.5 h. Saturated ain-uonium chl-mdc {'·.? ml ) and amm· mhim hsdrexide «,4 mL) were fel>. J, and Ore m i\re re- n ax e.xtreaeJ w ί t Η I: kk\c I he organs lay er xs.s concert Rated under vaetmm and the residue was purifn'd by chromatography on silica using 35% 1 tO.-M. hevinex t,· gree 0 48 g ((%%} oj me (hie compcune. ax yellow oil 11 NMR (-10() MHr Acetoncfe) 9 2.78-2.83 (m. 2H), 4.40 (t, J = 9.2 Hz. 2H), 5.76 (R ../ = 3,2 Ife IH), 6.04 (s, 2H), O7fe80 (m, 2H), 7.28 (1../= 8.0 ½. IH). MS 187 (MH').

Fxample 202: 4~ \mi«n-5-(k’tt ahydnd'uraa-2-y D-Hl~beuro(c]11.2.61 (hiadia/hie-2-2-fexide

624

Prepared .re in Example 111 t’-nn ^-xuifan'ioylamfno-A-'-Ootr.'xhydr.iinran-.?sl)h.-:'t 'onun’e (I xanfee ’refe m -2% yselo ax a w-tile x-d'd ^LH NMR (Inn MHz, f/MSfe.M p I 91-2 65 In- '1H, 2.21 -2 28 tm Hi). 3 8 :-3.8) (m. : H) 3 '’2-3 9 - (m, I H\ 5 23-5 2 7 (m, IH) ~ 02 (d,./ 8.0Hz. HQ, 7,30 (4,/-7.6 Hz, Hfe 7.51 7.6 Hz, Hl), 7,9-8.5 ^read, 2H),

10.94 (s, HQ. MS 268 (MH?).

ί /..ndd.'.LslJ.CYa: femimmwI mnmMw)eR.fe J:Oi'uian-2-\hhei..'Oimn.e

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2-Amine-e-U,Wfe d:<'kw.m“2-y 1 iMtw,wjtrnc (Example 202b) (0 24 g. ) 2> nunolk 10% Pd,<..’ (0.24 gk and ammonium formate (2.40 g. 3s. 1 mmol) were refluxed tn McOH (25 ml J under nitrogen tor 1,5 h. I he tnsolubre solids were filtered out and dtreaidcd. and the +>4\ent was removed undet xaeuum. I'bc resultant residue was dts+axed ns Fn » \c, eashed wtt'u sat mated Nu»C<h and Brine, dried over Mg$O₄ and concentrated under vacuum. The residue was dissolved in anhydrous DMA (2.0 ml..) and was treated with suifumoyi chloride (0.11 g, 0.97 mmolk The reaction mixture w® stirred under nitrogen for 30 minutes, quenched with water 15.0 inLj and extracted w irb Ft' >Ae t3x50 ml), f'hc eoinbmcdextract was dried oxci MgSf ;₄, filtered and concentrated under vacuum. The crude product was purified by silica gel prep-TLC u+mg 95'’- ErOAv hexanes to give 45,(»(t Ε’,.ι, j ihe kite e<· up> t: id as a u hue +·.4:3, H NMR (409 MHz, Acefeie-A) <; 1.71-1.78 (rm I Hk 2.02-2.07 (rm 2H>. 2,45-2.52 (m, IHk <90·.

9; < m. Hi;, 4 Ip 4 I 5 pn, IHk 5 ^f*8 yi,./ ('ML H), c e o x t uie.iu. 21 i ). ⁷ ?*> '’A ^! tus, IHk A-'·,5H1- 2Hkf ??ih,-,d\Hi) MS ?6b (MH ).

E sample 203: d-Ammo-fed-ipyridim-2-yOpropoxy»41 l-beiszo]e]11.2,6]thiadinzine~2,2 dioxide

Prepared as in Example 11 i from 2~χηΙύηκρ.ljtwn<>-t>-(S-(pM;diti-2 yl)prepoxy)ben.zoni.trile (Example 203a) in 58% yields a while solid. ⁵H NMR (400 Ml lz, IR)SO-AH)2 Γ (quint 7 e s'Hz 2lh. 2 (i, / 7 2 Hz. 211). 4 N ip.,/ ., (ί H/. 2Hk6 oO (d, J - 8.4 Hz, I Hl 6.73 (< J^:::: 8.8 Ffe 1H), 7.19-7.22 (m, IH), 7.29 (d, J 8,0 Hz, IH), 7.44 (t,

8.4 Hz J H). 7.68-7.72 tm. TH), 7.92 (s. TH), 8.36 (s, IH), 8.49 fd../ - 4.0 Hz. IHf 10.94 (broadsJH). MS 333·;MH I

Fxutnplc 20hi 2-Sufeni<w lamin»-<'>-(3-(pyndiu-2-yOprop-axyjbenzemtrile hepmed <.+ in I’xarnpk 111 a irem 2-.iniirii.:--G-(3--((iyiidjii-2yhpr>'p>'Xy tbeti/ouw de f I vnupte 2tbl·) m 9“%, <. fed _as a white solid. T1 NMR (400 MHz, DM86>-A) 3 2.15 (quM J - 6.4 Hz, 2H), 2.92 (t. J- 7.6 Hz, 2H). 4.15 (t, J - 6.0 Hz, 2H), 6.93

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Example 2(Hb~ 2-.Misini>-O-{3-{px rdin~2-\ Dprope' \ )l-en/<<nthib.·

Prepared as in Example 199b fruin S-mlrw-iH3-{px rditi'2yhpi>:p>:.’<y'»bciizoiiii·He (Example 203c) in 85% y re-id a- a ulute '-'.nJ. ^lH NMR (400 MHz.

2.12 iqurak ./ o 8 Ha2H). 230 (t. / 7.2 Hz. 2H1. 4.02 ((../ m-4 Hz, 2H). 5.99 (s. 2H:·.<·.U (d../ 8.0 Ik. Hb. 6 33 id../ 83 Hz, l Η). 7.14- 22 (m, 2H). 2/'· (d. ^? 8.0 Hz. Hi), 7.67-7.71 (in. I IH 8 49 id. J 3J< Hz, IHi. MS 254 iMH )

I \a nplc 203c 2 Nrre e i3 fpx id ' 2 · l)p'> wMRv.i nut e

Prepared as in Example |x% from 5 {pyi din-2 xl'ipropan I -ol 2.6 dmiimbeiiz·miuik m \ icld as a while MM ⁵H NMR 1400 MHz. HMSOMlO 2 21 (qumt,

6.4 Hz. 2Hi. 2 95 tu./ ~.2 Hz. 2H). 4 31 (ι../ <\4 Hr, 2H), 7 ι--/22 ini. IH). .2c <d. / ’ nHz iHi. % Hhii ?Hi 7 86-”9.'(m. 2Hj, 8 48 M ,·' 4 x Hz. IH) MS ..’Id (MH ) Example 204: 4-.Amino-5-124pyridin-2-yijethirey pIH-henzn|e|| 1,2.611hiadiazint-2,2diexide

Prepare^ ax tn Example 111 trotn 2··Μ0»ηοΗζπηι·<>·6·{ 2-ip\Mdin-2·· yl)ethoxy)beuzoe une (Example 2.04a) in 22% yield ax a white solid. ^:H NMR (40() MHz, HMSO JOd.TjOn../ 5 6H?, 2H). 4 4i._f·,./ 5 o Hz. .HR 6 59 re. </ 8.0 Hz, HI), c 3 (d. /

- M Hz, IH), 7.28-7.31 (m, IH), 7,40-7.46:(m, 2Ή), 7.75-7.80 (m, IH),633-8.52 (m,3H), 10.91 is, HI) MS 319 s MH )

Humph· 20-1,1. 2-Su i famoylamino-n-i .'-(pyridin-l-yi'ieR'a >\ν)Ηζ·ι zona rile

Prepared iw in Example 11 la Irc-m 2-a:nino-n-i.?-(pyHilin-2yhethoxy ιΙχ’-νοΗΐΓίΗ «Example 204-bi in 07% yield as a while solid. *H NMR (400 MHz_v DMS(M.)M??o ^f“<> ΜΗ 2H) ' 3 r ./ 6 ML . Ί I) , 00 re,./ ΧχΙΙ/Ίί). MM.?

- 8.-4 Hz, 111) Ί 23-‘7 26 (ra. SH i. 7.39 (d,./ - 7.6 Hz, IH), 7.55 (L.) ^:: 8.4 Hz, 1 H)_; 7.73 it../ -

2 Hz. iH). 8.51 (d. ./-4.4 Hw IH), 9.42 (s, IH). MS 319 (MH )

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Example 204b 2-Ansins.>-6-{2-{p©> sdin-2-·, he-b-,-χχ Jbctj/ominle

Pi enured a- in IRanipk· 2© from 2-nitr0-6-,2-{p©ndin-2-©bpiopoxy)bexrzoriitnle (Example 221/ m ©0% > rekl a^ a whm· .Mid. 11 NMR «400 MHz. DM©*. ©fe) a 3 J8 (t.,/- 6.8 Ha2Hi.4.3©(1../ 6,8 Hz, 2Hk 5 9~ (/210 © 25 (J, J 8 4 Hz. 1 Hi. n.32 (d../ 8.4Hz. Ill), ’ P <j.J ©OH.'. Hik .22 %2<< (in. IH}. 3 φ. / I OH/. Hb ⁷0-.%w IHi.sS'. id. J 4.4 Hz.. IH). MS 240 iMH >.

I sample 204e 2 \ρ.ω 6 ι2 f a©nJ. i 2 - bethoxObem© nh.L

Prepared a.- in Exam-tie l©⁷< from 2-(pp«:dm-2\berhanol jexI 2.»· JmtUoberiZ'-imHk m ©2‘ < \ icld as a wlkw. solid ’H AMR 14W MIL. HMSV-.M 3 3 I⁷ n../

6.4 Hz.2Hi.4.©4ii../ /4 Ha 2Hl 7 23-.2“ ρυ. IH). 7.41 id../ 8 0 Hz. IH). ~ //©(m, 2HL 7.86-7.91 i.m. ?Hk K fe χ 5.2 <_{. IlH Μ© 2O(MH }

Example 205: 4Ambm-5~(i5-melhylixoxazol3~yl)methoxy>-lH-be«zo|cni,2,6|thiadiazinc2J.-dioxide

»27

Prepared as in Example 111 few 2-suliam0ylamino--6-((5-metliylisoxazol-3~ •el)mzdio\\)benz©nitnk (Esarnpk' 2O5ai in 83% vieid .-- a ©©bite solid, ’ll AMR (400 MHz. DMS(Lfe) 32.42 (/ 3H). 5.40 (/ 2H). 6.3c fe ill). 6.65 (3,,7 - 8,4 Hz_? 141), 6.81 (d, J - 8..4 Hz, IH), 7,48 (I,./ 8 4 Hz. IH>. S On (/ IHk © 40(/ Hb II.Oj A. I Hi. MS 399 (MH ).

I \ f tip'e T’/i > bi tan «/E i<r © ««© sr- tin i-o ,,/.4 ^s dkr dio^s © k>cn ’«©'lit ik

Prepared as in Example 11 la from 2απήΐΗ»·(<·({5·(ηνίΙηΙ/ο\δ/ιΊ·3· ybmeih'-xyIhen/oriiinle f l·©ample .221-} .*> 8© ’<>, .eld -a a uhitc .-obd ii <\MR <_xW(i MHz, DMM’JMd 12 ;A. Mil Akn .11).6.46, JR ‘ 0 ic.</ 8 0 Hz. I HL 7 19 / ©9

Hz, I.H), 7.30(,- 2H). 5%?. ( 8 χ Hz, 1 HL “ ''3 >,s IH) Ms 309 (MH }

Example 208b 2 AwaoOfe mefm %e\az I 3 \ limefneo© )l CEWWiiile

Pizpaied as m I ©arepie sObb uom 2 n© me'h© ηοχ,,,χΟ 3 ©l))ae'h> s©? 6 ,(reset e , m le (I 'tpie , 0©» I .t ©^s ‘ > s > kbn a\elli>\- ij ’ll AMR MOO ROH O'AOM 4 2.42 (s, 3H), 5.19 (s, 2H), 6.07 (/ 2H), 6.31-6.33 (m. 2H), 6.37 (d,./- 8.4 Hz, IHk 7.20(L J

8.4 Hz, HI). MS 230(MH ).

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Example 205c: 2-i f 5-Mclhylisoxazol-3-yllnicthoxyl-O-mmde?./onin de

Prepared as in Example 187c .from (5-mcthylisoxazol-.>-yhrnciiianol and 2.6d'ltn'ftoa /.'itrji e i' s/,· . x»cU as .,y <Jl<m solid Ή NMR i Ψ0 MIL·. HMM s -i 2 9? id ./ 0.8 H/. 3IH. 5,50 re, 2 ill, 6.38 (d,./=== 0.4 Hz. HI), 7.83 (dd. ,/===· 1.2, 8.4 Hz. IH), 7.91-7.98 (m. 2H) MS2uO(MH )

Exampk' 206: 4-Asni»o-5-<2-cyclopnipytetlrnvy plO-benzo|e|| l,2-.6|thindiaxirie--2,2diuxido

IXiHg θ.._χ

628

Prepared as in Example 11 I -rem 2-stdktinox lannno-w2cvclopropylethexylbenzonitr'ile (Example 206a j in 94% vicki as a while solid. ^!H NMli (400 MH.·-, DMSO-.p) 3' 0.11-0.i 5 (m. 2H). 0.41-0.4S ί m. 2H), <i -0 SI fm. Hh. 1.73 <q. / == ο s I|_z. 2H), 4 21 u../ o.S Hz. 211). 6 M id../=== 8.0 H.\ llllo 77 ul. /==== 8.4 Hz, IH). 7.46 (1.,7=== 8.4 IL·. Hh. 7.87%. Uh. -S.39 is. Hh. III) MS 282 (MH ).

.Ly.d.frlpk.-.Ory.. 2-SuUanmy lanmuM-U-vXctepiopy lefnexx ΐΟοη/οπΕπη

Prepared as in Ib.amp'le ..1.1 la from ,2-anii·m-M^-cyclcpropyk-tboxylbonzonitrde (Example 206b) in SON, yield as a white solid.⁵ Fl NMR. (400 MHz. HMSO-to.) 0 0.13-0.i 7 On. 2H ·. 0.41,-0:46 (m, 2H). 0.82-07 On. 1 Η), 1.64 (q, ./ === 6.4 Hz. 2H), 4.16 (t, J === 6.4 Hz, 2H), 6‘to(J../ 8 0Hz. HH.-14^../ iMI/.OB'Mcp,

H h. MS 282 (MH l

Exaraple 206b· 2AminO6-(2-cx-ete:S-epvteihoxv)benzGmtrite Prepared as in Example 199b from 2-(2-cyclopropylethGxy>6^itrobenzouitnte (Exaripk OO m 90% x_;V d a.- a ' Jbm ,..1 ‘1 i NMR MOO MH -, DMSO-./ ) 0 0 13 0 16 (n., 2H). 0 40-0.45 (m, 2H), 0.81-0.8? (m. IH), 1.61 (q, ./- 6.8 Hz, 2H), 4.04 (t, J - 6=4 Hz. 2H), yCb. 2 H). (-.11 U,</ 8.0 H? UH 6 32 id. ' 8 X Hz, HI). ” 1%·../ 8.4 Hz. 1 Hl, MS 203 fMH )

F sample 10%' 2 i2 Cxetenroip k-thexy > o mro-een/omi'-dc

Prepared as in Example 187e from .l-cyclopropyletbanol and 2,6dmiuobcnz-'Ri-uic in SpO- yield as.. yelioxx Oil· Ί1 NMR (400 MHz. DMSO -,/-3 re 0J 5-0 20 tni.

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2H). 0.43-0.47 (m. 2H). 0.44-0.89 (m.. IH), 1.69 (q, J-6.8 Hz. 2Hk4 H <r,./ i. 4 IL· 2H). “ 73-7,% (no II Ik “.-86--.93 (;n. 2H). M\ 233 (MH ).

Example 297: 4- An«a»-5-(hy dross rnetby IM I l-bmvo{e] |1 x2,6|ihjadrazim'“2.2--dm\ide

62'3

Meoaicd a-. n Exas ' >le 111 .' es m>> 3-(xol; .myJan. nMberzs I .υ.ο.οο (Example .'07a = in 83<. \ ieU as a wbue solid 11 NMR (400 MHz. DMSO-'i. j <) 4,oO (χ. 2H: 6.62-6% Im IH), .04 (d,7 ~ x H IL·. HH 7 0''^! (d../=== 7.2 Hz, IHg 7 51 (t,./ '⁷6Hz. Hi), x?3<bmads 1 H). c.,\6 < %·% χ. IH) 10%N, Hi) MS 22? (MH )

1.'2'.<Β31)ί:_:...?.Ο ?..·.1' ?-C > ,mo-3-( so | knnos I a mi p o the n zs I a cel. uo

Prepared as in Example I Ma fre-m 3-a.mnm-2-cyanobenzyl acetate (Example 26b) in \ ieid a white solid. ^JH NMR {400 MHz, Aeekme-J·.) P 2.09 {<, 3H). 5..24 fr 2in. O.6 (bnad x. 2Hk 7 38 Md. 7 ==0.8 '2 Hz. HI) 7.66-7.7%™. 2Hi 8 40 (bread -= IH) MS 2’WMH ).

Example 207b: 3-A m irm-2<yanobenzy I accrate

Prepared as in Example I 99b from 2-cyaiSO~3-niirobenzyi acetate I Example 207c) m $ p>, _{s t} s gw ci I 1 NMP (100 MHz MelParn I-.,,) 6 ’ 10 (λ, 2H\ > |j p ?l h, <> , (= id, · ’ ^s IL· IlB.n 'Md <’ x 8 Hz ^;Hy ''8 (ί, ? X IL·, III! MS'9l(\llM

l.sd:l)X=lc..207c; 2< yano-3milr<?benzy 1 acetme

Acetic anhydride (0.84 m.L, 8.8'7 mmol) w-as added to a solutien of 2(h}'<kQxy:methy])-6-nifrGhepxooiiriio (Example 2O7ds ¢0 > g, I unbolt nuidme (0,86 mL, 10.6 mrmd).. and DMAP (0.22 g, 1.77 mmol) in CH -^f I, (10 nd k and χίοκίΐ for 24 h at rt. The mixture w.a w i.dwd once v.=6= \c()lI (I M. 20 mL). dried svih M_;’X= = „ aeut emraled and pu=i0ed b\ c=mmi.Hm’iaplry eu xdsea 0-=00 t Hy M. 10 g'\e (be 0) e compeer.e m ameuul <>fo >0 g (⁰2*‘ij ax >1 sehem '«'he *H NMR {--06 MU \ HMSO~</ ) Λ 2J2 (-. '11). {-. 2H), “ 49 (= / === 8.0 Hz, IH). 8.06 (dd.../==== 0.8, 8.0 Hz, 1H),8.37 Md.,.3 == 0.8, 8.0 Hz. IH).

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Sodium borohydride (92.0 mg. 2.43 mrnoi) was added m a solution of 2 ibrniv 1-6:iiir>»heuzonitr:lcs Example 207cj (0.86 g. 4.88 mmol) in MJ.HI {38 ml ; and ΓΗΓ ;38 ml.) at 8 C. and w;w stirred at that temperature for no more than 30 mist, foe reaction was quenched w;tb H< 1 (b XI. -I st- nsi ). followed by addition M w.;=e=' Mj _sm ). and bone (50 ml ). The mixture w ;»$ extracted with EtOAc, the combined extract was dried over Mg$O*. filtered and concentrated. The crude product was purified by ehraniatography on silica using the solvent gradient CH_;t Η ·ΌΗ01y'MeOH (8:2) to give ths tide compound in amount oft 1.32 g =, A··,.), winch used nnraeduHcly re nest step Ίΐ \X1R (400 Mlle. l)\N >-Λ> 0 4 (d. J ‘^x 6

Hz,2H:. 3.87 (i,../ === 5.6 He. IHk .0? (r, ./·==· A 0 He. ill). 8.0~ (dd,.,- === 0.4. 8.0 Hz. IH). 8.28 (mi../- 0.8. 8.0 Hz. IHk

Example 207e: 2-Formyl-bmitrobcnzorntt-ik l.l-Dimcihoxy-iV.A-drrncthylrnelhananime (13.5b mL. J 02 mmol) was added to a dutum <>t'2-mmhG-6-nim>be:wom?rile ),= ' 0 g. 925 innioh tn anhxJunis DMF (u0 ml.I under iiitu-geM and was heated at 130'r' |<j; 15 h see naicr )300 nil.) was added, and the rcsulnmt J.ak precipitate· was <,mLx led m libration and dr J unde: xac-usm Phesphax buffer {pH , /50 ml > -md then NaKh ( -=0 g. 187 mmol) were added to a solution of the dark predpiute in TI1F (350 ml and surred. a: rt lot 3 h. The mixture was extracted with LiOAc, tbe combined extract was washed with brine m I dried wnb Xlgsfb Hi.- tllrrare w.w ..'encemrate·.! and tbe residue was plained b'x e=w<>n· ’nphy on sdica using m> sets an gr.'du-rt h/xancs / Ό \c I-' ghe 3 0- g (1:9%) of the title compound as a yellow solid. ^SITNMR (400 X4Hz, DMSO-» A) 0 S J 5 (t,./ 8.4 Hz, 1H). 8.41 (dd,./ - 1.2. 7.6 Hz, 1 Hk 8.62 (dd. J - 1.2.8.4 Hz. I H)_s 10.25 (s, IH).

Exirmple 208: (,F)~4~Amin<w§~(4~oxo~4-(propyIammi0but2tmylaxy)IH benzoicllliS^ltbiadiszme-S^-dioxldc

S3©

Prepared as in Example 1.1.1 Oom (fO-4-(2-cyano~3~(sulfamoyIamsn«ophesioxy)N-propylbnif2-eumni.de (Example 208a) in 19% \ mid as a white solid. ’ITNMP (100 MHz. Aeetmu--.'A:··' 0 8“ r t, ’ 7 2 Hz. Hh, I -17 (hex,./ 7{'Hz,2Hk3 II-,rim. -UH, 8 Vw_q J

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Ha 111),6/()01../ b.O Hz. Hh,i-.77(d. / I lh. 6.87 (d,./-8.0 Hz. lHi.7.2“.MlWs. 2H),~ M n. I Sull·. IH). 8.1’9 ibr.-ad χ. Hli A5. sp. s _v HU MS Mv (MH i.

I xautpie 2Qxa {£1--1-(2-1 'ymn>-3-{-mlfainaylairimdphe'ioxA }-\-ρι. py I biit-2-em.cmlc Pp.-pared a- in r x-nuplc 11 la lre-u (/- )-4-(3-.m)if)O-2-cyui8-paen> xyj-V propx ibm-2-cn;.tin:dc Ibxainplc 2^f.R4>) in 87% y i-Jd ;re a ul-ne re-nd. Ή NMR {4Γ>0 MH?. DM8( >·</·) -»O.x4 {t, </ .2 Hn 3H). i .43 ti-cx. <7 6.x Ha 2H). 3.R6 iq. ^;' 6.8 Hr. 2H). 4.90 Hi, ’ 2.x Η?. 2H), 6 I s id, <’ 15 6 Hz. IH), 6.~04'.'' on, i H), o % mJ. / 8.8 Hz. IH). 7 17 (d. ./ 84 Hz. His. 27 fmo-id -, 2H). 7.57 (-../ 8.8 Hz, IHk 8.13-8 Ιό (m, IHk /52 (broad s. Hi) MS33’>(MH j,

V xareplc 2080 -(£> 4 i5 Amine 2 exan<»phera v »-A ,>.<>py lbur-2 cun _sdc

Prepared h* in Example 199n n--rn (/, )-4.(2<χ3ρο·3._:)ii:<'pnen<-\y p\-pu>px Ibut?-cni-mee <1 χ,αηρχ- ?Oec) η; ”> x'jeld ax yellow χ?.Η II AMR ( 100 ΜΗ.' ΙΛΝ l-.Z,)d 0 rd it. J - 7.2 Hz, 3H). 1.42. (hex../- 7.2 Hz. 211}.. 3.06 (q../- 6,8 Hz, 2H). 4.77-4 70 (m, 2H).6.04 (x. 2H). ¢-. I l-n.20 or:. 2H). «· 35 id. J - 8.4 Hz, I I H. 6.<'7-f'. 74 (m. 1 H). ”.l8 it../ - 8.0 Hz, 1 I I). 8.11-8 14 (re IH). M$2i-0(MH }.

E xample 2O8e: ί/-3-4·(2-I y ano-3-^:r-,'phrne>xy)- R-ptopy Ibui -znaii-id·.;(£)-4-Broni0-N-prepyIbut“2“Cpamidc (EUkitt M.: Famham, A. M.; Janes, N. F,; Johason, Π M · Pnhnan. D. A RpxZ/c-kxV5, cm e 1987 22'!) p ) | g p 0 mmol), 2hyds'axy-i -r 'icbenzc-nrril·,.- (0 I 1 g. 0.88 mnrM, potax-nmi xarbooak (0 3° g 2 81 mmol), and IS-er-.wxn-6 (0 11 g u 42. n-mM) pore refluxed in acetone in nil ) f<>? .? b. and then ρ·>ιικu πιο ice water (45 ml). The rexuhant precipitate wax esUkvted bx llltreron io give 0 16 g < '9 \q ef the till componrid a- an oil v-J-re solid. ΊI AMR (100 MHz, DMA-. <> 0.84 i, / 'll?.

3H). I 52 «hex ./ - / 2. Hz. 2Hi, 3 On (q.,/ - ή 8 H , Hl) - 0 ' - J J ’’ x Hz, 2H). 6.16 id, J Iί 0 H ' :Hi (> . 1-6 7x (m Hl), 6'? (d ,/ 8 0 Η , III) ' 88-' ’*6 (m, ' 11} 8 ^!!-8 I (nt HR Example 209: (5)-4-Atuirtii-5-((I-iieety h^/'^lidiii-i-yiJmethnxyi-l.Sbciw[id[I,2,6|tMa(lraziiM^2,2-diexide

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Pt upas ed ax m I xatnuk' I ~6 hon fN)-2-ar'.>in-Mi l-aceh m ia>!.dm-2 utm.'dw >ben, = .wt:tk (Fxatnp'e 2()%ti tn 10% \m d ... „ ubi)c xobd ^!Π W1P (4()() MH/. DMSO-Λ) ?> i .93 (rm 411). 2 o0 <% 311». 3.50 (m, 21I). 4 09 all / 10 0, 6,2 1I.·. IH), 4.24 (dd, ,/ 19,(). %-llz. HD 441 (n: HD. oa'O id. / S 2 11/. IH). 6A~ (.1,./ .8.5 H/. HD. 7.4o <t, J

5 11/. lH),8.l2(brx UH. 8 33 tbt s. 111). 19 <>3 (bf -. 111). M< 3.M s MH ),

I xauipie 29% {,s 1-2- \n =.η;> .-=-.-=,=, 1 = pt t cl On .-2-y I )i nc it .= · y tbet t zoo t t- de )’o a M%'<iW^:O:s et t5)-2u 2 -cyano- 3- niin’phcnc-.xy >=ncrhy I )py = mlidtfmim cblotids' s I/O mg, 0 4u mmol) (Examnk 209% tn 1 HF (5 tnl.» were added Ft Ν' (i .M ι-l . 0,47 =ntnel t and a-_ou I chlonde f?o Ul . 9 50 nttu>>l). I'be meet ton wa.' anted at rt b« 18 h, dhow J and diluted u irh Fr« ΜI {.?(; ml ) 1 lv,_ resulting soltuion wax hydnmenmed (20 Bars m-mg ION, P>= C a,' the eivaNs·, I p-=n /«.m^-kmon, dy reaet-en miMrue was ec.ncemr.ued (e paw ide =he mle compound ¢61. rag, 51%) as ;= clear syrup, MS 260 (MW),

Example 2O9b~ (,$)-2-((2< yano-J-nitrophenoxytn-iethyDpyrroliditnum chloride

I'repatee <=-< tn = xrayile !=>=> Itotr t xA, .'•''ui' <(.?->xane-1n>tn'pnen..y,)n-b (h\ Dps: :obj=no-1 k=^!. (Fsain 'le 20')% m 8' ‘., \ old ./ m oll-wlrte

A11 Mb .''S (MH -Mi ’)

Exmnpje 2.09c (--bW-R ity 1 2-((2-.:yanoO-nitrophe:u>\ytraethylipy = n=jid 1 ne-1 carboxylate

Prepared./ in Example fwd iD-ra 2 <·>-·li=iu hemp” tr Io and {>=..,v,7-bo=y I fmdro'xinerhy t)pxrtoudmo-s-e,trh».\x.ate in 3'=% , k-ki w a 1 so id Ή NMR (109 MH? PMSO-AD) 1.40 (-. 4|D. LSI (m. IH), 2 0< m. 311), 1 Otm.2lD,4 Ox (m, HD. 4 M pm 2ID. 7.7^=0.,/ ’.HI;. lll)v0%(m_s2H).

Example 2HD R\y4~ATiiin<^§*((l-propi<>eylpyr)F«MdiB”i“yI)meth»xy>'Wbeu.zo[i:|[L2_$6|tliiadrazine“2Jdmxide

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Prepared as m Example Γ76 hont ί x>2-amitso-Ml l-propsonylpyrmlidin-Ss bn;. '.hcxCjben/misLd. HA/mph* 2 Orem .\>sied t$ an --B-uhm xebd Ή AMP (.-00

MIL· PMm 1 Oi ο. I 8 H? Un ί 9- {m. '-Hi 2 3. f,m, 2H), λ im. 2Hs 4 J ; (dd ./- 50.0 -' 0 Hz. I H>, 4 27 (dd ./ ‘68,5 OiL·. ΙΗ·,0.·Μ {ns. Ill) c % fd. / 9 Hz, HH.6.92 id,./ -,8.4 Hz IH). 7 k-(t../ -8 2 IL' dll 8.09 (br <:, I Hl. x 34 (br s. i I h. IΟ Ή (hr s II!) MS U?(MH }

Example 2I Ba: (.’>)-2-Amine-6-tf i -pmpionylpyrsOlsd-'n-z-x l)metb^>xv)benzonsfnle Psepared as in Example 209a from (5)-2-(i2-cyano-3mitvphcnoxy Imethvllpyrrolidinmm chloride (Example 2 = Obi and ptopionyl ehlmalem 90% yield as a clear syrup. MS 274 (MEE ).

Example 211: (S)~4~Amirm“5“((l~bui.yrylpyrrnlidhi~2~ybmeth<>xx)~H7~ benzob'l 11.2,61 thiadiazme-Jjl-diisxide

633 \__I ^x

2sc%m.a a- «' ; xae. >k I 6 how %s 2 m ne o if J .xihirepMR') dm 2 y s)mcd).>'V< sPcis/oute de si mmole 21 la) m ‘ΚΑ \ e/J as _.n wt'fw um -><*hd ΉΝ slR AOB MH?, iniso /jdn.xxu../ A Η?. 3H). 1.54 _fq. ’ 7 ? Het 1,94 Im. 4HI. 2..:6 (.</ 7.5 Hz. ?H >, ? lx (m. ?Hs 4 (0 <'m, IHk 1 on. HE, -> 13 (m, 1H). r> id. ΜΗ.’ I Η), ο X’* (d, J- 8 6 Hz, 1 Elk 7.47 (t, J- 8.3 Hz, IH), 8.08 (br s, IHh x 32 (br s 1H). 10,-)3 (hr ¢, IH), MS 30%MH j.

I xamp^:e ?> b( (5s \mm>· x pj betwylpmo idm 2 yIjmri mxmber.A'mHik

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Prepared as m I sample 29¾ frren (.χ)-2'((2-8>ί;ϋ,>-3nitrophcrsoxy jmelhybpyrrolidmmm chloride f Example 2()9b) and butyryl chloride 8· .n 9(1% veld as a late -nJ MS 238 (MU 3

Example 212: LV)-2-((4-Amia<i-l//-benz0|c||i,2.6|thla<Iiazine-2.2diaxide-$~yloxy)inethj 1)Λ'-methx Ipyrrohdine-1 -carboxamide

Ο H

Prepared as in Example 176 from (.$’)-2-((3'amino-2-cyanophcnoxy hnclhylpAΊ<.ι Ήρ <»>n ne ' s/fboxamJ. (1 \ apk 212.) n V'. s.s'iu ('in Ihd't seis’ ’liXMR (400 MHz. DMSO-Λ) 0 1.89 tm. 4H). 2.60 (d../ - 3.9 Hz. 3Hk 3.20 (m. 2H). 4.01 trn, iH), 4J6 (m, 111).4.32 sm. IH). 0.23 im. IH) 6/>2 Id../ ?,2 Hz. IH). o.>9 ul.d 8,5 He. 1H>. ~46 (t.Z

8.2 Hz. Ilh.x.l'HbiV. MH,827(h: -. IH). 10.92(=,. IH). MS354AIH ).

Example 212a: (5)-2-((3- Anmm-2-Csanophen o mk^dreA’-methylnxjioI dree-1 carboxamide

Pszpased as m P vmmk 20¾ Ο,,-υ (M 2-((2-0^./.,--3 iiifr0phettoxy)methyl)pyrrolidinium chloride (Example 209b) a«d methyl isocyanate in 53% s .'das.· ssb-e·, ?d M's mMH '

Example 213:

.V-ethylpyrreikHue-l -carboxamide

Prepared as in Example 276 trom. (Ni-S-ilM-anrino-S-cyaRephenoxyimeihyl)-?/i :K'.'A irePdu'c-l -sd.b.-sa nsre d x^nph 2' k.) m « s re id <- .-a ma sold H \Mk (lOuMHz. HMSO-.M0) p'xj. 7 r 9 Hz. uHt. I 9<j (n . 4Π) M)s<qmm..^f oMh.Ji b > 20

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P:CWS2608/0Oi50

2017200704 02 Feb 2017 (re, Hb. 3.51 ini. HI), 4,00 {dd../ R 7, 6.7 Hz. 01).-1 rid·.)../ 9 7, \i) II \ 00.43,%%. IH:·. i-2~(d.,/ -.70/, 00.0.62 id., / 8,2 0/, IHl.o SOsJ. / 8 3 Hz OH. ~ 4ml / 8,2 Hz, IH). 8.20 {br s, IH). 8.26 (br s. 0 0, 10.91 (s. 0 0. MS 368 (MH ).

I xantpie 213a {,Μ-2-p, 3- \%ii:<>-2wx anoplretre»' x )tne*bx 1)- V-et ty Ipsm-heatc-l carboxamide

Prepared ax is- Example 20°a from ί Λ)- 2- ((? -ex,:no-anitropbenoxy)methyl)pyrrolidipium chloride (E.xrenpk 20 ^!b\51 and etbx I isocyanate 'in 100% yield as u white solid. MS 289 {MH ),

Example 214: (#)-2-(.( 4-Amiae-16M>enzokHk2,6Hhiadiazme~2,2-dioxide-5-yioxy)nwthyO··

V-p ropylpyrrolidl ne-1-cn rtmxamide

Prepared >- tn Fxantpk· 2% tiutn i.x>-2-((3-c>iiino-2-c_>wri<»phciicxy treclhy h-V %'pylpxrn'jid:Ht-l-c.ulx'\a>mde {Example 214a) m 37'*«yH-ld a-, an off-'ahiL? s/bd Η AMP flOO MH/, HMSO-aM 0 0 Se μ. > ~ 6 Hz. Mb, I 13 %c w,./ ^9 0/.20),192(16.411).3 01 (m, 2H), 3.21 (m,_: 1H), 3,33 (m, H I), 4.02 (dd_?,/ - 9,7, 6.4 H% 10). 4.18 (dd,,/ 9.7, 5.9 Hz. 10),-1 3-1 (re, HI), e 27 M, / 5.e 0/, IH), 6,62 {.I,,/ M 11/. iHUxW SMIzOH), 7.46 (i, J = 8.3 Hz. 1H), 8,20 (br s. IH), 8.27 (br s. 10). .10.91 (s, IH). MS 382 (ΜH^:).

Examnle 214u: {5 )-2 -u3- \ndno-2-eyanophen®xy)reetbyl)~;¥-p_;ropy tpx rroItdiue-1 carboxamide

Prepared a.- ir t xarrtk 20°a (rennM 2 {(2 </xero-3:,'ltenhenewlrxlb-Dparelk'tmim ehbreA (Example 209b) and preps! reeeAn.de m 100% yield as a. white solid. MS 30.3 {MH }.

Example 215:3“(4»Aniin0“2_$2~dtexide”lII“benzolc|y_?.2,6]thindiszm”5”ylOxy)~2',2⁵“dimetIiyb N'-propylpropaaatnide

WO 21W1S4221

P:CT/l.lS2dWOOb4

2017200704 02 Feb 2017

I <> - stared so. nt on of 3-1 RsnlMmm 'ammo- ’-cxam'-pnem+x)-2 ?-dimerhy l-Aprupylpropimarmdo (18.5.?. g, A.'/·⁷· mmoli l Example .: 15.i) m I.s(.)l1 (IΆ ml.) wa$ added ,\a(;H xeuttmu<2 9 A. >.? a ml.) a- n-v-m temperature I he reacti-m mixture w as then returned fur 2 his ..-/•j die '.xu't’oa v a+ .et 'ple'e p 11 (' 11 e wlwen v as oo ed m 0 (' arc ueiitralreeu carefully wnh 10% aectic add and the ptecipoate was collected lo tlhtatum and wa+hsd witn wat-.-r. I be piosluet was fuitho: puiified bx rexrx+taliu'ataan fi-m Et⁴ >H H.t»(t .4;. d>n.-d undei vacuum to g;\·.. the title compound + a v+lut·.· solid ΐ: 3.5 g. 3«). M p.. 225-22·'' '+'. H +MR (I9o MIl.U'AlSu-H ).H) b(t.J 7 I He. 8H). I 22 k nil). . 3k pn. 2Hi 3p. _κ | t-SHz 2H), 4.07 is, 2Π). 6.59 td. J - 8.0 Hz. I is), 6.71 id. J - 8.0 Hz. Hl). 7,44 (i, j - 8.0 Hz. ill). 7.82 nJ 5.OH/. Hi), 7 Ή {s. HI). 8 M <s. HR 19 0.+;+. Hl; MS 4- <Mll }, j 5a; 3«(3-+nifairi0ylaminO“2-cyaoopbcnoxy)-2.2-djrnethyl-N'prepyl

OS1 propanam.ide

R: a sel’dton t-f ''aminn-S-cyanophenoxy) 2.2~litnethyRApre>px Ipicpan ernee <10 ·.· ^ς9 92 miroli {r.xample 215b) m DM Λ (50 nd,) u as added sutfamoyI chloride (13.85 g, 119.84 mmol) at 0 under nitrogen. The reackon mixture was hot· +nnci: at room tempemtme trndet nitrogen tbi + h+ ^Tben dibn·. J unit > re's \c washed sucee'sheh wnhAaHCO- brine armdme’ Aa.oO. littered and evaporated b· g+c theHrtle emrpiwwd a-a i>ff wbhe w>he t la 2 g S %'· II AMK {'OU MH . HMSO-m) 9 9 'O(t ,l '6 11/ HR, I 2rd' OH). I M (m, HD +()1 tq.i 0 5 H.·, 211>,-db (+./11>. 0 A: (d b S.4Hz_; inVl.bdJ 8.4H/. IH) 7.24+. 2H) ‘ 5bt I bHz, 111).7-((1 s ¢. IL . IH). 9 42 (+. HD MS 455 (MH ).

EA4mgle 2I5b: 3-(3-amiu0-2-cyanophenoxy)^2.2-di.mei^;hyl”N-propylprepanamide

Mgihyd A_;: To a solumm of fe2-+ yan.litepbenoss)-2.2-dimethylsNpropylpropatwmidc (305 mg, 1.0 mmol) (Ex unple 21 Se) :n E'p »\c ;2^:a 0 tr.1.) was added 1(1% Pd/C (50 mg). The suspensiem was fitted under cn atmosphere (4'IR at room tempcrawre overnight. The Pd/C was .filtered, off, and washed, with EiOAc. The filtrate, was concenkated

WO 20(18/154221 .PCWS2(H)8/045050

2017200704 02 Feb 2017 muter re<Juc„d pu'-reae and ike te.-idnc nax pus<lied by chromatography >·η sdica gel statnig xx ilk 50% En ¹ \v m he remcs to gix>- rhe ntk x, mtxnnd i2o 7 j^g, ·Γ''λ } ax a xxhrh. solid MS 27o (MH i

MsfeodB. Γη a solution ofS-kyteoxy-2.2-<bmcthx i-N-preipxlpr<-paiK>nu.k' <20 ~ y. Ο I,'. m<d) lb ’vunpk .115d) m dfy HIE <500 mi > b-h c,·. e'ufre suited \aH {< 3k m rmner.d oil 7.64 g\ 0. i 9i moll m small pordcns at 0 ' C under nitrogen. The reaction mixture was men xxmrncd to r>»>in ienipe>atere and surr-ed muter nitrogen lot i hr lo d-re soludou \xax χίοχχ R added at r>><>m tempos-al uro 2-uniii;<,-<'Mlu>>r<>hciuonilriic ί 17.3 g, 0. j2“ snore in ΠΠ·' (100 ml ) and the reaction mixture refluxed overnight itrider nitrogen then cooled ·,1οχ·χ·η to room tempemmse. qnciiebed xx sth bints, and extracted re ith En > \c te.'M The combined organic lax ere '.sere xxashed x\nh brine, dreed oxer MreSO}, exajxnated and ike residue xxax cry %dli/ed frmn En i Ac Hexarc Ό c’xe the compound as a χχ hue-rohd <J u.5 g. 4,·χ%). M\27<-'(MH )

Examp c2’k 5-(2 -cyano-3-.nitFOphen0Xy)o2₅2“dinicfnyl-N-prGpylpropan3nuJe

To a. semiion <4 3-bxdroxy-2.2-dinitthxl-N-pr >p % cyanamide {t g. 10,0 mm>a) {Exaiupte 2<5ej in dsx (Hl· s?0 ntL> xxax xe:e:alix i-rued ViH (H)*' <m nenered e<., 4<R· my. re; 0 mn<>-B n: 'anal port mis ar n '«' a ider m*t> yea 1 ire- ic-iction a-jxm.c x-ms mrecd m i; re ''eei n 5 ge tor 2 hi- H> '!»---> hzn r xx.re addoe \6~dm reberzm’ i'l (ί n ·>. tel ' mmol), and the reaction solution xvas stirred ;n 6 ^CC - RT under nitrogen overnight. The reaction mixture, was mu-nehed with brine, and extracted with EtOAc (3X). The combined organic layers \xoc xva-liexi xxnli bsme, breed >recr Na.S» V Mrer ex .spmatmn et'mc xolxent. the indite xxas pcru.ed bx ebreirategi uphx on >i rcu ee ck,.mg λ'th h'>% I tOAe m hexuuex n give me title i,Oinpo;snd a,- a hale xeltexx Μη! U 21 g. J'* <1 MS .Mo s }

E^ad^Jl^.Ehydi-oxy-2,2-dirne(hyi-N’pi-opylpropauurn_ide

Method A: A solution of methyl 3-hydroxy-2,2whnu-thxlph)piomate i2.e- g. 20 mnnNland n propylamineP 31 g. ,><! mmol· xxas heated a‘ l »0 ( under tn'crexy-xe for 10 hm The exoosshc amine was removed under vacuum to give the title coniponnd as colorless oil (3.18 g, 10084). MS =60 (MH ).

Method.B: To a solution of 3«bydroxy-2.2-dimetbylpropunoic. at id i 2^.0 g ¢) J M mol), propylamine (i 5.3 ml... 0.186 mot), and HOBl (25,1 g. 0.1 <8e mol) in dry d'ehh>r<>nrethnm (500 mL) \x as added EDCl (35.e· g, 0.186 mmol) at ro<‘m tompemixire under nitrogen. Ths reaction nnxtuie xxtre then -triied at loom tensperainw' under nU'ogeu oxenug r, fhe uactiep

31.0

WO 2008/154221

P:CT/l.sS20W0OiS)

2017200704 02 Feb 2017 owuhed with biHR', and exiructed ί tOM (SA.). The combmcd or genic layers were washed wuh saturated NaHCCh solution, dilute HCI. brine, and dried ovci Au'Sth. I xapmarion ».f the s-dxent mukr teduced pre-sutc eave the til=c t-cmpounC as nob-' les. ef. :5 2 g. Γ'.,» MS .cP t MII s. Example 216: N-(l-(4amino-2.2d»oxide-lH-ben/.o|eHh2»bHhtadia/.in-5yIoxy)-2‘ mt‘thxlpnipna-2*-yl)benr.amide

Ftepai. d as in t 'amp=e 215 ft etc \-{ -fJ-M. fart=>y lamm,-7-,. x anoph.'rc\x )-2nicthvlpropan'2'vbbcnzainide {Example 216a) tn 93% yield as awhile solid. M.p.: 235-236 ''C. ^!H AMR {460 MHz, DMSO-ajd I 4 = (--. OH),4 % (s. 2H}.t,(ri {J J x ' Hz IH',. n (d J ==Mill/ =H|. M-’^:.5I (m. '-ill. /'S (d. J 7 6 Hz. 2H). 7.96« 1 = 1). S. 1 7 κ '= H). h.-i m IH). 10.97 (s. IH). MS 389 (MH ).

Exapp>le..2l6a: N-(':-(3-su.fatroylamino-2-cyanophcnc5xy)-2-metbyipropan-2· y))benzamlde

Prepared as In b.x.tmple 215a ?ri m A-s I-'3 ;;mino-2•cyimophenoxy )-2Why Ipiopaa 2 ybberrzamide (hAampk 716b) in 9Χ’·,. yield as ., white seltd MS 38'^J (MH ).

I sample ’Inly. A-f i -ί .'-amino-.?-exanopbenc-xy )-2-metbx'=propan-?-ybh/='i.'. mid© Prepared as in Examnl·.- 215b (Method M item R-(l-(2-cy.iiX'-'WH'opncne.xy )-2m>'thylpw'p,i=i-2-i n/.mnde H xampb 'Ή>·.'> n '>6% s A' <w a whites·,) d MS .06 (Mil )

E.8‘3Ptpk..2.1tLs'.;. A‘-t i “(2-cyano-s-ntm>ph'^,n0X'y)“.?-nk':hyhf!i>pan'.?-x liber/. mde

Prepared as in Example .715=: tram A-(l-hydr('-xy-?>m,'ibylpr<>p.tn-2~yl}hea.'.tmidc (Boyd, R.N.: Hansen. R.H.( hm. . 1953 ’5, 5x9(0 and 2,6“dinnr_vbepKoniirj!e in 61%yield as a pair yellow sol = d AIS Μη,,MH 1

Example 217: 5-(neopeafykm j-lH-benzelcU 1.2.6lihiadiazsa~4-amim'~2.2-dkiude

Ο: H

Jl xJ ' A 5' \ /

NH_Z

639

311

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2017200704 02 Feb 2017

Prepared ax in I sample 215 uon: 2-^dtaniny lainni<»-/is'neopentx k>u Ibcn.rent: ik' dXainpk 2 ^!· 7a i m 73» x id.l ax a whire xolid, Ή NMR (400 MHz, DMS(W.).> 1 (M k W 3.-80 (a 2(1).6.% {d. J - 8.0 Hz. ί!Γ>. o.77 (d. .1 - 8.0 Hz. HI). 7 45 _u. I 8.0Hz. 1 Hi ?.66(χ. lHi.S49(x. Hli. H) 99 t s. HI). MS 284 (MH >

b χ.ίΐίΐρΐν 217a, 2-'-udatn<p l.:msn>.-G-(ne>-pe.jtx'.ox- tbcr.A>inin e

Prepared ax in Exanink- 21 % from 2·umtn>· ·6·<ηο> peitfx ϊ<λλ'iber./··πιΐίtΜ (Example 217b) a; 92*·,. yield. MS 2x4 {MH » ('an ire > 2 . nine n t.,„opc m <>xx) nron t Pe

Prepared a\ m Example 215b (Method A) from 2-(neopentyloxy)-6· nu>-p<ike-nude si '..rarplc .:1%) m %'*< suid MS 205 (MH '1.

I x.tiaple 21 e 2t-icopemx loxx )·’·>·nmobeiurain sic rep sreu a.> in. Exaninlc 21 % from 2,2-d:Otmby ln:<’pan -1 <·! mid 2.6· ea«(.oberr*»nru ·· n xd% yield. MS 2 >5 {MH )

Ixampk 218: 3-{4-aiiimo-2i2-dioxide-IH-benzo|t‘Hl dfr<>|ihiadsazin-S-yloxy)-5-/2 (benzy loxy H’thy 11-2 '.2 ’-dimtthy Ipnipmmniidt

Pixpared ax ra Ρχηη.·ρ1ο2ΐ 5 Rom l-t?-- ilfrrioylmni'i<‘-2-cyauephcaoxx I χ·(2· sben x ,'X'· E.hO 2 2 dir.aS'.prepmiainide s I ' \iple 218.»> ra Ή'⁴ < xu\d ax . M< .e re Μ H AMP (400MHz.DMS<>-miO 1.22 (χ. Mb. 3.26 (ψ J k8Hz.2lh.34i (kJ- 5.x H/.2H). 4 (Γ st,. ?Hk I 36 {c ?Hk‘>60{J. J 6 He. HP·. ηΊ sd. J ~ G Ha IH). ' '.9 ” .% ( n. AH). 7.43(0 J - 8.0 Hz. 2H), 7.91 (s. IH), 7.97((, J - 5.8 Hz. IH). 8.34 (χ. IH). 10,93 (s, I Hi. MS 447 (MH'), breniple2s8a; 3 t3 •'v.lfatnoyl.miira? ex.craphertwx} \ {ber.zxlev Jetlix-) J,2 dimcthylpropsmam ide

Prepared as in Example 215a from 3-(3'amino-2-eyanophehoxy)-5-(2tbeiizyii'xy)£slixl)-2.2-disnethylpropitnamide tExample 218b) in 100)0 yield. MS 44? (MH ).

Example 218b: 3{3-;a-sitno-2 -cyariOphctio5:y)-N-/2 -(beiizylox:y)eilwi)2.2-dimzihylpr&patiamide

WO 2088/154221

P:CT/DS2SW0OiS1

2017200704 02 Feb 2017

Prepared as m Example 2 ΐ 5b (Method B) from N-t2-tocnzvloxvk'thvil-nh·.\-2,2'8.nb'thd'v. rm.nnnk (P sample 2 rec I .-nd d-mmmi-e-rmmMvk/mmrec kj x2. yield. MS ?or {MH ).

I xampie 21 xc \ g2-( ben. \ n>sx Eghsb-.'-Uy dto'sy-2,2 -ibst'c^hx preparanudc lo a solum.’:) <»f3- Ip dre-xy -2 2-drerethy lprepau<’h. .re id (2.¼ g, 20 tnnre.b. 2i benzy l·-xyrethumfminc (3.02 g. 20 m-uol). and HOBt (2 71 g. 20 re-nob ;n dp. drehioretnethane f I RO ml ? m added I DC* (3 82 g, 20 mm->P> at n·,·;·) tempo atutc tm-lre titnrecn I ic rc,reu<-n mstmc was then stuicd at; ·,-m rempc:armc ure.k-i mtfogen .-sermght, I ire reueiien w as quenched wnh bnne. and extracted with EtOAc 13X). The combined ocgnnre laycra were washed wdh .satuiared NjliCO .-olunon. mh:re HCl. wm.. and m-ed >' c; b>a,S<). \fren os.tpi.retl··) <>' *i so'^ent.'heics due s'<λ· pj ’κΙΝκΐ >iinu m mhx on m ac cl.*n ~ w b 40% .fctOAc tn beware- to gre<. the t’Oc compound a- col>-H-.-sml (4 x^ g) (’ - rek. M’s 252 (MH ).

Example 219: 3-i4~araim>-2,2~dioxide-ni-'be8ze|cH l,2,6|thradiazirt->yloxy hydroxyethxb2'.2’dimrthylpnipaaamide

I'o .. s.-Rsmm of 3 (4 remro- III reuzo c|| ^.ol’dnadi^zu'-^-xk'-s 3-2.2 drex deV(2'-(bem'y ]-.>xy kdnb 2',2' J'aretbxIptonan .-mere -.1 xampe 2.8. 112 .mi, 0 25 mm<>R a. EtOAc EtOH/THF (.1.1: L 20 0 ml.) was added 10 ’’· I'd C (50 mg). And the suspension w as sbrrce n'uk's an aen.'/pherc <n 11 at Meir tem'MXUte for 2 hrs. fire I’d C w-,:s Altered MT. and w.-el-red with MevH 1 ho f-lnabun was ο,-r-com rated timku reduced pressure, and the residue was punf'icd hy recrystallization from r tOH t-- give the title Os.-mp-mns! as a white s-.>hd 181 mg) in ’’(f'esre'd %\MK-J0PMHz, PMSC i ? M-, < ll\ 3 M re. .1 oOll?, Hl '· 3? re, J (- 0 Hz. 2H), 4.05 (s. 2Μt. 4 bl p, j p.0 Hz, ' Hl. 6 59 id. J 8.0 Hz. I H). (>.9 (J J = s.O Hi. lHk~ 43 it, J AO Hz., 1 Hl. /.~S(t.J 6 0 Hz. Hij,'\%'(s. IH). x .% (s. lib. 10.93 (s, IKE MS 357 (MH ).

Example 220: 3-(4¾ min0~2,2“diwde~ 1 H-benzo |e j 11,2,6lthMiazm-5-yl»xy>?8-(4 ’^γ~ mefhQxybeHzyb-^^^dimefhylprapanamide

WO f M221

2017200704 02 Feb 2017 π H

O'S f: %

,.OMe

I i V Η Γ 1 ΝΗ·> ·ίΧ X %L ..X..% ~ r

642 O

Pi epared as m I sample 215 iron? 3-(3-suli anes lannne%< sanophem >\y )-\-( Imedais'.beuy l)-2.2-dimemy Ipropanamnle (Example 220m in 92% \i< J ,- a whr? mbd H \MR mm) MH ·, HMSO-%)0 1.25 % ml). %>« K 3H). I =2% 2H). '=21 td.J 5,hIIa2H).

J SHlviiuNvU ?' HP Hl). 6 %MJ 8 0 ii g 2Hk 0o (J. I s 0 H '. 2Ib.~44fr.J 8.4 IL\ Hl). 7S7t_x IH).s3l H. IH).oH%lJ R-iL·. lib 10,95 (v 1I ii. MS 433 {ΜΗΊ.

I \mnp=e 220a 3-{3-xul tamo\ la= mro-2-ey m<=phcb>-sy >-N-t 4-inc*b. \\ Χ·ιΐζ -41-2.2di m et h y I pro pananii de

Prepared as in Example 215a iiom 3”(3-amino-2-cyanophenoxy)-N-(4melh0xybcnzyi)’2.2-dtinethylpropunami'Jc (Example 220b) in 100'··. yield. MS 433 (.MH r

Example 220b. 3-(3-aroino-2 -evunnpheno xy j-N-f 4-metbox\ benzy I >-2,2-Ji methylpropamwide

To a solution of ik(2-eyanU3-niux>phen<>xy)-N-(4-nyeihoxybenzyl)-2;2-di;msiliyipropanamidc (LI S g. 3.0 mmol) (Example 220c) m diglyme (30 mL) was added dropwise-a xelmmn <9 SnCL 2H-G {2.0¾ g, ° 0 ηηηοΠ m ve»uem=ateJ l R Ί f 1 ' ml '> a? o Use waemm ιοί suite uas then Onml al 0 t for am Aber I hr The reaction solmimi wasftemtabzed \$ ilh 2 N N.a’H at 0 'C. and exacted w nh I % \c {..’XI I he e'-nbired · rg.,nie layere wwc washed v, tth brine, dried over 'Na^S'O*. After evaporation of the solvent, the residue was purified by chromatography on silica, gel elming with 50% EtOAc in hexaries to give the title compound as a white solid (0,91 g) in 86% yield. MS 354 (MH ),

Example 220c: 3~(2-cyano-3-niU0phcrioxy)-N-i 4-mctboxybenzyl i-2,2-Jimethy I reopanarnidc

Prepared as in Example 215c from 3-hydroxy-N '•(4-methoxybcrreyI)«2,2< me H < >p an Jep'jf' 4. ''fldiits¹ 'o Jim hni ?ή> eJ ='i-wlew m solid. MS 384

314

WO 20AMM221

2017200704 02 Feb 2017

Example 220d; 3-hvdroxy-Nd4-mctboxybenzy I $-2.2-31nietbvlpropanamide Prepared as m I xampie % fr<im ?-h\dioxx-2.2'dimi.ihy lpr->p .ume .$eni and 4-ηπ'ΐ·ι<»ΧΛΐ)οηζ\ kcuine re ©7’ ₍> xreld ax .: Arc -.did MS 258 (MH )

Example 221: J-{4-amhw-2.2-diuxkit‘-iH~beuzi>|c]H .2.P|tbiadiazin-5-x foxy)-\,2\2'inmethylpropaaamide

643 θ

Prepared asm F sample 2f' frmij %kinuu<>-2-sy<mo|'hcnox). )-\ 2.2riiretay ipri'pananud.' (fxaeipL· 22 3 in 6’2’ > - x d u a wh/e ^'ad H \MR 100 MHz DMSO~iA) <) 1.21 {'·, <>H) 2 8S >;d. J 12 IT. 3>b t <»< is. 2HI. ba>0 «d. J δΟΗ*. Jil 6...72 id. J X OIL·. Uh. 7-M p, J Soliz. iH).7.S0{q.J 1.2 Hz. IH). “ K Hi). o. % (-. 1H). 10% p., Hb MS 327 (MlT’l .Example 221 a d-t.'-xuluanox lannro-2-ey an<»phcj.>>sy $-5.2 2-6 etuihs bpwm-.SiarnHk Prepared as .in. Example 2 L5a frQm. 3-(3-:irnino-2~eyan0phcrioxy>N.2,2UijnerioJpief'dnanuJ.' (FxampL· 22 = b)-n <3*'*.. veld MS $2“ $MH $

Exmngle^Tlfe: 3-:(3-ammo-2-£yanophenoxy)~N_?2,2-irisr$ethylpsOpananride

Prepared as in Example 215h >; Method At Oom e-ίz-exano-X-rnii-tpheiioxy sN,2,2~b'hncth\ Ipropanamid.: (Fxumph.· 221 el in '15% ield as a 'Mule solid. MS 24x {Ml I 1.

I \ann> e 22 b. ^? (2 «.x.ao 3 HWqmv.» so $ \ 2,2 As ne^!n^Ip= = maua.-nii >.

Pupated as n. Fxare.de 215e fi> m ' hsctexx \.2.2 PmKthx ipxooan;.'iisce (Example 221 d) and 2,6-dhiitrobebxamlriIe in 77% yield as a pate yellow solid. MS 378 (MIT ). Exuinnk' 22 $ d e-hy do-xy -\.2,2-5imseihHpre'iai$amax.

Prepared as in Example 2ISd. from -methyl' S-hydroxy-d ,2-dimeibylpmpa.ftoate aridxnetliydamweί»:5χyivki. MS 132 (MH ).

Example 222: 3>(4“4ηιίηθ“2“θχο«Τ2“011η^ϊ0Γθ«ιηΙηηζοΙήΐ“5“Χ^;Ιοχχ)2,2··4(Μ€ΐΙινΙ«·Ν“ propylpropanamide

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A -wh-finn > 4' A 4 .?-< y a no-?· -ί 2.2-di netlo 1-3- >x> -.%prap> Imnimfipropoxy)nk< ip k.irbameyRIru/anndc ό ©amph· 222 n fl H mg, 0 '· mmoli and AaOIh 2 A. u 3 ml i m EtOH (5 nd.) 'A as stfecJ η 100 ( umler nitrogen β·’- 2 In/ Mier ending io ioom tempcratme, th·.- clear re.ietmn <οΙη·ή··η fibered and the filtrate nas earetuli© οοι-ϊγΜι ed ©\ Uh 10 * o -\cOi I c ith © igorous sdrrsng at © '(.' I he resuham nr·..ciphatc άa© collected by filtniib'.n v, ashed v,it:· v,mc: and rh»n 20 % Ed bi w sa\i \> goc (he fired pn-daet (M mg'· m %'As :ck? M ;m off-wlnte ©olid. Ή NMR (400 MHz, DM©« > d, > e 0.73 (t, ./- 7.4 Hz. -·Η ), 1.2 i (a 6H), 1.33-1.41 (m.2H>.3.OI {-.j.J ~.4 Ii?. 2HL <0© /, 2H). o.M id. J ^: h.OH?. I Η), o ©9 ul. J ©0 Hz. IH). ~.42 H. J 8.0 Hz. I Hi. 7.47 A, ΙΗΐ.“.7<Ηι..ί 7.4 Hz. IH). 7.84 (/ HR. lO.p(>_Vs, Hi;· MS 3l·-} (MH j,

I sample 22da A··;2 c\ano-3-s2,2-dirretksI 3 >-s< 3 (ricpMami mlpjcpe'.©'·ρ1ιοη'-1 carba.moyl)benzamidc

Prepared ax io Example 146a from 3“(3-amino-2-eyanonhcnox\')-2,2-dimethybNpropyl-propamimide (Example 2.1:5b, Method A) andbemmyl isoeyaimte m 85% yield 8© ® whitgsolid. M> 423 (MH

Example· 2221: 4~smiuc’5(se6pePtyloxy)qtrbmzohft~2( 1 H)-imc

$45

Prepared as in Example 222 from %(2~ey:m<>3(ik-epcniylosy »phem leatbamo© Rbenmmids' (Example 22Ln w °O’ ₍, mJJ / _a -Ahiur solid. ^fH AMR (40() MHz, DMSO-φ) Ο 1.03 (s, 9H). 3.90 {$, 2H), 5.96 (/ 2H). 6.1'5 (d, J -7.6 Hz, IH), 6 ^s0 (J, J 7 o Hz A11), ⁷ s4 R, J ~ 6 11/, JI), 22 (--, Hit MS 24 8 (MH )

Example 223arN-i2-evano-3-(neopcntYtexv)phenvkarbamo©'l)benxami:de

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Pi upas cd as m I umpk I l6a fr> >*u 2-^'inro-o-ί ncepctnx os x M-/:1/00.*r='.c ii x nnpk' 21 “bl Χί<ΐ ben, <% iseevmaic tn %% ,?e-d =- a whr^ scjJ MS Mg {\tj| i

Example 224: 5-(3-melho\x -3-mvlhy Ibaloxy )-1 IMiv»za|eU1.2,O|thiadia/in-4-ami^e-2,2dioxide

648

I'tcpaicd as w Exampl·.- 21 6 t_Juin 2-sbii.nuv\ la wno-=/-(/ inciln-x/ -3mclhylhutuxyibenzomtrilc i Example 224a) in 52*',. yield .\_s ,j hde solid. Ή NMR (40=0 MHz, D.MS< ’-iO.i 0 I.In Is, nil). 13)8((,.1 6.2 He. 211). 3(.- ^;<H), 4.1 x {t. ,1 o.2 Hz. 2H i. x,5? id, J S.OHa IHj.0.73 (d. J 8.0 Hz. IH). 7 43 6.1 x «' Hz IH). x 25 (s. 1H). x 30 (s. IH >. 10x9 (.-. IH). MS 314 fMH ).

I sample 224;r .Nsrafames Hminc-i-N-m-c-bexy -3~roeilwlburo\v)ben?.mhtnL

Prepared as in Example 215a from 2-umm&6~(3-:mctboxy-3mcihy lhrh>M 4 c-'.zeti.nf.e M xarepk' 22 lb) m ’>5*% yi JJ MS 314 ?MH 1 yairque ? 3·% 2 a.inico o i? me'h -xy 3 'Uc< wln=.'.\>xy sKm. em'rf.c

Pscpared as m Example 2l?b{Meth=?d .\if-om 2 (3 m-.-ihoxy / inerhMbuwxy)·ό· nitrobenzonifrile (Example 2.2.-k) in 62% yield. MS 235 (MH ).

Example 224ο: S-iS-niethoxy-S-methyltaoxyl-O-nitfobenzoniEite

Prepared as in Example 215e ΕΌΐΒ_:3·’ΐΒ0ίΙκκΧ¥·>ί3·-ηιεών&ηί«ηΕ-ο·Ι and 2,6-rlinitrobenzoniirili·: in 52,% yield. MS 265 (ΜΗ%

Example 225: 3“(.4-amin0-2,2’di0xide-l H»benzo|ci mefhoxyeU»yl)~2\2’-diiftethyIprepaaamide

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Prepared ax sir I xainplc 2 ΐ 5 Iroru % d-sdkmoy larem<>-2-c\ auepircnoM )-\-(2mcfn0XvcihylH2,2-dirrielhylpropanamidc (Example 225a) in 12% yield ax a while xokd. H AMR i-300 MHz. DMS< re% 0 1.21 (x, MU S.l.' re, 311». 3.17-3.22 <jn, 2H). I 28 _u. J <, 0 Hz, 2Ph. 4.07(8.21-0. 6.59((1 J ===-8.0 Hz, H-h, 6.71 (d J ·== 8.0 Hz. ill), 7.43 (t. J === 8.0Hz. Uli. 7.87 (s, IHh 7.91 (t, .1 === 5.6 Hz, ΓΗ), 8.33 0. I Hl, 10.92 (s. IH),MS 371 (MH).

Example 225a: 3--(3-sullamoylamino-2-cyanophenoxy »-N-(2-methr_;xyethyl )-2/-dirneihyipropanatrudc pic > a>.( a - >n >· x >n >> 2 I' ί a ere ^Λ (- m\‘ 2 o , ><>jlu oxx l A (.' methox\c?by0 2.2 dnucilreIp-j'-paaanudz (Example 226b) m 4k'> y?elJ MS >7 {MH j

Example 225b: .3-(3-amim-=2-eya»ophenoxv) - N -(2--me^ioxyeth¥l>2.2-dimethylpropanarmde

Prepared as in Example 215b ( Method A) from 3 -(2 -cya-jp-3-nitropher:oxy)-N(2-nie-bexycthy i>-2,2-dimethHph-p.mamidc (Example 22v) in Ή” re.ield. Ml; ?9.' (MU } Exampk 225e: 3-(2-eys:mo-3-nitrophenoxy)~N-(2-meihoxyMhy1)-2.2-dimeihylpropana-riide

Prepared ax in Example 21 5e from 3-hydrexy-A-(.:-mcthoxseth\ = >-2.2duwethy ipr<,>p:man-j de {Ex.»nple .?..:8dl and .? (>drm?n-henimmnie m 55’o yield. MS 322 (MH ).

Example 2254; 3-hydroxy-N-(2. -merhexy cdiy 11-2.2-dwethyipropanwhde

Prepared as in Example 21 Sd {Method A) FMm methyl Ί-by Gm\y2d>n=C'byiptepaeomc and 2~m<lboxy erhanamiue hi 10(%. yield MS i /ή (MH ).

Example 22h: A-i'dHd-amhin-p.SJ-dh'nkk’-lH-lii-sizoleHl^^lihiiHliaziu-S-ykrey-SAi''dimethyfprapyi)pr9pi»»itmlde η H

648

Prepared ax in Example 215a from N-(3-(3-amino-2-eyastophenexy)-2.2dimethyiprapyd)propioriam>de (Exanipi-.. 226.U and «mfamoyl chloridfc m 17% yield ax a white solid. ^!H AMR (460 MHz, DMSO-.-M n 6/3-0 On {a·, 9H), 2.06-2.11 (m. 2H), 3.07 (d, J = 6.0

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Hz. 20). 5 74 (., 20).6,^ {t. / S i H., IID.oMtdJ 8 χ Hz H 1)./41(6 / RlH'.lH). /93-7.9.8 (bl 20).8 3Mhrl Hi). io Ή (h>x. Hb MS 355 (MH >

Esatnpk 22ea. \-( '>-( 3-anmio-I-i. Astophatn re )-2 d-retne'L·. itnore i)pippiciK.resee

Prepared as in Example 218b t Method Α» from \-i ⁵-i 2-ey fau<»-3-ntt»0pluno> χ )2.2 dtmctbxIpjopx itprepi» natmdeH \amok' 22ub) tr. I»¹»’/ x<dd MR 2% ί Mil )

Exampk 22(m /-(5-(2 vxano 3-nm>-phererey bd.d-ditr.ethxlprepxb·’» <ipt» r„umdc Prepared as m Example 215c from N-t3-hy;lu«.re 2.2 dtnuthx ipjopxbpRtpi'-ttotaidc Ihdinpk' 22ne) msd 2.-n dM'itb-ivnzoritj Ic .b M \> x .dd Ms 30f. (MH ).

.L>.anipk..22.f.<s... N ( 3-bxdtoxx 2.2-d.-tu-thdp-<‘

Prepared ocxouh.se t t tc'.Preuta.M&>·'>: R \ . Hawser. RH / (''t'». Ά .

1953. 7.5. 5Μ(-) f:_C4!i j s.iuwao-2-BMhx (prepare I ol and kemrex ’ ebb-refr ns M'¹- yjeld re a white solid, Rio )60 (MO ·

Example 227; 1-(3-(4-amme-2,2-dinxsde-lH-hx¹tizoK'Hl.2.6(0(1:^4)4/)(1-5-04(^)-232^ dimethy lpropyD-3'-ethy hneu

649 *’n >are< as n ^v s tre > c - (rem i ι ί > -ult ire %' ·κ' s χ p xtt >a > ¹ dimethylpropyQ-S-etbylixren (Exumpk 227a) hi 55% yield as a white solid. ^{H NMR (400,MHz, CMSO-re) 5 0.8.8-0.% ire. 90). 2.90-2.9“ (m 20), 3,(/ (d ./ 6.4 Hz, 2H). 3/2. (s. 2.H), 5.75 ft../ 5.6Hz. 1 Hk 6 07 tt./ 6.4 Hz. Ob/· 5(>{d.</ 8.4 Hz. )H). 6 re id,./ o.Miz.lH).

7.39 (i. J s.4 0r. IH), R 6? (bto IH p x.25 φ(\. IH l I O.M (s. I Η), MS 370 (Μ H ).

^! (3 (3 stAhmox kian.so _ cyanopho'rexy) 2 ? Jmiethi ipuspy Π ? ethyl ores

Prepared as in Example 21.5a. from l-(3-(3~ariiino:-2-cyajisphesioxy)-2,2dtmeihyipropyi)-3-ethyhtrea (Example 227b) m '00%xsod Mx 3 OtMO j.

psample 22 ?h j -(3-(3-a.ipinii-2-gy;mopbenx>xy )~2 2-xlnoeth)4pri>p)'l.)-2frethyiiirea

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Prepated as in I sample 2 ΐ 5b { Method M f><«is 1 ( '-(2-cy aw- t-nnr.pln-'no©© )2 2-dnnetiiy Iprvpy l)-3-eihylnres t Example 227c) m 90% y rekl MS 291 (MH ).

Example 227c: )-(3-t 2-€yan0-3-nmOpbenox©')-2.2'dmreihyIpr>my 1 )·.--cih» hr.c..

Prepared as in Example 2I5c from I-e-hyl-3-(3-hydro\y-2.2-djinethyiprepy limca (Exampl». 227J) ,;.«j 2 n ..hmm hcuzomti to m 4~'<· y.eld M© 32HMM )

Example 2276: i et hy 1-343-hy dr·.>x©·-2.2-dimethylpropyl)nre&

To a solution of 3-ammo-2,3-dimcthylprop;m··1 -ol ί 1.03 e, 10 mmol) in dry 1.4dioxane (20 ml) was added di<jp©x tsc ethyl isocyanate (6.7I g, IO mm»· > at ·»»η: tempciature tmder nitrogen. The reaction mixture was then stirred at loom temperature under nitroger) overnight. The solvent was removed under reduced pressure-to gi ve the tit le compound as evk'ilexson f I 4 g. )(?(?%> MS I5 (MH ).

Example 22S: 3-(4-amhW'2,2-dinxidv-lHbtnz(»|cHL2A>|thiadiazia-5-yk>©y )-.%-butyl-2Λ2'~ dlmeth© Ipropanamide o ti '•fi 8 <

a

65d

Prepared as Hi F’sampleJI? msd la fr-etr 3 (3'.«inmo-2-es;.k>.p wirexy j-X-lmpl2.2 JnnetLxlptepananink (Example 22S..;· and .wihbmo-1 ehfekk re ·+'' .yield as a <©lrre/< id, ^SH HMR(4(K>MHz,DMS0-fe)dO.78 a J- 7,2 Hz. 3Hk 1.14-02001¾ 1.33-1.37 (m, 2H;·.. 3.02-3.07 (m, 2H), 4,07 (s. 2H), 6.60 id, J κ 0 IV. I H)_: 6.71 id../- 8.8 Hz. 1 HL 7 14 Ct,.,/ x I H.’ IH). ©Op. / ©6 Hz. HR. 7 91 / IH). < 33(.- HI). ERLM.-. Hi) ©1>369(MH

Example 228a: 3-(3'umitK©-2*cyan&phenax© )-N-butyl .’,2-b.m.ihybropammiide

Prepared as m I xnrnplo 215b ( Method X) tnym X btity I 3 i2 cyano 3 nitrephen-'xy ; } 2 dimethyh'topa*'.m''de (Example 228% m /“% y reki MR .^0 tMH '»

Example 228b N-btit© o <. vyano-lLnitmphenox© I U dime-hy Ipropanamide

Prepared as in Exampl: I5e from N-bUtyi-B-hydrox© -2,2-diinethylpropatiamide (Is, n'le .red 2 nti ο n '<mif le tn on' > \ c. J MR ·> 0 (MH )

Hamp Ήχς X-burel->-H e <>xx*' 2- nc( r< ^xopaix ntue

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Prepared ax ns I sample 2156 (Melli<<d Ai ftotn meliiy 1 khxdioxx -2.2dimeihvlproparK»<de and n-hntx I amine m 101'% y tdd MS I 4 t Ml I ).

Example 22% Α-ξ I -(4-amiim-2.2-dioxide-1 H-bvnzo|eU1.2*b|fhiadiazia-5-y loxy )-2’melhy lpropsn-2 ’-ylibuty ?ami de

651

Prepared as in Example 215 from 5-( l-(3-si;lfamoylainino-2-cya'iorhenoxy)-2nie(hvlprepan-2-y I ibaiy raimde < E sample 229a) and sodium nx dioxide in 54 ₍> x iekl re a wb.de sebd. ^!H NMR (400 MIL·. DMN< jJO 7_Μ?<./ 2 Hz. >H). 132 O. Mi). i 4'- I 44 (m. 211).2 (1(1(1../ 7.2 Hz. 2HM 24 ^.211). nr(red. / 8 0IL·. ΠΙι ή % (J. J .-. 4 Hz. ill). 7.44((../-8.4 Hz, llh.7.77(s, IPh. 7.82 (jy H i). 8.42 (s. Hi). 10.97 (s. 1 Hi. MS %5 (MH i.

Example 229a: N-(1 '(J-sulfamoylammo-z-cvanopbcnoxxd-i-mothyipropan-x-x'l)bidyramidc

Pienareo a - .n > xanzre 21 % jori 5 (I % -010020-: ι<» ilum s' 1 2 niedbIpomaii 2 x Abutxianode {I .xaireik 229marc MiJairoxl erbink m I(»(»^o<. redd MS o55 (MH').

I xuirnk 22 ?b \ (j q 4 .'i)ire-2-exa'iorhen>'X'< ί 2 nu.hson<»r.i>. 2 xllbutxian.i.k Prepared as in Example 215b ( Method A) from N-(l-(2-eyan0“3-nitropben..exy)2 nicdwlp'f'naii 2 ' Oi uh'.an. .L (Ex.or.rk 22%) .n b'10% x ,</e MS 2/' f MH /

I samp e * ⁿk \ t 1? ey.-no 7 ‘mOpit-rov) we‘!r ip e>| a' ? xllbiz^ -rnde Prepared as in Example 215c fem 5-( I -hydroxy-2-nwrhylpropan--2·· _:yl)burynimJde (Example 229d) and 2,6-dimtrebenzsnitrde in 72%.yield, MS 30(i (MET).

Example 2.%d χ (I hxdioxx. 2 rae'hy reooan 2 xilbury'annde

Prepared according (0 fne iiivratme i8oxd. R.5.: Hairrer. R H </ 9^f;? i'k-m. S'<a'. 1953. ?5, 58^i:>6) from 2 ain;ix<,>-2-mcihyiprop:m-1-ol and btnyryl J:\>>joe m 3?^f'.>yield MS Ha) (MH'k

Example 230:

methylpropan -2 ’-y 1)-3 · -el hylii 1 ea

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Piepame a- in Fxan.pk 215 Uotn 1-(1 {S-sulia'i». x afi.'iie-d'vxan.'pben.ixvl'dniedtyh^,r’’pan-2-x il-3-cthy hirca {Example 239a) tn 37% ysdd a- a whde mhd. ^!H NMR (400 MH.·. DMSO-Λ) 4 9.92 a./ ~.2 Ηλ 3)1). i .27 a, M I). 2.90-2.% pn. 211). 4.2 = % 2H). 5.% <L 7 5 2 Hz OH. 5’>%s. HD. a 59(0.7 8 0 H., J Hi, u % -.,411/.111).^42 6../ 84

I)?. lib. 7% (s, I Hi x 34 is, Ub. 1094«. Hl). MS 356 tMH ).

Example 23(*a l-f I-iS-samneoy lami;sO-2-eyanc>|=hc:T0xy)-2-meU:y pi->pa.ί-2-yI)-3ethylurea

Pa-pared as Bi Example 215a fiu-u I -i I i3-;m0ik'>-2-iy;mophcn<’\’d-2· nerbx Iptepan 2 \l> erhxhaea tl-xampk 23(49 ar.d '-n%m<% cnb.mce w 190’ ₍. xidd. MS (MH ».

f xampk 239h = ij-amme 2 e.anophe tow) 2 i'Ktbx Ipropa i 2 xb 3 eihylinca

Pivpaicd as Η» Example2i 5b ( Aklhod A) fiom i -(1 -f2-cyano-.3-nm-ophen0xy)-2-mvrbx lpiop;m-2-y 1» i-ciln kaea sb sample 230% m xb₍- x idd vis 277 (\f}i ?

Example 23pc; I i l-f 2-ey an<?-3-mn\>ph-ziuxxx ) 2-mediy Ipr·.-pan-e-yil-3-eihymrca l’iBeared -=s w Fxampl-z 21fe floe» I--..-1%I-3% -hydtoxx-2-ineth\ lpiOpaa-2yl)urca (Example-23.04) a.t)di2,6--dit)itmben3x7'nitrile m (>5% yield. MS 307 (MW).

Example 2304:. 1. -ethy1”3”( I “lw4rexy-2-me(hylprepau--2-yi)urea.

Prepased as in Example 22'\l bem 2-air%a>·„’ methyIpn-pan-1--.4 and e?hxi Eoeyamite m 94% yield. MS 161 (MH'd,

Example 231:4~i4~amim»“2.2~diexide-HM>ei»w[e|i L2,6HI»iadiaziu~5“y loxy?~2'~ methylb«taa-2^?»l

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Prepared as m E cample 215 dans 4-{2-cy ano- )-(siilfanmy iamitnPphcnexy )-2nulbx lhutan-2-yl acetalc t Example 23 l:u hi 20% yield as a white solid. ^lH NMR (-400 MHz. DMSO-u'H 4 IJ 5 k Ml). 1.89 life -5.4 H21Ik 4.22 ft../ o.4 Hz. 2Η». 4.52 t+. tH). p5~ pl.

J 8.0 Hz. IH), 6.73 (d. J - 8.4 Hz, IH), 7.43 (t_s J-8.4 Hz. 1H), 8.22 (s. 1 H)_s 5.30 k. Π I), 10.87 (s, IH). MS 300 (MH ).

Example 23 bi. 4 a2 -cyauo-3-t-ml mtnox b.iwmo'»phen<»xy) 2 · methx Ibntsm- 2-y I acetate Prepmed as nt Example 215a ?h>m 4 t '-a-rrn'o 2-eye mphem-xy)-2-mc:bxlbmaj 2-xI acerate (FAuinple 23 lb? ;.md -mifana-y l ehlorsde tn 100'\> xseb.l. MS 342 {MH ).

b sample 2311> 4 {o-astmi<»-2-e a-!-.?plictn>xx ) 2 snetlp ante ι-2-yl acc;.:H prepared us in Example 215b t Mctlmd At from 4-(2-cyauo-3-nitropheno.xy)-2methylbman-2-χ I acerate (Example 231c). MS 263 (MH ).

I' ample 231 c: -H 2 -cyano· 3- int, <.??mcpa + 1 2 mHhx .bet,. > 2x^! tce'a’e so asoimio·? of.feo-hydrexx-'-nic’bxIbuU’xy pb-nikPhcnzonikile (I sample

231-.1} (2*-0 mg, I mm-»!?, trix’tbx iustvinc (3 cqmv.}. asts.1 DMAP (03 cqmv ) in. dry diehl->r->snethasi·. (20 rnl xxas added dmpxxsse ae-.ly l ebb-side {1 ? equh.) at 0 Ύ coder isit?> -gen. The reaction mixture was tlten -.tmed .0 0 C room tempetalme ox et mg hr. fbe ο.ίχ'4<'·η \sa-s dilo’.-J w ^:h l ΌΜ' ua+h.-d ve'h br \\ nd dUed oxer S<RO< \'iei aapor.niew ofrbe $x-iyeiit. tl-e residue was purita d by cbrosri.Pograpbx on feica gel Hutmg wsd- 20% FsO \c sn hesanes to give the title comppu-t-l ί i 3⁷ mg 1 <>} MS 2’)? (MH ?

Example 23 id: 2-(3- hydmy~3 - me t b x b ui dxy)~6~ni tobe rm wi tn.lt?

Prepared as in Example 21 V thrn 3-mcihylbmano-1.3-dml and 2,6dinhrobcnzomtrilc m 81% yield MS 25 i (MH ),

Example 232: l^^-nmiim-J.l-xljaxiilx^lEl-henzGlch' U2.0]ilmuliazin~5-ytoxy)methyl)~2 ethy lbufisn-1 '-<>1

6S4

Prepared as_:in Example 215 tn-m 2-etln 1-2-((2-memy 1-3{\t/far.oylan-iino)pheaoxy)methy()butyl ace-.η» {Example 232a} m 20?-« x leld >tx a white solid.

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2017200704 02 Feb 2017 ^!Π AMP $409 MHz. DMWsLi <>0“?-p w.elb I 21-1 HhaJitt. -3,-3 '%?:$. 2Π). >> SO tw2H)%92tbrs H%o%ul. 7 M$H,·. Rh.6 ~M6. / x 4 1% II·. ~ 40 <\-/ x 4 Hz. Hl), h.16 (brs. 21% 10.91 {br--. Hl·. MS 32MMH ).

Example 232a: 2-((2“Cyaoo-3dsuifatno$4anmK)jphcru;xy}meihyU-2-cfnylbatyI acetate pjeparcd as tn Example 215a 1: = --6 2-tt3-armmt 2 vyanophe i==xybneth\'.$-2· ed - jtx'.aeetcU >1 x ».apl> 2'2b) »,J ., 6.=-.¹ Cdo.’de ,n ..eu Η AMK {400 MHz

HMSO u ) 31$ xo {L J 6 Ivj-Hk I 3 I 43{m,4l% I 31% 3 X? {.-. 21%.-.% %. 21% 6.98 {d, ,Z 8.8 Hz, IH). 7.1 3 {d. J --- 8.4 Hz, I H), 7.25 (s, 2H1, 7.54 (t. J 8.4 Hz, i Η), 9.46 {s. Hi).

Eyampk 232b 2 {{^J. antreo· 2- u anophe.mxy bituhv 3-2 -crux ibut-1 ae.-u-.re

Prepared as tn Example 215b (Method A: from 2-%2-cyano-J·· uit$>phen··xy imcihy l·· 2- eth\ =buty I .uchite t 1' xample 232v) m »= % y _iehJ ^;h AMR i -ipp MHz. DMSO-Αι 6 0.79 (:...7 - 7.6 Hz, 6H). 1.34-1.41 im. 4H>. 1.97 (s. 3H). 3.76 {s. 2H). 3.94 (s. Mis, 5.9'<s 2Η).ή.2ί {d.,/== xOH.'. !Hm>j= (4...= ==8.4 0.-. IHi 7.15(1 ,7== x 0 Hz. Hi}. MS 291 (MH $ .1..\ϊ<161Ρί’._:...2.3._;'.<’..· 2-((.'-ey 4=¾=-3-=6:=ophem x- jme:by l)-?.-e:h\ Ibuly I acuate

Prepared as re I xmnple 23le fo.-m 2-{2 e?hyl·2 {hydr» \ynwihy lihmoxy)·-x nifrohenzorutrlie t Example 2 32-JI and acetyl cbfottdc tn 82% yu-ld, MS 321 (MH 1 sampte 2-26. 2-{2-edw 1-2-(hydroxymetbyhbutoxyI-b-mm benAm-trile

Prepared as ir= Example ?l \ %==o 2 2-d=er6y lpropanc-l_v3-diol and ? 6c.mtmcer’/'im-n e re xo%'.re,d H AMP = 160 MH 1 AX)- c »0 0 < 0 t' <’ nll'bllt ’ $ i(p .z 7.6 Hz, 4H), 3.33 (d. .Z- 3.6 Hz, 20),.3,96 (>, 2H), 4.57 (:,,7- 5..2 Hz, H i), 7.74-7,76 (m. Hi). 7.84-7.96 (m, 2H).

Example 233: 3-(4-anHno~2,2-djmide~lH4H-nz0|cnE2.6|ihiadmzm-5-yfoxy 1-232*dimethylpropw-1. '~ol

65δ

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Prepared as m f rampk' 215 tiom 3--2-..=.ano- U(sulfanmy i-amib-.:|pli>-'nexv )-2.2dimcihyhpropyl acet-ate (Example 233a? m 30% yield as a 'white sohd. Ή NMR (400 MHz, DMS<)~«)db.94{s 6Ha3.29A.51 tm. 211), 3.xx is. 211), 5.01 ft,./ == 4.4 IL·. 1H).n.5x pl,./ = 8.4¾ 11-0,6.71 (d% 8.4 HzJH), 7.42 (1,./=== 8.0¾ 111), 8.14(5, IH), 8,3:2 (s, IH), 10.92 (s, = H). MS 300 (MH k

Example 233«: 3--(2-cy;mO3--t =m I fumoy l«m inolphenoxy) 2,2--di inethyipropy I acetate

PscpafCd as m b sample 215a ^?.·ι 1-ammo 2-ey a mphem-s-. 1-2.2 dimethyipropy I acetate (Example 233b) and sulfamoyl ehlonde m *o0% vield. ^lH NMR (4()() MHz, DMs< > re ! 0 0.99 %, AH). 1.98 (s, 3¾ < «5 is, 2H). 3.9) is, 2H). 6.91 (d, ^! S.4 Hz, IH), 7.12(8.-/ x 0 Hz iH), .23 ts.2H), .52 (t, <’ *0 He. I Hl. 9.45 « IH).

V sample 233b 3 (3 :mmi=?-2 cy -mupheroxy i 2,2-di nethxlp=== wI ,=.0.1,no

Prepared a.·- in Example 215% Method -\l n==m 3-i2-eyai=='-3-ui?=ophcnoxy')-2,2· dlmethsiprepyI ,reet ne (= sample ..’33>:? m '%y =ek- Ή NMR ( =00 MHz, Ι)\Ι8(.%·.)d 0 °8 % Mi), 2 B0(x, 3H) 3 75(s,.:il) 3%) (s, 2H)%.99 _κ. 3H). 6.17 id, ./ == 8.4 Hz. IH). 6.31 (d, ./=== •x4 Hr. HI), ”J5(E ^?* 0 Hz HI).

3-(?-ev iro-3-nitropbenoxy)-2,2-dimethylpropyl acetate

Pirpaied as =n I sample 23 le 9 *m {'< hyetoxy 2,2 dimeri/lpi= n> xy) 6 :1=(0 bcm ows'arie 11 sample ..0881 and acety I ebMudc m ev% y H NMR t400 Mli^?, I 'A 180 j/,) d i fH =s, nil) ? i;0 ^\, SH) 7 o> « ’ Π) l 02 i- 2H) -0- (m I H), / xn~ = em ,'_iV %p,

Han'pb 2^-¾ % 4-hyd i>x\-',?-di 'i> WIproposy 5-6-0==1-(6,,-== -cma: e

I'repaiec as re = \m\ik' ‘l·· .rer '?/ ne=h\ ;p op me-1 5- bol u?ndmm-m.-n'<mmi=e m /3*'syiekl Ή NMR = P90 MHz ΟΜΑΟ-,/ρ _f> 0 9 I (s, ι·Η>, 3 29-=-3= (n= Ji). ’( 9^ς <s Ji), 1 (M <3. / == 5.6 Hz, Hi), 7 (-% ’ Ί im, lH'>, ' x 1-7.90 Cm. 2H). Example 234: N~(4~(4~arnhH>2,2~dh>xide-lH~be&Z0leH Π2χ6ΗΐΒηύΕΛζίη~5^1<χχν)ΕηΗ1)-acetamide

NH,: 0.

NHAc

Prepared as in bNanml·,- ? I 5 frijm N-(44%c%an<.>3fsu’famoy'kmiim>)ph>. cosy VnUy =),a etzmxn’tl samp'e ^ = 001== 7p^c „ y-iald H. NMR (100 MH',

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DMSO-%).= 1 4s-l 51 (m 21 DM Si (_3i. -Hl, ) 03-3 0o (ng 2111. 4 14 t.../ (>0H/.2Hi. 0.59 ul. ·/ s.o Ha 1H). 6.73 (J. J === 8.4 Hz, III). ~ -3 fr. 7=== 8.4 Hz, IH). 7.~S {.<IH). 7.84( nre. JIIj.8 32 (sJH). IO^k |H) M> 327fMH ) \a>up=e 2 Ma \-pi-t 2 <y:m«>-3-(=.^1: mam kme.ra)ph>no' \ )l ul·. haLCUnnude Prepared as B: Exanndc 21.% fps-u N-(4-<3-;annm-2··

Ο',·.ϊ·<.:>ηα!>·\\ ’nap krevk-'injc d xamp c 2340) and .'υΠ·ι.η?’>. elfmnde m 00'3=- s and H NMK (ΨΧΙ.ΜΗ?. DMS%fr.>.-^; =,%.= 54un.2Fk = 70.1.72 (m, 2Hk 1 (_s, 3H). 3 %-,%)·> (m, 2H>.

09 < t../- 6,4 Hz, 2H), 6.93 id, 7 === 8.4 Hz. 1H), 7.13 (d. -/=- s.O Ha IH), 7.25 2H _h ?.% _n,./ x 0 H.\ IH). ~.χ5 (hre.lH). 4.% ta Hl).

E\an-pk 234n \ <4 {3 uinin>--2-eyauoph->noxx)imt\fr.b.cpi.nu.e Prepared as nt Example 2l5b(Mo^!n=d Aitlwn Vi4-t2 €=..0:==-3 isiUreWcn·'a Jimp. Dawrenudc (I xamp=e 234,.) tn a?'' < y t.-ld Ή NMR dm MHz, DM8O frO 3 I 5.: _{™, 2H> | =,= ,-: -·ρ (:n, JI). 1.77 re. 31I). 3.03-3 08 (m 2H). .5.97 p.,/-= /,.x Hz. 2H). 5.95 <b .21-1).0.18 {d. 7 == 8 6 Hz. (d../ === /.<> Hz. IHi. 7.15((.7== S 4 Hz. Hi},'·.83 (brs.lH).

Example 234c: N~(4-Q--cvano-3~mtrophgu(>xy)hntYl)aget.i=-(nde

Io ;= xek’tio·'. <=i 2-(4-s=nin0butoxy)-6 iufr<»benzort>friie «.Example ..'.MJ; t?38 ng. 1.0 mtnqlk mcmy latrnnc (3 equtt.). and I.A1AP (0,1 equiv.) in dry' dichkxerne’haue {.’0 .nL; was added diopw we ae> tyl ehDruh fr 5 eqwx ) <n (> °C under-nitn-geii fbe =-, aer-on mreuire was then stirred at 0 °C - RT overnight The reaction was diluted with EtOAc. washed with brine, and df:i-J e'-c Na-SO.. XPe? .-sapcjahon - a (he μΈem t=u- resabn was panfEw =n e u,m <m <» aplw e< sf.n a c'm rewul '(f’d K’ksw rbi t le < .nreounJ (I as nii’ '“’JO. MS 278 (MH ).

Example 239d. 2-(-i-a:ni:nx)bntijxy)~6mitraben-zonitri_:kt z\ solmim; of fert-birty14-(2-cyanO3-nitrepben,= \> )hu(y Icarhamaie (Example 234e) (67 .1 mg, 2 mmrn.) in DCM/'TFA (1:1,20 ml.) was stirred at room temperature for 2 hrs, fhe sehsnt wa> n.nnwed unJet t ._suium to m\c tk^ mk o-mpeun.· (o'^s8 mg. .00^ι’<>» M8 2*o iMH').

Bwnnlv- 2*4e uiPbuty 1 4-t2-c<am>-3:“nifrophenoxy)butylearbainat®·

Prepared a? n= Example 215c Oom ten ί«4χ I 4 Io «Jmsxbrny ka- t.urme .:=,6 2.8 dnms<d\m/-.'muPc ra 7% xsekl .w a p-ke y>11·.*w mid H NMR (40t) MHz DMS(»-fr 1 'I.wis,

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MI). 1 52-1 .55 (m. 2111. 1.72-1 '«•(m. 2H1. 2.44-2 99 f m. 2H ),4 24^,./ <-8 IL·. 2H), Pre.

Ill: 7oR-~.72 Rn. HR, 7.S5-7MR(m,2H>

Example 235: 4“(4-amia©-*2,2-dsexlde“lH‘beaz0[c||l,2^|t:hiadiazi»«5“yl0xy)fb«tyl xnlfamate

65?

Prepared as in Γ xampk- 215 from Ε(2-8ν:·Η\>-3-·(^η)ίηη8?\·;·η·;'ίην)ρ}·8·5θΛγ)68ί.γΙ wManxtV (F'.re^'b· 2-Mrem 31%-. teM 11 NMR (400 MHz 1ΛΙ8υ-Μ)<>. HI 7¾m 2||\ 1.85-1.91 (in, 2H)_? 4,07 ((,,/=== 6.4 Hz, 2H), 4.18 (t, J - 6.8 Hz, 2H), 6.58-6.60 (m_} IH), 6.74 (d, J - 8.4 Hz. IH), 7,42-7.46 ret. 3H). 7.79 (MH), 8.32 re. IH), 10.93 (MH). MS 365 (MH »,

Exampie 235.¾. -M2-cy ano-.HsnOanioy lammc)phe>t<* <.y sbmy I salunimre

Prepared as m P cample 215a fr>>m 2-.:mine-tw4-de! l· brnybbinedp. reiMosy »bat<>v. tbctizoimiile tl xamy=e 235in and mlfatno·.I chbm.re m M% yre'.d. MS 3x2 {Μ +H.4..0-.

l23.il.UAl>k:..235b:. 2-arninG-60/44tert-butyldim_A'Ahykiiyloxy)butexy)bcnz.o':ntriic

Prepared as in. Example 245b (Method A) from 2-(4-(tertbureIdjinctfo. IsjR brexIburev 1·η·ηΜ··.Ί^η*Όηηπχ (Fsaarplc 235el m 70’ _w x scM. six ^2 (HH 5

Example 235e. 2-(4-(- erf- t-tify (dimedty Eire Ioxy Ibtsrews l-6-ntit>-ireuzoratiile

Prepared as in Example 215c from 4-(tert-buiyfdjmcihyl-siiyloxylbman-I-ol and .2s'6-dimtrobcnzomtrilc m 25'28 vtdd as a pale yellow sol id. ^lFI NMR (400 MHz. DMSO-dR) 6 0 01 MR 0M O'-rap. Ml) I u Mtm 21R . > j M .in 21R. I <‘-r IL 21 ) 4 2n (t. / 0 4 Hz. 2Hl. 7 e8-7 70 _Hn. Ore. ~ M-~ M Hr. 210

Exampk· 236: d-(4“nminn-2,2”di0xide-'iHHienz(s|c](l_>2,6]thiadiazia“5--ylaxy)“bnta»“1'^!--s)l

65S

Prepared as in Example 215_: frem 4“(2-cyano-3-(88i&moylam:inG)phenoxy)buty 1 sulfamate (Example 235a) in 2% yield. ^;H NMR (4()0 MEL·, CDsOD) 6 1.69-1.73 (nt, 2H), 1,95WO 20(18/154221 .PCWS2(H)8/065050

2017200704 02 Feb 2017 l η (m, 2111. M'.JfL./ o.4Ha2Hj. 4 24t-.,/ e 4 IL·, 2H >. ο M -b,u Mm, HH. o ~5-(-.~~ (m. II!), ~ 45 (m,/ -8.0 Hz. Hi). MS 286 (ΜΗ

Example 237: 3-{4-n«HfiO-2,2-dmide-lH-benzo|€H E2,6|ihradiazHi“5-y.l<Ky )-2'rne t by 1 p ropa n 1 ’-el

NH₂ ΟχχΚ^-ΟΗ

659

Picpared a- n- Ρχ-η-ψίο 215 (km- 3-(2 cyano- l-lredfanb-y ,ηηηυ jpkciHv ; 2,nef iy Iptepx', ,-eennc sEx..nnp,e 217?» :n MS yic’,,1 ,-χ „ a>'.te \o'.t,l ^fH NMR ( 4)0 MH?, DMSO-</,).·; 0.04 id, / χΗ),2.Ο·»·2 13 (m. (Hl, 3 3e-3 42 (m. HE, 3 4η·3Λ> tm. HH.

4.00 < J../ = (-4 Hz. 211),4.5-1 |), ‘ ~ 5 6 Hz. IH'j.o <1 ./ ” n Hz llh.6 ,’Ό {d J ~ 5 4 Ha

111),742(1,,/ =3.4 Hz Η H. 5.05 (brs, 11E, 8 24 (hrs Η I), Hl9 I {x. IH) Mx.'.50(MH !,

Example 2,3,7a.l 33-(2-cymm-.E(sM:;.srooyb.iny_:n0)phene.xy)-,Nn-eihy (propyl acerate

Piepatod a-, in s xan pte Ι,Μ vr; EM nn’e- ’-..xanopbenc-xy )-2-me*hy rptopyI iKV.atc (Exatr.pl. '3ΉΙ and xmlmrey I vhlottde <r. <-”<? y tdd ^lH WIR J00 MH'?, DMSO .. >) 0 I P.' <d / r 5 Ha ME. 2<H KMH. 2 33 7?/ (m, '.HI 3 99 4 0 (tn, Hike 94 td, / x <t H,’ IH), 7.14 (d, J - O Hz, IH), 7.26 (s, 2H), 7.55 it,../ - 8.0 Hz. IH), 9,47 (s, IH).

I wmip.c 23_; > t > tn <> ' o >i< s mcihx ί n j et \

Prepared as in Example 215b (Method A} from 3«-(2>cy<mG*3-nitroptedoKy)-2-.

nu thy Ipjvpyl ,\'>. ι,ϋο <J ' ample 23 Ml m /P'esi.'kl Ή \MR(I6OMH? DM'50-,< >> do 99 (d, ^f ?H/,3H) ,'.(MK5H) 2 ί')-? ’’ (.m = Hl VI' (J, ? > Hz 2lE,39'-i(l< (tr 2H).5te (s_; 2H), (-. 19 td../ - 8.0 Hz, I H)„ 6.32. (d_; J - 8.4 Hz, IH). 7.16 it../ - 8.0 Hz, IH)

Hamp 29 <, 2.jo-m <vle·' uk neK ' <>px’ u. ,

Prepared ;n< in Lxeniple .231-.: fre-m 2-( 3-hy(iri>xx-./-meths pr-.jp>..AS M 'etrevn e 'etr le t M a uple 3 ^?di .Ή aceix! b attee in ΕΆμΑΙ E \MR t Pill MIL· DWO.</ ) 0 s fί 1 <d -/ 6 5 He, all) ? 00{-<, 3Π) ? 28-2 Ή fm, H) ( 0-<-1 08 tty 2H), 1 I 5 rd, ’

6.0 IL·, 2H). /./I-’' '3 fm 1 H). ’.m- ‘ ‘7? Cm, 211).

I scnipse 2 ^{~d 2-( l-Heioxs -2-n'elhx ptopexs j-i'-'atiohen 't>> itf le

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PrepasreJ as so I xusopk 215«. fere 2-suclby Ips opa> re-13-xlire and 2.cdisutfe'cn/onihire sw 3% acid. MS 25? (MH '>

Example 238: 3-(4-nmifiO-2,2-dmide-Hl-benzo|e}| 1.2.6| dfedlazm-fetow Jpropan-1 '-ol

086

Prepared as hs Fx-uuipk' 2 i 5 Iron· 3-f 2-cy arefe-preiiam-.A kwreuelphcnos.x -p?\ pv -tJtaswaic f I sanspre 2.>8a) ns fe% sold O NMR (400 Mil/, P»MS()--/?> <) 92-1 ya. 211).

55-3 59(%. 21b 4.29(5 ./ MHz 2lb.4“9«L ? 4 s 11/. ^JH).fefe5%in. ·Η|.<·7]o73un. iH).“ 1?<L / x.4 0/. 10).8 s2 Are. Hh.S 2e «bre. I Hi I0o9%. Uh. M8 2~2 (MH \

Hanspk 23m 3 (2% u_!re-5-(.rel?j-skn):.(ureK»)phcn<’xx)prepx i sulfamate Prepatcxiasm ί x.(snpk'2)5a re so 2 annsre o (3-:sxJu s^pre-rev 'tbcj-.z-nnui-e

x.-.mpk _.·>8Ν red selfamcM chl-ud. re //. yck· Ή NMR M00 MHz. HMS% <6)6 2.1 I

J4(m.20fe 17.42) (η.. 4H}. fe6 M. / Μ» Hz. 101. 3 (Λ > ” nlfe Hl). 2fes.2Hk 7.4s) re, 20). 7fe (1../ 8.4 Hz. Hi). 9.46 %, Hi).

): xureplx 2)8b 2 //uu> 7. (3 hxdscx^psxxx>\x ):us\'<wundx

Prepared as in Example 213b (Method A) from S-iS-bydrewprepoxyEh··· mtrebcuzsmiti ile (Example 23m> in 100% x :3/1 Ή NMR (4()0 MHr. DMSO j ) »'< ’ '% 1.85 (ni, 2H k 3.52-3.56 re. 2 H s 4 *0 (1,./ 6 4 0z. 2 H ?, 4.54 (t, J = 5.2 Hz, f H. 5 >3 (s /1 6J >) (d../ =4 8.0 0¾. 1H). 6.30 (d, j = 8.4 Hz, 1H), 7.15 (t j = 8.0 Hz, 1H):

Example 238c: 2-(3-bydrexyprepcxy)-6-nifebenznnifrilc

Prepared as in Example '215c fr-m prepane·· 1,3-diel and'l^dinifrbboiz^nitr.ik in M% y MJ 6 a pale yelkm ^kxl 0 NMR Mms MHz. HMM? cM p | 89 1 93 >.m, 3H) 3 5«· 3 M (m. 2H),4.30(t,./= 6,4Hz. 2H). 4,61 ((. J = 5.2 Hz. Hfe 7.71 “ 4^. IH? /8? ⁷’> (m. .'lb Example 239: §*(bntyIthio)»i H~benzo(cj[ 1,2,6)thiadiazisM-amine»2,2-dinside

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Prepared ax in Example 2I5 from 2-^11301=/Iumi:t<’-6-(bmyIth-o'lbcHzmntide Η xampk. Akim s?'< y^.idaxawhne^'tJ HAMRplOOMHz DMSO-.M-> 0 w it ./ // Hz VH), 13':-:% tm ?H ι I ' M Wire ?H) %'(t, / ' ' Hr ?H> t> pt / s4Hr ,H> 7.12(1 ./’~7 6 Hz. IH), 7.4 j %./- 7.6 Hz. 1 Hi, h I2«hs 2H), 1I.()2 (hrs. IH) MS2x6(vlH ) I%.^:iLPi2Lsl2.3%'_: 2-snifamoyl.retine-i - (bins hlne- ibenct mitrile

Prepared as in Example 21 M fh>m ..'-.nmno-b-tbuls ithiolbenz-miulie -Example ? Mb) io ?6% y ie)d. H AMR (400 MHz. DMSO-.·?.) 0 0 % (t,./ - 2 Hz. ΜI}. 1,3b- I .4- ire. /10, iy!-l6!{ir., ’ll) h/it ^! / ο H . ,’H) ’’25-/.'/pr. 3Π) ' 33-’ >6 (nt, Η Γ» 6 ’ it / 8 4 Hr. IH), 9.50 (x. ill).

I xmrpk 2796 2-,'etna-<>-( mtx :h,<e Kts/pnirde

Prepared as in Example 215b (Method A) from 2-nliro-6-(bt.tiyitltioibeozonkrile if wrere/ '.At m S 3 sl> d H AMR t )O0 MH/.CDCh) ,6 H p. ’ ’ ¹ Hz HI), I l.'-i >2 (nt 2H) I ¢3-) Mim ?H), 2.9 7(6. / - 6.8 Hz,.2H),4.43 ibrs, 2H), 6.82-6 54 (m, IH), 6.67-6 .M) tm sH) ' At (i ' S 0 Hz. HI).

I sample '.''^iGe ?-nhre-(-(botyiihiedbdnz6aitnM

Prepared as io Example 215c from bitkne-l-thiol and 2,6-dinitrobenzonitrile in Whi yield, NMR (-100 Affix, CDCJ.O 6 0.97 (t, J- 7.2 Hz. 311), 1.42-1 55 (m, 2H), 1.70-1,77 (m. 2H), 3.09 (I,./ - 7.2 Hz, 2H), 7.63-7.69 ire. 2Η», 7.99-8.01 (m. 1H).

F varaple 246: 6H4~ammo-2,2~dio\ide~ 11l-beozoo'll 1.2,6]ibimliazhr-S-y lexy )br\x 1 sulfamate

6S2

Prepared a$ io Example 215 from. 6-(2-cyan0-3-(sul&moyIa'miBa)phenoxy)hexyl xb'.tmxne (F\.mtp'.e 2 -Oat tn -io”,, \?e d H AMP (-Uh) MHz, DMMs ) d p3 I 0? (m. IH)

1..'s tm. ?Η), i 4? (tn. 2H), 3.64 it_: J - 6.4 Hz. 2H), 3 ?8 f. J - 6.4 Hz, 2H), 6.22 id, J - 7.6 Hz,

330

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UlhWuiJ 'Mb. lilt. «(CH), 7 0 it 1 ML Hl·. 44<s. Hl·

19,56(-.. Hl·. MS 393 (MH ).

Exatnpk 24%: o-f 2-cyano· l^suh-'tsox latimmlph^mx'x )bexd -* iPcmate

Prepared as in Example 215a from 2-amtu>>-i>-v'>-hydt0'.S’bexyl<ixx sbcii/oainik' (Example 24Gb) and xulhtmayl ehlonde m 2()%yield. MS 393 tMH ).

F ^χΒ(Γ.)>„ %0> 2 . ili'O n tn jxdl V l./XS l(A ·. k'.tl.’<mtf lk'

Prepared ax m Examine 21 5o (Method A) from ? (6 o drex'- bev I» xj)⁽· .!-.(?> v’h-e.nhde 11 sa uplc 2.9Α.» m *^!'’<-· u .</ XIS 23b ^MH i

Example 24(>c: 2-to-hydiO.xyhoyloxy)-o-mtrobenzomtrtle hep ned (a in Exam >h. 21 % t'_uxn j.xattc I n die'. atM 2.o dinm 4 i./zemtule n;

vs¹ < xicld as a pne ) Jf \x ail .1 M^v .'(<? (MH )

Example 24 H 5-(4-amin0-2.2~di0xide-lH--htn£0|tHl.2..6hhiadiazm~5~xlo\Mpentyl sttilamate

Prepared as in Example 215 from 5“(2-eyaup83-(8ult¥m9ylgm:m0.}-ph8n<>'xy)p®W^ snllainare (Example 2- M tn 44% . ic d H NMR (400 MHc DMN( ( %) <>. (»' pit. 2Hi 33 (m, 2H). i .47 (m. 2H). 3,66 (i, J - 6.6 Hz, 2H), 3.79 (t J o.n I Iz, 2H i. 6.22 (<k J · 8,0 Hz. 1 H5, 6 ^s~ (J. J SOHc. Ή). 7(0 (x.2H). (Hp.J JI) ^43% Jl·. 95 a. Jlk 10.5 f', 'll· MS /79 tMH )

Example 241a: 5 >(2^ah9«3<su1fafiioy1 amino )phenoxy)penly 1 sidf&naie

Prepared as in Example 215a from 2-amift0-6(5“(iert<

h«m Idimeths Nils k>xy)pcm bxy)berizomtn1e (Exainplc 241 b) atKi/suifamoyl eMoride in 26·.%· yield Mx39(MH ).

Example 241 b: 2-aminu-6-(5-(tert-buryldimcthyhilyl0xy)penn^,loxy)bcnz0nitrife' Prepared as iti Example 215b (Method .4) (rem 2-(5-4rcrs:--hLityidimci:hyl•^i.lyloxy)p^ntyloKy>6i-mtr0l5et>2iOiiitrile (Example 241c) m 93%> yiekl. MS 335 (MW),

Exa^Ig_2^^y2-(5~(tert~butyIditpethyfeilyl0xy)peirtyloxy)-6-tiitreben:zo»ifrile

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Prepared as in I sample 2l5e lbw s-(rert'baiyld'nie*b\l-^'ly a»xy ipei4a(i-l -ol arc

2j'-dHshrebcn/eniiS de as a pare reliev·, xelid in 3©.. \ j JJ. MS tn 4 {MH )

Example 242: 5-(4-ii«uno-2,2-dmide- 11i-beazo|e| I 1,2.6|diiadia/m-5-s laxy (penfan-1 '-ol

664

Prepared a- in Example 2¾ from 2-su'damo\ laimno-o-(5-hy dn-xypciiH'resy ilvn/eioube {Example 242a;· m 5.2% y relc *H AMR {200 MIL DMSO-uM <> I .'A.

I 49 fin. Ml). I ““-I -84 {in 2H), 3 31- 0 44 {?m 2Hi. 4.N (i J >- 4 11/. 2H). 4.« {in. IH). (».59 (d J Soil- lHl.(>.~4{d. J b'.OH;. HD.~44(U 8J)Ha Hl). ~ Μ (χ. Hli. ©34 (x. Hit 10.93(/ Hi). MS 300 (MH ).

Example 242a: 2-xiPfam<;yk<mns>-©/S-hMrexy pc'U©Ιον» Ifer/omnia.

Prepared as in Example 21 $a from 2a.mii«j-6-(5-(ivi't· nmy idmuthyAdy. ίοχχ )p-aiy I, \y iber.A»miMe (I xamp e 24¾) and .-ullaateyehl<» idem -% yield. MS390 (:MH ).

Example 243: l-(4-amino~2J-dsuxHle-iH-he?izo|rn h2.6hhfadiaziii-5-yktxy)-2'.2\4'frimsihy Ipe sdass-3 ’-nl

66S ^0H

Prepared as in Example 215 from. 1 -(2-eyauo-3.-(sult¥moyUm.mo)-pheuoxy)2.2.4-tnnredn lpcmuu-3 y I aec/ire (I sample 243al 'u '· y rek as w lore send H AMR (400 MHz, 0MS<M) 0 0.76-0.78 (d, 3H), 0.93 (/ 6H), 1.05 (s, 3H), 1.86-1.89 (m, IH), 3.18-3 J 9 (d, 1H). 3.73-3.75 (d, H< 3.99-4.02 (d, 1H), 4.98-4,99 (d, i H.), 6.57-6.59 (d, J - 8 Hz, 1 H)_? 6A0-6 “2 (d, J - 8 Hz jH), 7,43 (t,:J - 8 Hz, IH), 8.‘J> (s, IH), 8.43 (s, IH), 10.88 (/ 1H). MS 34.' (MH i.

Example 243a: b-^-cyuno-B-wulfamoylarmnolphonoxy· i ? - irimethylpentan-B-yl

Hgeiare

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Prepared as nt I sample 215a tr>-m I -(l-a>mn0-2-cya>t<»phen>-xy )-2.2,4on '.et η lp> m m-3-y 1 ax.rated xan.pse 243 υ and .-aHam-'sl eM-mra. m Ή'%yredd MS 38-5 (MH s

I sample 243^ ; -(>-anmre>-2--ey ;mophci:>-'sy )-2.2,4-8 nnethx ipenunt-.'-y = .-.retatc Prepared as η) I sample 215b yMctb-d M f.v.n '. (.' cxj»'x>-3-mi.«'phc)'.‘-X'V· 2.2.4“mnieihylncntan-3-yl acetate (Example243c) -a 83%yield. MS 365 t\IH )

V sample 2-3e~ i t2·e-are--3-att.Μ .no'd 1,2 4 t< m.,b_?'.-rei tan 3 x'. rectal Prepared a.- in Example 23k from 2-{3-Ityre<»\y -2.2,4-0 mrelky ipcntyh-sy j-6ratrebcare-mtide (Example 24-d) and .rectyl chkatdc tn 5Ο'\> y reM. M'· 335 (MH I.

Example 2a3d 24?<-bxdrexx 2,2.4-tumetbxΙροχχ loxx)*>·.m <re>em>.>.nt) lc Pre-pat cd as m Example 215c lre-n 2.2.4-utmctky Ipvr'.ar.e 13 do-I area 2.6dmttiolretreunmne tn *’0% - redd MS 2.93 I MH }

Example 244: 5~t4~iraetby lildollratoxyM I l-benzefeH 1.2,6|(hiadiazht-4-amiBe-2,2-dioxide

MH- CL

- 'gm

Prepared as in Example 215 from .?-$t':iramoylamino>6-(4i net ax lint 'ht >reilc zen net'xampk' !h) i '^iJ < 15 H NMR ( {’{’XP IA*xC-(/»d I o3-l 6 (tn,.HP) I 8<'>-l '^SP (m, 5jΠ 2 02(- 3||) 2 48-2 .'3 t(m 21Π, I !<>(' 21Π. t< ?/»n 60 (d. J 8 4 Hz. ΓΗΕ 6/2-0 “di dM 8,a Hz.HH. 7.4 ML I IH}. ~ M re. Hl} .νίχΜΙΓ). 1002 (w IH} MS 3H- (MH k

E wimp t 2 >la 2-su lan «>' an !-<'». div InMt'cb x-Μχη oretftl.

Prepared as in Example 215a from 2-ami.n;0-6-(4-(methyItliio}~butaxy)benzonitrile (Example 244b) and sulfamoyl cblc-ridc in 663« yield. MS 316 (MH ).

I rempse 2-re-) 2-cmrc-re-( l-um'dre dm-ι rm-v, i xmzomreL'

Prepared as in ('sample 2 L'b (Method M Horn 2-(4-(-n.nhy khiolbut-,sy}~6~ nUrobcnzonhrik,' (Example 2-1-5% i_n w., -, Md MS 21“ (MlI t

Example244e 2-t4-tmc*byld«»-»hun'xyl-b-mlrolrenj'i-mlrde

Prepared a-- m Example 215c from 4-(metliylthio)baraft-i-ol and 2,6dmmolreu/omuiic in x9-₍.yidJ, \(x dn {MH 5.

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Example 245: 5-t4-i raeibyIsulfl»yOb»les3)-1 H-be«?.e{e]|1 x2fo]ihiadkuiaM-amm£'2,2dfoxidc

687 O

Γ<» a sobuien = 4 5-*,4-{inedty libtoibamxy :-1 Η4··οη/==^Π 1.2 ,i'khiadf:i/ni-4-;tti'.ine-

2,2-diexi<.k' {Exm=iple 244: = % n:g, 0.25 nimel) = n D¹' 'Μ t'lld Ο.Ή (290.20=140 was added Ml PUA {1.0 όψη» : al loon: lewpcraUife The rcaedon 0=:-.1=::e was uku skned at soon: leinperaiiirc «uendgbi. 1 he sel-enl wrw es?.p>.'=ate=d unde:· = cdih.ed pr=>sure. and the residue was p=i<:9ed l·'» c=Mice:apliy ett sshea erl el-inng ά.ρ. : %= MeOH j: d’chk η-ίκί Ltue *. ge.c ι=κ = :f:e e=m:p<.:rid :% _n.g %'..).- a e hie s.-hc ΊI AMR {COO MH \ HMS(A_fA) <> 1 74-1 _itu 2Π). 1 XS-1.95 on. 2H), 2.50 is. 3H), 2.68-2.73 :m. HI I, 2.77-2.8301:0 Hl. 400 {·, 2H). 6.58(-.AO (d, .1 8.4 Hz, I Hl. 6.73-6.75 (d< J - 8.0 Hz. IΗ I, 7.44 (t, J - 8.0 Hz, IH), 7.79 is, IH), 8.33 :s. i Hk =O,<»2 (s, Uil. MS 332 {MH :

Exampfe 246: 5-(4-1 me{byi§uIfonyI)butay)-lH-benzniej[l,2,6|ihiadfezik~4~smimw23~ dioxide

NHj Οχ/Α/Χβ/

......¾

X^z

668 ° °

Prepared k$: in Example 245 from 5-(4-(methylthio)butoxy)-lHnen0>,e|j 2 t-’lnt.1::,-/0-- i-an' r 2-m =^:6.0 (1 xatrpl 2 Π»'w tbe ’e.u i=n wit' - ecu xa’eni oi Mi i'B 1 .- e -a ''tie m-I <. .11 8<” ’ > -,.. d H AMk : :0:: Mi L DM80- /3 .- , 80- { _{< »_t,n 210 i 91-1.95 01-,211).2.93(^,30).30 8(0 214). 4.18 (t, 2H), 6.58-6.60 (d, 1 -8 4 Hz, Hl)j '3=-.‘A<>1 .1 8.0 H/ = Hk 44 3 .1 s 0 Hr. : Hi, 7 % (s. i H}, 8 3 i =x. Hi}, 10«’ _{x Hl) MS

3l-x = MH'j,

Example 247: 5-(3-(Bierhy hhiQlpr^rsxyy-IH-tM'aziileip^Jilt.hiadiazm-d-armae-SiS-dioxMie

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NH₂ 0+^xx^S^ ¢09

Prepared as in Example 215 from ^«snl'&moylamino-^fSr.uere. hni.qpb poxy ibcr.;'>>nn*iic {1 xarnp 2 1 \u tn fed ’HMiRt 100 MH? I'M^t '-.M a' 2Ό5 m 3H1. 2.0.\ tm. 2Ht 2 % (t. J - ”.2 Hz ?H). 4 21 (·, J -- ο -I Hz ?H). 6.3‘U·. <M id .1 3.0 Hz, HD. 6 Vt'./x (d. J == 3.x HzJH}, '’.·?? (t, J == 3 0 Hz. HD. 7 % is. IH). x.33 0= IH).

is. HD MS ,m..^! (ΜΗ V

l.:2i<mipk...2.+..A' ?-snil.imt>y lammo-t'-t?-· medtyhht.' tptopoxy )benz>m drib. 1’iep.m.d aa io bX.imple .215a from 2-arntno-6-i .klmetbylihioiprope-xyibenzonilrsk' Uixample ,?4’h! and cht-.khIc in ίΌ⁴'., x jcbl MS hi.? {MH }

12x;hhj2k..247b;. 2-umine-6-(3-(m<thyhhio)pr0|X.>xy)benzonitrile

Prepared as m Example 2 > ?b (.Method A? from 2-i3-{ o.nh+tbx ),xopo' x )-bnitrobenzoniirile (Example .247e) in 98'?·, yield. .MS 22?· (MH').

Hamp <. ?-(2-tm mxl ne'p opoxx)-'> m tube v. m t’

Prepared as in .Example ’’ I ><· Item 4“(inx0hylthic>)byia»-I -i>l and 2_S6dmikobenzonitrile;..in 89% yield. MS 2.\3 (MH '

E xatnpie 248: 5-(34 met by k?H8myl)pri^oxy)~ IHHwnroleU 1,2,6) rbhulmrin~4~amure~2.2~ dwxide

078

Pie·sated as in Example 248 from 5-(3-(methyl· biolpropoxy)-i Hbcn.zoic][l ,2,e]t.hiadtazb--4~am.me-2.2-d?o.xide (Example 24) by the rcaetion with L0 equivalent of MCPBA as a white solid in <H>%y kid ^SH NMR (400 MHz, DMSO-JD 42,18-2.22 (m_s 2¾ 2 54(.s.?lh. 2 75-2.~xpo. Hh 2.89 2‘iMju. .H).-20t; I <UH/, 2Ht. b o0-o M id. J .4 Hz, IHh 6.73-6.75 (d, J - 8.0 Ηζ,ΙΗ), 7.44 (H J^:::: 8.0 Ife, IH), 7.83 (>, 1H), 8.30 (>, 1H), 10.92 (A IH). MS318(MH^;).

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Example 249; 5-(3-uaeihy KulfonyDpropoxy }-!H-beozo|e] [ 1 x2,6|lbiadiaziii-4-amiac-2.2dioxido

S71

Prepared as in Example 245 from 543-(methyithio)propoxy)· I Hben ’<4e]| 1 J.nphsadHirm 4 amrae 2.2-dioxtue (r vtirple 2-t~) re (be > w.on w m> 3 π e ju.xj.enf <4 MCl'B \ ra 8 % _? .ck; ,κ a uhih .oI d Ίΐ NMR (%0 MHz DMSO 4 * > 2- 2 V on, 2Hk 3.00 <s. 3H k 3.26 (k 1 ~.n Hz. 2H x 4 24 0. J 6.4 Hz. 2Hk 6.60-6.62 id. J 8.0 Hz. I H i.

t. ~2-<\74 {d. J 45 0. J 8.OHz. ΗΠ.7 9 (-. IHkr 31 U IHk 19,9-.(.., iH),

MS 334 i MH ).

Example 25(h 5M2~i 2-ethoxy ethoxy)eihoxy k11 l-benzolc}| 1,2<bHhiadiazin-4-atnis}e-2,2dioxide

672

Prepared in uxasuple 215 from .?.-sr:lfamoylammo-6-(2-(2c.h'xMl'ox'.8 t-oxx)lvrz>mru e d xatrpl 2^0,5} m ^s ’ exielj H NMR (<30 MHz 3VS(m/,i 4 i.06 (r I 7.7 Hz M0 3 V-3 13 < n ^,{b ? 17 ft 2H). 3.5s (r. 2H) 3 8i ({.210. 4 2« Ο 2H), 6.0(1-6 «2 (J. 1 8 0 Hz J ny. (3/-6 % Hl J 8 0 Hz. Hl}. ~ 45 (t, J 84 Hz. Π I). 7.99 Π Ik 832 (a IH), ).(),97 6k 330:(MH'^;).

£ 'amp t 2^ς(Η 2-su l.m <>' Hr 555/-^-(2^2-4^6^6.0 jv Ohe'x '>’a nzorir k

Prepared as in Example 215a from 2-amrao-<S-(2-(2i ibexretl 6\' »J\xxx V.x'5'Z'rutssk· (1 xamp\ 2 kkx) and sahansex 1 v<. ossee if’ re?^! ₍, \ u J M\ 3 >0 (MH'k

Example 250b; 2-amiito“6-(2-(2-ethoxvoihoxy}etl50xy;beriZonitrde

Prepared as .1« .Exampk' 21 So (Meth/d A.) ftptti 2-(2~(2~eihQxyethoxy)eihoxy)-6~ nitrobenzonitnlc (Example 250e»in 48% xieid MS 251 (MH'k

6

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Example 250e; 2«(2-t 2-ethoxy cfnoxvlethoxy)-o-nurobenzonmi le

Prepared as m ExampL 2l5w uoni 2->,2-v.dm\\e'h.'xy )>-'than,4 and 2,edinibobcnzeuinile in a6^,!i. xiekl. Ms 2x { UH ).

Example 251: 5-(3-mvtIiyk-ydopealyless ?-lH-l>enzo|€H I Jk6)ilHadiadn-4~amine-22l· dioxide

NH₂ Os

673

Prepared as in Example 215 from 2-suU'mnoylamino-6-i3njethykweh-penisloxylhcn 'emuHe il'.xampk· 251«; tn 45% v-cki. ^:H NMR (400 MHz. DMSO<UH>0.97H .04i m. 3Hk I 2.x-I .Him. >H), I/%' 63 un. 4H). 2.31-2¾ (m, I Hl. 4 95 M12 i m, IH), 6.86-6.5* id. i ~.ί» H/.l HU n («''aaO ί,!. J x.4Hz. I H ).7.42 s t. I x.4Hz. IH),<->97.72 (rm iH). X 30-i- .% (m. IH) 16.92 (x, Hb. MS 2m>(MH s.

I:\ample25 a 2 '-mfam<\'- k;nmb--(<-f.3-mcrhy leydopcmyloxx )i.>cnc<mimk .Prepared itvExa.mpte 2.15a .from 2-amna-6--(3ϋ.οΰιΗ.ν\ο1υ:Χη(Ηχ·:νΜ6οη.·>ΊΜιθν (Exampk 2Mh) and sulkmox 1 cbloi.dcj'i 52⁰yκId MS 2% (.MH ).

Example 251b: 2--amiuo--6--(3-m£thyieydopeuty loxy)benzomtrite:

Pfepared as tn Example 215b (Method V 1-=/0 2-t3-mctbylc>dopcmy ksxy )--6nitrobeezonitrile (Example .25 = c) in 98%yieid. MS 217 (MH ).

Example 251 c: 2--(3-methyfcyreIppenwloxy)-6»aitrobenzoaitrjle:

Prepared as.in Example 2150 from S-nKtby k'yek'jx'nuaol <md 2,6dindrobenzenifrilc m 7()% yield. MS 2.47 (MH ).

Example 252: l~El~(4--amin0“2.2--dmxide~n-i~beirxo(cni,2,6|tIiiadia.aO-yIoxy)-2^,s2'~ dimethyiprepyl^S’^’Aoiefhe-vybga^iiHrea

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674

Prepared asm Example215 from I (3 (o .'Ulh.noy'.am.no 2 ey.nb ρ«ίκ-η·»χχ) 2.2 dimHhytpmp\li-3-(4-mvtbox\bcnzy ipn-.a (Example 252a} m 77% ytdd :w a xxhire solid. ‘H NMR Mint MHz. I >MS< > d 0,92 %. nib. < <% id. I υ.4 Hz. 2lb. 3 32 (s. 21b. 3 <<' _!?< jb. 4.t)t'(d. .1 n 0 lb, 2ΗΠ, 6 29 t ·, J 8,0 Ho. 2H|. p.v i(J J x 0 ILx IH). n i {J. J 8.0 Hz. IH),bJ4<d,.l 8..x ib.2HL 7 0t._ul..l 5 x lb. 2ib. ~.4a p. J x G Hz. iH). NC b. iH}. S.34 (a IH), 10,90 (s,. IH). MS 482 (MH’).

Example 252a: 1 i3t 3M.d?';;moy hunt;io-2-cy:nmplh.moxy)·2.2·4ιη}·>·ΠηΙρΓ<?ο>1) 3 (4· meth- >xy htnzyl)urea

Pts. raree ₍i'< tr ΐ xar.plc Ni'b n ('* t' <nr η > ''-ά anepbe wxs 1 tlin-edw tptepyl >-3-<4 - methoxy nenzy l.ntrea < Example 25?h) and xull.imoy I '..bieHde in ;0k^l\> sreld MS4n.y (MH ).

'Example 252b. l-(3ri3’ajnin02Cyanephepoxy)-2,2”dimethylprapy|)»3--(4methoxy’benzyl )urca

I'tepared ia Example 215b (Method B) from I •(S-bydttwy dimoihs Ipiopyl :~3~pl-moths·κ\benzyl mre;.i {Example 252c) and 2*amino-6’dr:e?oocnz>>nil'iie irnd% yieU MS 383 (MH ;

Example I-t 3-hy ·8 <y-2_s2''diineih.ylprepyl)~3~(4~:methoxybenzyi)urea Prepared as in Example 22d fn»m S-am-rsm? 2-dimeihyl.propati-3-el and 4-nWthoxybenzyl isocyanate in ωθ% y sol I Mo 26 (MH =

Exanjpk- 253: 5“(prop~bynyf)“HLbenzt>h.‘|| 1,2,6|ihi3fljazi.B4-^ti»i»V”2^2~di<>xide

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Ihcpaiedax ml sample 215 Irom 2-^<Jfani<pldmii,<'-<_>.(3-(lrnnc*h\^'b'.mf>)p-.\n\ l}K'ii,'eumiic (Exampk· 25 bo m Itb’x x ;dd ^!li NMR {-WO MH/. PMSCW. )<» I 25 (-> 2H), 2 Io (w ?H j. /-{J. J 8 4 11/ 111).-,21-7.23(0.1 ~ S Ik. Hh 7 45 (r, J %li; III) MS 236 (Mil >· bvtmpk 25?a 2--mf.m(<reLmiim· t'-te^u-inetlty kilslh' <w I rendiixm/onm le \ MkrnouM 2-mum »> (3 (turK-thyIrely llprop I y twbhejtzoi'itj le 11 x.miplo 2?3bi (55⁷ i'sg. 2 Π mm-'H and\H ά* MhitNf'g. ρ» πη <>Π ro Ore 1,4 jrex-tn. roti uu t rots reduxed unde< :nlrog<m for 2 days. fbc Mroii xros m aporatcd mate? redac.-d pw’xsUi-e. and the icssdtu· wax nnreficd Ip ciuomatography >-u niM gd ekniuc '.x nit 7p% ER sac m hexanes io go e rhe title comp» mnd (51 n-g 5‘Ά ,-. white '-> hd MS 398 t MH '»

V x.tmpk· 2531> 2 .rennu· (<-«3 {(innethyMhbp-<’?! vnylmeuzu.nOilc Io uxime-J solution of I? hncihyii prop· 2-ynyi Isilane (1.12 g. 10 mmol), d-amino o- lm inobcnzonitnk' (Kiauben. Η. Il ; Solkiodi, 2 He. idiamoxxo. C J , Cjpo(--la. R. 1 : Bell. S 0 ./ (

1981,.24. ⁷·4?μΊ 9 g, 5 mnroh.Cul <Od'· eqno 1 in liiethylimme (%» ml ) ά ax .Joed Ι\1(ΙΨί·,). (0 I equiv.) at room, temperature under nitrogen. The reaction mixture was then refluxed under n-trogen overnighi. The ro-hud wax ·..'«.apotaied. and rhe '..<idne wax nn.aed wnn I 'MAe v.alei The organic layer was sepat ated. u -. :e washed with brine, and dried over Na <$C h- 5ftei exapvbthon *('toe χοΚοή, the r.-^'dae vro..' perhed by eravUKUOgiap ty on xibca gel elming n (th

Mo Jxe *be re le torr >oimd { M ax s >re a ¹ quid MS ‘M iMH).

Example 254:5~((2-methyIcyelupropyi)methGxy>1 H-benz»[e| |1,2,6 jthmdiazin-4-amm e-2,2dtoxide

NH-> Ο._χ

Δ,_ S76 V.

Ticpaud a.’ ir s xacmlc 111 from 2-mnino-0-{{2meioHMeh-props. Bmei ro a ibcu/etmn e mlkan.de (ex ar Me 2''4M m no % χ idd pmxtarc ol di.retereeixomei.j.'Hl \MR (400 MHz, DM\«' d >M) I--().40 (m, I Hi, 0.54-0,58 (m. i H). 0.76WO 2068/154221 .PCT/DS26W0OH8

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8?<βϊ, l Π), 0 99-1J 2 (m. 4IP>, 3.9(--4 53 (m. 2H), o.^x-e M mi. HI), n.c%o ~7 i in. Hlk 41“ 4? tin. Oik “ 9“ (s. NK). 8 38 re. NH). il>97 %. Nih. MS 2x2 (MH ).

Fxainpk 2'4a 2-aH!%o-o-{{2-nvlky kseh'pb'pylhrcdb-v·.: >ciiA>3ii'fk' -MK.rihk' Prepared as in example 90a (rem 2-ammo-6-((2methyk'yeloprepybniethoxyIbenzonitnle {Example 254b) in 100% yield. Ή NMR.(400 MHz. HMM %J, s 30 34-6.36 (re, IH i. 0.51-9.53 (re. (Hk 0.77-O.9 (m. IH). 0.95-9,9“ _tin, IHk I 041.09 (m. 3 Hl 3.92-4.93 (m. 2H). 6.86-6.88 /bin. 1H). 'Ή S/lMbm. 31% 7 48-7 52 (bin. 1 1% 9.53 (bs.NHk MS 2x2 (MH ).

bvtinpk 25% y..-nicrhy lexHoprepy 1 imcrhoxx)ben?·-mb J:,· .-oli-tien <d 2 o.2 mctlp level -po-p' l)ineth. v i 7» iw.sX'aj- unde (cxa.nple

254m i(:.29 g. | ,2^A imnol) in EK?Ae MOH I I f39 ml > was l-xd:(»gen;i-cd in an H-cubc appaemre using 10% Pd C as un/y -4 I be s.-dutma was e\ ap-jated io give 2·;.ιιηιηο·η·(ί2· meihylmelopropybn'Mhov sbenz· mil rile (0 2kg 79%} as n yellow oil M$ ?0^?· (MH }.

Exrnnpk 254e: 2-((2-meiby leyJopropy bmeiboYy )-n-oitn-benzonitrile

Prepared as in Example 1--9 from i .'j-mefhylcy ei<>pi>>py I i-neihanol .md 2 -dudnsnvri.'oniniie in xlAyield Mx.'33iMH ;

E-ompte 255: N54^feutyl--lH--beHzo(c||1^6)thiMia^nM!-^<^®»in^^*4ioxW

Prepared as in Fsample-1.11. fTom2~aniino~6-lisoburyhimmx>)bei'7-snittik' sulfamide (I xarnpk 75.%) in 23 %yiekUH NMR MOO MH/ HMSO-dk '< 9 9-. _u , j _r χ -Η) I 88-1 -%(%, Hl) 2 84 0 .1 o 8 IL· 2111.8 87(}.) 6 I H/. \ll'>. 6 8} i.Hj Οχ H/ j s fl IL·. HH.-%Hc s 8 0 Η/. ΠΒ. 7 2o<f, J 5 , U '. Hl) “88(%. Mh'>, ΙΟ Ο (χ \H) MS 269 (MH ).

2-ammo-6-(}sobntylammo)bcnzonitrile sulfamidc

Prepared as in,Example 9(la fn>m.2-am.ino~6--(isobutylamino)he'^,i 'eii\ii e

i.Px unpk 2 >8b) ..-.-0- -jm-J )-. ;ΐ% -χχΐ sj.-p v phoui .ere isml ci rmsfiexir’oa MS 2-° .'MH )

Example 2%b~ J-amimfe-ffebno. ksniiiiojbenzonitrile

3=40

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Prepared as iu P sample ')=db bon: 2-t =.ν?ί uUltininAMtMKi). er J>'lc t1 sample 2 '5 H: re'*·. ) told. MS I9=i (MH I

F.xampls 2~'5e. 2-t tsebuu lammM-tMmr-.ds'monPrib.'

Prepared a- m Example 99c uom ^.u-dmittobem >mmik' ,m.l metbskmurc m 92’_t, Wlsl, MS 220 (MH ).

Example 256: 5-({i-methx Icvcbjpropsbmeifeoxs »-l II-ben/o|eH 1.2,0IthiadiazhiM-amiav-2,2dfemde

Prepared as in Example 111 fj->m 2'amin<vb-u lm>..nh5k'\_l.'k'>:>tx>p}br_:-u.'0u-iX})bei-/'>nHttk. mllam-ried sample .,'5<>a). m .% side. ^;H NMR t496 MHz, DMSO-dj-(844-0 4ή (m 2H). 9.59-6 (m, ?Hk 1.2 (s --Hk 5.9b is 2Hp ¢..% (d

J == M Hz. IHk 6.66 (d, J == 8.0 Hz, 1H), 7.-13(9.1 === 8.0Hz, IHk 7.83 (bs/NH). 8 40(% NH=, <’ k t% NHk MS 2<x2 (MH ).

Example 256a: 2-a»iino-6-((l-methylcyciopropyDmeth0xy)beaze«itrile salfamide Prepared as in example 90._{from_:2-amme-6-((l = methyk'yclopix>pxbmethoxy)benzoniniie (Example 256b) in 100% yield.. ^lH NMR (400 MHz, DMSO-dj -.10 90-0 '· 1 (m. Ί H <d >3-6 ό (re. .?Hk i .20 _t$, 3H)_; 3.89 m. 2H), r> % (d. J 5 o Hz. (lib 7.1 ,-..27 tbs NHu ’ ’0' .1 MHI/ llir.5l((J = }!lHAlin')45(N Mh MS 282 (MH k

I cimpte ¹ '61):. 2-=iminc-(=~t,t, I -merh} leyskxprepyDmerboxylbenzonitrik··

Prepared as in Example 254b from 2-n l-metbyleydoprop} Omerhoxy l-omtrobenze-mtriie (Example ?Ν6/) In 88., yicM .a a sekow oil. M.S 203 (MH ).

I'ampk 2be 2-(t,Lmeibxle'<k>pt<>px Rnelbexx )-9-= aitebcu i>=Ntde

Prepared as in Example I M>d from, fl -meihylcyclopwpyl )methanol. and2,6diniuobcnzoniiTiie in 65% vield Ή NMR (460 MHz, DMSO-d.··.) 6 0.44-0.46 {ir. 2H i, 0.57-0.59 (m<2H), L22 (a, 3H). 4.0n (s 2H). 7.67 (ddj === 1.6 Hz, 1== 8.0 Hz, IH). 7.85-7.92 (m₅ 2H).

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Example 257: 1 -(2-(4-a«dno-1 H-be«zo|eH 1.2,6| thiadiazin-5-yloxy)ethyl)pyrrolidiH-2-oae-

2,2-die Ode

^5>repui-:d ax in Example111 from 2 ianmo-b-i 2-( 2-oxopx rrohdm-1 yb-.ih6\;lbca^A -n=ttfie xnlbnmdc H-wmspL' 25a > -n 45 < Jd Ή AMR (-00 MHz. I AISD.

dMol.94<q, .1 ~ 2 Hz, 2H). 2.28(-.4 7/> Hz. 2H L 3 -U % J 1 Hz, 2H), 3.nx tl. J -= 4.4 Hz. 2H). 4.23 {t, .1 4.4 Hz, 2H1. <-.59 id. I 7.6 Hz, IHk /-.70 (d. J x 8 Hz. IH), 7.43 (t, .1 === e.4 Hz, I HR 7.82 ibw AH), 8.2 = (hs. Mb. 10.98 (/=, AH). MS 325 (MH ),

Example 257a; 2-ummo-6-)24 2-oxopyrmhdin -l--s l)eih<»xy IbenZ'-nmile sulfamide Prepared a> in s/xani-d-e 90;.t -rem 2·3ηηη·<-/-(2·(2·οχορ> rroUdm-ly h-.'ihox\)bcnz--j’:=tnk' {Exampk' 257b) in 0)0’9. yield. Ή AMR (400 MHz, ΓλΜ>·< l-d.>5 1.9’4 (q. I 8 ί Hz. ..'Hi ? ...I H J Μ* H.' ?Hk 5 W 3 >5 )m. 4H), 4 ?i {), J I 8 Hz, 2H> 0,94 ib\,

1H). HHd, .1 ~.6 Hz, Hl). ” 24(/=, All·), 7 54 <?. J 2 Hz, IH) )49₍/_k AH). MS 326 (MH ).

I simps' ,> ' ο 'nee o ^{f f} x- p' <>bdm - ret»%' )bc ' \'nr»f<

Prepared ax m / ample 254b fh>m 7 nmo o s''-. <v mcwlidin yi)ethd'<MbdnzonitriIe-..'(Example 257<) using tri'fluoro/hjfOl hexa fluoroisopropanol (1:1) as solvent m {’{’Ms > ’c MS ’hx'MH 1.

Example lore l-rihny-h-t2~(.l-oxopyrrohdm-1-yi}cthoxy)benzi>nitrile

Prepared as_:) n Exon o'·.- ) t -<xi n - an I -(2~l\yd.roxyethyl)pyrrs31i<1t'n-2~one and 2,6Ornrrobe ά nr π > . 'I M reek) Mx'OHMR )

Example 25S: \5~<'3~me/hexypropyl)-1H-henzn|e||l,2,6ithmdiazim'-4,5~diamim'~2.2-iliaxide

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2017200704 02 Feb 2017 ^Pfep«cd ii= Exampl,-«9 Own' 2 an'. :<= 6 13 mctbexy pi> py Um iv)l uvomune sulhnmdc : Example 258a) ns 69 % \ idd. Ή AMR (400 MHz. DMSO-./.·.} 3 1,7-x I >5 un. 2H}, .>.%<>..]. 9 <·?. Hz ./ =^11,211)31.^511) 3.4..' {{ ..,/- 6.0 Ha 2115 9-Hk 7 Mill; AH} ¢-26(6 ./ 8.4 Ha IH) 6 34 id J ' f 9 Η/, Hl). 7.23 (r ./ - 8.9 Ha HI) 7 xx (x AH > 10.6-Hs.AH} MS 28? (MH >

l.vd'DP.k' 2.2%. .?am:=-«>-‘>-<3-mcih= Xy piopylummo)lx'nA>mirile suit,,mice

Prepared ax ir= Example 90a from ..-mninn-auMmerboxxpropy )annno'>bi.mzonitrite in 65% yield ΪΙ NMR (400 MHz, DMSO->%) 9 1.74-1.7-; p_u, 21H 3 H u:. > u x Hz ./ = 7.2 Ha ,H> ^j. . )O,MHM 3«H / 6 2 Ha..Ή k 5 96 (),./-86 Hz AH), <> ' (c./-x.8h.\ IH), 6.79(4,./-8 0Hz_: IH:, 7.09 (s_r Alb). 7.31 (t../-xOHa IH) « 6« u, AH} MS 285 (MH).

s,:mp=e 2%π 2-:;·υίηί'-ο~(3~ηΗ<6οχ\ρΓ»>ρχ kmiinotPenzonbrile

To a sotatiodbf 2^(3.«.meihoxypropyiamino)-6-nitrobenzonitr9e (Example 258cJ (9 38 8 2 IS mm··:) in : ιΟΗ (20 reί?: άas added uHM-ex·. rse (1,26 ml 12.1 mnmi} fhen IO‘_;, Pd=C (I 32 g) was added, and the reaction mixture was refluxed at 100%.' for 20 m inntex. cooled :<> ioor' =emp,'raii=re, fiA-red n\>uyn Ce :le w mel' v,.a u M'e·I w ill' I lOH (1-= % i'll ), and evaporatedto give 2~am.ino-643-:n£thoxyprs7pylan?ino)feeni:.onstri'le (0.43 g, 84 %) as a colorless oil. ^!H NMR < 400 MH?, DMSO-%: 3 1.71-1.77 (m, 2H), 3 JO (q„ J - 6 8 Ha J - 6.8 Hz, 2H), 3.22 (s, UH, 3. Vp.,./ 3 2 Hz 2H ),5 55(1.7 ' 2 Ha Al I), -.o3 D. Ml-i, 5.% (d J “<> IL·. HR. 5 93 pl../ x.dll/. Uh ¢- 98 p. / 8 0 Ha Uh. MS 2(kuMH :

Ε5.ίΕ11Ρ.Ι:-:..2ΐ.8.<'.:' 2-( l-mUboxy ρΓορνΗππηο)-6-ΓυίτοΙκ:η'Ζ0πιΙκ.Ηο

Ihejxucd a* m Example 9ik uom 2,<--dii:ifeobenzonitril_:e and 3methoxyTro}.\s=ambR' in 83 '^!-u:e=d ΊΙ NMR(400 MHz. HMSO-m.) <1 1.76-1.81 (rn.2H), 3.23 (s. 31 11 7 2%3M(m, 211) ./ H.. MU. n D-p../ -I X Hz. Ml). 7 % (d ./ x x' 11/.

IH). 7 42 (0.,/=== 8.0 Hz. IH). 7.60(1,./=== 8.0 Hz. IH).

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Example 259: N5-elbyl-l M-beozoicj [1 x2,6ltbiadiazisie-4,5-diamine-2,2-dloxide

NHg ΝΗ..,,·^Ζ

6S1

Prepared as in Example 111 from 2“8mlno-<%etbylamino)bcnzonitrilc sulthmidc

UreremL 2S%; m S'A srJd ^:H \MR HnOΜΠζ, l)MSt%%3 I I8{t I hMI/.Mb 2>M2lll.5<(U 52 H\MM. 630%, J ” r Πζ. IH}. 6.38 (J. J %H;,lin M

J S.OH/, HI}, %·<. Mire, lO6.\{s.NH} MS2H (MH }

Γ xanspk' 25%: 2-anmm-m-(e*by laminolbenz-mitrik' xulla-nice

Prepared as in Example 90a from 2-.imino*Oae)h\ ΗηϋηιΊΙ^'ηζηηίίηΚ' «Γ sample.

2?9b) hi 47% yield. H 5M.R. MOO MH.'. DMSM-.4 ί 3 J 1-1 ft J 2 Hz HI), 3 I %?« 22 (m IH) -'M<K Ml). 6 is 01 J >'Mk 'H).b ”2 01 J SOH/. HI} 7 02 {% Mire. 7 M pj 8.0 Hz. HH.9,:4 ths, Ml). M< 241 <,MH ).

Example 2^% 2-.inifi;>-<-(ctb--lainmoJben, >ί j(< de

Prepared as in Example 254b from 2-(ethylamma}~6~niirobeHzoniiriL· f Γsample· 259c) using TrifitmrefetbnnolZHexafiuoroisopropimol (2: () as solvent, in 81% yield, Π NMR tlOo MIL·. HMSOMde i ja _iL j 7 2 Hz. dH 5 '6% 22 211} 5 11( Λ I 5.2 H ·. Ml).

%IO,XH? %2<d. I .mIIIMIIm^^I SOIL·. Hh. 7 00 ((. J ? t Hz, IH), MS. 162 (MH ).

Example 259e: 2-(eH;yian;mo)-6-uitrobenzonitrlle

Prenauu a- m ι sar ok 9t\ .ren 2 u % utioeen, <ⁱ m.:k m. .> 2M ei Me/iiue

Molmion in THF m 88 '8, yield. *H NMR (400 MHz, DMSQ-ίό) δ 1.13 (i. J - 7.6 Hz, 3H), 3,26-k33un.2H-.i>-ⁿ(m.J 5.2 H \ MH. “ 22 (d, J 9 2 Hz. IH}, 7.42 (J. J M) It .IHVGO (t,J 6 4 Hr. IH). MS b:>2 (Ml H

Example 260: 'N5<2-(beazx Io xy jeihyl'hl.I^beh^o^Hi^.^Hludai'aaifte-^Skfttiamin.^jZ’dioxide

Λι^ίΙ

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Prepared .is m example 6’0 iron; 2-and?R>-i'-{2t benzyloxy )cthylamino)bcnzoninde suifanudc (Example 2e0a) in 68 % yield, ’bl NMR (400MHz. ΓΑΙ^Μ) 4 '25(9% OIL·,. I (U 11/. 2lb3%« J 5 oil/ 2H), 4.49(.

2IH. 5.91 (k J === 52 Hz. Nil). 6.28 (d, J === 8.4 Hz. IH}. 6.40 id, J === 8.4 Hz. IH), 7.23 (I, J === X.O Hz. IH), 7.25-7 Eu. 5Hi. 7.90is. Nil·), lO.bx « Nl-b. MS 347 (MH ).

Example 2h0a. 2-amino-6'(2'(bcnzyioxy)c(hy4amino)benzombilc sulfumide

Prepared as in Example 90a from 2-amino~6-(2fben yl-.'xx )Oylam:WpK.'='=/-.mre% (I '.ample 2fO^:n m-5 < Ml NMR HOOMIL·. ^!.T>Cb) ' 3.% (q. J =- 5.2 Hz. J = 5.6 Hz, 2H). 3.57 (?., J === 5.6 Hz. 2H), 4.49 % 2H), 5.76 it. J === 5.6 Hr. Nib.

6.55 (d, J 8.4 Hz. IH). 6.72 id, J === 8.0 Hz, I HP 7.12 ix, NH,>). 7.25-7.32 im. 6H).9J2 is. Nib. MS 347 (MH ).

Example 200b. 2-.mnno-6-f2-(bcnzyi>'X'< refr=\ laminolbe= ι/moi; Jr

Prepared as m Example ^<J0b imm2-f2-U'C%yl>'.\y K'thx Lnmno'>-6mirobenzmildle(Example 260% in =()0% yield as .= brown mi ^!H NMR (4()03Hk, CDCl?) 3 32” (q. J OH.'.J 6,0 Hz. 2H). 3 « J 5 6 Ik. 21¾ 49 re, 21¾ 34 _G, ( 5 y Hz.

NH), 5.67 (s. Nil·), 5 x4 {dJ 8 0 Hz, 1H), 5.95 (d, J === 8.4Hz, 1H), 08 % J -= 8.2 Hz, IH), 7.30-7.34 (m. 51b, M-- 2t'8 (MH ),

Example ?60e· 2 (-(hen/xioxy)ethylatrnno pi'- mreebeez·.’nitrite

Prepare·' a'- tr I x m ale “Oe m i ' ri\i/\ rexx let pi = n s e n = '’.O u nd'v ’.c XMm '} e tr = % y t> d H NMR (I06MH > > «' »2 ' 6' =,=] I = ' H ' I '< =>

Hz, 2H), 3.59 (i, 7 - 5.6 Hz, 2H), 4.49 (s,_: 2H). 6.47 (f, J % 5.8 H% NHj, 7.23-7.31 (m, 6H), 7.43 (< J - 8.0 Hz, IH), 7.58 (I, J - 8.4 Hz, Hi).

Example 261:2~(4~amino-rH~b«nz(i(cHl,241iEhdhzia-5“yfemiu0)erimsoE24’di6xide

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NH:· NH.

ΌΗ

603

A s-.'km> >i: of N -t 2-ibcn/y lo.sy t-Mhy kttnino)-ί H-benzo[c]rL2,6]thjudiazitie-4.5diammewA-dtoxsdc t Example =%') tO.lO g. 0.29 uunob m I tOH t20 nl '· wax cluigvd x> t% 30 mg of l0%> Pd C and H· baboon and '-fined at room rcntpereunc for 24 hour/ fhe rcaetmn nuvuie wax bluned trough t clue w hich wax washed with HOB, the combined organic phases were e+q··-ta-cd. and me tcxsdue hj*- purdk-d + flash ehu mah-g-aphy u^i.ig a IX'M McOH 19:i) sokmon as eluant, re give 2-{d-j-nt?s<»-IH-betsz<jie}| ’•.Jddrhiadt^tfs-Syks-innoK'rhasKjl··?.?d.--sjdc{bdxr^,X7 ⁵HAMR{4OOMH_i.DM'Mjm _t>3 II (qj 5 6 IV. 2 2H).

3.58-3.59 (tn. 2H), 4.84 {bx, IH). 5.<84 (t. J ^::: 5.2 Hz. .NH), 6.26 {d. J ^::: 8.0 Hz, IH). 6.37 id, J ^::: 8.4 Hz. IH). 22 (t, J - 8.0 Hz, IH). 7.k6 (s. AH » 10.65 tbs, NH). MS 25? ·ΜΗ I.

Lvaniph· 263: 3-{{4-.4mhn>-11 bbtawoie) 11 x2,6|fimdiivln-5-x lov hnethx h-ApropyIpipeHdme-l-eadn.reamide-'2,2'dioxi<le

Prepared ax in. Example 111. irons 3~t('-atniao*2Tqy&nd^henoxy)fn©th'yl)~^ prbpylpipefidihe^.l'-Garboxiiinid. xelumide (Example 262a) in. 88 % yield. Έ NMR (400 MHz, DMSO-d_{.) <) 0.81 {L J =- 6.8 Hz. ? I h, 1.23-1.43 (m, 4H), 1.60-1.63 (bru. 1 Η), I -81 --1.84 (btn. IH), 1.99-2.05 (bm, IH), 2.67-2.75 (rn, IH), 2.80-2.85 (w, IH), 2.93-2.98 yu. 2H), 3.71 (bd. J 12.8. I Ht, 3.90 tbd. J == 10.8, I HL 3.98-4.08 yu. 2H). o.44 {d. 3 === 6.0 Hz. AH). 6.o2 (d. J = 8.0 Hz. Hb.6.o{d% 8.4Hz Hb.”46(t. I .L4H\lUL7 8f)ts,\Hl. 8 ^(.s.AHo O95ts. NH). MS 396 (MH ·.

Example 262a: 3-((3-amino-2-cyauophc.noxy)metliy b-N-propylpipendme-1 carboxamide sulfamide

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Prepared ax hi I sample Opa fr,m 3-(( fe.'umo-2-exawpheia·xy im/lnh-Apmp© ipqxndmc-l -sa:bwxami,k (iAampk- 2O2M re 100 *·. © 'eld ’ll AMR (400 MIL·. DMS^-d, s 3 0.81 ii.J 7 2 IL·, W l.M-l.44<m. 411). I η I -1 m 4 {lire. Hb I 85-1 87.0^,211),2^0-2 ~5 t m, 2H L 2 4are Οχ <_ϊη. 21 Ik .> 78 « M. J 12 c- Hz, 1H), 3.93-3.97 ( m, IHk 4.01-4.10(m, 2H), ©38/1.1 (Mlle. A|b.6 4©_{/ i ©8 1L·. Hik7 ln/L 1 x.4 IL·. HI). 7.27/, AHL 7M (/ NH). ” y r. J © 4 H<. H k 4 0» /, AH) MS 39f> (MH ).

I sample 2e2;> 3 {{3 amt i© 2 e'au-q’henoxypneihyih-N-pfC'pylpipcridins’- l-caflxkxairiidc Oreo tied a - m Exam >V 254© f pm 3 ((d-cyanpre-ndrcplwwxy Ancthy ILA·· p:<a> lp<>u Mtiie 1 ea- ©<>xai:ndc f Example WLl m ^!-’\>©red Μ©3ί⁷(ΜΗ k

Kamp/ 2©2.<. 3 ((2 oaao 3 mt <»ρ!κη> xytm.'.hxl) A p./Mpmci'dine I easboxanud. Is» a solutionofz-nnrere-ip.pci dm-3 yimetbexy'•benz··ηΠ(\Ε- hydrech unde s Example 2<LLb 10 IO g, o 34 mmol) re flⁿ {© mb I ’-.re re added tuefii© laaurne ο» JO ml . 0./0 mmol) and prepy bre-eyamite (0 05 ml. 0 52 mmob and iiv reaction mbiute w.n <mreJ at r.i. under nntx^goi) fa ? h-re then fiberce; and evaps© rated, Ν» give S-{(.?-<'yano-3 nitrophem©xy )nk^,'ih©l?-X-pP'-pylpiperid:n».l-earhi'-xamids'(O.I3 g, 100 %). Ή AMR (400 MIL· UMSO-d, i 3 0 ©Mt, J ' ? 2 Hz ^:·ΙΗ, 1.3-01 .·<·' tm 4H). I 0.2-i .t-4 (hm. Hb '· 87-1 9© (hm, 2HL2M 2 ⁷⁷ tm. 2Hk.. <>3 2 98 in. 2H). a, (KI J ? 8 Hz IH). 3 Kx {E d, J 12,8 Hz, Hl) 10“ 4 3(m. Hb 4 I” 4?0(ra, ΗΓι 6 38ieJ - © IL·. AHL : ~l bdd, J I 0 IV, J x 0 H - ill), ' 88- ' 9 I (re Hb Mo -< I {XIH^:)

I - <' -~ⁿ uem-tp'ps'r dm- L·© breilw'© 'benrer ,rek- η» Jtece ©Hue

Prepared a- tr e©,ii'ijlc !<><> t am tcrt-'i 0© ' ,, - \aoe-1mtrei©K’n..s© )i»i> thyl)p:p> risUn.-l-i arhs»©y bee (IMreimk’?O2c> m 48 % © h-\| MS M.’ (MH )

I x.imple 2i'2t k»n-hury 1 3-o.?-ey 3ns>-.Vnm»>ph<mi>\y)meth© I ipiperkbm-1 carboxylate I repaid, ,ix re I xreM Hs tiem -H ⁽\l >-{b©sl s>©»ri'e-b© ’Lnpe ij-ae-'carb-exy kue ure.l z.o-dudtrohen/omtrde >o 5© A» © i·, kl MS 2<->3 ΙΜ-Ή-Boei Example 263: fi*rt~but©i 3~R4-amsHis-lH-henzG|eHl,2,{>|thiisdmziii-5” yluxy )meihyl)pipcndiue-l-cm'lm©yPate~2,2-dwxide

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685

Prepared as in Example 111 fro tn tert-butyl 3--{{3--;nnino-2“ iWe.rmpiiab sy rai-.-th'-bpsp-.mdme I vaibuxxbtte-nh'arasd.- (Fsa.nple 2uk-.t. \e.-pmt> ire pH above 3 ηρυΐί acidification, to give terl-batyl 3-((4-amino-1H-bcnzo[c][l .2,(\hhiudiazia-5·· y icxyimctbyrip-peridine-l carboxyia?c-2,2-dt--x:dc (33 rag. 23 ^fH NMR (400 MHz. D' SD d ?o I 27 I 40(1-. _c2 I ί<(.(Ηη. IH1, I % I ,\'.(hr. Hb 2 h 2. 2(!>n, Hl). 2 .'94 <m. ?H), * %-3 /1 {hr:. HI» 3 83-,-86 (hm. UB -lOa-tkt. J ’ 2 Hz, ..'Ib 6 % (J.) ,x 0 Hz. IH), =>. 7'7 {J 1 = .8..: Hz lH?.7.4f»b. j =8.4 Hz. Hb. 7 m(%. .MH). 8.37 (re. NH|. |t)95(x, NH). MS 311 [M-H-i3t>·..| .

bx-impie 263a- tert b-ayl/ ((3 reran < ? cy rem phenoxy ):nemy bp.perdmc I c.-:oo\y lam sulfernide

Prepared -w tr. I x made 90a m r.. re:: buiy 13 tP atnra.>

cs.r= -> 'en *s\ met wbp <et dtn> I Cc ^nd fori'. uglc >%; t pen >χ tan =w N ,oH IM (I S='-> ml, i .-6 mmol) was added -to the ice-eiwled reaction medium triggering formation of's stscky orangy malerial Wa{g; w.w p.jnred anas and the n rid-te diluted in Ριϋ.-Xr. and exi/araed >> gt'e k*⁺-btl\l ί-{{ s-am v>-2->xanopbeaoxxItre/bxΙίρηχοη ne-'-_K nlnwxkt tO I g, 84‘kl HNMRt-RMMHz HMSfo%% <-. t fo (bs IHlI 1 <-3-l 6o .%m Ή) '90 83 (htn 1 Η). I .Sfol 93 (bm IH). 2.7x~2.8S (m. 2H), 3.74-3.78 (bm, 1¾ 3.92-4.04 (m., 3Hl 06 id. .1 -= 8 I Η/, llb 7 15 Id. J == 8.4 Hz, IH).. '7(s, Mb}, 7..56 (b J === 8.8 Hz, IH), 9 47 (% NH). MS J I %:ril-Rocj .

F.h.'U.’.'-P.k...^:.''.!?.·. k'H-butx I 3-((.foin-m-i-2--cyanopk.moxx Imerln bpipeiidissc-· I -earboxvkut Prepared a-· in example 2841? iron- ter=-hnvl 3-((2-cy;wo-3nittophendxy)me'th.yl)pi)K-ridine-l-carlx>xx late dixamyk· 2<»2e) in 100fo> > fold a- an oil. MS 232 [M+H-Bbejc

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Example 264: 4-Ami»ft-5“(b’a«s-2-methyIm clopeatyloss )-1 ZZ-benzo[c|[1,2.6)thiadkume-

2,2-dknide

To a solution of 2-anhno-6>Gnn?s-2-tneihylcyclopcmtvloxy )benzonitrile (Example 2<'-4-.U t s 0 mm f’ e'^Jj :nmob _JP dmu'sL·. 'acetamide le nJ I mrecr X wax added suL:.m-.n i ehfrade (3 cqulv.). The reatinm mixture was stirred at room temperature under N? for 2 hours, ddmed wnh eih-4 aeci.ue (SOnd ) and .pu-nehed w'lh wares {26 ml ) fh. ay r \ >acc separated, (he organic extract w as e\apurare-J IThan<Ί (1 ml.) end .unic-aU' Xa< Bf <2X. 2.5 emm.1 were cou-ecuu'. cly added io ihe re-ubsc 'Phe rebuking mixture was Ireaied at 90 '’C foi lf> hour-. The workup was performed ax in Example s ΐ 1 \> pres ide the desired product f lob mg, X») as a while pmxdei. H X MR f 400 MH/. I ALSO-Md i.02fd. / 0.4 Hz. 310. 1 20 Hm Hl). I i (hs -,31B. I b9_f!n. 01),2 I2(m, lM).2 24im. HH,43-₅h w '.HI.nraMd. ? bOHc. IHV>M (d, ./- 8 .0 Hz, IH), 7.45 (t, J - 8.0 Hz, IH), 7.73 (bt s, I H), 3.35 (hr s. IH), 10,96 (hr s,. IH), MS 296 (MH ).

Examnk 2e4a: 2*Aminb.^»(?r<m₁^2ⁱ-meth.vlcycl0pentj loxy Urenz> mtrlle:

Prepared a- m Example 11 lb from 2-fo‘'<.w-2-meiby mcleprerea s\)-6eUolren <·*, U ,k (E\o,npk 2ο-<·Μ to „n v. thv. mk imu'poaad n. ei ant l *ree xid,’ ,s a v? oifoss oil Ίΐ XMR (Mio MIL·, t DC Rd 1 04-,,1,7 2 Hz. 4Π, I,2Mra, UH. 1 72tm, IH). I 8) _{5C.

H),_:1.99(m, 2H), 2.26 (m. IK), 4.28 (m, ΓΗ),4.36 (brs, 2H), 6.18(d,./ = 8.4Hz, IH), 6.18 (d,

8 Hz, HD. > ixii </ .- 4 ID. IHi MS 2‘MMH I

Example 2o4b, 2-(;<';</'·.> 2M<-iliyIcyxlopenty loxyt-b-niirebenzouifriL·

Prepared as in Example 111c fro.m 2,6 difotrobenzonitrile and 2 methyk-yclopentanol in 65% ax a yellow solid, MS 247 (MH ).

Example 265: 4-Amin«>§~(((2J?,3Ofi)-'3,4’dihy(in)xy“S’methaxyieirahydr0iursm’-2» y l)methoxy )·· I .H-benzofoi 11 <,2.6| thia<tozine-2,2-dmxide

349

WO 20(18/154221

P:CT/hS2(H)8/065058

2017200704 02 Feb 2017

To a solution of 4-A mi 00-8-( ((2//.3-8-4/)-3,4.5-triny dioxytetrahydrofuran-?,x-In-tebo''y 1 I//-xm, o\ ||. ,?,r''bs>vba/ire-? '-d umoc (I m nple .?<·>,P ί / mg, 0 (>.'(} jmaol) :n sirs rocthunol {' ml..} wm addesl triiluoroacs’tie aeid 0 2 ml.) and tbs': mixiure wax lef-uxcsl overnight. The resulting solution xx'us evaporated to dryness to provide the tide compound as a Mme pcrodrr p 28 nr, ΐΟΟ'¹., rniMmv .simeoraTs I '> Ή NMR ( H’O MH', IJMSCM) 0 p I tx, Nil?]. 3.22 (x, ?dh, 3.M. (d../ ^::: 4,0 Hz, tH}. |3 9,3 im. HH}]. 4 -2 pre. 3H), I 30 {rm llh.1'1 fr. HI}. i I 85{d .,/ 4 0 Hz, ^; di}] 9 ’:.} ibr x 2IH, (d .7 x Oil/, Hh, <'>M (d ./

Si) Ha IH), 7 V {t. / l-Oil.·, HD ? 95 <s, Hfj.x-H ro, HI), 11,00 {< IH), (J O| {χ αΗΗ h.xampk' 2n5a: 4-Ammo-M{{{2.)(.35.05/)-3,4.5-trihsdroxytctrah>dt<>furan-2-s I msi IhexD1 //-benzo^ H 1,2 .Mtbiadiazl m-2,2-9 tex ide

To a suspension of 4-Amino-5-(((3u/.4//,6./.,6a/< }-6-nwthoxy-2.2dim<^>tbyhx‘trahysirotbro[3.4-.d][l.3]dioxoM-yl)mt‘thoxy)- i //-benzole 1| 1.2,6]thiadiazins'-2.2dioxide (Example 2656) (15 mg, 0.038 mmol? in water (1 ml.) was added trinuoroacetie acid (0,2 mL) and the mixture was heated overnight at 80 C, The reaction mixture was evaporated ίό dryness; to famish the title compound: as a white solid in. quantitative yield (mixture of d'asteroomeix - 10 I} 'll \'MR _vt00 MHz D\N ml j 0 H. pm MH, -U2 Im, Mb, 4 35 (n„ ΠΗ.5 02 (v Hh,G.o.3(d.d x Ο Η v H t % se. ' tt 0 H , IH) ~ 4 7 .1 ,/ χΟΗ',ΗΠ 8.03 (brs, HH 8 - (brs. Hl) HH, .1.1Ό0(hi a 0 Jh[

I xampte 2O5u I- \n-:u·*-5-((( IjR. ί/?,ο/ Oa/l-n-nMboxx -2.2di nei xhenmx.h mop 1-./(1 i|d<>x>l l-xlhro hov )-1 H-.xn o ][, 2 pda RfC/im·

2,2-dm’side

Pu-pased as m h sample 11 i tfnm 2-Mlfmm‘slxn)U<<m-^p..A\4.ktu7,txuM eeivtboxx 2 2 e.m..hshcinib'3 <4' <? ' -M ]| ι..ηΑ0. 4 <-Ρ,κΜ,<αχ il'eazom..i.c H xamp e

205V m ~3% yidd us n heme xohd. H NMR s400 MH/. HMSO-dM 3 ? .28 is, 3H). 1.41 (s, 3H).

WO SW1S4221

2017200704 02 Feb 2017

l.'-:(x,?lb 4 00() 7 ⁰ 2 Hz (H).4 3? ==1=1 / -2,100Hz H), 4 m _i(-,j / 52,3811. 1H ·, 4.63 (d,,/ - 6.0 Hz, 1. H). 4.82 (i,./ === 6.0 Hz, 1HI. - 02 ί s, 1111 6 = -4 i J. ../ === 8.4 H; IH), 6~0<d../ 84Hz, lib 748() / 8.4 Hz. Hl), ” % (br Η I), 8 43 (h v = Hi. re 02 (b. w Hl;·.

bxumnk 2o5c 2 Sid fames l,< nm<»·(<·((( %/> ,4A',c>/?.6a// t-b-mcrk?v< 2,2 dnnuby hetrahydremcol3,4m'y 1.3|loxM-4·\ llmvthox’s )bem>arh'ik

Prepared .re ijiPvmtpic Illa h=-m 2 ammo· (((3a/i.4R,i /7,6,=/2 ) o· mcth> <y 2.2 duncthvhcrrahydruh5ro|3.4..rfj| 1.3ΚΟοχοΙ··4·νΗ;·η%θοχν)6οηζ;>π:ΠΊ;& (Example 265=,1) re 77% s .',d as .= wh-tc Wid Ή WIK =.400 VI V, C1X .reel 34 re. Mb I Ml re, Mb. ' ,>3 is, MH. 4.08 ire. 210,4,5Hud../ 6 4,->10. IH).4,6%d../ 6,0 HzvH), 4,~>> (1./ e.O Hz. 1 lb, 5.01 is. Hl:·. 5.25 *br re, 2H),6 7U(J, / 8 4 Hz. HO, ”,28 (N %<. .30M, / 3,0 Hz. IH1. .51 (t, ./ 8.4 Hz, 1H).

I: \.iirek 2656. .?-Amm'>8 -{{(3.t/?.4/?,t»/i.nj/b-r-m...4h0xy-2 2dim<n.hyhei.rabydrefurr.43,--l-i<KJ ,3]diox· >R4-y llmMboxy )henz= I e

Prepared as in Example 11 lb from 2-((=,3^//.4//.(./?,6,vs}-(>-methexy-2 .:dimethylK-rrahydrofuro[3_:4-d][)3]dioxoM~yl)mclho\y bb-mtmixuzenitnle (Example .252.0} in 40’,. yield ax wlmkrex xiklre mmerial ^}H AMR 1400 MH., CHCk) s> I '3 re 3H). ', (x 3H), 3.33 (a. 3H >, 4.05 (nt, 2H;. 4 45 (br χ. 2H), 4,56 / ™ 6 0», 3 0 Hz I Η), I 66 {j. / q.o Hz,

111). · 8? =(ir J ./ η 0 11/, Hl) > 00 re = H) 6 21 (dd, ? 0 S, <·' I 11/, = H» ¢= 33 ? JJ,./ 0 8 3 I 11/, ΗΠ / 20%../ == 8.4 Hz, Hl)

Example 265e~. 2-(((3a£,4/?_t6/?,6a/?b6-Methoxy“2,2~d!m©thyhe:trahydn3&ro[3,4 = 'ΊΡ - HJ^;oxe1- l~s hmcil'''-xy)-6~m(>Mvr' -own s’

Prepared ax in brearenR’ 11 le from ? 6 dmmN'cn/onhtiie .red u^a//, 1/?,6/<,6η/ΐ)·· n-mcikrey.-2 2-dime'byh.,.-.rahssiiMuro^3.4-_{/^ (..'Idimol- Hylpn· thnnM in OM y IMd .ts white x.H I H MIR = 100 MU ί OC'30 I % ,_s UH, I I) (s MH 3 V 3b} 1 Μ ω../ 2 0 H Hb,4 24re, H-b 4 <>0 (br ).. / « 0 Hz IH), 1 6 ‘ (-1../ === <· 0 H '.. IH), 4.36 (br d,./ 5=011/ IH), 5.01 (a, IH), 7.35 (d, ,Z 8 4 IL·. Hi) 7 ”2 ¢,(. >’ === 8.4Hz. 1 H), 7.87 (dd,,Z === 0.x 8 I Ha IH).

F xmaple 2M>: 'l-AmirsmS-ittO^.SaS.^aS^bS'f-'/JCre-leiramrthyhetrabydrn-Sa//hisIkJlilhrenlofkS-hjMkSOi/ipyra^^^ hmrihuxy hl/f-beswkH 122,6ΗΐΗκύί^ζί»β-24~ί1ίοχίί1«

WO 2088/154221

P:CT/DS28W065058

2017200704 02 Feb 2017

688 ^s>tcp tut ts re * xat >1 264 1 re ' rec no r ttt j/i?a >' 8, ' x > >) 2 . \r .treed:' tcuobsu υ .·>.)// h-p 3·.Ηοό:ο; 4.x < 4’,5 ./jpyon ' _? .rnizhoxy >bo v> r nd. t Psample m 2’. ) tub as a Imo ^-bd H NMR t400 ΜΗ/, PM3O ..3 p 29 t-. 3H).

I cl _Vs, 31b. I 38 H. 31b. I 4/is, 31b. 4 6 tm. 2Hy 4 I »{h c. ? 8re ire, HI'·. 4 36tdd, ?

Ι.2.Χ4ΗΛ IHk4.1l (dd../ 2.4,5 2 H?. 110.4.44 (dd ./ 2.4, H'· 9 Hz. I Hk 4.67 {dd../ 2.4, MOL. Μ0.5ΛΗ4,./ 4 8Η/.ΠΗ. i-td(d. / δ 0 Ik. lib 6 (d../ z 4 Hz, I Hk 7 45 tt / z I Hz, Hb / % (bt ' ΙΟ δ H pre- HI), I99,x<h · 111'· M%|s<reMH )

I sample 26mr 2-Ami no-6-s 113a/i 5aN.8aO,xbA)-2.2 ,7-u.b am cd > I ictmhs di >-3 7/b-sl 1.3 Pts>Xs>l>-|4,5-/?,.r.5^,-ifipyraH-?-yl!moihi'-\y?bcm'{miR:k'

Pt> >atc< as n · \ tre > e 11 > betr H ·> <> vt' 5 ·> x <..% x|~M ' ⁷ ’ tett'iMncthvltetrahydrO’dkiWbisP dOdjo^x0k7{4,5-2>:4^,,5--<-/)pyran-’5’yi)methcsxy ^benzonitrile (F\.t:apk' ?66b) *.t <)ο.η.ηΐ/ί.\ο } .ek* Ή NMR {409 MHz DMSOojp I ?x -> 3H). I 31 % 3Hk 1.37 (x. 3H). 1,39 (_s, 3H), 4.05 (m. 2H). 4.16 {dd, J 4 9, 8,.\ Hz. IH), 4 3? tre 2Hk 4 t>7 / 2 +, S b H ’ HI), b 4 {J, ’ 4 8 Hz Hk <> 91 ·, v ·, Ή'>. o .'' ,J, / x 0 Hz ί H), ' '' tti, ·' 8 ’· H? IH), I , <t. / 8 I Hz ' Hl

F sample 266h· 2-N tin>-6-(^3:;??.5:;S,xa.\',8b5)-2,2.’’ ktetrank-·by It·.·)? ah\dto-3a//bis[] ,3'idi0XQlQ[4,5“d:4’_!5'-_i:^py_ran.5,y|)_:i^._eth0xy)benz(mftrile:

Prepared as in Example Hie from 2.,6 diniirobenzonibile and !Ί7'9ί./Ν5:»5.8η3'.86.7)-2.2,7//~:ο{ΓΒηχοΡ·νΙίο:ϊ·;Λί';\·’4!··..ί-3η//-6ίχί 1.3|dioxoIo[4.5^:4‘.5^!-t/|pyran-5s Inneibitriol in 59 % yield as while sticky material. MS 498 (MH ), 424 (MIRO )

Example 267: 4-.Amino>5-(I -t.’-methoxyetby'·)-; /7-1,2.3-kiazolre-x.4)-1/-6 benzo[i?][i.2,61th.iadiaziac~2.2-di0xidc

WO 2008/154221

P:CT/DS20W0OiS4

2017200704 02 Feb 2017

hopnod J'in Exampl..- Hl time 2 sidL-.mmla ihpv >(! {.2 KieU’.<-\schub H? Ι2,3··ρ·ί3ζ»;·Ι··4··νΙ)Ιχ:ηζοηΗπ1« (Exumpk' 26~a> in 78% y kid, Ή NMR ι40θ MHz, loMSH-.L) 3 3.27 is. 3H), 3.7.8 {t,<7== 5.2 Hz. 2H), 4.59 U,J === 5.2 Hz, 2H),6.90 (brs, IH). 7.09 (dd,./ === 0.8. 8.() Hz. iH), ?.2??{dd../ 0*. 7.0 Hz. lH).7.5x(t. I f Hz, I Hl. 8.15 tbr+. IH?. 8,32(+, HD. 11.09(b) +. HD MS 323 <MH )

I: sample 267a· 2-S),iifamoylm?im--6-(| -(d-irrerhoxyethyb-l/M .? .vi.'ixzpbdybbcnzonitrile

Prepared as in Example 11 la fam 2~ammo-6-(l -(2-ntethoxyethy!)-Iff-1 ,.2,3triazoM-ybbenzotntnlo iExample .>Ίό m 90% yield. ’ll NMR (400 MH.·. ItMSO-^i <) 3 28 (x.3lb 3.’°(i J Hr. 210,4 66 X ’ ~ 5 2 Hz 2H 5. 32 (Or <, 21D. 7 <>0 i dd. 7- I 2.8.0 Hz. IH), 7,76 (1..,/ === 8.0 Hz, I H>. 7 82 (dd ./ 1 2. S 0 Hz. I H?. 8.0-i (s. s Η I, 9 52 (to s. 1 H).

Ls3H?PSk-h'...'.b 2 Mnm<> *> {'. (2 'nempxu'tby l'> NV 1.2.3 'naze 4 y Dbcmzm'.'ttsL' ΐ o a -> '-mow pf | bt'vi'io .' mcthexycth.me {5 00 g 3: ^κΓ' mh m DME (.'5 mL), waz added C-e urn a ide { 1 equix.? .md the mixture was heated at 51? 'V to Is It mr+ I oe reaction nrxmre was Odevc wrb wator (75 inLt and -. xtrax-ed web dmthsl cth- i ' n,' + gams extract was dried over MgSCk and concentrated to furnish 1-azido-S-inethoxycihane as a yellow teim-l fres .lAle 1 ’’dd me ? ^vi t mm-.to was ;.iJed to a -a>hiib n of Xmns -tediVKylbenzinntrile (250 tng.. 1,76 rnnv-i? (I sa-nple 26c) in H,O irw'-BaOH --1..:2 (15 mL) and the solution was treated consecutively v nh ,+odmm ascorbate (0 26 I mmoh and CuSO> (0 035 mmol). Ike .reaction mixture was stirred A wont ittnperihirc tor-lx hoars, diluted, with water and extracted with ethyl acetate. The drgaine c.xmu 1 was .hard .we; MgSCXt and pnrified over silica gel (oihy 1 uc-eiate/hcxanc 6:4) to furnish the tide, compound a.« a white solid in 88 % y.;_c|j Ή NMR (100 Mi Iz DMv >m ) <1 ' 2h <s. Hb. 3 % (l. / 5 2 Hz 2H). 4 2' (♦. / 5 2 Hz 2H), 6 13 t br s. 2H ?. 6.89 (dd../ 1.2, 8.4 Hz, IH), 7.09 (dd, J === 1.2, 7.6 Hz, IH), 7.36 < J === 8. -1 Hz, Hl) s 52 _iX HD \is 2ms sMH 1

WO 2068/154221

P:CWS2608/065050

2017200704 02 Feb 2017 ahvn¥hnn.tethvK4,!i:c «2 92 -. s2 7 tnni«>b etdiv IMS i 15 ml ) wax <.ldcd undei NN Cut I) (hO mgi. PdcPPh ), < fed j-ig) -.nnl the mixiute wa. reirred at 8Pi V b-· 20 homx. fhe rcaeiton mixture was couled down to lempetaiitre. ddmcd with ethyl uecnne and washed wmt brine Hie organic layer was evaporated and the residue was dres-axed m nicthan<’l 120 nd ). treated w.'-h IM aqueous NfeH solution {I 05 eqmv.? and stirred at o--m temperature n-t 1 Is-ur Methait-d was csaps-i.ired i>t?\-.nd -he aqueous iesuhie was cxtiact_s.d with (Ή»χΊ . diicu over \fe-' and pi-feed --χet side.-, gel redo i .ixctute hesanes 5 25) b tm.jixh the desi cd product -a ‘fee Meld as lig’m 1 ?.l, w ..oi-d 'H NMR (400 MIL·. DMSO d i > 4 5 - p, H), -.2- fe s, 2H), o % fed.

= 0.8-.7,6Hz. lHk(i.S2fdd. 0 8. 8.4 Hz, I lb. 7,28 tdd../ “% 8.4 Hz. lib MS M3 (MH ). Example 268: 4-Armne-S-(fara«-3-y 10 ί //-henzuh’l 11,2.61thmHazme-2,2~dio.Mde

690

Prepared w in b'xampL· 111 fem 2-su i'amm. feur<>---(Οκά-ό-νΒΙχ'ΊΛ'ηΡηΙ(Example26§a) in 47%yield as a beige.solid. ^lld NMR (400 MH?, DMSOfe}do 31 (hr s. 11H

0.51 (dd,./^::: 0 8, 2.U H?.. 1 H). ” 03 fe 2H} ' ?2 (dd../“ ”.<\ 8 6 Η..' ΐIIl. ' Ή (t, / ^: I 6 11?

IH) 93<dd./ 08, ΙΟΗ? '10 S IH'>JHto_SxHh \h2i-h\lli) .fe0_;'Rl8i:’..26.6>.i;. 2-Sultamoylan-iiiiO“6-(furan>3-yl)benzonit.riic

Prepared as in Example 11 la front 2-aniino-6-(funm-3-ynbenzs>nitrile (Example 2086)% 63':;, yield as a white solid. ^lH NMR (400 MHz, D.MSOfe·;) <) 6 97 (dd. J^::: 0.8.. '2 0 Hz, lib. 720(/ -. 2Hfe 4<<(dd,,/ 0 8 “o U.·. lib ~ ^4(dd. / Ox.x.OB. : Η i 7feife m) Hz. 111). “ 8%},,/ ί (Ήζ UH, 821 (-Id J 0<\ I Ml; '.Hl o IRilrx. IH)

I %anq e 2-0 i 2- \m re tre>-_v n?a -fel,! _t nzoniirilc

Prepared as hi Example 1.29c fem feran-S-ylboroiiic acid and 2-3111100-6bromobenzonilrile in 743,.- yield as a yellow solid. ^!H NMR (400 MHz. CD(?h) ό 4 .51 (br s, 2H),

354

WO 20(18/164221

P:CWS20W045650

2017200704 02 Feb 2017 %m(dd.7 i.2 X -I Hz. Hl·. 6 78 (dd,./- 1.2 2 6 Hz, 1 H). 6.82 bld../ 1.2. 8.0 Hz., ί H). 7.31 t·../ 8 0Hz J Hi. “.50% / i.d Hz. lir>.“%,JJ..Z I 2. i.n Hz. IH).

Example 269: 4«Amiao-5-(thi^heH-3-yI)-1 H-benzo|4tlA61thhdiazhie-2>dioxide

¢91

Prepared a-in Example ill frem 2-sidlasno\ krndno-b-Hbiophen-d>hben/omtrile (Example 269a) in 52% yield ax a beige solid. Ή NMR (400 MHz, DMSO-<i.) 6 ?.82tbrx. Hh. 7.05 (m 3Hk~.54%./ KOH/. IK). 7n7_im. Hl·. 8.%%' -.. Hl·. 11.13 (relH) MS 280 i MH k

Example 2e%: 2-Suiiamo\ k?:uino-b-(thf<'phen··.'> llbrnszonmik

Prepared ax m Exam,de 11 la Ire-n 2 a mro n clie-ken-3q Ohre zenraue (Example 269b) m 60°« yield as a while sohd. Ή NMR 1400 MHz. DMSO-%) 0 7,31 (br s, 2H). 7 42 (dd../ 1.2,2.8 Hz. 1 H). 7.43 (d, J I ft Hz. 1 Hk ? 5 (dd. J - 0.S, x.O Hz, i Hk 7.70 (?. J

81) Hz. Πli, “73 {dd,./ 2.8. -.8 K.\ IH). .ss Ml.) 1.2.2.S Hz. IH), 9.48 (br s, IH).

Bx^nipfe269b02-Ammo-6-(thi^:ophenM-vl)beaZomtnig rremared a- in I xarmk 12% ;sori ihmphcn S-xlbraraac acid and 2 mnrio ny (ms-.'Krzomtulc ,n ’M yeh' a\ a Ixngk. sored K SMR (400 MHz. DMx<» c (p< ( 2Hkk.7O(dd.,/ 1.2 lnHzJH),6.77(dd../ ’ 2, 8 4 He. 1 Hk 7.3i (dd../ = 7.6, 8.4HzJH), 7.38 (0.1,,/- 1.10 Hz. IH). 7.6b(dd. / = 2.8, O Hz, IH). 7.78 Md. /- 1,2,2.8 Hz, IH). Example 270: ^^AiWfethykycioprbpylHIJ-^eazol.cin^.pM^iazia.-^^mi»^!^dioxide

633

WO 20(18/154221

P:CT/l.sS20W8OiS)

2017200704 02 Feb 2017

Λ sohmen Μ 2-^ρηπ·.'-ΐ·'-{-.--dinEelbs«jiopi’opstic {381 pniok 7j mg} ((Maniple 2”0a) .aid sulfam-w I chkmde if ”2 μ reek 66 nig? m DM X (1 -nl ) was ,-ηπχΜ at wm temperature. After i Im-m- -he rcactmu mix; urn wax dilaud with NJjH (I \ Ό umc-l 572 pl } and water i -30 nd ί The preeq'iuue w..ts 6 lured >.-ff. washed with wale: (3 X 5 nd.) then dresohsd m ΓιΟΙ1 (10 ml. 1 and NaOH ( IN, 953 pLi was added. Ihe reaction wa- beared to SO =' w-th st'jiaig Xuet «ntipienon the s<»h cat weie m apouued a id the residue was patη-:= cred between wair; (20 mi i ,nsd ctbet {5 mLI I'M aqueus laxcrw >.s t-x-racicd w tth etho(2 X 5 mk;. then acidified to pl I 3 with I \ I16I 1 he precipitate was eoli-..cud. washed w iih Water dik'd in xacu»· to gh a the desired pr-».luei = 5=9 n-g ·>8%) a$ an cm-w.hu·. sola I ^:H NMR idoo MHz. HMSO-A) Jo.6k)(m. IHk 0% «. 3H) 0 ^tm, IH). 1.20is IHk 2.4s (m. IH) 0*8 (d. J 8 Hz, IH), 6.92 <d, J S Hz, IH). 7.21 (hr. <, IH). 7.39 u.J 8 Hz. IH), m-42 (hi re IH), 10.74 (s, I Hi. MS 2eb (MH i.

Exainpk 2⁷0a: 2 ain=no-6 esdopropylbe-i?.' -ifonu

To a deguzed solution of z-aimno-b-bretnobea/'-iutnk (s51 pmr>i, 168 tug). 2.2dimethylcyciopropylboronic acid (ι 10='. pns-i. 126 mg ιι1 cample 2^01.-1, and Cs,>CQ: (2.979 nmol, 970 mg) in.DM.E (3 4 mL) and w.der if.fo pl I was :%0·,d retfa.kis(03phciwIphesphino)paliadinm(O): (43 gmok 50 mg) imfcr nitrogen and the reaction rsuxiure microwaved for 2 hmirs a( 160 ⁰ C. The reaction mixture was cooled id room icmperaturc and extracted with ΠΟ \c (3 .\ '= ml ) flu combined organic layers was washed once, w'ith brine (5 ml..), dried met '•«idmm sub Me. Ghe> e.l and .wapnnitod Tbe crude product was purified on silica gel (EtOAc bexauss I {>%-η0^!'m tn gi\c the desired product (? I mg. 45%) as a waxy, yellow solid ’ll NMR t-OO MHz, <ΤΧ % JO.82 (m, HI), 0.*2 K 3H), 0R5 ire, l Η), I 33 (s, 3H)„ 1.92 (m. IH), 4.36 (br. a. 2H}, A a (d ./ - 8 Hz, 1 H)_: 6.56 ink ·/ - 8 Hz. I Hf, 7.20 (t, J -8 Hz, =H).

EN<2niple.270b' 2,2-dimethyleyclopropylboronic acid

To a solution of I -bromo-?..3.-direediyicydop%>p:me 7.-18 mmol. 1.115 g) (Example .?.7='k) in anhydrous ΓΗE (2.0 mi..) was added 113=.-1.i (S 23 mmol. 1.7 M in p-mtane, 4.85 mL) dre>pwisc at-78 * C under .nitrogen. After 1 hour si - '*' G» tnm.ethyIbGra.te (8.23 nniioi. 920 pl.) was a.kk.-d and Hit. reaeum: mixture w ^l-rieo tor 2 ii-nns at -78 '' ί', wanned to room temperalure, stirred for l hour, and quenched, with .§ai·· NlfoCl wlution (20 mL). The

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2017200704 02 Feb 2017 reaction trtixtme was dilmed to a total \olumc of 100 mL with DCM and treated with HCI MN in water. 22.45 nnnoL 3.74 mln. The layers were separated, the aqueous layer extracted with dmholromctau<. (2 X 5: = nd k the corubnte.1 otgaiuc iaveis wets' w .wked w it t bime ¢25 nd ). dried ovet -f'dttttn sul=._;te. lihewd and evapotated The = endue was domed wuh acetone (50 ml) and a few drops ofx-atet. thcis uiuftniy c<’=tc .-:r.iat_vd=..-.000 b· sac 214 -ng 125 Γ »ief product ax an ofi-white soltd. *H NMR (400 MHz. acetone··^) oil.00 im. IΗ I, 0.13 (rm I H), 0.755 {dofd.J 4 Hz. 8 Hz. Hlk 9 no5 (d MJ../ 4 Η/.χΙΙλ Hlk 1.3%-. 3Hk 1 46;- 3H). 6.81 (s, 2 Ht.

I xantpie 2~9<- s -b’otno'2,2-dnncdty ww ebpt .-pane l<= a suspension <4 /nte (dtM. 50=.4 mmol, 29.88 g) in Id’ Hl {2:1 nil I was added Ht'i (12 X. 5 mi tat 9 ' C. A sohftton ef LlMibroino-l.l-dtmediy L\cb’pjopane (Lx.2 g) (exantpk- 270dt m IT >K {2:) nil } was added n- the mixture <wer 1 loiitGle with stirring. The reaetum m:.xtur>· was idb'-wcsl io warm slowL te soont icmpetahire o^enught The /ine salts woo. Mlewd effthr-.mgl: a pad <4 ¹ elite. the Celtic washed wjtb ft< ?H (50 ml ). att-.l the icsebiug s>4iiti<m patlitmned between v. jttr (290 ml.) and pemam' 1209 nd ). Flic uqueou- layer was Im thia estuRkd wuu pcnkmc <2 X 100 ml j. and the combmcd = .= game cxu.wts successwelx washed with xxatci (4 X 75 tnl i, brine (25 mL), dried over sodium sulfate, fi Irnred, and si.<pe.aud^A> g '.es ths ptedue* I ’..% ° %„} ,lS v iL.de. eoi. as* L * td }’XMKt40d MHz. avc.ore ί D'2 to A o. 4 Hz. o He. 1 Η), 1.02M2 ofd. ^: MLMI/.ili) 1 1 J(x. 3H); 033 (s, 3H), 2.963 (d of d J - 4 Hz, 8 Hz, IH).

fxan'pk 2~t'o ' -d'btome-2.2-ibmeflA Ic^cDt'n>pan.'

To a somimn of pentane \200 nd.) coaled M -5 · C svas added isobutylene (457.? nmei, 25.68 g) fl-How.Ή by potassium tett-htttuxsde i54°,2 mmol. ¢.3.63 g). Then bromolorm (4^-) “.7 mmol, 4() 0 nt I ) -was added siw_fpw ise x% it'n vmw'ons stirring m er about 1 ίκηιτ at - - ' C. Tbe reaction mixture was allowed to warm slowly to room: temperatere and then partifioned between penlane (i 90 ml.) and water (299 mL). The aqueous hr. er was ex {reeled with pentane ¢2 X 56 ml.;· and fne eembmed oigame I.aess washed wttb water Μ X 75 nd.). Lime (59 ml.I, d==ed over sodium; sulfate, filtered amt evapora.tc.d. The orange icshlnc was pushed through a. silica plug eluting with pentane. The soheut xxas evaporated to give the desued product to5.70 g, 57 3%) -;s a A'loilc.w ._M H NMR (W9 MHz, acstore-./,) 01 3% Mik 1.505 μ 2H).

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Example 271: (-.tMians-S-t 2(nrethaxymethyl)cyclopropy luHLbenzolcH 1.2,6]thindla/.in-4aminc- 2 ,2-dioxide

6®3

Prepared ax m Example 2”0 fj-.m-s (-. )-U'ans-2-amir:0~p-(.'.^;(m·. I boxymefbxIkyeloprvpyl)bcnz<-nmtl·. {example 2’’Lt) and svJfamoyl chloride in 34% a$ an oll-v.hste solid ’ll NMR {-<-00 MHz, rid ’^!n (m, 111). 1.1% tm. Hi). I 340 (m. IH).

2.2x2 urn IH) X <d ofd. J x Hz, H· Hz. Hi), 3 252 (x, 3H>. 3.5'M id =0 d, / 5 Hz. IP Hz. lH).‘>.XG2{d,d x Hz, lib, 6.355 id. > 8 Hz. IP}, H,.7 x Hz, lib. x.39n ibr. $, Hi), x 47? (be s, lib. Η) X23 t-, Hl), Mb 2x2 {MH }

Example 27la; { )-u.iux-2-aramo-ira2-une'h' \x net sybcyclopropyllbenzonitrile '’repiiu <s tr >· xu >h 270. t <> n ; ta.>>2 p ueP t<¹ <> mclhy t sm clops ορ\ Ibos an tc .stsd {exan spk 2 1 b) and 2--at nine-6-bronsobe· txouitrde in /4',. yield a? a y el lew jsh btow η η ;;x\ >phd, ^!H NMR (400 MEL', D.MS* }-m.) 4 0,93..’ t re, 2H), I 341 nn. 111;, I x9(m, I 111 2 324-H). 1 3M {.1,,/ όΗ'.21Η. %W{'th _s, 211). u 14X(J. ,Ζ X H'. IHt, r 55%d. / Mk 111% 1^0.,/ SH/. ill)

LMwfe,271b: (.t)-trans~2-{ methoxyrn.ethy 1 )_uw e l< ‘propydboronic add

To a soluhen of ^<,a4-trans-2-(:nmhoxy'methy l)cvclopjOpyl)-4.4 ^{ζ ς}- emunerhy)L3.2-dioxaborohmv·. (10.0 mmol. 2.121 g) (example 27 = % dissolved in THb io4 ml..) wa.s added NaKl (30 0 mmol, e 417 g) and \\ate> 116 mL) The reaction mixture wits stirred: ai twm tetnpeiinus^ to; 3 itetitile.s dun *reat.J w tth aquemu·' Hi. I i2N, 3 33 nd ). I La macron m xlmc wax xtnted }<>; one h<o= at iootn tenepcr.uure, paiirtored wnb Et< = \c s 100 mL), the aqncojs layer extracted with EtGAC (2 X 50 mL), the combined organic layers washed with brine (25 mL), dried ever sodium sulfate, filtered, and evaporated. The mixture was- taken up hi acetone, 'seated w'th a kw drap.- m'nciet, red e.ucmht cxupera.ed to a x'sceu.' era whiJ. <· only sends Ik'd at loens tempuanns'm ewe the rextred pioduet tn .p.unimaui c m Jd ’ll \MP (-+Ό

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MID, DMSO-%) A'4U67 {m, ilb. 0.324 (nt 1H), hn, Hh. 1.055 (m. IH), 3,099 (d ofd. ./ 7 11.-, K?b/, Hb, 3 586 (def 6,./ 7 H? iO ID, IH). \20b D. 3b), 7 344 re 2H)

E37010k.~7.I c: (' )-ttans-2-(metkov.>nethy’?n cl·.ips] % l,5 ratcframei b\ I.1₅3_?2«dioxabo.ro.lape.

To.: sokmi'U of(E?-?p-inodb-\spieO’i-ens;>-4 1,5 5-k'B‘an\^rfh\M,3 2dioxaborolanc (32 2 nunol, 6.3710 g) in anhydrous toluene {50 nil..) under nitrogen wus added dtctbx I /ine f0.5° M in hexanes. 32.2 ιηηι<Ί. 54 n mi }. folhracd by ( H;l; (4^ Ox mmM, 3.% ml ) Thu Hash was heated la 50’' <' under n’ar-.rerem. Afte’ -I horns, another potmm of diethyl /mu {54.8 nd I aral < Ή Ί >;3.0.3 ml ) added und beared oxcrmgte tinder uitiogen. The reaction mixture was cooled to room temperamre and quenched with saturated aqueous NHcCI (50 ml.». The rcuetion mixture was partitioned with ether t200 mL). the layers separated, the <a gaisie layer washed 'Aitkbnne (25 ml.), dried ex-ar mdmm sulfate, filtered and tx apotaied. The residue was purified on silica gel (Et'iAc.hexane;' HL, ϊ 5%) -.<i gjs- the desired product (5.'>52 g . 81.3%) as ,i liglu-xchuw oil Ή NMR (400 MH?, uccb-nc) 12 (m, I H i. (L8O4 ι ,η. IHLOQLhm HiL ll72(m, lib. 3 .iMtdJ,,/ <>b/,IOH? H11, 3 -1 {<14 / Hl, \IOIL-. ill·. ? ”<u(s xib

Example 272: (E)-4«44~amtno~2,2-dioxo~l

; >. , m> * >t 0 ' * (4 a i,h o <’ Tl ,i (' ' \ k fob. I era 1;

re rreo <.]( % ( u et - a-1- im to-^-' % O' w e f %' Hol 1' oM (1 \ar> pk bm Mil (5(0 pl.) was .ulds'd \c( 41(1/ ird » and ware-i (40) u( and (be rehtnor heated e>c-irebt at 45 ' (' The solution was cooled to mom temperature and the solvent evaporated. The residue was triturated with boiling water then cooled to room temperature. The restthing· solid was collected and w ashed v> i th w ater to give the desired product (69 mg, 80%) as a light yellow solid, ^lfI XMR(400MHz,DMMmLu>2:m5(q, ’ 6 Hz. 2b h %>x (q. 7 o 11.·, 211), 4,<Nl {{, <’ p H/ HIV. I86{d of·, I K. ,lob' )1)6/((0% 'Ml id ) X Η/ Ή)

WO 2(8)/634221

2017200704 02 Feb 2017 ~ 022 (bt x, Hb. /988 (d. J Ml- IH). ~ 4o© (t. J 8 lb. Hb, 8 )88 (A x. Hb 10 WJ (χ, HI;· MS 2©8 (MH ).

Example 2 7.3: i )2)-5-(4-1 tetnthydro-2H~pyfan-2-y loxy ibuf-1-eny 1)-1 Hbenz<j|eni,2<,6|thiadiaziM»4-amine».2,2“diexide

NH₂

Prepared as in Example 270 iron» (E}-2-3mi:i<.'-'©-i4-(ie.lrahydra~2H~pyran-2~ \ k'x© jlmt-J-ensbhen mmoik' (example 23a) and xudanu-y I el'dence m <'>!< \ >ekl ax an onw hi/· send. ^SH AMR J 09 Ml 1,-, DMSO- A) A1,459 pn. 41 b. I 310 (m. 211), I /00 on. 21b. 2 479 (q. ί == 6 Hz. 2.H). 3 428 nn. 1 H). 3.528 (m. i Hi. 3 655 pm. 2H). 4.579 (m. Hi), <· 200 id of / == Hz. b> Hr. Hb. n 823 (6../ == H Hz IHt.b ©67-hr. x. Hi) ©AM (6../- 8 Hz IH).

.6,./ -== 8 Hz. IH). .-172 (t,.> ==· x Hr. Hi), © MH (br x. Ill) 10 “45 A, HR MS 3x: {MH ).

Examp e ¹ '3a (l·')-' - zniiv--W( R(.e'ranyd o-?l Rpyr a- Ή |_Ox\ tbuM enyl)benzonitrile

Prep-nee a» tn > x.»r.pk' ‘<0j .re uJ )-1 1 © χ-tc'r, ae’'nl- M pa Sd pyran-2-yiox;y)biii~b'enyb-L3,2-di':.>xabo:i.>kine {Example 273b) and 2-a.miu.o~6~ btombbenzonitrile in 47% yield as a yellow gum. ^lH NMR (400 MHz, CD<T.) Λ 1.570 (m, 4H), 1 ;2<m. ?H). I ©37(m. 211) 5o.©{q </ o Hz. 2H). a 8.. j|b 3.8-9 2H)H38'{hr s, 2HE 4.635 (mJ H), 6.423 (6 of t,../ === 7 Hz, 16 Hz. IH). 6.586 (d, </ === 8 Hz, i Η). 6.710 (d.../ 16 Hz, IH), 6.905 (4,./- 8 Hz, IH), 7,237 (t, /- 8 Hz, IH),

Example 273b: Π ) 4 -1,5.5 fenamcthyl .: {4 (rcnahydre - 2H pytan 2-y'.oxylbm I cm I >· I ..EJ-diexabotvlan·,.·

Neat 2~(bm-3-yny.foxy Hi'tramdre-2H-pynm (12,8 mmol. 2.0 ml..) was treated a .h p 'a, upCiexH ⁱ rent , /8 ml i , »<(' { nr. e· o’ii ge© XUer ’ x atx anelee» poojen of pmsoblbbrane (12.8 mmol, 1 ©6 mL) 'aa, added and edntihded heating at 60 ^φ C. V'lei © hei’.ix, the roa, -rer nisire.- wax e Jmed w sin h > a ©ex (30 ml ) a id treaied .Irep?- ix? w d© water (1 pil,). Jirring until gas evolution eeased. The layers were separated, fee water layer

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L'xisacteJ wub hexanes (2 X 5 nil ), the combmcd otganii, Lisas xsasbed wjib brene {5 ml i. dtk-sl ον a inagncsumi sulfate, filtered. ami e\ ip<mUcsi fbe srtalc pr-.'.biU '.s,,... pmHied on xibea gel (LtOAs hes.mro 10% t<- ?(t%|i<> gise the product! 1 e. %'% me d) a,- „r <m! Ή XM9 (400 MHz. CDCLi <* 1.262 (x. 3H), 1.531 (m, 2H). 1.699 (rn. 1Η I, 1.812 (m. IH). 2.409 id of q,./ 2 Hz, 7 Hz. 2H), 3.495 (_5n, 1 HL 3 832 (m, 2H). -4.503 (dot'd..I - 3 Hz, 4 Hz. IH), 5,5?3 (d ofs, J 2 Hz, 58 Hz. IH), 6,634 (d oft, J - 7 Hz, 18 Hz, IH).

Example 274: 8~(4-ami«U“2,2-dioxo-l H~beuzo|£| H,2,6|thiadiazin-5-yloxy)o£tan-l -ol

696

To a soiulinn of .8-(3-amino-2-eyanophcrmxy)octyl acetate' (746 (unol, 227 nig) in I AD (3 in1..) was added still.mmy i >.hiO; ide (I 4Έ mm·»!, I 7.? mg) and pyridine <4 -17b mmol 362 pl..}. The reaction mixture wax stirred at room temperature until completion, then quenched wnh sal. NaHCCp (15 mt) and s- did NaCI added.. The prccipate was collected and wilted with water. The wet precipitate was suspended m,EtQH (15 mL) and treated witn NaOI I i ..,°52 mmol, IN. 8.95 mL). Thereaction mixture was refluxed until completion then cooled t<< room tesepcianna. Must of tL· Et*. Hl and water wctc resumed m xacuo, then the waetion nnxuiie w o s-' xeo i 'Xab- (I > ml i es i -c.» u wub cd >' < ^!> \ ? ml 1 ff\<cd f' ouyh e 0 E a u FTFE Trit,/then, acidified with .10% citric acid/water solution to pH 4-5. I be pt ecipw.te xs :,s filtered off, washed with w.Uet and dried te give tte„ desn'cd product 146 mg ro 3'm as ,m offMtee reuid Tl \MRκ400 MHz. DMSG-%) 0'1 2M pm olh, I 336 (m. 4H). I 785 (punch 7 Hz. 2H),3.V:h pi ,/- Ml/ 2H) MM _r ./ - 5 Hr 2H),o %(i ph J = s Hz HH 0 ’2Hu, / xIL. HI) / 128_{( / Μ|_λ , '9o-.m ' IH) 8 T»(hr χ. Hli, ItW is, lib Ms 2)? (MH’).

Example 274a: S-i3~amms>-'-ey an. pre ».»\νι, acetate .A solution «>f χ-κ2<χοηο- >-n Ucpl eno' x )m, ,yl acetate (802itmol, 268 mg) (Example 274c) in EtOH < I ? mL) was nydrogenated m an H-cube apparatus using ION-HMd? as s'atalx -a 1 he -.c'.w on \s v > xaps'.at. j c> gn e s-ι -<-..mmo-'M x.mooncnexs loctx I ccetate i 2 >^! n g, 244 nig). M.S 305 (MH )

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F\<itnpk' 22,±b x-( 2-cy di=> -3-·uEopbcnos - Joels I uckiic fi--byvb--xy >·Π’Ί<?ν >·6·ηη>··ί’·.·:!,'οηη»{'.ο ix% t,nol, 235 ,n<>) (Ex-ma/l.. 274c> uas dissolved ?n dry DCM ( = 0 ml s eo-ded to 0 <., and treated sueer-sh civ άilk pyridt-u(3.216 mmok 269 gl ) and acel-I chloride (1.698 inrnob I I4 μL). The reaction jnixturc was -mned and db -red 6' n,unis)ouly t-Hoem Omp>.iamrc \\ hen (he c a.t >>n v.a·- complete. ibo volatiles were removed tn \aeoo and the ..rude product purified on silica gel (10% to 50% I: t(JAc in hexanes) to give the deseed product (268 rng. 100%). MS 335 (MH ).

I ' ι Pj>i.e.274c; .Ms-hy drossoctyloxs )-6-nitrobenzor»trile i o a s-Ncjon of I .S-ociarodtoi HS” mm-d, %<'-> mg) in fHb <dry. 19 ml.) was added 2,6renii obe .-’em >i e {. 29 ό»ό'. 2-0 see,) am. HIM. {.8(1 οοίΊ '%{,, ί Ihe to .< t.<>n iz.stim uas snn-.d lot 24 bom's ,_{r ηκηη leiupcrontre an evap.-Kued. Tbv > Is teodue '.sas tiiumned with 10% mine acid '\an.-t and sohd \aCl added. I Ik- precipitate >>.3s c·. kxted , ua.-hed unh u.mj. d= s-.'j ;n vavuo and (>uiihed er sttic-i ecl t4{.)% tc> lGif’. FtOAc tn be.xancs» to g-ve tise Ues-red p-oduei 1255 mg. 62,3%) csa puif-sb solid. MS 293 (MH ),

Example 275:7-'(4-aminn2,2-di0x0-UI-htnzo|cHi,2d>|thiadmzin-5yk>xy)hepian-l-ot

697

Prepared as in Examph.· 274 from ‘?-(3-amino-2-Cy am phen· re' )hepts 1 acetate (Example 275% and sulfamoyl chloride in 79.4% yield. ^;H NMR (IGG MHz OMbf)-/ ) 9 I 329 (nt.%1). 1.495 fm,4H), l.Xi H.pcnlet,./ 7 H/, 211». S..C8 tm./ 6 Hz. 21iI. 4 154 (k 7 Ml/. 2H), 4.331 {?. / = 5 Hz, IH), 6.605 id.../ - 8 Hz. I H.k 6.752 (d. J 8 Hz, IH). .454 {t. / 8 1W 111). ' x 23 {In s. IH). 8 35x (H s. i H). 9)¹ Ho {s. IH» V6 3.' x ·. Ml I )

I s.amp^:e ?3a / t3 atreu.· ..’ lAaaopbC'nwy Ibc'Vyi aces <c .>aid<. as in Example 274a from 7-(2-cyano-3“nitfopbcnoxy)bcf)tyl acetate (Example ob) i <'%= yield- MS 291 (Μ.ΡΓ)

Example 2 ?ob: 74(2*cyah0-3-ilittbphcnoxy)heptyI acct;tie

Prepared as in Example 274b from } v-hx deoxy beptyioxy )-6••mtrobenzonitrile .(Example 275c) in 100% yield. MS 32) (MW).

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F\.nn?k 2~%\ 2-(7-% dm xyhep0 low E-O-mircbeii/einufie %r iiu^! a- m I'sanipk 27% iex^^e; 1⁵Bl '(.pfae/d άUL IkllB-i} ίί-m. 1.7hcptancdiol m 65% yield. MS 279 {MH ).

Example 276:9-(4~mmm>~k2-dinxo-1H-bea/e|eH l.kbl ihiadia/in-S-Unxymoimtt-l-ol

S9§

Prepared a- in I xanqne 2”-l from 9-(3-.Hnifi,t-2-e> tiu-pPm/xx )n<>m I aret tie (Example 270;d mid sulfamoyl chloride in 623% yield. 'H NMR (400 M.Hz. DNISO-%) A1.250 ύη. xH), 13*81 (:u. 4H). i .791 s pentet, </ 7 He. 2H ), 3349 (,.:../ 6 Η?, 2H). 4.135 ΐϊ. .7 6 Hz, 2Hk 4.301 %,% y h_z. j h i. <-.565 (d ./ - 8 Hz, IHl.iv'x (d 7 =- s Hz, HH 7.434 ((../ -x Hz.

Hi) hh (bi If!) x .MMh <, Hi). if)9?l <<- Ill) MS%>(MH) ' % 9-f3-4mino-.\ey an/phe:V>v.'in<’nM aecl.ife

Prepared as in Example 274a from 9-(2-cyanO’3-nilrcphenoxy)nonyl aeekuc (Example 276b) in 993% yield. MS 319 (MET)

I- xample 9 (2 vyano 3 nib «phen <v< ):,io:,iyl aeebue

Prepared as in Example 274b from 2“(9“hydrGxynnnyl£ixy)-ft-nitrobenzonitrde _f Example m'M0% y ieM. MS 349 (MH », .Example 276c; 2--(9~bydroxyimiiyWy)-6”nitrobenzonitrile

Pi/pareu as jr ί χαγόΕ / le texec/t OBi v\<n< te’> *ee Inn I > 3 1svtrajneihylguamdfee) from .1,9~nrmanedior and 2%-dinHmbenzon.ikile in 30.7% yield, MS 307 (MH ).

E xample 277:N~(5-(4~ainlmf~23~dioxo~Hl~benrokin (2,6){hiadinzin-S-xkm ?1κ*χχ1)~2~

In d i'oxx~2~mei by Ipropammi ide

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Prepared as in Example 274 h-=>ns 1 -(6-(3-amino-2-cyanophcnoxy)hexs-lamino)-2metnyl-1 -oxopropan-2-xl acetate (Example 2?7a) in 65.5% yield. Ή NMR (400 MHz, DMSO,<>> 0' I 20 = Ο- nH), 1.2/-9 (m, 21b. I 399 i m, 4H), l.’^-i0 prentet, / ” Hz, Mb. 3,O3<- re. ^!

Hz, Hl), l I 30(1 Z nHz. 2H).5.272 (x. ilb> re'<d .7 8 11.- IR) (T2S {.1,.7 bl'.db •%3<->U.Z SH; bn. >U(tiT t. db. · <%H (br.-., lH).x 32<>(hr s Hi). U>92l(s Rb MS ,W₍\!H ).

Example 277a: I -f o-( j-an> mre2-c\ anepbenare )hc re lamn t<»>-2-nreihy I-1 -oxopropan-2 -yl aecia tc

Prepared a- in Example 274a (rem I-(M2-cvam>-3-nm=»plicst>>xy mexyiamrne)-2med^!.yl-l->-x=-pr='p.m-2-y I .rectalc (Fxamplc 2~4b) m 94 4% \ k'M. MS 3-82 AHI ) .Example-277b: I-1Μ2-<λ ano-3-tni'= -phea>-\y i'k'xx ancmO-2-n'etk'. I-1-, x»-pH-rem-2-\ > acetate

To a solution ofiert-butyl t'-(2-t\' anreZ-nmor-henore )herelc:.ibama:e =,3 >3 μηιοί, 121 mg) (Example 277c} in dtxoanc (2 mt) was added con. HCI (I mb). After 15 minutes die solmMu r.=s emK-enre oed in \ ^cue and dried on high \aum-n, Fite cnal<‘ l ΚΊ sail suspended in 1% M (dry. 10 mb) and nemed with pyridine (2.m<4 mmol. 215 μΐ.) and 1chl> ·!=?·;'mc-hy 11 =?’<oprep;m· 2-y I ace-are {1,332 mmol, r’3 μί c I'lre reaction m-basc η re refluxed teder a nitrogen atnidspbere until clear (6 hl. Own c»«=lcd to room temperaiwi and the volatiles removed in vaen-e The residue was purified on .mIr-u gel (40% to 100% EtOAc in hexanes) to give the product (117 mg, 90%) as a light yellow Ikax) oil, MS 392 (MIT).

Example 277c: tert-buiyi 6-t2-cyano-3-mtR'pheuoxv ib^xdcarbamate

Prepared as in Example 2:.15c from tert-bud I =- hx d= = <re hexx ka- 'x=maic hi 53,8% yield as light ycliou -olid. MS 3o4 (MH ).

Example 278: b(6--(4--anwnO“2,2dinxa“lH”bgnzo|cH'I,2,6]thmdia2in“5~ytoxy)hexyl)urea

766

A s-.-k;,i>-x of I (6 (·* .'mro-2.2 dn-v lH-ben.> c][1.2/']finudj,\xa 5 y: -\y fhexy Π 3 s-l mc'rr-xy ixrezy'.'iurca (I 22 Ltm- l, >8 rag) J xamp c 2 ’9) m LK'M =,2,5 ml) v.a\

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2017200704 02 Feb 2017 treated wuh TFA ( 2.5 ml i the κ’λΙ,οη mixture- was stared at '««ms tcmpetatiirc for 4 h<'Uis, men me volatiles were ? i. mos cd au.k: a % earn > -f mil < 'yen t te od\ ί es.due ·.' .> t' u i mu d 'ink ether, the precipitate collected, washed. with ether, then dissolved in MeOH and evaporated to g.vre tik·desired pteduet t44 nuJOtfe > tdd) H NMR (400 MH/. DMx< >·<ί > d I 3<>4 ire, i-Hk I 812 ipcniet. ’ 2 H? 2llk 2 ^!! B < to t, 211k Π ' I <.d J Hz 2H). *% _{{ ./ H/21H, 5.3 49 (hr s. 211 χ 5 S94 (br s, .1Hj. o *S07 (d. J == <8 Hz. .1 ...Hk 0.75.2 (d../ === 8 Hz. IH). 7.456 it../ h 11/. IH). 824 {bi. s. sHk 8.3% (hr. s. Hh 10.095 is, HH, MS 350 (MH ).

Example .279: l~(6~(4~tmiisto2,2~diox0”lH~benzo|ci H,2/>phiadiazisi~5ykixy)hexyl)~344“ methoxybenzyl)«rea

lire sti-p-Aib-H <>f <<-(4-.=mmo-2,2 di. \·· IH be-w. k%l,2.< puiauweni 5·

Η·.\ΐ )I=i-mp I anumum ehl>-=ide fji<6μηι>·1. 52 tr.gid xamplc NSt'q i dii Dx'M i^f'ml }w.w stieccs-oi-H added FtA^! (.3.32 μην»Ι,46μ| ) anil l~usjesanat<nnetliyl)-4’methoxybenzene (183 pmol. 2.0 pkl. The reaction was stirred for 4.8 hours at room temperature then concentrated in saeue He. ·/-.χΐι.ι. was washed with waut, dried, tLxo puid'cc >·ί Mica yd {26’ e to itofe I tO 3e \j hexa.iesl u· eise .he oex./eu oioduet e>4 η,Λ, xl atos.ded H NMR. v *00 MHz.

I)>1 v¹ > k'l <>Ί ,29i· ioi, 2H). ...3'' t tow 4lb. ' ,“Ή iuenut, J r Hz. 2H). 2 fed ./ o 11/, 2H), 3 <895 (s, 3H),4.086 (d, J == 6 Hz. 2H). 4..131 1=,./=== b Hz, 2H}.5.83t. {hr. 1../=== 5 Hz. IHk 6.141 (br. (,.7=== 6 Hz, IH}, 6.585 (d,./ === 8 Hz, I Hk 6.727 (d,,/ === 8 Hz. I Hi. «> E«b (d../ === 9 Hz. 2H}. 7.137 id. ,/=== 9 Hz. 2H), 7.4.33 (t, J === 8 Hz., IH). 7.803 (br. s, 1 Hi. 6321 (br. a. IH}. 10.926 (S. IH), MS 476 (MH ).

Example 280:6~(4~a.mis5o-2,2~dioxo~l H-benzofc)11.2,6| thiadiazia-5-yloxy)hc.xan- l-ammium ehlonde

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702

Tq a salute =n of ttct-bu^'16^(4-8^1110-2.,2-410^0=1 H“bsazo[c](h2.61tlnadiazi»“5« yMsy jl-vxx lost l-amate {1 IS aie, 28e v.-uoh (Esj.npk 2s 1 m da χ,ι.κ {.' nl ) w. *- added con.

110(1 nd >and tii·; sointjOB stHjcd at :ovnt tcn'peu-.tmv l>a If mi.rates I te s-,mcnH v-ere removed in vacuo and she residue t= iturated w ith not cthand. Λθο= coo'ung t<’ room iciupcjuture, the precipitated was collected, washed with hot ethanol. and dried in vacuo to give the dost red product 5b tngto2..9%l as an off-white powder Ml AMR {400 MHz DMM'm/.j p'l 367 (m, 411), s 529{pcmct. 7 7 Hz. 211). I “95 (petdei / 11 \ 2111 2 41 (br m, 2111. 4 144 {. .7 “ 11?, 2111. 6.59b (d. 7 - 8 Hz, 1H). 6.733 (d. J === -8 Hz. IH), 7.440 s t,./ === 8 Hz, 1H). 7~25 (br. .+, 3Π1 7.705 n_{sr s}. IH). 8.350{br. s. HI?. 10.954 (s. Hit. MS H3(Mll i.

Example 281: terl-bwty 1 (h4-amiao-2,2-dioxn-1 H~benzo|c|i 1.2.6)thiadiazh»-5y h wy the \vIcarhamate

Prepared as in Example 274 frum tert-butyl 6~(3-aminO~2 cyanophenoxy)hexylcarbamate (Example 281 a) and sulfoo-tey i chloride in 59 5% yi-.--d; Ή NMR (400 MHz, DMSO-^) h i .274 (m. 2H), I ..339 (s, 9Ht. 1 3M (tn 4Hk t.“79 (prmtet,,./^:::: 7 Hz.2H?. 2 (q.,/ 0 He. 2H), 4. = 22 (t. J b Hz. 2lb. 6 5b0 id.,/ 8 Ηλ HH). b.‘“22 (d. 7 s

He. llH.n /5 -thr i.J ό Hz, 1 Hl. 7.428 <t. J * Hz. i H). 9,-=)8 (br s. IH?. s 323 (br.+. IHk ΙΟ0.Ί {.>. IH). MS 413(MH'}.

h-sample 28 la: tert bmyi t< (3 amine 2 cyar.ophs’m xy ?hexy le-nbamayPrepatetl as in Exampk· 2 '^r la t'ro-o ten-hniyl b-(2~ey:mo-3ivjrepbcno' xlhexxlcarbatn re t example > n qu.unihnwe yekl MS HI (MH 1

Example :2^2ii^<?~(l^:H-pyiwl“l'*yl)et!iexy>lii*be)BZ0hniX6Ufeia<iia4n4»a-mi»e“24~ dioxide

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Prepared a- in Γ xaruple 2a Imm 2-( 2-( I H-p\ rrel-) -y herbexy 5-6ampvtbeh/oniidie (I xarnpk' 282a) .ml =-//Grey I rekrde tr <><> t>%xseld ’ll NMR {-'-i »(> Mik. DMSO-nX)O'43%{nrrelb.-992n. 7 2 Ik. 2H). o 598 =.1, J S Hz. ΐ Η> n NO td. / 811/. HL·. 6 X !n 0..7 ' IL· 2ΓΗ '' '-'.Ν' (;, 7 X Hz. Hi? lx (bi s '.IH 8 ?xx ( v ||j_K 10·Η(> (s HI; MX Ifi’iMII 5 .Lx.9.9W.Ls'.,28?-(.'-( I H-nysnJ-I-'. Doth->\s m -aminobeim>nmtk'

I’scoarcd a- n b\ai'>L? la fj ,> n (] H py; i el Okfkov. nuri'ivnzenurle fl'sample 2821.9 .n 85 2% void MS 228 Alli ).

b x ampk 2X2 ly 2 -(2-( I H-py.no 1*1 -yl jcthexy )-6 -nitrotenzonitrife

Pr, pareu ns »n l-xannde mod h-m; 2-fJ H-py1-\ Ikiharei .·<α(2 <>“«liijweben \nre; e ri

42.?%yield M\25_fx{MH ?

Example 283:5-(2-(1 H-pyraxel-l-yljeHmxy ?~1 H~be»zo|e|| l2kfcHbi»diazin~4-amme-2.2dfoxide

Prepared, as in Example 2'74 froffi. 2-(2-( IH-pyrazGl-I-yQefouxy)-6.afhitt<?feteon.itri.le (Exahipie 283a) and sutfanimd chloride in 54.5% yield.. ^!H.NXffl.(4(®:MIfe, DMSO-^s) 14.406 (l J 5 Hz. 211,. 4 %‘d (t../ 5 11/. 21 h t· 266 _v. ./ == 2 Hz, .1H), 6.893 (d/J - 8 Hz. IH), 6.689 (d.<7= 8 FL·.. ;H), 7.44? (hr -. 1 H). 7 425 o. J <. ILy IH), 7:805 (d,../- 2 Hz, Hl) x I (br - Hi) s 301 - Ilh. % 'G '· o HI) Mx (MH )

Example 383a: 2-f 2~< 11 l-pyraznl-' -s ). tnoxyNd'/ nnwberre'nip' L·

Prepared a.- in Example 2’Ma from /.-(2-(1 H- psm/ei -l*yl}eth0xy)-6i'UrebcnzeiUirl.'fl \cnple .\x3b) n 16 ' ‘<>y ek, MS ^n>,i\lil '»

Kan-pb 2x3.9' 2-(2-(IH- pymzd - -s.i/ί is>xxrobeo/vnilnie '367'

WO 2{W1M221

2017200704 02 Feb 2017

Prepared as in Example 2l$c Gem 2-( iH-pwa vl-l-vl)cthanol and 2,6-dinitrobcnzonitrilc in

89.2% vid·.1. MS 259 (MH ).

Example 284:5-(2-(3,5-dhnetln l-lll-pt razal· t-y Octboxy )-IH-Benzo MH L2.6|tbradla/la-4amiae-S^-dmxide

Prepared as in Example 274 from 2-i2-i3,5-dm!cihs]“lH-pyrazo:“l“yi)ethoxyi-6armnobcnzonitrilc (Example 284a) and sulfamoyl chloride m 18.2% yield. Ή NMR {4:81 MHz. HMM = -(0/: >')2 Jim; is, 3H). 2,215 is, 3H). 4.313 u../ 4 Hz. 2H I, 4.3% (t,./ 4 Hz. 2H:. 5.091 is iHl. 6.584 (d,./ - 8 Hz. IH). (>.645 (d.../ ==· 8 Hz. IH:, ? 4 18 ft,./ - 8 Hz, IH). 8,395 {br. s, 1Hk 8 n ' (hr s. Hi:, 10 585 (s, H: MS 3 9. {MH

Exampk. 28 la 2-(2-{3.5-dimethyl-] H-pyra?.ol-l-yhcthoxy)-6-aminobcnzx>nitriIe Prepared as in Example 274a from 2-(2-13,5-dimethyl- HI- pyrozol -1 -y l)eihoxy)6-nittohenmnhrile (>. xample 284b) in 69.3% yield. MS (MH :

[..>..9.η.;Γ.Ε).354ρ. 2-(2-(3.5-dimcthyi-l H- pyrazol -t -x Ikda-w :-o-nHtolx'J:Z->nhrile

Prepared αχ in Example 21 5c from 2-(3.5-dimetbx Pl H-pyr.izol-l-> lielhand and.

2,6-din.itobenzomtrife in 90.7% yield. MS 287 (MIT).

EXPERIMENT4: Biological Assay

An HEK293 eul line demaiht· (Chandr.^hekar ·#«/.. C\ii 100. 703~⁷l1,2000) which stably ..-xpres-cs Gul5 and h ΓΙR2 hTI R? (I <7 i>.^: Pr Xnri A .?<>’’ X / ί '3J 99, 4<''°2-4mk< 2002)=, <s Ιπί.ηηαποηαΙ P-id'e-Aer No 35'0 0 > :)01 S7o: v<a- us=. d m biehy seal assays in as^odanoti nuh mcw-ls ing compmmds w- = h ^acel taste enhancing properties.

* 'ompet.ru- wac ir.t alsckcud h ..-cd on th*.» aetw six oo tA hTI R2/hTlR3-HEK293-Crtrl 3 cel: Ime Li e/aw/w. Aeth ny was determined using an automated fluorometric imaging assay on a FLlPR instrument (Fluorometric Intensity Plate: Rc-dc:. MoLeului IXs.c..-. Sunr> >ak. < 'A: idesigraKd Fl ll‘R .u-sas: CJN lli-'U ere ebn.s (dc.ugumcd eb'Uc x-*¹) were -ceded ιηΐ<< 3x4-wdl plat·..- (at app'<*xnnau.h 5:\000 si. 11.- pc; welt)

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2017200704 02 Feb 2017 m j niemutn comaming DML'M I <iw ukre-se t Pm ίη<»μοη, Carlsbad. *' Άι. 10₍· -.hahred fetal box me -^ιοιη {Invitoiien (. .e ΐ -kid. C \Ί 100 I eib ini Peu'edl.n < i. and 100 ug/mi Streptomycin Uⁿ' ^reg-ti. Carlsbad, t' \? it i m ^1, 20021 { rec alre. Imeinationa) Publication \<:<. WO 03/001876).

S-9 cJls wcic grown for 24 h--n?s ;a 3 'C. S-9 <cli< were then loaded with Pre c.iUim-i dye I iik> 3AM yMolceiilm ΙΜ^κν. H'.geu·..⁽ift) 4 μΜ in i phosphine buffoieu sdme (0 PBS) -tmv'.raec i.; .-.i -,-u I C M. fot I boa. at loom teiup-.i.'.'ui.- \fiei re Maecui-.m w»tb 2? rd P PBS, sttnndauo;} was peib-inred m 'die Fl IPP msi· reiere· .are at »<-<- u lempe^anire by me addiib-u of 23 μι P PBS suppleincnu-d wuh comp-rends at eoueeniiuib-ns voncspondiug b- mice itmes the desired final U’-rel ί Mtmuhiuou Ii

Cells were incubated w-uh me compounds 5 i ~ 5 .nniuN»· ,m.d then anemei stunuhxuon was perlotmcd m the HJPk instrument uy the addition »-l 25 u'. of l> PR^K supplemented w ilh a sub-opiimal concentre lien of sweeteners (po-ducing .dwut 5 - to .30''recepCn re io ny 1 < xu mdMre~s ^!:

Akcrn.uweh auer replacement with 25 μΐ D-PPre oerweil sbrouianot) was pcitbimed in -be I i IPR iiiMrurneni at loom tenipetaiiu-. by add oc --f 2’5 ui D-l’BS supplemented with different stimuli.

Typical sweeteners used include, bat are not hm.u.u .« D-Glacose, D-Fruetose. Sucralose, Aspartame mid Sucrose. Receptor activu was then qH.'miiiu*d by detenu-tung die nis,ne,’looie^e s c nc en - ιιηγ¹] i exrita’on ifure^- ₍rn , nis-ip 1 i ret norm Pi, ate -n it'» basal fluorescence m-ensiiy η'οοΊΐιηΜ Am re stimulaiio’·' Compere nds producing an. increase in sweetener-mediawd receptor activity were chosen for further s so <. usual <n . x ς i re i uiion- p»> c i ‘ Ί e ami n e 4 pn pci t

In -hi\ iobow assay, a fixed xoncenniHi-m of c-impounds was added in dnpb'cates η > 10 eonse> mixe cfournns < 2t) w el ft te-tali dicing stimulation 1 1 y ptcal compound concentratforib rested w>. re 300 uM 100 μΜ 5(t μΜ, 30 μΜ 1C> μΜ 3 μΜ and I μΜ. 0.3 pM. Od μΜ, or 0.03 μΜ, After the 7.5 minute ineifoation period, increasing concentrations of sweetener {to generate a dose-response curve) was presented, hi the same wells, in duplieatos, during stimulation 2, The relative efficacy of eompbtmds at. enhancing the receptor was determined by the calculating· the magnitude e*M slvfi 'n rhe Fl\< for the sweetener. Enhiiucoincnt was defined as a laee iFC-·, Ri esnondmg to tire FC,? ofswcciuners.

WO 2038.834221

2017200704 02 Feb 2017 «k-temuncd m the aRrare -of tire. re c e<>'up.'uu>l dsxided I x t ic 1 C of the v\ ucreuci. determined in the piesencc ol the ice compound. in some embodtnrents, t-otHpounds haw ail I\>.R hetxxecu ,ih>>ut I h .s-„ ' I > and al-oui 1600. hi .Hirer embodiment^ ceuipoinreK bare an f( _t.R Ireuxeen about i,2'^x and ulrnui 566. h= si ill other esnbodinretii'·, coinpounds haw an Et\< R berreevu al-rau I 56 and about 166. In yet -Hirer embodiments, coinpounds base an £( -=.,R .between about ι o / ' h and. about 50, hs stih otbcj »n: x<»dnucnt e- ir.Maud- at about 5^f> uM baxe a t H ,R κ-ίχχ ,en about I fn.<! '' iI read ah.-at ; -600, between about = .25 and about 56’6. between about 1.50 and about 100. o; I ciwcen about 1 (e.g.. - I) and about 50. Assay result.-' fen cc-my-Huds are illustrated in 17-. nL· 8 below.

In one illustrative exampk·. the pre·incubate.I muoh-se 1-( -_t.R ar 56 uM m one group of specific o-mpotmds ?' the present tnscution generally -nice- from 0.73 n> 5 20, white the c->-sumulmion .wcraiosc f-f's^R at 50 uM for the same gi >up of c<»mpouriids gone:ally ranges from 0 ’..' t-> -I 4n to another illusira-ise example dv. -.o-siinu.il aed '-turosc I C·..R nt 50 uM for one group ot spec·tk compounds of the present ins era-on g-..ncralR range-; ftom I 30 n> -I a>, the co-stimnlation s-reialosc I C .R al >8 uM for the same graup --1 eon-pounds generally uu'.ges from 1.73 to 24,09, and the co-snmulatum ftuct--sc H <,R at 58 ρM for the same group <4 compounds generally tanges fiom 6 El t-.« 4 an, lu another illustrative example, the coStimulated sucrose ft % at 56 u\l t.xs one group of spec Ole compounds of the nn-*» ra invention generally ranges from i (K io 2 it, the ca-sumuiatiob sucralose fC-.>R at ?0 u\l fo- the same g:oup ot'ceeip -mvs gz wr.foy ranges from I > to H <>3 imd 'he c- -Ί mtdat on fora k'se Fik-R at 50 g.M for the same gteup -= co=np·-i-rais gera rally ranges from 0;» to J .78. In:another illusrrahxc example the Cv-co-mbaied sucrose FC _t.R a- 50 pM u-r one gr-'-up of specific compounds of foe ρ’-..<·,.-ο· inx enuon generally ranges 6-uu l 27 m .1 .lo.5b the c- -st mtiUtioh sucralose FC-.>R al 5t,> pM for the sam·.- group -= e<>mp.amd\ ge tallv ranges from I.,48 to I ' / O'- .we foe t e-ra 'lukrao -. iuetose It R at ob uM fra the same gteup - t compo-mds generally ranges from 0.68 to 9,56, In another illustrati ve example., ihe eo-siimulated sucrose 15' '...R at ,-Al rex out- ,.Ό-ηρ ofsp.-eifi.' tompounds ot fo.· pre-ml raxemton generally ranges from 6.88 to 36.66. the costimuiaiiou sucralose EC;.=>R at 56 μ.Μ for die same group of compounds generally ranges Frau i ,07 to 161.15. and the costinetlauou lreeto*e FC ->R at 56 gM for the same group of compounds generally ranges from. 8.71 to 7.09, In. another illustrative

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2017200704 02 Feb 2017 example, the co-stirnukued sucrose EkfoR at 50 μΜ for one group of specific compounds of the prexenl mre'nn.'n goiumb© ί mges from I fo ‘e “ ‘be ee-x^irmlatm-i ^ι,α,',oxc ia’.,R .-.1 J) μΜ fer the same ;p<-up .Hjp>amds general Ex ntiigc^ from 3.©6 to 4“,S9. and tire castim-ikiueii tiuet'-'C EC <>R at 5© μΜ foi ihv xamt gioup <4 cotizpoundx gciretaU© saugc- fruin 0.92 to ο 0” hi Jib-?ber :11usi?,un c example. ?he c> .-t=inulated mcb-sc Et. -, R ar 50 μ \l ?'> i one group of.'Po.ifte e>-iupmmd.x --fme present mxemion gwreralh umgv from I .30 n> tonlT tuc <' .uamiifitam soenOoxc ί¹ h-R at 50 nM l<n tbc -mrc μ· up of e-m pouad» ^cncotky ranecx from l.2on> 20-t 9©, mid ure e<»-siiinuk^!.tion naerexc- b\\,.R a? 59 μΜ fortliv sa-ire gmmoef compounds gene-ally ranges Oom 1.14 io 8.37.

EXPERIMEN T 5: Snect Flavor and Svect Flavor Enhancement Mrasmemrtit Hsing Human Panelists Conducting n Scaling Fest

Rist samples containing s-xpcrtmemal e·impounds ©sere compute-1 io a dosc-resp-·π.χο curs e for neixcised xwe-.tncsx rnton-my of sweeten-., m l<i.r..b as los -..-©ample, sucralose, sucrose, fructose and other sweeteners} concentrations to determine equivalent -mcetncxs -mens;':}

A group oi eight ot more ptmcfok- tasted solutions including sweeteners at various coneentratb-ns. as a ell as the expenrnem d compound both with and without added sweetener Panetixtx th-, n mX'd sv,cemexs uw.-rwip at all x.-mpics on a structured horizontal tine scale, anchored fn»m 0 to I .© u here (i ,-gualx m- xvre-.-inexx and 15 equals equivalent, sweetness to a 15% sucrose sample. Scores for sweetness intensity were averaged across panelists, Then using the average scores andfor equation of the line for foe sweetener dose-response curve, equivalent sweetness couceniyarions were determined for foe samples containing experimental, compounds.

Snh:>,-:, had he>. n pre© iou-d© fam-bane, t a ©ii lire key ah-ibu’e ia<>- >m-l v, . re reamed to use the 0 to 15 point line scale. Snhicctt. (vthwd from, eating or drinking (except water) for at least 1 hour prior to the test. Subjects ate a cracker and rinsed with water several times to clean the mouth.

Sncel.-mu MuPenx .ore psex:.,kd a?.; Aide range of e-meentiaPonx xireh a- i(”J ppm, 2i)i? nnm. 300 ppm. -^;i)i) ppm. md 50(i ppm foi suetal.^t, ur heiwemi 0% and 12<_: for sucrose or fructose, in order to create a doxe-rexpousc cine. Samples containing experimental

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«.'ompounil were pi /ρηχό bmh akmc anil m a 100 ppm ../:/ aio-c solim’ou or re <>’’i. -mcrese or fiueU>sc sobihrai Ah samples -sere m.iik' up in k-v- --«'dm.re :)ΐιιΙο ?H “ I ki mdei .re . id dispersion, solutions can be made ap in 0.1% etbuool.

The sreimiem nmc -.h-pi. ised m 20 red \ «'tomes mto .o s. upto uips ~rJ sei'-ed ?o die .subject- m loom rem.unume Ml -jmplc - were pre.-cuted m i-rad·muzvd c,unkrbal;mec«J order to reduce response : κ-s Further. η%,. -=/-,m,-as ,4 iesung max bo used to check panel pi/vi.siom

Subjccis ia-ncJ cad· -annpk' indhideally und rare sweetness imensnx on the line sedc piior ?o tu«,n‘m> the next sample, .Ml samples \xeie expc/imw/d. 'subieeis may icfasie ihe -uiuples but >.an ,-mx u-c rhe mme of -ampL g \i.n Sub eus nusi s. ise v nl· -rah; nenveen samples. Eating an unsalted cracker between samples may be required depending on the samples lasted.

i he -\ore< tor ,.ach rumple were <nerag>..J m.re-=s ^.ubjeeis .mJ standard error urns calculated. The d«>se-rvsp«.:nse curve was plotted graphically, and. this may be used to ensure the panel is rating accurately; /.&., increasing the concentration of sucralose should correspond, to ;nerea-=/J axerage -\i>re-< foi sv.ccin,.re \ ,:-w,,y AAt'A \ fact- ;s being samples ,md p.mehsis'> and multiple comparison tests (such as Tuboy’s Honestly Signified! Difference test) mm be used to determine differences among samples and or pane lists. A 3-wa.y A.NO VA, xyith sessions as the third factor, can be used te determine it there is any difference in the ratings bmueen sessions.

'hoeompeoms ·..-ice io mi- I xperemem. n.miely. •xu-'uxnmd-. ·. J m t .'I .«se ropresem.Hive compounds of the present invention including compounds of structural· Formula (1) .mJ Us xubgtmerk formulas;

The results of human taste tests wi th a compmind: Cl are found below. Table-1 m-lu-aics ih'n Hid pM compmmd C 1 in >00 ppm suexdo^e ia- s-Aocme-.·- eqirnaiont to ppm sucralose, Table 3 mdientes that 100 pM compound Cl atone has. no sweetness, and therefore can be defined as a true sweet enhancer ,

Table I. to erage sweetness scores for $ .;Hou- sucralose -ampler, sneiudmg I «hl ppm -uientloxe wnh Hili μΜ eempmind CL n 52 iff' Pammsis .x 2 icpheates). lukey's xrekie i .109 (o.

0.05). '

Sample

Average

Skuniard

Tukey’s HSI)

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		Error	Sigmfmmwe (S%)
100 ppm Sacra lose	llililll	0.3	A
100 ppm Sucralose r 100 pM €1	10.2		B
.200 ppm Sucralose	10.4	0.5	B
360 ppm Sucralose	H.5	0.4	Be
400 ppm Sucralose	12.3	0.4	C

Tabk 2. ,X’> ,?3>_’a'suclFcss scere's Pm IPO μΜ s'-Huponnd <Ί are ov. si-dimr ·> iffi r. u P'(15 Pauxhxix \ 1 reps luki.y\ sabre 0 IS6u; 9(>5)

Sample	iif	Sta» da rd Error	Tukcy \s Siguificmwe (S%)
Low Sodium Buffer (eontai us rm sweeteners)	0.1	liilillllllll	A
100 |t.M 7	0.1	0,1	A

The results of human, taste<tests with compound C2 arc fsund below.. Table 3 indicates that 100 μΜ compound m 100 ppm .mcmimre has sweetness equivalcm to about 600 ppm sucralose. Table 4 shows: a dose response curve of Compound C2 with 100 ppm sucralose vshreh sh-*’A.s th;;· the tmcemcv- of suemiotre ts significantly enhanced by addition of increasing anx c ' - 8 ·» rm I ('2 I al le x «'3»<n ^>i mar 100 ιιΜ > o opou’W ί 2 ale? h'*«· ’ M re t<>

\wcomvsx. cred rhereh-re e.m be defined a- a mu. -uix'i cs-hamcr.

Table 3- Average six cetmws scores, n ~ 1.2 (12 Panelists x I rep). Inkey’s value - 2.449 (a ~

05), 2.209 yr == 0J0).

Treafment	Average	SI>	St Er	Takey (556)	Fukey (10%)
10Oppm Sucralose	7.4	1.7	0.5	2411 fa:........	..........a.........
2O0ppm Sucralose	:0.4	= .9	0.6	1OW : : :	f f f f b f f f f
300ppm Sucralose	10.5	2.8	0.8	11% iff 7	: : : : : : : b : : : : : : : 1
40Oppm Sucralose		2.4		iff = = ibc) f f f	f f f fbe f f f f

WO SW1S4221

2017200704 02 Feb 2017

600ppm Sucralose |	13.0 b.4 0.4 |	V .......:	........0........
JOO pM C2 + IGOppm Saeralmse |	13.3 H.6 0.3 |		.........c.........·

Table 4. .Average awcetac: vak-e ^::: 1.584 {« ^::: 0.05), i.

Treatment

106 ppm sucralose ^;- 3,12 p.M C3

100 ppm sucralose -r 12.5 pM 1'2

J 00 ppm sucralose + 25 pM C2 like

Average jSD

St Er (5%) Tukey OOM

100 ppm sucralose

UM) ppm sucralose

200 ppm sucralose

300 ppm sucralose

400 ppm weisitow

100 ppm sucralose

374

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Table 5. \s a age sweetness .-cm ro. η 12 ij 2 Paiidisls v I ropj. ΓυΕ··/» vahte 0 p.

Treahumtf	Average	ii	iliiii	Tukey (5%)	Tukey(KJ%)
0% Sucrose	0.0	0.0	0.0		/////////////////////pi}}}}}}}}}}}}/}/}/}}}
100 μΜ €2 in LSS	lllilill	0.3	0.1		:|||||||||||||||::
2% Sucrose	2.4	1.0	0.3	b	b

The result of lutm<m taste rests with compound C3 are found below· ί ahi. < indicate-: -h:s ipp pM ecmnound m IOO ppm sucralose has >v. eein-..^s equivslant to about between 200 and 1{ψ ppm sucralose. Table 7 indicates that. 100 μΜ. compound €3 clone has no sweetness, and theses-re can be defined as a true sweet enhancer.

fable t>. V- craze vaccines'. χΑ-rcs. n IS I i 3 Pandits \ I rep) I ukm '$ xalne - ?. ?33 (<».

'Frontmen 1	Average	||	Bill	Oiioiiiiii	Tukey 110%)
100 ppm Sucralose	0.3	1.3	0.4
200 ppm Sue ro lose	9.1	2.0	0.6		/:S:S:S:S:SKSfBSKSS^
100 ppm Sucralose r 100 pM C3	9.8:	1.8	0.5	lOHb/Tv	:::::: W :::::::
300 ppm Sucralose		2.8	03		::::::: 0® :::::::
400 ppm Sucralose	11.2	2.3	0.6	b	:.......C.........

Table 7, Average sweetness scores, n ^::: 13 {13 Panelist > ί rep). Titkey's value^::: 0.906 (« ~ θ_:θ2.)Λ.θ:ζ11..ί«.::ϊθ;1·Μ...............,.............................,...........

Treatment.	Average	SB	St. Er	Tukey (<%)	Tukey (.16%)
100 pM €3 m LSB	0.0	0.0	ixo	13111% NT : : : 2	? N
0% Sucrose	o.o	0.1	0.0	:: .......	............a ...........
2% Sucrose	2::::::::1.8::/%	l.o	03	ABNNNNB-N:: N :: : :	::::::::: ill i i i i i i i i

be mxuhx .-t hwnm· ta.ue i-.-ste wnb . c-impeund C4 are fmind he'ov. 1 .mlc S indicates that 100 μΜ cempmmd C'4 in 6% sucrose has sweetness equivalent t® 8% sucrose. Table 6 indicates that 100 pM compound €4 alone has no sweetness, and therefore can be defined .w a ιπκ· sweet enhancer.

WO 2068/154221 .PCTTS26W0Oi58

2017200704 02 Feb 2017

Table 8. Vreare· s<\cen:gss <>>»es for wivm sncr-.-w sumpks. nremdiug o% sucrose wnb 100 pM compound €4, n ^;:: 28 i 14 Panelists x 2 replicates). Tukcy s value ^::: 1.09 J (a^::: 0:05), 0.976 (o 0.10).

Treatment	j Average |si)	St Er	| Tukcy(5%)	Takey (10%)
6% Sa cruse	η 6.6 p	0.2	.............................................. ...................................................................
8% Sucrose	8J Iz.l	0«
6% Sucroset 109 μΜ C4	......ΐ..........,····..........,···-··	0.2	f...................................... b	ΒβΒΒ^ΙβΒβ
..........................................................................
9% Sucrose	i P	1λ4	liiiiiilllll
10% Sucrose	j 9.6 10.6	OJ	e 5

Table 9. > rage ^aeetncs^ steres, a 14 {1 a Panchos \ | rep) 1 ukey's \ aloe 0x~u(a

0.05k 0.784 to^:::: 0.101.

Trent meat

Average SO St Er Takey(S%) § Takay(10%)

100 p.M €4 in LSB

0% Sa cruse » Sucrose

4% Sucrose

6% Sucrose

The results' of human taste tests with a compound C5 are found below. Table 10 indicates that 100 μ,Μ compound C5 in 6% sucrose has sweetness equivalent tv 9% sac' ore, Lible 1 ϊ mdrcatcs :h.n 100 p\i compound C5 alone bc> m- ‘'weetness. and theicfoic can be defined as a iru·.' s'v vet enhancer.

WO 2008/154221

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2017200704 02 Feb 2017

Table 10. Avcraac Sweetness, π ^::: 24 (12 Panelists x 2 rep I. Tukev's value^::: 0.832 (u 0» OS.

/1.744 07 =-- 030)1.............................................................. '..................’....................................................

Treatment	Average	111	Si Er	llllllllllil	3Wy (W%)
6% Sucrose	7.3	III	0.3	iii3liiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii
8% Sucrose	iiiiiil	11	0.3	l|||||||||:||i|i|	:iiiiiiiiiiiiiiiii||i:iiiiiiiiiiiiiiii:
9% Sucrose	8.6	ill	0.2	be	be
6% Sucrose t- 190 u'M C5	iiiiiii	0.9	0.2	illlllllilllll
10% Sucrose	9.6	ill	OJ	d	d

Table I L Sweetness, n ^:::: 14 (14 Panelists x I rep). Inkey's value ^::: 0.981 (n ^::: 0.05).

0.877 re (’.IO?

Treatment	Ayersgg	SD	St Er	Tukvy (5%)	Tn key CKI%?
LSD = 100 gM £5	illlllllll	Illi	0.1	liiflllliiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii	iibiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiibiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii
0% Sucrase	0.4	1.5	0.4	: : 1: lllla'·· 1 : : 1	iiiiiiiiiiiiiiiiiiifiiiiiiiiiiiiiiiiii
2% Sucrose	llllSIIII	0.8	0.2	b	llllllillllli
4% Sucrose	3.9	0.7	0.2	1 :i :i 1 i i i i: i: i: i: i : : ?i	<i : : : : : : : : : :-^1 : : : : : : : : : λ
6% Sucrase	:5.7	0,7	0.2	iiiiiiii//il:dliiii: : : i:	I: : : : : : : : : : d : : : : : : : : : i:

The results of human taste texts a i th a compound C6 are found below. Table 12 . i la .are .h'z ’ Or μΜ t mrpmmd ( 6 n·* ( % M'crew b.w χν c'nrex >v.m.- m re >t n>nt 10* <, sucrose. Table:..13 indicates that 100 μΜ compound CO alone has no sweetness, anditherefore can be defined as a true sweet enhancer.

Table 12. \wwr Sweetnexs t- 28 (H Panehxtx \ 2 tep) Γηχι\*< xalne 0 818 (o 0 05),

().732(0.=- 0.1b)

...... teatmeat		SD	St Er	Tobey (5%)	Tukey (10%)
6% Sucrose	O:	1.2	0.2	i i : = a .........	..........a.........
8% Sucrase	8;3	1.1	0.2	b	b
9% Sucrose	8.6	1,3	0.3	iiiiiiiiii: i fiS :::::::	be
6% Sucrase -r 100 μΜ €6	9.3	1,0	0.2	i'iiiiiiiiiiii i'4d :::::::	cd
1.9% Sucrase	9.5	0.7	0.1	lliiiifil / 2 1

WO 2098/184221

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2017200704 02 Feb 2017

Tubk 13. A'.crage Swcctncx-. u 14 =J4 Paucb'lx x i rep). fukey’s-ahic l 238 (u 0.0-).

Treauuem	Average	ill	Si Er	Tukey (5%)	Tufcey (10%)
0% Sucrose	0.0	ill	0.0
LSB = 100 uM €6	llllllllll	in	0.1
2% Sucrose	llllllillll	iii	0.2	b	b
4% Sucrose	llllllllll	Illi	0.4	Ί lhdd||||:.C: 1:1? : : : : ?
63S Sucrose	5 5	iii	0.5	d	d

The > csnlt- Mhunsm iaxtc sesix w uh ccmpi mud <17 are touinl helm. fable 14 indicates that 50’ μ\1 conjpomKl (% in o‘\> -ncri-sc has 'ucc-ne-s cqu^alcnt ta about 9'6» shuo-w.

Talik 14. Ax crape Sweetnesw u 2o <J3 PaucbUx x 2 rep). fukey A-alue 0*02(0 0.0-).

O.ol<2(o ^: 0.10).

.........................Treatment	iilililll	III	St Er	Tukey (5%)	Tn key (.1058)
63d Sucrose	6.5	TO:	0.2	:7rr2::::::::::::: ::3::2 :::::::	::::::::: :U ::::::::
8% Sucrose	8.5	4.3:	0.2	b	b
9% Sucrose	8.7		0,3	flllllllhd 111 i	: : : : : : : : : b : : :
6% Sucrose t- SO μΜ C7	O	if	0.2	b<: :::::2	: : : : : : : : : h. : : : : :
1.0% Sucrose	9.7	iOS	0.2	2:33::-:::-:::-:: =0:: 7:::2	::::::::: S: ::::::::

The results of human tM tets with a compound C8 ate found below. Table 15 indicate; that 100 μΜ compound C8 in o% xuerose has sweetness equivalent te about 8°·» sucrose fable 56 mdre.Oes that 100 u\l comp-aav <'S alone bus η, -;wewnes-' \r<1 'heoa'ore can be defined as a true sweet enhancer.

Table 15. Verage eel 'e-s r '\(l I ΐ’.·η?ιί-8'? ep) I os?' A s due 0 o') ; χ «Ό-; 0. ‘'('<8 < p {,’ 10)

WO 2068'1M221

2017200704 02 Feb 2017

Treatment	Average iSl>| $t Er | Tukey (5%) | Tukey (1(1%) ΐ
693 Sucrose	7.0 H .3 0.3 [ a Γ a Ϊ
6% Sucrose r (99 μΜ O	8.2 Ϊ l.3j 0.3 J b b ί
8% Sucrose	8.4 H .51 0.3 | be | be ί
998 Sucrose	9.0 i i .01 9.2 | be | e i
10% Sucrose	9.1 | ’·.(> 0.2 c I c |

I abk 16. A\. i.i”,c SvotiAs, i. 11 {*4 Pam-tore \ = <·ρ} I jkcs N v due I t>2*’>·χ ^{'^! fe) 0 921 <?. OJOY

Treatment	ί .V erage SDi	St Er ΐ	Tukev ($93)	Tukey (10%)
095 Sucrose	i 0.0 0.0 i	0.0 I	—
100 pM O bi 1..SB	0.2 0.31	ο. i 1	—
2% Sucrose	2.0 0.9 ί	0.2 i
493 Sucrose	4.1 1.4 |	0.4 |	7: tovjBjBC·:: w: b : : : : :	A//////////
6% Sucrose	5 SsT ΐ 1:.4 s	0.4 i	>7>3Ν··Ν··2^γ i: i: to : : : : ::

s he rcxidtx .-1 burrem ta.-ae wnh c-impe-ind C'9 are found below I aide I ” indicates ibai iron· about 10 about 55 uM conip>-nnd <'9 -n 100 ppm re'crj’.ose -has sweetness eqmvale 4 ti> abcm KL· ppr. xbcie we l ι'Ίο K ir»n a >.» to it uo n .ήοο» 0 >>ah. ' uM compound <9 alone hex no sw octoo-w mid d-ei'.fore defined as a true sweet enhancer.

WO 2008/154221

P:CT/DS2008/085050

Table IS, Average Swceiucss, n =» 22 (I | panelists x '2 rep). Tukcy's value ^::: 0.693 (σ ^::: 0.05},

0.619 ux ^::: 0, lib.

The results of human taste tests wi th a compoundOS are found befow, Table 1. 9 indicates that. 25 μΜ compound CIO in 6% snew»re has xw ·. ojjk-w ,-qyk au m -o about 8%

Talik* |9. Metage'v ect xws s' 's d 1 i^neiM*- ' 2 op) bkC'XvJue u I ; j <>?>*?

0.668 (u ^::: 0.IO)

Treatmcai

6% Suerose

6% Sucrose +- 25 μΜ CHI

8% Sucrose

9?ό Sner wse

10% Sucrose

Average i SD

Tukev(5%) i Tukev (10%)

380

WO 200S/1S4221

2017200704 02 Feb 2017 lulae 29 indicate-, :|u:t 2^C< uM <0 vomp.niros 4'10 akm, to- no whcI'ica,and therefore can be detmed as uue sweet -..nbancera.

Table 20. Avcuigc'sweetness, n 14 i 14 Panelist- x I rep). 1 -.iRvy'- white 0 °57(u O.O'j.

(»56 to. ^::: 0.10?

Trc«t.meu4	.Average	SB	Si Er	Ty key	Tito (103S)
9% Sa cruse	0.2	iiiiiil	0.1		333333313333331
LSB-i· 25 μ:Μ CTO	liliilllll		0.1		l3333333333B333333333i3
2% Sa cruse	2.8	lilli	0.4	b	b
4% Sucrase	lllllilllll	1.0	0.3	iiiiiiiiiiiils	3:3:3:3:3:3:313:3:3:3:3:3:3:
6% Sucrose	5.9	0.3	o.i	d	d

Hie results vfburnai: (a-tc k-t- wuh a compound (11 aw found Kfow I <4 le 21 indicates that 50 μ.Μ compound C11 in b% sucrose has sweetness eq ai valent to about 8% sucrose.

Table 2L Average Sweetness, rr ^::: 15 (15 Panelists x 1 rep). Tukcy s value^::: 0.905 (a ^::: 0.05). ffhlO tu y 0.10)......................................................................................................................................................................

Treatment	Average	ilill		Tukey (5%)	Tukey (10%)
6% Sucrose	6.5	0.9	0.2	:: .....	I///: ;i· ///
8% Sucrose	O	0 9	0.2	3333%:·:·://:	: : : : : : : % : : : : : :
6% Sucrose L 50 p.M CU	8.4	1.0	0.2	b	b
19%; Sucrose	9.4	0J	0.2	::3333:% /::····	::/// iC: :::::::
9% Sucrose	9.4	0.7	0.2	///////C·: ///	/////Ο///

The results of human. taste tests with a compound Cl '2 are found below. Table 22 indicates that 50 μΜ compound C12 in 6% sucrose has sweetness equivalent to about 9% -10% sucrose.

381

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Table 22. Average Swcctne? 0,44() (a - 0J0)’	•re π ::: 26 (13 Panelists x 2 rep). Tuhey*s value ::: 0.492 (a | ΐ ΐ j Tukev ί }
Treatment	Average ΐ SD ΐ St Er ' | Tukev (10%) | ' ΐ 1 (5%) ' I

6% Sucrose	1 6.5 I ii.-S ί 0.2 I a a |
8% Sucrose	s .X.2 1.0 0.2 b b I
6% Sucrose 4- 50 μΜ Cl2	1 9.0 Ϊ 0.8 Ϊ 0 2 ΐ c c 1 Spssssssi:sss>ssi(ss;:s ...........................................................................................
9% Sucrose	I 9.2 Ϊ 0.7 Ϊ 0.1 | e c | 1 i i I I |
W% Sucrose	1 9.4 1 0.9 1 0.2 | c c |

The results vt'human lbU’ sreN Anh a cempeund <T3 ·λ· found b-dow . 1 able 23 radicate» that 2'^x μ\1 compound < 13 n= t>% sueiusc ha^ sweetness οψ,ιηraetit t.: admit X¹’ i sucrase.

Tabk 23. Awragc Swcctnesw u 2nd·' Ikntub'ls χ 2 >cp). I'ukey’s -vidua 0 0?0 (n 0.0^).

Treatment

Axe rags.'

SD I St Er

Γη key 1 .........

’ i Tukey (10%)

6% Sucrose

6% Sucrose + 25 u.M (.'13

8% Sucrose

9% Sucrose

10% Sucrose

The results of human taste tests with a eonipnundX' 14 are found below, Table 24 indicates that. 50 μΜ compound C14 in €%' sucrose has sweetness equivalent to about 8%~9% $UG

WO 2SW154 221

2017200704 02 Feb 2017 labk 24./Xwtape Sweetness »x 2nd2 Paiscb.'ts x i >q>, 14 Pam-lM.-' = rep). fakm \ < i.jc i::AZi:~±L:::..97ib..7WL.:.d.::W:J7L..........................,................................................................................................

Treatment	Average	SB	MBI	Takey (5%>	Tukey (10%)
6% Sucrose	iiiiiiiiiii	i.o	0.2
876 Sucrose		11	0.2
6% Sucrose 1· 5(1 μΜ €14	llllllili	1 3	0.2	be	be
9% Sucrose	lllllllii	11	0.2		cd
10% Sucrose	lllllllil	0.7	(,kl		d

The results of human taste tests with a compound CIS arc found. below. Table 25 mdiedic» ihat % u\l compound < 15 m t>% suetose ha^ sweetness eipuxmeat m ;m<n»i % ,.-10% suenwe.

Hbk 25. Axmaae Sweetness ». 2% 11 Pawb'tsx i rep, 14 Pan..bn-s ι>_-0 lake' s <. due ^: 0.o%< (o ^::: 9.05), 0.617 tn ·= 0.10».

.........................T realm cut.........................	Average	II	liil	Titkey (5%)	TukeynO%)
6% Sucrose	6.7	0.9	0.2	55444:4449:5;; 44 :·	::::::: :4= ::::::::
8% Sis erase	8 1	1.0	0.2		: : : : : : : b : : : : : : : :
6°-» Sucrose + 50 μΜ €15	9.1		0 2	WWWfWt > > f-H :·	C
10%; Sucrose	9.2	0.9	0.2	% ?	::::::: 4:::::::::
9% Sis cruse	9.3	07		ffffwlW : : 44 :	............ ::::::::

7’κ κ ','l·· e*hi ma< UW Vslsttieiuri rend €% no h>u\d eek>w la\. 2o eidieau - thJ 2^ s M t,empo, nd < 16 n t *' > a cmsc las sw^. λ u ux.u.iU^e .'»<>'» '0° .02% suerme. Table 27 shows a dose response curve of compound €16 with. 6% sucrose which shows that the sweetness of sucrose is significantly enhanced by addition of increasing amounts of con-pound < 16. Took· 25 SHdreau.* that I -I 11 uM compound €16 m 50 ppm suemiosi.- has sweetness equivalent to about 200 ppm-300 ppm saemlose. Table 29 indicates that 25 uM compound €16 in c-% fructose has sweetness eqaoakml between. €% and 8% fructose. Table 29

WO 2008/154221

P:CT/DS20W0OiS)

2017200704 02 Feb 2017

Hsdieatex that 25 μΜ e<uup<'=md Cfo ab-nv bax hide or no wxcenicx-. and therefore >.an he deihred as a tri!·.· sweet cnlua^et

I tilde 26. .\\C'Ui.'c S

Ο.Ο’Μιο 0.10}

Treatment

6% Sa cruse

8% Sucrase

9% Sa cruse

10% Sucrase

6% Sucrose + 25 μΜ C'lij

A v e rage SI) $t Er ΐ 1' u k ey ($%)

Fukev (10%)! ' ΐ

--------------------------------}

-I

Table 27. A verage Sweetness, a ^::: 30 (15 Panelist, x 2 rep). Tukey'x value^::: 1.138 (a ^a

1.043 (a ^::: 0.10).

Treatment

6% Sucrase +^v 5.64 μΜ Cd a

Fukcy

6% Sa erase

6% Sucrase + 2.82 a.M Cl 6

8% Saeruse

6% Saerase + 19.75 p.M C16

19% Sucrase

123» Sucrase

Average I SD

6% Sucrase + 1L29 a.M C16

6% Mcrasv 28.22 aM Clb

384

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P:CT/l.sS26W0Oi58

2017200704 02 Feb 2017

Table 28. Average Sweetness, π ^::: 28 (14 Panellists x 2 rep I. Tuhcy's value^::: 0.909 pi 0 O^X 0.881 £·.'.^::: 0. i 0).

Treatment	Average	si>	St Er	Tukey llllillll	Tukvy (1.0%)
50 ppm sucralose	iiiiiiiii	0.7	0.1		ih 11111 i*t 1111111
1.00 ppm sucralose	lllllllll	liil	0.3	llllllllll	llllllllll!
150 ppm sucralose	llllilfll	1.8	0.3	cd	ed
200 ppm sucralose		1.6	0.3	illlllllllfi	d
50 ppm sucralose * 14.11 pM itllllllllllllll	llllillll	2.3	0.4		1 : : : : : : ::^1 : : : : : : :
300 ppm sucralose.	iiiiiiiiii	liiii	llllll	llllllllll	22333333123333333

Table 29. .Average Sweetness. u ^::: 26 {13 Paueli-Us \ 2 rep) Tubes \ - .due 0 H o Ο (H), 0.639 (a^::: 0.10).

Treatment	.Average	lliill	St Er	W (5%)	Takey(1G%)
6% Fructose	6.9	€0	0.2	32-32 :¾ ......	.........a.......
6% Fructose-r 25 p.M €16	:3333112 3 3::	El	0.2	b	b
8% Fructose	8.6	0.8	032	233332 sC-: 2.....	2 2 2 2 ic 2 2 2
9% Fructose	9.3	0.7	0.1	112303 2 1	j:::::: i::::::
10% Fructose	9.5	0.7	0.1.	d	d

Table 39, ^-2/=9,./^,-06^,- e -Πi I”> Pane m- ^x * cpl I '-ex'-'due (=-1- ,γ - ().0m 0.4“91 a ^::: 0.1OX

Treatment	.Ave rags	Sl>	St Er	|i|l||(il||	Ta key (.19%)
0% Sucrose	0.2	0.5	0.1	l!!!!:lllli&l|<l|<l > > > > i	illllllll l&. llllllllll
LSB r 25 pM €16	1.6:	0.8	0.2	33333333333331^133ii i: i: i: i: i	............a ..........
276 Sueruse	2.3	0.8	0.2	b	b
4% Sucrose	: 2 2--.4222333::	:11	0.2	llii^illl II II II II 1	liiii :& iiiii
6”« Sucrose	5.8	0.6	0,1	3333333334331! 3222	............0............

WO 21W1M221

2017200704 02 Feb 2017

The n-xidlx of hij'nar laxlc aith u>>inpeimJ (Ί7 rec Ibired hJov,. 1 abA 31 'ijJrevik'x -h,;', ; it\l e<'n?x· e:dΚΊ7 in ©A hex k\,v‘ikx- _ci iw cm re about 9\, 10’ >-Ui.u>s>.' Fable 32 mihi.au> Ob.it © pM uonipmind (Ή atone bax huk' «·ι no re', reinre-re and ih-.-i'ckue can be dctnv.4 as u unv sweet enbanc-ci.

1’nbk' 31. Average Sweetness. n ^::: 28 (14 Panelists x 2 rep;. Tukey’s value ^:: 0.657 j.^::: 0.05), p-588{a_;;;_:_0J_0)_;.............................................................................................................................................................................

Treatment	Average	lllllillii	| stir	Taker (5%)	Tukey Hh%)
6% Sucrose	liiiillii	1.2	1 o ? 1 '	iiiviliii:
8% Sucrose	iiiiiiiii	0.9	0.2 I	llllllll
9% Sucrose	llllillll	0.8	ί 0.2 I	lllllillii	llllllllllllll
6% Sucrase -t- 8 μΜ €17	9.0	1.1	Ϊ 0.2 I .3.-13.3.3.©Are/AAAA.	Illtliilil	be
10% Sucrose	9.6	0.6 | 0.1	iiiiiiiii:	: a : : : : : : : : : : : : : : :

Table 32. Average Sweetness, n ^:::: 28 (14 Panelists x 2 rep). Tukey’s value^:::: 0.497 (u ~ 0,05), 0.425 t« ^::: 0,10).

Treahueat	Average	(HI	Si Er	Tukey ($%)	Tukey (10% i
0% Sucrose	0J	(i.4	0.1	lAlllllyS'l))) a 1	11111:111111-
LS8r8gMCl7	0,2	0.5	01	Illi©©© ! ·· - -11 ?	11111 -A mi©
23« Sucrose	2.3	0.7	0.1	'l:l:l:lAlll-i?A i i A A 1	a : : : : : : : : £ : : : : : : : : : ::
4% Sucrose	4.5	1.0	0.2	d	d
------
6% Sucrose	5.8	0.6	0.1	1111111:91:: 11 :	.......................

386

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EXFERIMEN Γ 6: Sweet Flavor and Sweet Flavor Enhancement Measurement

Using Homan Panelists Conducting a Paired Comparison Fest lest samples ceistafiiiiig exptrin rental eomp>-=imis arc pre rented in pairs =<* t|_Rρ:.ιιι·.'·1% and they are οΆ,λΙ ?c> detet'nime which of dre sample is swcvici A moup of ΙΩ-'μ- or more panelists paitieiputcd in each te.< Sub-ects rcfranK-d horn eatma m d re=a nig t except water) for at least 1 hour prior to die tc-a. Subjects niic-ed wnh water several times to clean the mouth.

Ad samples arc pi epared with ethanol i=i on-ace disnersi-m of the compound m solution, fins nivludo samples wtotoitt compound, ;dl -ns are· hakmc-.u f-=^f» fk viharad.

Sample.-- etc-foe piepared with k>w redmm nnifci ipH 7 I: in p.eec ofwatet, Bufoir -.untani.·' 6.0^2 g of Μ '1. 8 444 -> .·> ka-lil’f i₄ and 8 8$^ g of KH - Ate m 40 L of OH f -'..η·.·’ kampf. re hime'- are usually ?0 ml

In on-., paired cempanson icsi th·, panelist is preaertted with two different, samples and .raked to id-.niity the -ample wbich is sw ...eier I he sampM v. iil-in a paired comparison ΰ..·η are presented in a randonmred. coutoerbii.meeJ order. Panelists have up to a I minute delay betwecn tastc: tests to clear the motnh of any

Binomial probability tables arc used re determine the probabiilty·' of the correct number of responses occurring: for each tost at al ph.·: =-0,05 .

The results of human taste tests with a cornpoundClS are found belo w. Table 33 .η In .nos ‘.hv garni s’s peiceixcd <>''<- b’ ι» lose · 160 nM € 18 re- being, -ignm'amh' sve. rer tn m a solution ?; 6% Fructose (p-O 05}

Table 33. Sample selected as more sweet by panelists: n = 26 (13 panelists x 2 reps).

Samples	Teltd
6% Fructose	o
6% Fructose + l(fo pM 568	7%: si-TT
Tmal	26
Confidence	0.991
67-6 Fructose v 100 pM Cl8	0.009

387

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(p-vahte)

the results efbumat: Lblt c'-B with a compound C19 are found fo-low, 1 able 34 indicates that panelists perceived 6% Frudose t 100 pM C19 as being x«g»Jtteat4K ovcetcr than ο sokm-n of <·% Fructo·. (> -0 05i

Table 34. Smnplc selected ax more xwec? by puucbxtx: si 24 ί ] 2 panelists .< 2 tepo.

Samples	Turn!
6% Fnictuse	6
6% Fructose + 100 μΜ ¢/19	13
	24
Oml'klenee	0.977
6% Fructose t 109 μΜ C19 (p“ value)	0.023

The results of human taste testsiwith a compoimdOS are found beloxv, Table 34 . ί Inatcx .he precis > jetceised *>' < I i>foe 160 p\H 20 ax 'vi a χ gntfo. m v*, < te d'-t a redm en - . bfo I itu.ex? tp Oil') Iewl, % ecex that 0*0 ,Λί co up Hive C20 alone nax link* or no .swaeua-'x on n-i>\re U 'perbnenl 5?.

Table 35. Sample selected as more sweet by pa-idists: n ~ 19 (19 panelists x I rep),

Sa tuples	Fest .1	Total
h% Fructose	Of	:// : 0 /
6% Fructose + 100 μ.Μ ¢/20	>*9 :	///TR//
(Ttoat Ϊ9 /49:HH

WO 21W1S4221

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Table 36. Average Sweetness, n ^::: 13(13 Panelists χ I repl. Tuhey's Value ^::: 0.753 (n ^::: 0.05 k 0.674 (α^;:: 0.10).

				Titkrv
Treat mwt	Average	Sl>	St Er		|rukey (.10% )l
				(536)
			•*^*^*^*^*^*^*^*^*^*^
0% Fructose	0.2	111	0.1		i a 1
LSB+ 100 p.M C20	0.2	0.5	0.1		a...................................]
2% Fruewse		Hill	0.2	::1::111111	Ϊ b I
				3ώ2^2ώώώώώ2;	4----------
4% Fructose		1:111	0.3
636 Fructose	5.9	0.3	0.1	d	||||||g||||||

I he results et'himiai: UMe h.'-H w i-h a compound (’21 aw hmnd b-ckw, , 1 able 3? indicates iha? p.;i:d:sis pcreei'.cd 6' < Kuetore.' - 28 ιΛί t’2t as being regie Oeaiub rewvei Iran ,·, solution <0 (>% Fructose tp -6.05 k Table >8 indicates that punehsN pcsedsed P% Frm.tose 25 pM €21 lias the same sweetness micnsiw than a solution of 7'V> Fructose,

Table 37. Sample rejected as n»uc sweet hx paudists: u 2^ 125 panelists a I rep)

	Test 1
i 6% Fructose	17:·|::::§447:::·:::·:
i 6% fructose a- 25 μ.Μ €21	1 20
i Tomi	ΐ 25
ί C'oafidettec	ί ¢) 999

6% fructose + 25 p.M €21 j 0.001 (p-vahre) i

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Tahk 38. S.mipk- xeketed as umre w-ecf by panelists, n 25 (25 pauJt.'l.x \ 1 rep).

Samples	'Test t
7®4s Fructose
6% fructose -t 25 μΜ 01	1 ·*>
i Total	Iiiiiii
Confidence	lllill
6% fra close L 25 μΜ C21	0.834
i (p~value)

EXPERIMENT 7. Solubility Betermmmton of the Compounds ®f the Preseat Invention and Their HCl Salts in Propylene Glycol

The solubility of the present compounds and their HC1 salts in propylene glycol n.w determined fa sh.Ae (hsk merited. Approximately ?0 me of (he Lwr •...xmpoiinj weighed out. end added to a 4-m.L glass viai, and then 1 ml., of propylene glycol was added to the xul The \nd «_vh xmite-itcd f >r sb mumres md Hku shaken to: .'4 hre on an ofmlal shake) +;( at 300 rpm. An aliquot of 20() pL of the .-solution wni transferred from the vial into a 1.5 mL couiri=foge vial and centrifuged at 12.500 rpm mr it) min.. An aliquot of 50 μΐ.. of the supern uant was diluted fey 100 times w ith propylene glycol. Then 50 pL of this solution wax further diluted 100 times with water and analyzed by liquid chromatography mass spectrometry (Cl 8 column with gradient elution with a .flow rate of 2,0= mL/mm, water with 0.1% trifluotoaeetic aeid as mobile phase A and methanol.-with 0.1% triflueraacctle acid as mobile phase B, mobile phase B % rising from 5% to 95% in 0.0 mm and then being held at 95% for 1.4 min}. The result of one exemplary mhub·lily text L xhmvn in fable .3.

Table A. Solubility of Compound C2 and .Its HC1 Salt i Compmmd | Solubility Average I Standard Oevtation j i___________________________________________j________(mM)_________I_________(mH)i

I €2 | 6.2 | 1.7| i C2xhydrnehlortde | 45.7 | 3.0|

2017200704 25 Jun 2019= ^n/;lAUPR

All publications and patent applications herein arc incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

The foregoing detailed description has been given for clearness of understanding only and no unnecessary limitations should be understood therefrom as modifications will be obvious to those skilled in the art. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

Embodiments of this invention arc described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise”, “comprising”, and the like, are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense, that is to say, in the sense of “including, but not limited to”.

The reference to any prior art in the specification is not, and should not be taken as, an acknowledgement or any form of suggestion that the prior art forms part of the common general knowledge.

Claims (63)

1. The claims defining the invention are as follows:

   1. A method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (lib):

   _R17

   A (Hb) or a tautomer or salt thereof, wherein:

   W is -C(R²⁴)- or -N-;

   Y is -C(R²⁶)-;

   Z is -S-, or -O-;

   A is -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁹ and R¹⁰, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

   R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl;

   R²⁴ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, -CN, or -NO2; and

   R²⁶ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, -CN, -OR³¹, -OCOR³¹, -NR³¹R³², -CONR³¹R³² or -CO2R³¹, wherein R³¹ and R³² are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R³¹ and R³², together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

   wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted

   392

   2017200704 25 Jun 2019 heteroarylalkyl, and substituted cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of -R^a, halo, =0 , -OR^b, SR^b, -S, NR^CR^C, =NR^b, =N-OR^b, trihalomethyl, -CF3, -CN, -NO2 , S(O)2R^b, S(O)2NR^b, S(O)2OR^b, OS(O)2R^b, OS(O)₂OR^b, P(O)(OR^b)(OR^b), C(O)R^b, C(NR^b)R^b, C(O)OR^b, C(O)NR^CR^C, C(NR^b)NR^cR^c, OC(O)R^b, OC(O)OR^b, NR^bC(O)R^b, NR^bC(O)OR^b, NR^bC(O)NR^cR^c, NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7-membered cycloheteroalkyl.
2. 2. The method of claim 1, wherein Z is -S-.
3. 3. The method of claim 1, wherein Z is -O-.
4. 4. The method of claim 2 or claim 3, wherein W is -C(R²⁴)-.
5. 5. The method of claim 2 or claim 3, wherein W is -N-.
6. 6. The method of claim 4 or claim 5, wherein A is -NH₂.
7. 7. The method of claim 4, wherein each of R²⁴ and R²⁶ is independently hydrogen, -CF3, or alkyl.
8. 8. The method of claim 4, wherein:

   R¹⁷ is hydrogen, alkyl, or substituted alkyl;

   R²⁴ is hydrogen, alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl; and

   393 ^n/;lAUPR

   2017200704 25 Jun 2019=

   R²⁶ is hydrogen, alkyl, substituted alkyl, heteroalkyl, or substituted heteroalkyl.
9. 9. The method of claim 4, wherein:

   A is -NH₂, -NHCH3, -N(CH₃)₂, -NHOCH₃, or -NOCH₃;

   R¹⁷ is hydrogen, methyl, ethyl, propyl, /'.so-propyl, //-butyl, Ao-butyl, .sec-butyl, /-butyl, phenyl or benzyl; and

   R²⁴ is hydrogen, -CF₃, methyl, ethyl, propyl, /'so-propyl, //-butyl, /'so-butyl, secbutyl or z-butyl; and

   R²⁶ is hydrogen, -CF₃, methyl, ethyl, propyl, iso-propyl, /z-butyl, /'.so-butyl, secbutyl or z-butyl.
10. 10. The method of claim 4, wherein:

    A is -NH₂,

    R¹⁷ is hydrogen or methyl,

    R²⁴ is hydrogen, -CF₃, methyl or ethyl, and

    R²⁶ is hydrogen, -CF₃, methyl or ethyl.
11. 11. The method of claim 1, wherein the compound is selected from the group consisting of:

    

    

    

    or a combination thereof, or a tautomer or salt of the foregoing.
12. 12. The method of claim 11, wherein the salt is hydrochloride or trifluoroacetate salt.

    394

    2017200704 25 Jun 2019=
13. 13. A method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (lie):

    R¹⁷

    A (Ho) or a tautomer or salt thereof, wherein:

    W is -S-, or -O-;

    Y is -C(R²⁶)-;

    Z is -C(R²⁷)- or -ΝΑ is -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁹ and R¹⁰, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring; and

    R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl;

    R²⁷ is hydrogen, alkyl, substituted alkyl, substituted acyl, substituted heteroalkyl, -CN, -NO2, -OR³³, or -NR³³R³⁴; and

    R²⁶ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, -CN, -NO2, -OR³¹, -NR³¹R³², -CONR³¹R³² or -CO2R³¹, or alternatively, R²⁶ and R²⁷ together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring, wherein R³¹, R³², R³³, and R³⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R³¹ and R³², together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

    395

    2017200704 25 Jun 2019 wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted heteroarylalkyl, and substituted cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of -R^a, halo, =0 , -OR^b, SR^b, -S, NR^CR^C, =NR^b, =N-0R^b, trihalomethyl, -CF3, -CN, -NO2 , -S(O)2R^b, S(O)2NR^b, S(O)2OR^b, OS(O)2R^b, OS(O)₂OR^b, P(O)(OR^b)(OR^b), C(O)R^b, C(NR^b)R^b, C(O)OR^b, C(O)NR^CR^C, C(NR^b)NR^cR^c, OC(O)R^b, OC(O)OR^b, NR^bC(O)R^b, NR^bC(O)OR^b, NR^bC(O)NR^cR^c, NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7-membered cycloheteroalkyl.
14. 14. The method of claim 13, wherein W is -S-.
15. 15. The method of claim 13, wherein W is -O-.
16. 16. The method of claim 14 or claim 15, wherein Z is -C(R²⁷)-.
17. 17. The method of claim 14 or claim 15, wherein Z is -N-.
18. 18. The method of claim 16 or claim 17, wherein A is -NH₂.
19. 19. The method of claim 16, wherein R¹⁷ is hydrogen, alkyl, or arylalkyl.
20. 20. The method of claim 19, wherein:

    R²⁷ is hydrogen, alkyl, substituted alkyl, substituted acyl, substituted heteroalkyl, -CN, -NO₂, -OR³³, or -NR³³R³⁴; and

    396

    R²⁶ is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, -CN, -NO2, -OR³¹, -NR³¹R³², -CONR³¹R³² or -CO2R³¹.
21. 21. The method of claim 16, wherein:

    A is -NH2; and

    R¹⁷ is hydrogen, methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, phenyl or benzyl.
22. 22. The method of claim 21, wherein each of R²⁶ and R²⁷ is independently hydrogen, alkanyl, substituted alkanyl, alkoxy, carboxylic acid, carboxylic acid amide, or carboxylic acid ester.
23. 23. The method of any one of claims 16-19 and 21, wherein R²⁶ and R²⁷ together with the atom(s) to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring.
24. 24. The method of claim 13, wherein the compound is selected from the group consisting of:

    

    397

    2017200704 25 Jun 2019=

    

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    2017200704 25 Jun 2019=
25. 25. The method of claim 24, wherein the salt is hydrochloride or trifluoroacetate salt.
26. 26. A method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (lie):

    

    A (He) or a tautomer or salt thereof, wherein:

    G forms a single bond with E and a double bond with D;

    A is -NR⁹R¹⁰, wherein R⁹ and R¹⁰ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁹ and R¹⁰, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

    B is -N-;

    E is -NR¹⁷-;

    G=D is C=S·

    Wis -S-, -O-;

    Y is -C(R²⁶)-;

    Z is -C(R²⁷)-;

    R¹⁷ is hydrogen, alkyl, substituted alkyl, arylalkyl, or substituted arylalkyl; and

    R²⁶ and R²⁷ are independently hydrogen, alkanyl, substituted alkanyl, alkoxy; or alternatively, R²⁶ and R²⁷ together with the atom(s) to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

    wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted

    399

    1AUPR heteroarylalkyl, and substituted cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of -R^a, halo, =0 , -0R^b, -SR^b, -S, -NR^CR^C, =NR^b, =N-0R^b, trihalomethyl, -CF3, -CN, -N02 , -S(O)2R^b, -S(O)2NR^b, -S(O)2OR^b, -OS(O)2R^b, -OS(O)₂OR^b, -P(O)(OR^b)(OR^b), -C(O)R^b, -C(NR^b)R^b, -C(O)OR^b, -C(O)NR^CR^C, -C(NR^b)NR^cR^c, -OC(O)R^b, -OC(O)OR^b, -NR^bC(0)R^b, -NR^bC(0)0R^b, -NR^bC(0)NR^cR^c, -NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7-membered cycloheteroalkyl.
27. 27. The method of claim 26, wherein W is -S-,
28. 28. The method of claim 26, wherein W is -0-.
29. 29. The method of claim 27 or claim 28, wherein A is -NH2.
30. 30. The method of claim 27, wherein the compound is selected from the group consisting of:

    

    

    or combinations thereof, or a tautomer or salt of the foregoing.

    400 ^n/;lAUPR

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31. 31. The method of claim 30, wherein the salt is hydrochloride or trifluoroacetate salt.
32. 32. A method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound selected from the group consisting of:

    

    

    or combinations thereof, or a tautomer or salt of the foregoing.
33. 33.

    The method of claim 32, wherein the salt is hydrochloride or trifluoroacetate salt.
34. 34.

    A method of enhancing the sweet taste of an ingestible composition comprising contacting the ingestible composition or precursors thereof with a compound having structural Formula (Illb):

    R¹⁷ ο I o'® Y I ⁿyv

    A (IHb).

    or a tautomer or salt thereof, wherein:

    401

    2017200704 25 Jun 2019

    A is -NH₂;

    R¹⁷ is hydrogen, alkyl, or substituted alkyl;

    H is -CH-;

    I is -CH-;

    J is -CH-; and

    K is -C(R³⁸)-, where R³⁸ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, -CN, -NO2, -OR⁴⁵, -OCOR⁴⁵, -NR⁴⁵R⁴⁶,-CONR⁴⁵R⁴⁶, COR⁴⁵, or -CO2R⁴⁵, wherein R⁴⁵ and R⁴⁶ are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, acyl, substituted acyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; or alternatively R⁴⁵ and R⁴⁶, together with the atoms to which they are bonded, form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

    wherein each of the substituted alkyl, substituted aryl, substituted arylalkyl, substituted acyl, substituted heteroalkyl, substituted heteroaryl, substituted heteroarylalkyl, and substituted cycloheteroalkyl independently comprises one or more substituent groups selected from the group consisting of -R^a, halo, =0 , -OR^b, SR^b, -S, NR^CR^C, =NR^b, =N-0R^b, trihalomethyl, -CF3, -CN, -NO2 , -S(O)2R^b, -S(O)2NR^b, S(O)2OR^b, OS(O)2R^b, OS(O)₂OR^b, P(O)(OR^b)(OR^b), C(O)R^b, C(NR^b)R^b, C(O)OR^b, C(O)NR^CR^C, C(NR^b)NR^cR^c, OC(O)R^b, OC(O)OR^b, NR^bC(O)R^b, NR^bC(O)OR^b, NR^bC(O)NR^cR^c, NR^bC(NR^b)R^b and -NR^bC(NR^b)NR^cR^c, where R^a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R^b is independently hydrogen or R^a, and each R^c is independently R^b or alternatively, the two R^cs, taken together with the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7-membered cycloheteroalkyl.

    402 •1AUPR
35. 35. The method of claim, wherein R³⁸ is hydrogen, (C1-C6)alkyl, (C3C10)cycloalkyl, (C2-C6)alkenyl, -OR⁴⁵, or -NR⁴⁵R⁴⁶, when R³⁸ is -OR⁴⁵, then R⁴⁵ is selected from the group consisting of (C1 -C6)alkyl, (C3-C10)cycloalkyl, -(Cl-C6)alkoxy, -(Cl-C6)alkyl-(C3-C10)cycloalkyl, -(ClC6)alkyl-NHC(=O)-aryl, (C1 -C6)alkyl-NHC(=O)-(C 1 -C6)alkyl, (C1 -C6)alkylC(=O)NH-(C 1 -C6)alkyl, (C1 -C6)alkyl-NHC(=O)-heteroaryl, (C1 -C6)alkylcycloheteroalkyl-C(=O)-(Cl-C6)alkyl, or -(C2-C6)alkenyl-O-(C1-C6)alkyl, wherein the cycloheteroalkyl is a piperidinyl; the heteroaryl is a pyridine, which is optionally substituted with imidazolyl; and when R³⁸ is -NR⁴⁵R⁴⁶, then R⁴⁵ is -(Cl-C6)alkyl and R⁴⁶ is hydrogen.
36. 36. The method of claim 35, wherein R³⁸ is hydrogen.
37. 37. The method of claim 35, wherein R³⁸ is -OR⁴⁵.
38. 38. The method of claim 37, wherein R⁴⁵ is -(Cl-C6)alkyl-(C3-C10)cycloalkyl, - (C1 -C6)alkyl-NHC(=O)-aryl, (C1 -C6)alkyl-NHC(=O)-(C 1 -C6)alkyl, (C1 -C6)alkylC(=O)NH-(C 1 -C6)alkyl, (C1 -C6)alkyl-NHC(=O)-heteroaryl, (C1 -C6)alkylcycloheteroalkyl-C(=O)-(Cl -C6)alkyl, or -(C2-C6)alkenyl-O-(C1 -C6)alkyl.
39. 39. The method of claim 37, wherein R⁴⁵ is -(Cl-C6)alkyl-NHC(=O)-aryl, - (Cl C6)alkyl-NHC(=O)-(C 1 -C6)alkyl, (C1 -C6)alkyl-C(=O)NH-(C 1 -C6)alkyl, (C1 -C6)alkylNHC(=O)-heteroaryl, or (C1 -C6)alkyl-cycloheteroalkyl-C(=O)-(C 1 -C6)alkyl.
40. 40. The method of claim 37, wherein R⁴⁵ is -(Cl-C6)alkyl-NHC(=O)-aryl, - (Cl C6)alkyl-NHC(=O)-(C 1 -C6)alkyl, or (C1 -C6)alkyl-C(=O)NH-(C 1 -C6)alkyl.
41. 41. The method of claim 37, wherein R⁴⁵ is -(C1-C6)alkyl-NHC(=O)-heteroaryl, or (C1 -C6)alkyl-cycloheteroalkyl-C(=O)-(C 1 -C6)alkyL
42. 42. The method of claim 35, wherein R³⁸ is -NR⁴⁵R⁴⁶.

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    2017200704 25 Jun 2019
43. 43. The method of claim 42, wherein R⁴⁵ is -(Cl-C3)alkyl and R⁴⁶ is hydrogen.
44. 44. The method of any one of claims 35 to 43, wherein R¹⁷ is hydrogen, or alkyl.
45. 45. The method of claim 44, wherein R¹⁷ is hydrogen, methyl, ethyl or benzyl.
46. 46. The method of any one of claims 1-45, wherein the composition is a precursor to an ingestible composition.
47. 47. The method of claim 46, wherein the composition is a solid or liquid concentrate.
48. 48. The method of claim 46, wherein the composition is a flavor preparation for a food or beverage product.
49. 49. The method of any one of claims 1-45, wherein the composition is an ingestible composition.
50. 50. The method of claim 49, wherein the ingestible composition is a food or beverage product.
51. 51. The method of claim 50, wherein the food or beverage product is selected from the group consisting of confectioneries, bakery products, dairy products, sweet and savory snacks, meal replacement products, ready meals, soups, pastas, noodles, canned foods, frozen foods, dried foods, chilled foods, oils and fats, baby foods, spreads, a cooking aid product, a meal solution product, a meal enhancement product, a seasoning, a seasoning blend, cake, cookie, pie, candy, chewing gum, gelatin, ice creams, sorbet, pudding, jam, jelly, salad dressing, condiments, cereal,s canned fruits, fruit sauces, a carbonated or

    404 •1AUPR non-carbonated beverage, a beverage mix, a beverage concentrate, soda, juice, an alcoholic beverage, and combinations thereof.
52. 52. The method of any one of claims 1-51, wherein the composition comprises one or more sweet flavor entity.
53. 53. The method of claim 52, wherein the one or more sweet flavor entity is a natural sweetener or an artificial or synthesized sweetener.
54. 54. The method of claim 53, wherein the natural sweetener is a saccharide sweetener, a natural sugar, or a semi-synthetic sugar alcohol sweetener.
55. 55. The method of claim 53, wherein the artificial or synthesized sweetener is a non-caloric sweet flavor compound, a reduced caloric sweet flavor compound, or a non-target caloric sweet flavor compound; and/or the natural sweetener is selected from a group consisting of sucrose, fructose, glucose, tagatose, maltose, galactose, mannose, lactose, glycine, com syrup or other syrups or sweetener concentrates derived from natural fruit and vegetable sources, erythritol, isomalt, lactitol, mannitol, sorbitol, xylitol, maltodextrin, and mogroside.
56. 56. The method of claim 53, wherein the artificial or synthesized sweetener is selected from a group consisting of aspartame, saccharin, acesulfame-K, cyclamate, sucralose, alitame, aspartame, neotame, aspartame derivatives, D-tryptophan, hydrogenated glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH), stevioside, rebaudioside A, sweet Stevza-based glycosides, carrelame, and guanidine-based sweeteners.
57. 57. The method of claim 52, wherein the sweet flavor entity is selected from the group consisting of cyclamic acid, mogroside, tagatose, maltose, galactose, mannose, sucrose, fructose, lactose, aspartame, neotame and other aspartame derivatives, saccharin, sucralose, acesulfame K, glucose, erythritol, D-tryptophan, glycine, mannitol, sorbitol, maltitol, lactitol,

    405

    2017200704 25 Jun 2019 isomalt, hydroganeted glucose syrup (HGS), hydrogenated starch hydrolyzate (HSH), stevioside, rebaudioside A and other sweet Stevza-based glycosides, alitame, carrelame and other guanidine-based sweeteners, tagatose, xylitol, high fructose com syrup, and combinations thereof.
58. 58. The method of claim 52, wherein the one or more sweet flavor entity is sucrose, sucralose, or fructose.
59. 59. The method of claim 52, wherein the sweet flavor entity is sucralose.
60. 60. The method of any one of claims 1-59, wherein the compound has a concentration from about 0.0001 ppm to about 10 ppm.
61. 61. The method of any one of claims 1-59, wherein the compound has a concentration from about 0.0001 ppm to about 100 ppm.
62. 62. The method of any one of claims 1-59, wherein the compound has a concentration from about 0.01 ppm to about 100 ppm.
63. 63. The method of any one of claims 1-59, wherein the compound has a concentration from about 10 ppm to about 100,000 ppm.