WO2017156177A1 - 3-phosphoglycerate dehydrogenase inhibitors and uses thereof - Google Patents

Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Description

3-PHOSPHOGLYCERATE DEHYDROGENASE INHIBITORS AND USES

THEREOF TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to compounds and methods useful for inhibiting 3- phosphoglycerate dehydrogenase. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various disorders. BACKGROUND OF THE INVENTION

[0002] Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first step in the biosynthesis of L-serine, which is the conversion of 3-phosphoglycerate into 3- phosphohydroxypyruvate with a reduction of nicotinamide adenine dinucleotide (NAD⁺) to NADH.

[0003] Certain cancers, including human melanomas and breast cancers, can have high levels of PHGDH. These cancer cells are dependent on PHGDH for their growth and survival as PHGDH catalyzes serine production and may also be a significant source of NADPH in cancer cells. Targeting PHGDH by small molecule inhibitors could be a therapeutic strategy to reduce cancer cell growth and survival. Accordingly, there remains a need to find PHGDH inhibitors useful as therapeutic agents. SUMMARY OF THE INVENTION [0004] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are effective as PHGDH inhibitors. Such compounds have the general formula I:

or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0005] Compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of diseases, disorders or conditions, associated with PHGDH. Such diseases, disorders, or conditions include cellular proliferative disorders (e.g., cancer) such as those described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

1. General Description of Certain Embodiments of the Invention:

[0006] Compounds of the present invention, and compositions thereof, are useful as inhibitors of PHGDH. Without wishing to be bound by any particular theory, it is believed that compounds of the present invention, and compositions thereof, may inhibit the activity of PHGDH and/or inhibit the production of NADPH, and thus reduce the growth of cells in proliferative disorders such as cancer.

[0007] In some embodiments, the present invention provides a compound of formula I:

I

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen or C_1-4 alkyl;

each of R² and R³ is independently halogen, -OR, -CN, C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’; or R² and R³ are optionally taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen or an optionally substituted group selected from C_1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each L is independently a C1-6 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, - N(R)C(O)N(R)-, -S-, -SO-, or -SO2-;

each R’ is independently hydrogen, C1-6 aliphatic, or an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R⁴ is hydrogen, halogen, -OR⁵, -CN, C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’;

R⁵ is hydrogen, -(CH2)m-phenyl, or C1-6 alkyl optionally substituted with 1, 2, or 3 halogens; m is 0, 1, 2, 3, or 4;

R⁶ is hydrogen or C_1-4 alkyl;

Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L¹ is a covalent bond or a C_1-8 bivalent straight or branched hydrocarbon chain wherein 1-5 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO₂-, -SO₂N(R)-, -(R)NSO₂-, -C(S)-, -C(S)O-, -OC(S)-, - C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;

each -Cy- is independently a bivalent 6-membered arylene ring containing 0-2 nitrogen atoms, a bivalent 5-membered heteroarylene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bivalent partially unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl or -OR;

each R⁸ is independently hydrogen, -CO₂R, or C_1-6 optionally substituted aliphatic;

R⁹ is hydrogen, halogen, C1-4 alkyl, C1-4 alkyl substituted with an optionally substituted phenyl, optionally substituted phenyl, -CN, -OR, or L²-R⁸;

each L² is independently a C_1-8 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, - C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; and

n is 0, 1, 2, 3, 4, or 5. 2. Compounds and Definitions:

[0008] Compounds of the present invention include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in“Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and“March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0009] The term“aliphatic” or“aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle,"“cycloaliphatic” or“cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments,“cycloaliphatic” (or“carbocycle” or“cycloalkyl”) refers to a monocyclic C₃-C₆ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0010] As used herein, the term“bicyclic ring” or“bicyclic ring system” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term“heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N- oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term“bridged bicyclic” refers to any bicyclic ring system, i.e. carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a“bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a“bridgehead” is any skeletal atom of the ring system which is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include:

Exemplary bridged bicyclics include:

[0011] The term“lower alkyl” refers to a C1-4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0012] The term“lower haloalkyl” refers to a C_1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

[0013] The term“heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

[0014] The term“unsaturated”, as used herein, means that a moiety has one or more units of unsaturation. [0015] As used herein, the term“bivalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain”, refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0016] The term“alkylene” refers to a bivalent alkyl group. An“alkylene chain” is a polymethylene group, i.e.,–(CH2)n–, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0017] The term“alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0018] As used herein, the term“cyclopropylenyl” refers to a bivalent cyclopropyl group of

[0019] The term“halogen” means F, Cl, Br, or I.

[0020] The term“aryl” used alone or as part of a larger moiety as in“aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term“aryl ring.” In certain embodiments of the present invention,“aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term“aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non–aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0021] The terms“heteroaryl” and“heteroar–,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or“heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term“heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms“heteroaryl” and“heteroar–”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3–b]–1,4–oxazin– 3(4H)–one. A heteroaryl group may be mono– or bicyclic. The term“heteroaryl” may be used interchangeably with the terms“heteroaryl ring,”“heteroaryl group,” or“heteroaromatic,” any of which terms include rings that are optionally substituted. The term“heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0022] As used herein, the terms“heterocycle,”“heterocyclyl,”“heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5– to 7–membered monocyclic or 7–10–membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0–3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4– dihydro–2H–pyrrolyl), NH (as in pyrrolidinyl), or ⁺NR (as in N–substituted pyrrolidinyl).

[0023] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms“heterocycle,”“heterocyclyl,”“heterocyclyl ring,”“heterocyclic group,”“heterocyclic moiety,” and“heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H–indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono– or bicyclic. The term“heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0024] As used herein, the term“partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term“partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0025] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term“substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an“optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term“stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0026] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen;–(CH₂)_0–4R°;–(CH₂)_0–4OR°; -O(CH₂)_0-4R^o,–O–(CH₂)_{0– 4}C(O)OR°;–(CH₂)_0–4CH(OR°)₂;–(CH₂)_0–4SR°;–(CH₂)_0–4Ph, which may be substituted with R°; –(CH₂)_0–4O(CH₂)_0–1Ph which may be substituted with R°;–CH=CHPh, which may be substituted with R°;–(CH₂)_0–4O(CH₂)_0–1-pyridyl which may be substituted with R°;–NO₂;–CN;–N₃; -(CH2)0–4N(R°)2; –(CH2)0–4N(R°)C(O)R°; –N(R°)C(S)R°; –(CH2)0–4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; –(CH2)0–4N(R°)C(O)OR°; –N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; –(CH2)0–4C(O)R°;–C(S)R°; –(CH2)0–4C(O)OR°;–(CH2)0–4C(O)SR°; -(CH2)0–4C(O)OSiR°3;–(CH2)0–4OC(O)R°;–OC(O)(CH2)0–4SR–, SC(S)SR°;–(CH2)0–4SC(O)R°; –(CH2)0–4C(O)NR°2; –C(S)NR°2; –C(S)SR°; –SC(S)SR°, -(CH2)0–4OC(O)NR°2; -C(O)N(OR°)R°;–C(O)C(O)R°;–C(O)CH2C(O)R°;–C(NOR°)R°; -(CH2)0–4SSR°;–(CH2)0– 4S(O)2R°; –(CH2)0–4S(O)2OR°; –(CH2)0–4OS(O)2R°; –S(O)2NR°2; -(CH2)0–4S(O)R°; -N(R°)S(O)2NR°2;–N(R°)S(O)2R°;–N(OR°)R°;–C(NH)NR°2;–P(O)2R°; -P(O)R°2; -OP(O)R°2; –OP(O)(OR°)2; SiR°3;

straight or branched alkylene)O–N(R°)2; or–(C1–4 straight or branched alkylene)C(O)O–N(R°)2.

[0027] Each R° is independently hydrogen, C_1–6 aliphatic,–CH₂Ph,–O(CH₂)_0–1Ph, -CH₂-(5- 6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =O and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen,–(CH₂)_0–2R ^{^},–(haloR ^{^}),–(CH₂)_0–2OH,–(CH₂)_0–2OR ^{^},– (CH2)0–2CH(OR ^{^})2; -O(haloR ^{^}),–CN,–N3,–(CH2)0–2C(O)R ^{^},–(CH2)0–2C(O)OH,–(CH2)0– 2C(O)OR ^{^},–(CH2)0–2SR ^{^},–(CH2)0–2SH,–(CH2)0–2NH2,–(CH2)0–2NHR ^{^},–(CH2)0–2NR ^{^}2,–NO2, –SiR ^{^} ₃,–OSiR ^{^} ₃, -C(O)SR ^{^} _,–(C_1–4 straight or branched alkylene)C(O)OR ^{^}, or–SSR ^{^}.

[0028] Each R ^{^} is independently selected from C1–4 aliphatic,–CH2Ph,–O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^{^} is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =O, =S, =NNR^* ₂, =NNHC(O)R^*, =NNHC(O)OR^*, =NNHS(O)₂R^*, =NR^*, =NOR^*,–O(C(R^* ₂))_2–3O–, or– S(C(R^* ₂))_2–3S–, or a divalent substituent bound to vicinal substitutable carbons of an“optionally substituted” group is–O(CR^*2)2–3O–, wherein each independent occurrence of R^* is selected from hydrogen, C1–6 aliphatic or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] When R^* is C1–6 aliphatic, R^* is optionally substituted with halogen,–R ^{^}, -(haloR ^{^}), -OH,–OR ^{^},–O(haloR ^{^}),–CN,–C(O)OH,–C(O)OR ^{^},–NH2,–NHR ^{^},–NR ^{^}2, or–NO2, wherein each R ^{^} is independently selected from aliphatic,–CH₂Ph,–O(CH₂)_0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^{^} is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0030] An optional substituent on a substitutable nitrogen is independently–R^†,–NR^† ₂,– C(O)R^†,–C(O)OR^†,–C(O)C(O)R^†,–C(O)CH2C(O)R^†, -S(O)2R^†, -S(O)2NR^†2,–C(S)NR^†2,– C(NH)NR^†2, or–N(R^†)S(O)2R^†; wherein each R^† is independently hydrogen, C1–6 aliphatic, unsubstituted–OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R^†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R^† is C1–6 aliphatic, R^† is optionally substituted with halogen,–R ^{^}, -(haloR ^{^}), -OH,–OR ^{^},– O(haloR ^{^}),–CN,–C(O)OH,–C(O)OR ^{^},–NH2,–NHR ^{^},–NR ^{^}2, or–NO2, wherein each R ^{^} is independently selected from C_1–4 aliphatic, –CH₂Ph,–O(CH₂)_0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ^{^} is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0031] As used herein, the term“pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1–19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p–toluenesulfonate, undecanoate, valerate salts, and the like.

[0032] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and

salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0033] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. In certain embodiments, a warhead moiety, R¹, of a provided compound comprises one or more deuterium atoms.

[0034] As used herein, the term“inhibitor” is defined as a compound that binds to and /or inhibits PHGDH with measurable affinity. In certain embodiments, an inhibitor has an IC50 and/or binding constant of less than about 100 µM, less than about 50 µM, less than about 1 µM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM. [0035] The terms“measurable affinity” and“measurably inhibit,” as used herein, means a measurable change in PHGDH activity between a sample comprising a compound of the present invention, or composition thereof, and PHGDH, and an equivalent sample comprising PHGDH, in the absence of said compound, or composition thereof. 3. Description of Exemplary Embodiments:

[0036] In some embodiments, the present invention provides a compound of formula I:

I

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen or C1-4 alkyl;

each of R² and R³ is independently halogen, -OR, -CN, C_1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’; or R² and R³ are optionally taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each L is independently a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, - N(R)C(O)N(R)-, -S-, -SO-, or -SO₂-; each R’ is independently hydrogen, C1-6 aliphatic, or an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R⁴ is hydrogen, halogen, -OR⁵, -CN, C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’;

R⁵ is hydrogen, -(CH₂)_m-phenyl, or C_1-6 alkyl optionally substituted with 1, 2, or 3 halogens; m is 0, 1, 2, 3, or 4;

R⁶ is hydrogen or C1-4 alkyl;

Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L¹ is a covalent bond or a C1-8 bivalent straight or branched hydrocarbon chain wherein 1-5 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, - C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;

each -Cy- is independently a bivalent 6-membered arylene ring containing 0-2 nitrogen atoms, a bivalent 5-membered heteroarylene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bivalent partially unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl or -OR;

each R⁸ is independently hydrogen, -CO₂R, or C_1-6 optionally substituted aliphatic;

R⁹ is hydrogen, halogen, C_1-4 alkyl, C_1-4 alkyl substituted with an optionally substituted phenyl, optionally substituted phenyl, -CN, -OR, or L²-R⁸;

each L² is independently a C1-8 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, - C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; and

n is 0, 1, 2, 3, 4, or 5.

[0037] As defined generally above, R¹ is hydrogen or C1-4 alkyl. In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is C1-4 alkyl.

[0038] In some embodiments, R¹ is methyl. In some embodiments, R¹ is ethyl.

[0039] In some embodiments, R¹ is selected from those depicted in Table 1, below.

[0040] As defined generally above, R² is independently halogen, -OR, -CN, C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’; or R² and R³ are optionally taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5- 8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] In some embodiments, R² is halogen. In some embodiments, R² is -OR. In some embodiments, R² is -CN. In some embodiments, R² is C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens. In some embodiments, R² is -L-R’. In some embodiments, R² and R³ are taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0042] In some embodiments, R² is F, Cl, -CF₃, -OCF₃, -OCHF₂, -OCH₂Ph, -OMe, -CN, -

. In some embodiments, R² is

embodiments, R² is F or Cl. In some embodiments, R² is -OMe. In some embodiments, R² is - CF3.

[0043] In some embodiments, R² is selected from those depicted in Table 1, below. [0044] As defined generally above, R³ is independently halogen, -OR, -CN, C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’; or R² and R³ are optionally taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5- 8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] In some embodiments, R³ is halogen. In some embodiments, R³ is -OR. In some embodiments, R³ is -CN. In some embodiments, R³ is C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens. In some embodiments, R³ is -L-R’. In some embodiments, R² and R³ are taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0046] In some embodiments, R³ is F, Cl, -CF₃, -OCF₃, -OCHF₂, -OCH₂Ph, -OMe, -CN, -

. In some embodiments, R³ is

embodiments, R³ is F or Cl. In some embodiments, R³ is -OMe. In some embodiments, R³ is - CF3.

[0047] In some embodiments, R² and R³ taken together with the carbon atoms to which they are attached and any intervening atoms form a cyclopentenyl or cyclohexenyl ring.

[0048] In some embodiments, R² and R³ are both Cl. In some embodiments, one of R² and R³ is Cl and one is -CH3, F, or -OMe.

[0049] In some embodiments, R³ is selected from those depicted in Table 1, below.

[0050] As defined generally above, each L is independently a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - C(O)N(R)-, -(R)NC(O)-, -N(R)-, -N(R)C(O)N(R)-, -S-, -SO-, or -SO2-.

[0051] In some embodiments, L is a C1-6 bivalent straight or branched hydrocarbon chain. In some embodiments, L is a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, -N(R)C(O)N(R)-, -S-, -SO-, or - SO₂-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -O-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -C(O)-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -C(O)O-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -OC(O)-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -OC(O)N(R)-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -(R)NC(O)O-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -C(O)N(R)-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -(R)NC(O)-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -N(R)-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -N(R)C(O)N(R)-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -S-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -SO-. In some embodiments, 1 or 2 methylene units of the chain are replaced with -SO2-. In some embodiments, 1 or 2 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, -N(R)C(O)N(R)-, -S-, -SO-, or -SO2-; wherein each R is independently hydrogen, -CH2-phenyl, phenyl, -CH3, -CH2CH3, cyclopentyl, cyclohexyl, -CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CF₃; or each R is independently hydrogen or methyl; or R is hydrogen.

[0052] In some embodiments, L is selected from those depicted in Table 1, below.

[0053] As defined generally above, each R’ is independently hydrogen, C_1-6 aliphatic, or an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] In some embodiments, R’ is hydrogen. In some embodiments, R’ is C_1-6 aliphatic. In some embodiments, R’ is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0056] In some embodiments, R’ is selected from those depicted in Table 1, below.

[0057] As defined generally above, R⁴ is hydrogen, halogen, -OR⁵, -CN, C_1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’.

[0058] In some embodiments, R⁴ is hydrogen. In some embodiments, R⁴ is halogen. In some embodiments, R⁴ is -OR⁵. In some embodiments, R⁴ is -CN. In some embodiments, R⁴ is C_1-6 aliphatic optionally substituted with 1, 2, or 3 halogens. In some embodiments, R⁴ is -L-R’.

[0059] In some embodiments, R⁴ is hydrogen, F, Cl, -CF3, -OCF3, -OCHF2, -OCH2Ph, -

embodiments, R⁴ is F or Cl. In some embodiments, R⁴ is -OMe. In some embodiments, R⁴ is - CF₃.

[0060] In some embodiments, R⁴ is selected from those depicted in Table 1, below.

[0061] As defined generally above, R⁵ is hydrogen, -(CH2)m-phenyl, or C1-6 alkyl optionally substituted with 1, 2, or 3 halogens.

[0062] In some embodiments, R⁵ is hydrogen. In some embodiments, R⁵ is -(CH₂)_m-phenyl. In some embodiments, R⁵ is C1-6 alkyl optionally substituted with 1, 2, or 3 halogens. [0063] In some embodiments, R⁵ is hydrogen, -CH2-phenyl, phenyl, -CH3, -CH2CH3, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3.

[0064] In some embodiments, R⁵ is selected from those depicted in Table 1, below.

[0065] As defined generally above, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0, 1, or 2.

[0066] As defined generally above, R⁶ is hydrogen or C1-4 alkyl. In some embodiments, R⁶ is hydrogen. In some embodiments, R⁶ is C1-4 alkyl.

[0067] In some embodiments, R⁶ is methyl.

[0068] In some embodiments, R⁶ is selected from those depicted in Table 1, below.

[0069] As defined generally above, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0070] In some embodiments, Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring. In some embodiments, Ring A is a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring. In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 7-12 membered saturated or partially unsaturated bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0071] In some embodiments, Ring A is saturated. In some embodiments, Ring A is partially unsaturated. In some embodiments, the bicyclic ring is ortho-fused. In some embodiments, the bicyclic ring is spirocyclic.

[0072] In some embodiments, Ring A is a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 nitrogen atoms. In some embodiments, Ring A is a 7- 12 membered saturated or partially unsaturated bicyclic ring having 1-4 nitrogen atoms. In some embodiments, Ring A is saturated.

[0073] In some embodiments, Ring A is partially unsaturated. In some embodiments, the bicyclic ring is ortho-fused. In some embodiments, the bicyclic ring is spirocyclic.

In some embodiments,

,

,

.

,

,

, or

[0075] In some embodiments, Ring A is selected from those depicted in Table 1, below.

[0076] As defined generally above, L¹ is a covalent bond or a C_1-8 bivalent straight or branched hydrocarbon chain wherein 1-5 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO₂-, -SO₂N(R)-, -(R)NSO₂-, -C(S)-, - C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-.

[0077] In some embodiments, L¹ is a covalent bond. In some embodiments, L¹ is a C1-8 bivalent straight or branched hydrocarbon chain. In some embodiments, L¹ is a C_1-8 bivalent straight or branched hydrocarbon chain wherein 1-5 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO₂-, -SO₂N(R)-, -(R)NSO₂-, -C(S)-, - C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -O-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -C(O)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -C(O)O- or -OC(O)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -N(R)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -C(O)N(R)- or -(R)NC(O)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -OC(O)N(R)- or - (R)NC(O)O-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with - N(R)C(O)N(R)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -S-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -SO-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -SO2-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -SO2N(R)- or -(R)NSO2-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -C(S)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -C(S)O- or -OC(S)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -C(S)N(R)- or - (R)NC(S)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with - (R)NC(S)N(R)-. In some embodiments, 1, 2, or 3 methylene units of the chain are replaced with -Cy-. In some embodiments, L¹ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)- , -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-, wherein each R is independently hydrogen, -CH₂- phenyl, phenyl, -CH₃, -CH₂CH₃, cyclopentyl, cyclohexyl, -CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or - CH2CF3; or each R is independently hydrogen or methyl; or R is hydrogen.

[0078] In some embodiments, L¹ is a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -SO2-, or -Cy-.

[0079] In some embodiments, L¹ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, -SO2-, or -Cy-.

[0080] In some embodiments, L¹ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -C(O)-, -NH-, - C(O)NH-, -NHC(O)-, -NHC(O)NH-, -SO2-, or -Cy-.

[0081] In some embodiments, L¹ is a C3-6 bivalent straight or branched hydrocarbon chain wherein 2 or 3 methylene units of the chain are independently replaced with -SO₂-, -SO₂NH-, - C(O)O-, -C(O)NH-, or -NHC(O)NH-. In some embodiments, L¹ is a C3-6 bivalent branched hydrocarbon chain wherein 2 or 3 methylene units of the chain are independently replaced with - SO₂-, -SO₂NH-, -C(O)O-, -C(O)NH-, or -NHC(O)NH-.

[0082] In some embodiments, the methylene unit of L¹ attached to Ring A is replaced with - SO2-. In some embodiments, the methylene unit of L¹ attached to Ring A is replaced with - SO2NH-. In some embodiments, the methylene unit of L¹ attached to Ring A is substituted with two methyl groups. In some embodiments, the methylene unit of L¹ attached to Ring A is replaced with -C(O)NH-. In some embodiments, the methylene unit of L¹ attached to Ring A is replaced with -SO2- and the adjacent methylene unit is replaced with -NHC(O)NH-. In some embodiments, the methylene unit of L¹ attached to Ring A is substituted with two methyl groups and the adjacent methylene unit is replaced with -NHC(O)NH-.

,

,

, wherein each -C - is inde endentl hen lene, ridin lene, pyrimidinylene, pyrazinylene,

[0085] In some embodiments, L¹ is selected from those depicted in Table 1, below.

[0086] As defined generally above, each -Cy- is independently a bivalent 6-membered arylene ring containing 0-2 nitrogen atoms, a bivalent 5-membered heteroarylene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bivalent partially unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C_1-4 alkyl or -OR.

[0087] In some embodiments, each -Cy- is independently a bivalent 6-membered arylene ring containing 0-2 nitrogen atoms, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl or -OR, wherein each R is independently hydrogen or methyl. In some embodiments, each -Cy- is independently a bivalent 5-membered heteroarylene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl or -OR, wherein each R is independently hydrogen or methyl. In some embodiments, each -Cy- is independently a bivalent partially unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C_1-4 alkyl or -OR, wherein each R is independently hydrogen or methyl.

[0088] In m m m n - - n n r n n , pyrimidinylene,

pyrazinylene,

[0089] In some embodiments, -Cy- is selected from those depicted in Table 1, below.

[0090] As defined generally above, each R⁸ is independently hydrogen, -CO₂R, or a C_1-6 optionally substituted aliphatic group. In some embodiments, R⁸ is hydrogen. In some embodiments, R⁸ is -CO2R, wherein R is hydrogen or C1-4 alkyl. In some embodiments, R⁸ is a C_1-6 optionally substituted aliphatic group, such as -C(O)CH₃.

[0091] In some embodiments, each R⁸ independently is hydrogen, methyl, ethyl, cyclobutyl, or -CO2H. In some embodiments, each R⁸ is independently hydrogen or -CO2H.

[0092] In some embodiments, R⁸ is selected from those depicted in Table 1, below.

[0093] As defined generally above, R⁹ is hydrogen, halogen, C_1-4 alkyl, C_1-4 alkyl substituted with an optionally substituted phenyl, optionally substituted phenyl, -CN, -OR, or L²-R⁸.

[0094] In some embodiments, R⁹ is hydrogen. In some embodiments, R⁹ is halogen. In some embodiments, R⁹ is C_1-4 alkyl. In some embodiments, R⁹ is C_1-4 alkyl substituted with an optionally substituted phenyl. In some embodiments, R⁹ is optionally substituted phenyl. In some embodiments, R⁹ is -CN. In some embodiments, R⁹ is -OR, wherein each R is independently hydrogen, -CH₂-phenyl, phenyl, -CH₃, -CH₂CH₃, cyclopentyl, cyclohexyl, -CH₂F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3. In some embodiments, R⁹ is L²-R⁸.

[0095] In some embodiments, R⁹ is -(CH2)0-5-CO2R, -SO2NHAc, -(CH2)0-5-NHSO2R⁸, - CH₂C(O)NHR⁸, -CH₂O(CH₂)_0-6-R⁸, -(CH₂)_0-5-C(O)NHR⁸, -CO₂R₈, -(CH₂)_0-5-NHSO₂NHR⁸, - SO2NH-Cy-R⁸, -SO2NHC(O)NH-(CH2)0-5-CO2R⁸, -SO2NHC(O)NH-(CH2)0-5-R⁸, -C(O)NHR⁸, - SO2NHC(O)NHR⁸, or phenyl.

[0096] In some embodiments, R⁹ is selected from those depicted in Table 1, below.

[0097] As defined generally above, each L² is independently a C1-8 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO₂-, -SO₂N(R)-, -(R)NSO₂-, -C(S)-, - C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-. In some embodiments, each L² is independently a C_1-8 bivalent straight or branched hydrocarbon chain. In some embodiments, each L² is independently a C_1-8 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, - N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, - SO₂-, -SO₂N(R)-, -(R)NSO₂-, -C(S)-, -C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, or - (R)NC(S)N(R)-, wherein each R is independently hydrogen, -CH2-phenyl, phenyl, -CH3, - CH2CH3, cyclopentyl, cyclohexyl, -CH2F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3; or each R is independently hydrogen or methyl; or R is hydrogen.

[0098] In some embodiments, L² is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with - O-, -C(O)-, -C(O)O-, -OC(O)-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, or -SO₂-.

[0099] In some embodiments, L² is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, or -SO₂-.

[00100] In some embodiments, L² is a C1-4 bivalent straight or branched hydrocarbon chain wherein 1 or 2 methylene units of the chain are independently and optionally replaced with - C(O)-, -NH-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, or -SO₂-.

[00101] In some embodiments, the methylene unit of L² attached to Ring A is replaced with - SO2-. In some embodiments, the methylene unit of L² attached to Ring A is replaced with - SO2NH-. In some embodiments, the methylene unit of L² attached to Ring A is substituted with two methyl groups. In some embodiments, the methylene unit of L² attached to Ring A is replaced with -C(O)NH-. In some embodiments, the methylene unit of L² attached to Ring A is replaced with -SO2- and the adjacent methylene unit is replaced with -NHC(O)NH-. In some embodiments, the methylene unit of L² attached to Ring A is substituted with two methyl groups and the adjacent methylene unit is replaced with -NHC(O)NH-.

[00102] As defined generally above, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2.

[00103] In some embodiments, the present invention provides a compound of Formulae II-a, II-b, or II-c:

II-c

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁶, R⁸, R⁹, Ring A, R, R’, L, L¹, L², -Cy-, and n is as defined above and described in embodiments herein, both singly and in combination.

[00104] In some embodiments, the present invention provides a compound of Formula III:

III

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R, R’, L, L¹, L², -Cy-, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[00105] In some embodiments, the present invention provides a compound of Formulae IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, or IV-k:

IV-h IV-i

IV-j IV-k

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R, R’, L, L¹, L², -Cy-, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[00106] In some embodiments, the present invention provides a compound of Formulae V-a, V-b, V-c, V-d, V-e, or V-f:

V-e V-f

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R, R’, L, L¹, L², -Cy-, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[00107] In some embodiments, the present invention provides a compound of Formulae VI-a, VI-b, VI-c, or VI-d:

VI-a VI-b

VI-c VI-d

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R, R’, L, L¹, L², -Cy-, and m is as defined above and described in embodiments herein, both singly and in combination.

[00108] In some embodiments, the present invention provides a compound of Formulae VII-a or VII-b:

VII-a VII-b

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R, R’, L, L¹, L², -Cy-, m, and n is as defined above and described in embodiments herein, both singly and in combination.

[00109] In some embodiments, the present invention provides a compound of Formulae VIII- a, VIII-b, VIII-c, or VIII-d:

VIII-a VIII-b

VIII-c VIII-d

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R, R’, L, L¹, L², -Cy-, and m is as defined above and described in embodiments herein, both singly and in combination.

[00110] In some embodiments, the present invention provides a compound of Formulae IX-a or IX-b:

IX-a IX-b

or a pharmaceutically acceptable salt thereof, wherein each of R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, R, R’, L, L¹, L², -Cy-, and m is as defined above and described in embodiments herein, both singly and in combination.

[00111] In some embodiments, the present invention provides a compound of any of the Formulae above or below wherein R⁶ is hydrogen or methyl. In some embodiments, R⁶ is hydrogen.

[00112] In some embodiments, R¹ is methyl.

[00113] In some embodiments, each R⁸ is independently hydrogen, methyl, -CO₂H, or - C(O)CH3.

[00114] In some embodiments, R² and R³ are each independently selected from halogen, C1-4 alkyl, -OH, -OCH₃, -OCF₃, or -CN.

[00115] In some embodiments, R⁴ is selected from hydrogen, halogen, C_1-4 alkyl, -OH, - OCH3, -OCF3, or -CN.

[00116] In some embodiments, R⁴ is hydrogen.

[00117] In some embodiments, R² and R³ are each independently methyl, F, or Cl.

[00118] In some embodiments, R² and R³ are each Cl.

[00119] Exemplary compounds of the invention are set forth in Table 1, below.

I-15 (racemic, single diastereomer) I-16

I-17 I-18

I-55 I-56

I-69 I-70

I-71 [00120] In some embodiments, the present invention provides a compound set forth in Table 1, above, or a pharmaceutically acceptable salt thereof. 4. Uses, Formulation and Administration:

Pharmaceutically acceptable compositions

[00121] According to another embodiment, the invention provides a composition comprising a compound of this invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in compositions of this invention is such that is effective to measurably inhibit PHGDH, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably inhibit PHGDH, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[00122] The term“patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[00123] The term“pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[00124] A“pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

[00125] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of PHGDH, or a mutant thereof.

[00126] Compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra- articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non- toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[00127] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[00128] Pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

[00129] Alternatively, pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00130] Pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. [00131] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[00132] For topical applications, provided pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00133] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum.

[00134] Pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

[00135] Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

[00136] The amount of compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving these compositions.

[00137] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the present invention in the composition will also depend upon the particular compound in the composition.

Uses of Compounds and Pharmaceutically Acceptable Compositions

[00138] Compounds and compositions described herein are generally useful for the inhibition of PHGDH or a mutant thereof.

[00139] The activity of a compound utilized in this invention as an inhibitor of PHGDH, or a mutant thereof, may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of PHGDH, or a mutant thereof. Alternate in vitro assays quantitate the ability of the inhibitor to bind to PHGDH. Detailed conditions for assaying a compound utilized in this invention as an inhibitor of PHGDH, or a mutant thereof, are set forth in the Examples below.

[00140] As used herein, the terms“treatment,”“treat,” and“treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[00141] Provided compounds are inhibitors of PHGDH and are therefore useful for treating one or more disorders associated with activity of PHGDH. Thus, in certain embodiments, the present invention provides a method for treating a PHGDH-mediated disorder comprising the step of administering to a patient in need thereof a compound of the present invention, or pharmaceutically acceptable composition thereof. [00142] As used herein, the terms“PHGDH-mediated” disorders, diseases, and/or conditions as used herein means any disease or other deleterious condition in which PHGDH, or a mutant thereof, is known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which PHGDH, or a mutant thereof, are known to play a role.

[00143] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and/or conditions wherein the disorder, disease, or condition includes, but is not limited to, a cellular proliferative disorder.

Cellular Proliferative Disorders

[00144] The present invention features methods and compositions for the diagnosis and prognosis of cellular proliferative disorders (e.g., cancer) and the treatment of these disorders by targeting PHGDH of the serine biosynthetic pathway. Cellular proliferative disorders described herein include, e.g., cancer, obesity, and proliferation-dependent diseases. Such disorders may be diagnosed using methods known in the art.

Cancer

[00145] Cancer includes, in one embodiment, without limitation, leukemias (e.g., acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma). In some embodiments, the cancer is melanoma or breast cancer.

[00146] Cancers includes, in another embodiment, without limitation, mesothelioma, hepatobilliary (hepatic and billiary duct), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, non-Hodgkin’s lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[00147] In some embodiments, the present invention provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient any of the compounds, salts or pharmaceutical compositions described herein. In some embodiments, the tumor comprises any of the cancers described herein. In some embodiments, the tumor comprises melanoma cancer. In some embodiments, the tumor comprises breast cancer. In some embodiments, the tumor comprises lung cancer. In some embodiments the tumor comprises small cell lung cancer (SCLC). In some embodiments the tumor comprises non-small cell lung cancer (NSCLC).

[00148] In some embodiments, the tumor is treated by arresting further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50 %, 75%, 90% or 99% relative to the size of the tumor prior to treatment. In some embodiments, tumors are treated by reducing the quantity of the tumors in the patient by at least 5%, 10%, 25%, 50 %, 75%, 90% or 99% relative to the quantity of tumors prior to treatment.

Other Proliferative Diseases [00149] Other proliferative diseases include, e.g., obesity, benign prostatic hyperplasia, psoriasis, abnormal keratinization, lymphoproliferative disorders (e.g., a disorder in which there is abnormal proliferation of cells of the lymphatic system), chronic rheumatoid arthritis, arteriosclerosis, restenosis, and diabetic retinopathy. Proliferative diseases that are hereby incorporated by reference include those described in U.S. Pat. Nos.5,639,600 and 7,087,648. Inflammatory Disorders and Diseases

[00150] It has recently been reported that PHGDH gene expression, dictated by IL-2R signaling, is a crucial event for DNA synthesis during S phase of activated T cells. Jun do Y et al., Cell Immunol. 2014 Feb;287(2):78-85. Compounds according to the invention are useful in the treatment of inflammatory or obstructive airways diseases, resulting, for example, in reduction of tissue damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airways diseases to which the present invention is applicable include asthma of whatever type or genesis including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma, exercise-induced asthma, occupational asthma and asthma induced following bacterial infection. Treatment of asthma is also to be understood as embracing treatment of subjects, e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or diagnosable as "wheezy infants", an established patient category of major medical concern and now often identified as incipient or early-phase asthmatics.

[00151] Compounds according to the invention are useful in the treatment of heteroimmune diseases. Examples of such heteroimmune diseases include, but are not limited to, graft versus host disease, transplantation, transfusion, anaphylaxis, allergies (e.g., allergies to plant pollens, latex, drugs, foods, insect poisons, animal hair, animal dander, dust mites, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[00152] Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack, improvement in lung function or improved airways hyperreactivity. It may further be evidenced by reduced requirement for other, symptomatic therapy, such as therapy for or intended to restrict or abort symptomatic attack when it occurs, for example antiinflammatory or bronchodilatory. Prophylactic benefit in asthma may in particular be apparent in subjects prone to "morning dipping". "Morning dipping" is a recognized asthmatic syndrome, common to a substantial percentage of asthmatics and characterized by asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially distant form any previously administered symptomatic asthma therapy.

[00153] Compounds of the current invention can be used for other inflammatory or obstructive airways diseases and conditions to which the present invention is applicable and include acute lung injury (ALI), adult/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD), including chronic bronchitis or dyspnea associated therewith, emphysema, as well as exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of whatever type or genesis including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, commonly occupational, disease of the lungs, frequently accompanied by airways obstruction, whether chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis, including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[00154] With regard to their anti-inflammatory activity, in particular in relation to inhibition of eosinophil activation, compounds of the invention are also useful in the treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues) including hypereosinophilia as it effects the airways and/or lungs as well as, for example, eosinophil- related disorders of the airways consequential or concomitant to Loffler's syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways occasioned by drug-reaction.

[00155] Compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, for example psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[00156] Compounds of the invention may also be used for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, treatment of diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory disease in which autoimmune reactions are implicated or having an autoimmune component or etiology, including autoimmune hematological disorders (e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Grave's disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren’s syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minal change nephropathy), chronic granulomatous disease, endometriosis, leptospiriosis renal disease, glaucoma, retinal disease, ageing, headache, pain, complex regional pain syndrome, cardiac hypertrophy, musclewasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ecodermal dysplasia, Behcet’s disease, incontinentia pigmenti, Paget’s disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivities, anaphylaxis, nasal sinusitis, ocular allergy, silica induced diseases, COPD (reduction of damage, airways inflammation, bronchial hyperreactivity, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation in conjunction with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison’s disease, lichen planus, Type 1 diabetes, or Type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn’s disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[00157] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is an disease of the skin. In some embodiments, the inflammatory disease of the skin is selected from contact dermatitits, atompic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, and other inflammatory or allergic conditions of the skin.

[00158] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, Juvenile rheumatoid arthritis, Systemic juvenile idiopathic arthritis (SJIA), Cryopyrin Associated Periodic Syndrome (CAPS), and osteoarthritis.

[00159] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is a TH17 mediated disease. In some embodiments the TH17 mediated disease is selected from Systemic lupus erythematosus, Multiple sclerosis, and inflammatory bowel disease (including Crohn’s disease or ulcerative colitis).

[00160] In some embodiments the inflammatory disease which can be treated according to the methods of this invention is selected from Sjogren’s syndrome, allergic disorders, osteoarthritis, conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis.

Metabolic Disease [00161] In some embodiments the invention provides a method of treating a metabolic disease. In some embodiments the metabolic disease is selected from Type 1 diabetes, Type 2 diabetes, metabolic syndrome or obesity.

[00162] The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of a cancer, an autoimmune disorder, a proliferative disorder, an inflammatory disorder, a neurodegenerative or neurological disorder, schizophrenia, a bone- related disorder, liver disease, or a cardiac disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term“patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[00163] Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect. [00164] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[00165] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[00166] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00167] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00168] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00169] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00170] Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[00171] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[00172] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00173] According to one embodiment, the invention relates to a method of inhibiting PHGDH activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00174] According to another embodiment, the invention relates to a method of inhibiting PHGDH, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound. In certain embodiments, the invention relates to a method of irreversibly inhibiting PHGDH, or a mutant thereof, activity in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00175] The term“biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[00176] Another embodiment of the present invention relates to a method of inhibiting PHGDH in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound.

[00177] According to another embodiment, the invention relates to a method of inhibiting PHGDH, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. According to certain embodiments, the invention relates to a method of irreversibly inhibiting PHGDH, or a mutant thereof, activity in a patient comprising the step of administering to said patient a compound of the present invention, or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by PHGDH, or a mutant thereof, in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[00178] Depending upon the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as“appropriate for the disease, or condition, being treated.”

[00179] A compound of the current invention may also be used to advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds which induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platin compounds; compounds targeting/decreasing a protein or lipid kinase activity and further anti-angiogenic compounds; compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; compounds which target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17- AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17- demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal^®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine/chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin. The term "aromatase inhibitor" as used herein relates to a compound which inhibits estrogen production, for instance, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozole is marketed under the trade name Afema™. Anastrozole is marketed under the trade name Arimidex™. Letrozole is marketed under the trade names Femara™ or Femar™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[00180] The term "antiestrogen" as used herein relates to a compound which antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. A combination of the invention comprising a chemotherapeutic agent which is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors.

[00181] The term "anti-androgen" as used herein relates to any substance which is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist" as used herein includes, but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[00182] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to topotecan, gimatecan, irinotecan, camptothecin and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, e.g. in the form as it is marketed, e.g. under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[00183] The term "topoisomerase II inhibitor" as used herein includes, but is not limited to the anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophillotoxines etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed. under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[00184] The term "microtubule active agent" relates to microtubule stabilizing, microtubule destabilizing compounds and microtubulin polymerization inhibitors including, but not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolides; colchicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastin R.P™. Vincristine sulfate is marketed under the trade name Farmistin™.

[00185] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[00186] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit the histone deacetylase and which possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[00187] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[00188] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g. under the trademark Eloxatin™.

[00189] The term "compounds targeting/decreasing a protein or lipid kinase activity; or a protein or lipid phosphatase activity; or further anti-angiogenic compounds" as used herein includes, but is not limited to, protein tyrosine kinase and/or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds targeting, decreasing or inhibiting the activity of the platelet-derived growth factor-receptors (PDGFR), such as compounds which target, decrease or inhibit the activity of PDGFR, especially compounds which inhibit the PDGF receptor, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds targeting, decreasing or inhibiting the activity of the fibroblast growth factor-receptors (FGFR); c) compounds targeting, decreasing or inhibiting the activity of the insulin-like growth factor receptor I (IGF-IR), such as compounds which target, decrease or inhibit the activity of IGF-IR, especially compounds which inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factors; d) compounds targeting, decreasing or inhibiting the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds targeting, decreasing or inhibiting the activity of the Axl receptor tyrosine kinase family; f) compounds targeting, decreasing or inhibiting the activity of the Ret receptor tyrosine kinase; g) compounds targeting, decreasing or inhibiting the activity of the Kit/SCFR receptor tyrosine kinase, such as imatinib; h) compounds targeting, decreasing or inhibiting the activity of the C-kit receptor tyrosine kinases, which are part of the PDGFR family, such as compounds which target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds which inhibit the c-Kit receptor, such as imatinib; i) compounds targeting, decreasing or inhibiting the activity of members of the c-Abl family, their gene-fusion products (e.g. BCR-Abl kinase) and mutants, such as compounds which target decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as an N-phenyl-2-pyrimidine-amine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds targeting, decreasing or inhibiting the activity of members of the protein kinase C (PKC) and Raf family of serine/threonine kinases, members of the MEK, SRC, JAK/pan-JAK, FAK, PDK1, PKB/Akt, Ras/MAPK, PI3K, SYK, TYK2, BTK and TEC family, and/or members of the cyclin-dependent kinase family (CDK) including staurosporine derivatives, such as midostaurin; examples of further compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; ilmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196; isochinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds targeting, decreasing or inhibiting the activity of protein-tyrosine kinase inhibitors, such as compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors include imatinib mesylate (Gleevec™) or tyrphostin such as Tyrphostin A23/RG-50810; AG 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG 555; AG 494; Tyrphostin AG 556, AG957 and adaphostin (4-{[(2,5- dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds targeting, decreasing or inhibiting the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds targeting, decreasing or inhibiting the activity of the c-Met receptor, such as compounds which target, decrease or inhibit the activity of c-Met, especially compounds which inhibit the kinase activity of c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds targeting, decreasing or inhibiting the kinase activity of one or more JAK family members (JAK1/JAK2/JAK3/TYK2 and/or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds targeting, decreasing or inhibiting the kinase activity of PI3 kinase (PI3K) including but not limited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and; and q) compounds targeting, decreasing or inhibiting the signaling effects of hedgehog protein (Hh) or smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib).

[00190] The term“PI3K inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K- C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in this invention include but are not limited to ATU-027, SF- 1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[00191] The term“Bcl-2 inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including but not limited to ABT-199, ABT-731, ABT-737, apogossypol, Ascenta’s pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2/Bcl-xL inhibitors (Infinity Pharmaceuticals/Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008118802), navitoclax (and analogs thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In some embodiments the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments the Bcl-2 inhibitor is a peptidomimetic. [00192] The term“BTK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against Bruton’s Tyrosine Kinase (BTK), including, but not limited to AVL-292 and ibrutinib.

[00193] The term“SYK inhibitor” as used herein includes, but is not limited to compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[00194] Further examples of BTK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2008039218 and WO2011090760, the entirety of which are incorporated herein by reference.

[00195] Further examples of SYK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2003063794, WO2005007623, and WO2006078846, the entirety of which are incorporated herein by reference.

[00196] Further examples of PI3K inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554, and WO2007044729 the entirety of which are incorporated herein by reference.

[00197] Further examples of JAK inhibitory compounds, and conditions treatable by such compounds in combination with compounds of this invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246, and WO2007070514, the entirety of which are incorporated herein by reference.

[00198] Further anti-angiogenic compounds include compounds having another mechanism for their activity, e.g. unrelated to protein or lipid kinase inhibition e.g. thalidomide (Thalomid™) and TNP-470.

[00199] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[00200] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are e.g. inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof. [00201] Compounds which induce cell differentiation processes include, but are not limited to, retinoic acid, α- γ- or δ- tocopherol or α- γ- or δ-tocotrienol.

[00202] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox- 2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2- arylaminophenylacetic acid, such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenyl acetic acid, lumiracoxib.

[00203] The term "bisphosphonates" as used herein includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibandronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which possess antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[00204] The term "heparanase inhibitor" as used herein refers to compounds which target, decrease or inhibit heparin sulfate degradation. The term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferons.

[00205] The term "inhibitor of Ras oncogenic isoforms", such as H-Ras, K-Ras, or N-Ras, as used herein refers to compounds which target, decrease or inhibit the oncogenic activity of Ras; for example, a "farnesyl transferase inhibitor" such as L-744832, DK8G557 or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of telomerase. Compounds which target, decrease or inhibit the activity of telomerase are especially compounds which inhibit the telomerase receptor, such as telomestatin.

[00206] The term "methionine aminopeptidase inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of methionine aminopeptidase. Compounds which target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof. [00207] The term "proteasome inhibitor" as used herein refers to compounds which target, decrease or inhibit the activity of the proteasome. Compounds which target, decrease or inhibit the activity of the proteasome include, but are not limited to, Bortezomib (Velcade™) and MLN 341.

[00208] The term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) as used herein includes, but is not limited to, collagen peptidomimetic and nonpeptidomimetic inhibitors, tetracycline derivatives, e.g. hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogue marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS-279251, BAY 12-9566, TAA211 , MMI270B or AAJ996.

[00209] The term "compounds used in the treatment of hematologic malignancies" as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds targeting, decreasing or inhibiting the activity of FMS-like tyrosine kinase receptors (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds which target, decrease or inhibit anaplastic lymphoma kinase.

[00210] Compounds which target, decrease or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies which inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

[00211] The term "HSP90 inhibitors" as used herein includes, but is not limited to, compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteosome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies which inhibit the ATPase activity of HSP90, such as 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.

[00212] The term "antiproliferative antibodies" as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan^®), PRO64553 (anti-CD40) and 2C4 Antibody. By antibodies is meant intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity. [00213] For the treatment of acute myeloid leukemia (AML), compounds of the current invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In particular, compounds of the current invention can be administered in combination with, for example, farnesyl transferase inhibitors and/or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP-16, Teniposide, Mitoxantrone, Idarubicin, Carboplatinum and PKC412.

[00214] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2^'-alpha-hydroxy ribose (arabinoside) derivative of deoxycytidine. Also included is the purine analog of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds which target, decrease or inhibit activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of the enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065 including, but not limited to, N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]- amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N- hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds which target, treat or inhibit the somatostatin receptor such as octreotide, and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (such as X- rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4^th Edition, Vol.1 , pp.248-275 (1993).

[00215] Also included are EDG binders and ribonucleotide reductase inhibitors. The term “EDG binders” as used herein refers to a class of immunosuppressants that modulates lymphocyte recirculation, such as FTY720. The term“ribonucleotide reductase inhibitors” refers to pyrimidine or purine nucleoside analogs including, but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and/or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1 ,3-dione derivatives.

[00216] Also included are in particular those compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; Zd₆474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibody, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

[00217] Photodynamic therapy as used herein refers to therapy which uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

[00218] Angiostatic steroids as used herein refers to compounds which block or inhibit angiogenesis, such as, e.g., anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[00219] Implants containing corticosteroids refers to compounds, such as fluocinolone and dexamethasone.

[00220] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanism of action.

[00221] The structure of the active compounds identified by code numbers, generic or trade names may be taken from the actual edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International (e.g. IMS World Publications).

[00222] A compound of the current invention may also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.

[00223] A compound of the current invention can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds being staggered or given independently of one another, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the current invention can besides or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is equally possible as is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapy to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[00224] Those additional agents may be administered separately from an inventive compound-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regime, the two active agents may be submitted simultaneously, sequentially or within a period of time from one another normally within five hours from one another.

[00225] As used herein, the term“combination,”“combined,” and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this invention. For example, a compound of the present invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the current invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[00226] The amount of both an inventive compound and additional therapeutic agent (in those compositions which comprise an additional therapeutic agent as described above) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, compositions of this invention should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of an inventive compound can be administered.

[00227] In those compositions which comprise an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy utilizing only that therapeutic agent. In such compositions a dosage of between 0.01– 1,000 µg/kg body weight/day of the additional therapeutic agent can be administered.

[00228] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[00229] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices risk clot formation or platelet activation. These unwanted effects may be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention. EXEMPLIFICATION

[00230] As depicted in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

General Methods of Providing the Present Compounds

[00231] The compounds of this invention may be prepared or isolated in general by synthetic and/or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples, herein.

[00232] In the Schemes below, where a particular protecting group (“PG”), leaving group (“LG”), or transformation condition is depicted, one of ordinary skill in the art will appreciate that other protecting groups, leaving groups, and transformation conditions are also suitable and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, M. B. Smith and J. March, 5^th Edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2^nd Edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, the entirety of each of which is hereby incorporated herein by reference.

[00233] As used herein, the phrase“leaving group” (LG) includes, but is not limited to, halogens (e.g. fluoride, chloride, bromide, iodide), sulfonates (e.g. mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.

[00234] As used herein, the phrase“oxygen protecting group” includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, and Philip Kocienski, in “Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4- oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate (trimethylacetyl), crotonate, 4- methoxy-crotonate, benzoate, p-benylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2- (phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4- dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl. [00235] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rd edition, John Wiley & Sons, 1999, and Philip Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, the entireties of which is incorporated herein by reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[00236] One of skill in the art will appreciate that various functional groups present in compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art including, but not limited to reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, “March’s Advanced Organic Chemistry”, 5^th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein by reference. Such interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below.

[00237] In one aspect, certain compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 1 set forth below:

Scheme 1

[00238] In Scheme 1 above, R’ is a group such as C1-6 aliphatic, 5- to 8-membered aromatic ring, or other functionality compatible with an ester; and R¹, R², R³, and R⁶ are selected consistent with formula I above and below and in classes and subclasses as described herein.

[00239] In one aspect, the present invention provides methods for preparing compounds of formula GS4 as described in Scheme 1. An optionally substituted benzaldehyde may be condensed with an azidoacetate in the presence of base such as sodium hydroxide or sodium methoxide to give intermediate GS1. Heating GS1 in a solvent such as toluene (e.g., at reflux) provides the indole-2-carboxylate ester. In some embodiments, the indole nitrogen is alkylated using an appropriate alkyl halide such as methyl or ethyl iodide and a suitable base such as, but not limited, to sodium hydride, potassium tert-butoxide, or potassium carbonate in a suitable solvent to provide GS3. In some embodiments, the ester of GS3 is hydrolyzed using a base such as LiOH, KOH or NaOH in a solvent such as a mixture of water and THF to provide an intermediate used in the synthesis of compounds of the invention of general structure GS4.

[00240] Alternatively, in some embodiments GS3 may be treated with appropriate reagents such as POCl3 and DMF to give GS5. In some embodiments, the aldehyde in GS5 is then reduced to a methyl group with appropriate reagents such as Et₃SiH and TFA to give GS6. Finally, in some embodiments, hydrolysis of the ester in GS6 provides an intermediate used in the synthesis of compounds of the invention of general structure GS7. [00241] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 2 set forth below:

Scheme 2

[00242] Scheme 2 describes an alternate route to prepare compounds of formula GS3. In some embodiments, treatment of an aniline with a nitrite compound and a ketoacetate of choice in a suitable solvent (for example, a mixture of ethanol/water) produces an aryl hydrazine intermediate that reacts with the ketoacetate (such as ethyl 2-methyl-3-oxo-butanoate) to provide GS8. Treatment of GS8 with TFA with heat, e.g., reflux, provides general intermediate GS3 that can be elaborated to GS4 and GS7 as described above.

[00243] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 3 set forth below:

Scheme 3

GS8 GS9 GS10

M¹ = CH₂, M² = NBoc

or

M¹ = NBoc, M² = CH₂

GS11 GS12 GS13

[00244] Compounds such as general structures GS12 and GS13 can be synthesized according to Scheme 3. The commercially available 3- or 4- N-Boc piperidone can be reacted with a reagent such as methyl (triphenylphosphoranylidene)acetate to produce GS9. Treatment of GS9 with ammonia in a suitable solvent such as methanol under pressure affords compounds with the general structure GS10. Acetylation of GS10 using TFAA affords GS11. Reaction of GS11 with methyl amine provides intermediates with the general structures GS12 and GS13. [00245] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 4 set forth below:

h m 4

[00246] In another embodiment of the invention compounds of structure GS23 can be prepared as described in Scheme 4. Treatment of GS8 with hydroxlyamine hydrochloride in ethanol provides the N-hydroxyimine GS14. Oxidation of GS14 with peroxy trifluoroacetic acid, generated using TFAA and urea hydroperoxide (UHP), affords GS15. Alkylation of GS15 with methyl acrylate using an appropriate base such as potassium carbonate produces GS16. Conversion of the ester functionality into the acid chloride using procedures well known to one skilled in the art produces compound GS18. Condensation of GS18 with diazomethane provides GS19. Treatment of GS19 with silver oxide and triethylamine in water/THF gives GS20. The acid can be converted to the acid chloride using oxalyl chloride or thionyl chloride to provide GS21, which is reacted with methyl amine to afford GS22. Reduction of the nitro group with zinc and ammonium chloride provides intermediates with the general structure GS23.

[00247] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 5 set forth below:

[00248] Additional compounds of the invention can be synthesized using GS25. Treatment of GS16 with methyl amine in ethanol produces GS24. Hydrogenolysis of the nitro group using palladium hydroxide in ethyl acetate affords GS25.

[00249] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 6 set forth below:

Scheme 6

GS29 GS30 GS31

[00250] In another embodiment of the invention compounds such as GS31 can be synthesized according to Scheme 6. Reaction of GS8 with 2-diethoxyphosphorylacetonitrile with an appropriate base such as sodium hydride affords GS27. Treatment of GS27 with ammonia in methanol under pressure provides GS28. Temporary protection of the amine with an appropriate protecting group such as a trifluoroacetate using TFAA and triethylamine produces GS29. Reduction of the nitrile and in situ acetylation is effected using H₂, Raney Ni, and acetic anhydride in acetic acid to afford GS30. Hydrolysis of the trifluoroacetate with base such as NaOH in water and methanol provides intermediate GS31.

[00251] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 7 set forth below:

[00252] In another embodiment of the invention compounds such as GS35, GS50, and GS51 can be synthesized according to Scheme 7. Reaction of GS15 with acrylonitrile affords GS32. Reduction of the nitrile using borane or other suitable reducing agents provides GS33. Acetylation of the amine using acetyl chloride (affording GS34), followed by reduction of the nitro group provides GS35. Alternatively, GS33 can be reacted with a sulfonyl halide such as methanesulfonyl chloride to produce GS49 followed by hydrogenolysis of the nitro group to produce intermediate GS50. In another embodiment of the invention the amine in GS33 can be protected with an appropriate protecting group such as Cbz using CbzCl and triethylamine followed by reduction of the nitro group using ammonium chloride and iron to afford intermediate GS52.

[00253] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 8 set forth below:

[00254] In another embodiment of the invention compounds such as GS38 can be synthesized according to Scheme 8. In an analogous fashion as described in Scheme 3 reaction of GS36 with methyl (triphenylphosphoranylidene)acetate affords GS37. Treatment of G37 with ammonia in a suitable solvent such as methanol under pressure affords compounds with the general structure GS38.

[00255] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 9 set forth below:

S h 9

[00256] In another embodiment of the invention compounds such as GS43 can be synthesized according to Scheme 9. Reaction of GS39 with potassium hydroxide and iodine in methanol produces intermediate GS40. The dimethyl ketal is converted to the ketone using TsOH in acetone and the hydroxyl group is protected with a TBDPS group using TBDPSCl and imidazole in DMF to afford GS41. Reductive amination using ammonium acetate and sodium cyanoborohydride provides intermediate GS43.

[00257] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 10 set forth below: S h 10

[00258] In another embodiment of the invention compounds such as GS47 can be synthesized according to Scheme 10. Reaction of benzylamine with acrylonitrile produces GS44. Reaction of GS44 with another equivalent of acrylonitrile affords GS45. Cyclization of GS45 with potassium tert-butoxide in toluene produces GS46. Treatment of GS46 with sodium cyanoborohydride and acetic acid in ethanol provides intermediate GS47.

[00259] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 11 set forth below:

Scheme 11

In another embodiment of the invention compounds such as GS49 and GS52 can be synthesized according to Scheme 11. Alkylation of GS39 with t-butyl bromoacetate using LDA in a solvent mixture of HMPA and THF produces GS48. Reductive amination using conditions that have been described previously affords intermediate GS49. Alternatively GS39 can be reacted with pyrrolidine to produce GS50. Reaction of GS50 with an acrylate ester in toluene provides GS51. Finally reductive amination of GS51 provides intermediate GS52.

[00260] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 12 set forth below:

Scheme 12

GS56

[00261] In another embodiment of the invention compounds such as GS56 can be synthesized according to Scheme 12. Treatment of 3-Boc-piperidone with ammonium chloride and potassium cyanide in ammonium hydroxide and ethanol provides intermediate GS53. Reaction of GS53 with GS57 produces GS54. Hydrogenation of the nitrile group with Raney Nickel affords GS55. Acetylation of GS55 with an acyl chloride of choice followed by Boc-deprotection affords intermediate GS56.

[00262] In another aspect, compounds of the present invention of formula I, or subformulae thereof, are generally prepared according to Scheme 13 set forth below:

[00263] In another embodiment of the invention compounds such as GS64 can be synthesized according to Scheme 13. Conversion of the acid group in GS4 to the acid chloride can be done using procedures well known to one of skill in the art. For example, the acid can be treated with oxalyl chloride or thionyl chloride in the presence of a catalytic amount of DMF in a solvent such as DCM to produce GS57. Reaction of GS57 with an amine of choice affords GS58. Removal of the Boc protecting group provides key intermediate GS59 that can be elaborated into additional exemplary compounds of the invention. For example, reaction of GS59 with an oxazolidine sulfonamide of choice provides exemplary compounds of the invention with the general structure GS61. Alternatively, treatment of GS59 with t-butyl(chlorosulfonyl)carbamate provides GS60. Reaction of GS60 with an amine of choice provides example compounds of the invention with the general structure GS63. In another embodiment of the invention removal of the Boc group with HCl/MeOH or TFA/DCM produces exemplary compounds of the invention with the general structure GS62. GS62 can be further elaborated using methods known to one skilled in the art to produce additional compounds of the invention. For example, treatment of GS62 with an isocyanate of choice catalyzed by CuCl or CsCO₃ or treatment of GS62 with an acid chloride provides exemplary compounds of the invention with the general structure GS64. For all protection and deprotection methods see Philip Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, and Theodora W. Greene and Peter G.M. Wuts in “Protecting Groups in Organic Synthesis” Wiley Interscience 3^rd Edition 1999.

Abbreviations Table

General Synthetic Methods

[00264] The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereafter should be considered to be disclosed. Temperatures are given in degrees centigrade. If not mentioned otherwise, all evaporations are performed under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20-133 mbar). The structure of final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art. [00265] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesis the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples. [00266] All reactions are carried out under nitrogen or argon unless otherwise stated. Optical rotations were measured in MeOH. [00267] Proton NMR (¹H NMR) is conducted in deuterated solvent. In certain compounds disclosed herein, one or more ¹H shifts overlap with residual protio solvent signals; these signals have not been reported in the experimental provided hereinafter. Analytical instruments Table

For acidic LCMS data: [00268] LCMS was recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS2020 equipped with electro-spray ionization and quadruple MS detector [ES+ve to give MH⁺] and equipped with Chromolith Flash RP-18e 25*2.0 mm, eluting with 0.0375 vol% TFA in water (solvent A) and 0.01875 vol% TFA in acetonitrile (solvent B). For basic LCMS data: [00269] LCMS was recorded on an Agilent 1200 Series LC/MSD or Shimadzu LCMS 2020 equipped with electro-spray ionization and quadruple MS detector [ES+ve to give MH⁺] and equipped with Xbridge C18, 2.1 x 50 mm columns packed with 5 mm C18-coated silica or Kinetex EVO C18 2.1 x 30mm columns packed with 5 mm C18-coated silica, eluting with 0.05 vol% NH3·H2O in water (solvent A) and acetonitrile (solvent B). Synthesis of Intermediates 4,5-Dichloro-1-methyl-indole-2-carboxylic acid (Intermediate A)

Step 1 - Methyl (Z)-2-azido-3-(2,3-dichlorophenyl)prop-2-enoate [00270] To a solution of sodium methoxide (11.1 g, 205 mmol) in anhydrous methanol (80 mL) was added a mixed solution of 2,3-dichlorobenzaldehyde (12.0 g, 68.5 mmol) and methyl 2- azidoacetate (26.5 g, 205 mmol) in anhydrous methanol (80 mL) at -50 °C. After stirring at -50 °C for 2 hrs, the mixture was warmed to 25 °C, and stirred for 14 hrs. On completion, the suspension was poured onto ice and the azido derivative was collected by filtration and washed with cold water. The filter cake was dried in vacuo and purified by column chromatography (petroleum ether/ethyl acetate = 10/1) to give the title compound.¹H NMR (400MHz, CDCl₃) δ = 8.06 (dd, J = 1.3, 8.0 Hz, 1H), 7.45 (dd, J = 1.4, 8.0 Hz, 1H), 7.30 - 7.24 (m, 2H), 3.97 (s, 3H). Step 2 - Methyl 4,5-dichloro-1H-indole-2-carboxylate [00271] A solution of methyl (Z)-2-azido-3-(2, 3-dichlorophenyl)prop-2-enoate (7.80 g, 28.6) in toluene (150 mL) was stirred at 120 °C for 16 hrs. On completion, the toluene was removed in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 12/1 to 5/1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ = 12.52 (br. s., 1H), 7.47 - 7.41 (m, 2H), 7.12 (d, J = 2.1 Hz, 1H), 3.90 (s, 3H). Step 3 - Methyl 4,5-dichloro-1-methyl-indole-2-carboxylate [00272] To a solution of methyl 4,5-dichloro-1H-indole-2-carboxylate (4.50 g, 18.4 mmol) in N,N-dimethylformamide (40 mL) was added potassium carbonate (6.37 g, 46.1 mmol) and iodomethane (10.4 g, 73.7 mmol). The mixture was stirred at 60 °C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo to remove solvent. The residue was diluted with water (30 mL) and extracted with dichloromethane (3 x 15 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 8/1 to 3/1) to give the title compound.¹H NMR (400MHz, DMSO-d6) δ = 7.69 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.9 Hz, 1H), 7.22 (br. s., 1H), 4.05 (br. s., 3H), 3.89 (br. s., 3H). Step 4 - 4,5-Dichloro-1-methyl-indole-2-carboxylic acid [00273] To a solution of methyl 4,5-dichloro-1-methyl-indole-2-carboxylate (4.10 g, 15.8 mmol) in a solvent mixture of tetrahydrofuran (40 mL) and water (10 mL) was added lithium hydroxide (1.14 g, 47.6 mmol). The mixture was stirred at 18 °C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was acidified with 1 M hydrochloric acid to pH = 3, during which a fine precipitate was formed. The precipitate was filtered and the filter cake was washed with water, dried under vacuum to give the title compound. ¹H NMR (400MHz, DMSO-d6) δ = 13.35 (br. s., 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.14 (s, 1H), 4.03 (s, 3H). 4,5-Dichloro-1-methyl-indole-2-carbonyl chloride (Intermediate B)

[00274] To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (1.00 g, 4.10 mmol) in anhydrous dichloromethane (80 mL) was added N,N-dimethylformamide (5.00 uL) and oxalyl chloride (780 mg, 6.15 mmol) dropwise at 0 °C. The reaction mixture was warmed to 15 °C and stirred for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound. The crude product was used in the next step directly. 4-Chloro-1,5-dimethyl-1H-indole-2-carboxylic acid (Intermediate C)

Step 1 - (2-Chloro-3-methylphenyl)methanol [00275] To a solution of 2-chloro-3-methyl-benzoic acid (30 g, 175 mmol) in anhydrous tetrahydrofuran (240 mL) was added dropwise BH3•Me2S (10 M, 21 mL) under nitrogen. The reaction mixture was stirred at reflux at 70 °C for 12 hrs. On completion, the reaction mixture was quenched with methanol (50 mL), diluted with water (230 mL) and extracted with ethyl acetate (2 x 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to give the title compound. ¹H NMR (400MHz, DMSO-d6) δ = 7.42 - 7.34 (m, 1H), 7.24 (d, J = 4.8 Hz, 2H), 5.36 (t, J = 5.6 Hz, 1H), 4.55 (d, J = 5.5 Hz, 2H), 2.32 (s, 3H). Step 2 - 2-Chloro-3-methylbenzaldehyde [00276] To a solution of (2-chloro-3-methyl-phenyl)methanol (26.2 g, 167 mmol) in dichloromethane (350 mL) was added manganese dioxide (116 g, 1.34 mol) under nitrogen. After the addition, the reaction mixture was stirred at 25 °C for 12 hrs. The solid was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography (eluted with petroleum ether:ethyl acetate = 20:1) to give the title compound.¹H NMR (400MHz, DMSO-d6) δ = 10.42 - 10.34 (m, 1H), 7.68 (t, J = 8.2 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 2.39 (s, 3H). Step 3 - (Z)-Methyl 2-azido-3-(2-chloro-3-methylphenyl)acrylate [00277] To a solution of MeONa (17.2 g, 319 mmol) in methanol (150 mL) was added a solution of methyl 2-azidoacetate (41.2 g, 319 mmol) and 2-chloro-3-methyl-benzaldehyde (16.4 g, 106 mmol) in methanol (150 mL) dropwise at -20 °C. After the mixture was stirred at -20 °C for 2 hrs, it was warmed up to 25 °C for 12 hrs. During this time a fine precipitate was formed. The suspension was poured onto ice water and the azido derivative was collected by filtration and the filter cake washed with cold water. The solid was dissolved in dichloromethane (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound. ¹H NMR (400MHz, CDCl₃) δ = 8.04 - 7.95 (m, 1H), 7.37 (s, 1H), 7.26 - 7.20 (m, 2H), 3.96 (s, 3H), 2.48 - 2.37 (m, 3H). Step 4 - Methyl 4-chloro-5-methyl-1H-indole-2-carboxylate [00278] A solution of methyl (Z)-2-azido-3-(2-chloro-3-methyl-phenyl)prop-2-enoate (20.9 g, 83.2 mmol) in toluene (250 mL) was heated to 120 °C under a nitrogen for 16 hrs. On completion, the reaction mixture was concentrated to afford the crude product as a yellow solid. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 20:1) to give the title compound. ¹H NMR (400MHz, DMSO-d₆) δ = 12.21 (br. s., 1H), 7.34 (d, J=8.3 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.07 (d, J=1.3 Hz, 1H), 3.89 (s, 3H), 2.40 (s, 3H). Step 5- Methyl 4-chloro-1,5-dimethyl-1H-indole-2-carboxylate [00279] To a solution of methyl 4-chloro-5-methyl-1H-indole-2-carboxylate (16.0 g, 71.8 mmol) in DMF (300 mL) was added K2CO3 (9.93 g, 71.8 mmol) and MeI (30.4 g, 215 mmol) at 20 °C. The reaction was stirred at 60 °C under nitrogen for 16 hrs. On completion, the reaction mixture was filtered and the filter cake was washed with dichloromethane (30 mL), the filtrate was concentrated to afford the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound. ¹H NMR (400MHz, CDCl₃) δ = 7.36 (s, 1H), 7.21 (d, J=1.5 Hz, 2H), 4.07 (s, 3H), 3.94 (s, 3H), 2.49 (s, 3H). Step 6 - 4-Chloro-1,5-dimethyl-1H-indole-2-carboxylic acid [00280] To a solution of methyl 4-chloro-1,5-dimethyl-indole-2-carboxylate (11.0 g, 46.4 mmol) in a solvent mixture of tetrahydrofuran (90 mL) and H₂O (30 ml) was added LiOH•H₂O (7.80 g, 186 mmol) at 25 °C under nitrogen. The reaction mixture was stirred at 25 °C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo, and the residue was acidified with 2 M HCl (20 mL) to pH = 3, and then was filtered. The filter cake was wash with water (20 mL), dried in vacuo to give the title compound.¹H NMR (400MHz, DMSO-d₆) δ = 13.14 (br. s., 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.11 (s, 1H), 4.01 (s, 3H), 2.41 (s, 3H). 4-Chloro-1,5-dimethyl-1H-indole-2-carbonyl chloride (Intermediate D)

[00281] To a suspension of 4-chloro-1,5-dimethyl-1H-indole-2-carboxylic acid (5 g, 22.4 mmol) and N,N-dimethylformamide (163.4 mg, 2.2 mmol) in dichloromethane (100 mL) was added oxalyl dichloride (5.7 g, 44.7 mmol) dropwise at 15 °C. Then, the mixture was heated to 40 °C with stirring for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound.

4-Chloro-5-fluoro-1-methyl-indole-2-carboxylic acid (Intermediate E)

Step 1 - Ethyl (2E)-2-[(3-chloro-4-fluoro-phenyl)hydrazono]propanoate [00282] To a solution of 3-chloro-4-fluoro-aniline (15.0 g, 103 mmol) in ethanol (15 mL) and water (15 mL) was added hydrochloric acid (37%, 30 mL). The mixture was cooled to -5 °C, and then a solution of NaNO2 (8.00 g, 116 mmol) in water (40 mL) was added dropwise while the temperature was maintained below 5 °C. A cold solution of ethyl 2-methyl-3-oxo-butanoate (15.0 g, 104 mmol) and sodium acetate (30.0 g, 366 mmol) in a solvent mixture of ethanol (75 mL) and water (30 mL) was added to the reaction mixture, and the reaction mixture was stirred at -5 °C for 4 hours. On completion, the reaction mixture was extracted with dichloromethane and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30:1 to 10:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ = 7.33 - 7.25 (m, 1H), 7.10 - 7.02 (m, 1H), 6.98 - 6.90 (m, 1H), 4.41 - 4.17 (m, 2H), 2.17 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). Step 2 - Ethyl 4-chloro-5-fluoro-1H-indole-2-carboxylate and Ethyl 6-chloro-5-fluoro-1H- indole-2-carboxylate [00283] A solution of ethyl (2E)-2-[(3-chloro-4-fluoro-phenyl)hydrazono]propanoate (6.70 g, 25.9 mmol) in trifluoroacetic acid (30 mL) was refluxed at 80 °C for 12 hours. On completion, the solvent was evaporated in vacuo, and the residue was diluted in ethyl acetate and was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, then dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 30:1 to 20:1) to give ethyl 4-chloro-5-fluoro-1H-indole-2- carboxylate (150 mg, 3% yield), ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate (700 mg, 11% yield) and a mixture of ethyl 4-chloro-5-fluoro-1H-indole-2-carboxylate and ethyl 6-chloro-5- fluoro-1H-indole-2-carboxylate (3.0 g) as a yellowish solid. Ethyl 4-chloro-5-fluoro-1H-indole- 2-carboxylate ¹H NMR (300MHz, DMSO-d₆) δ = 12.11 (br. s., 1H), 7.67 (d, J = 10.0 Hz, 1H), 7.57 (d, J = 6.4 Hz, 1H), 7.15 (d, J = 1.1 Hz, 1H), 4.47 - 4.19 (m, 2H), 1.46 - 1.24 (m, 3H). Mixture ethyl 4-chloro-5-fluoro-1H-indole-2-carboxylate and ethyl 6-chloro-5-fluoro-1H-indole- 2-carboxylate ¹H NMR (300MHz, DMSO-d₆) δ = 12.38 (br. s., 0.5H), 12.11 (br. s., 0.5H), 7.66 (d, J = 10.0 Hz, 0.5H), 7.57 (d, J = 6.4 Hz, 0.5H), 7.45 (dd, J = 4.0, 8.9 Hz, 0.5H), 7.37 - 7.26 (m, 0.5H), 7.14 (dd, J = 1.5, 5.8 Hz, 0.5H), 4.56 - 4.06 (m, 2H), 1.61 - 1.04 (m, 3H). Step 3 - Ethyl 4-chloro-5-fluoro-1-methyl-indole-2-carboxylate [00284] To a solution of a mixture of ethyl 4-chloro-5-fluoro-1H-indole-2-carboxylate and ethyl 6-chloro-5-fluoro-1H-indole-2-carboxylate (5.00 g, 20.7 mmol) in N,N-dimethylformamide (20 mL) was added potassium carbonate (11.4 g, 82.7 mmol) and iodomethane (14.7 g, 103 mmol). Then the mixture was stirred at 60 °C for 12 hrs. On completion, the residue was diluted with water (100 mL) and extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated. The residue was purified by prep-SFC (Condition: Base-MeOH; Column: AD (250 mm * 30 mm, 10 µm) to give ethyl 4-chloro-5- fluoro-1-methyl-indole-2-carboxylate (2.6 g, 49% yield) and ethyl 6-chloro-5-fluoro-1-methyl- indole-2-carboxylate (2.4 g, 45% yield). Ethyl 4-chloro-5-fluoro-1-methyl-indole-2-carboxylate ¹H NMR (400MHz, CDCl3) δ = 7.38 (s, 1H), 7.31 - 7.22 (m, 1H), 7.22 - 7.15 (m, 1H), 4.42 (q, J = 7.3 Hz, 2H), 4.09 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). Ethyl 6-chloro-5-fluoro-1-methyl-indole-2- carboxylate ¹H NMR (400MHz, CDCl₃) δ = 7.49 - 7.37 (m, 2H), 7.27 - 7.21 (m, 1H), 4.40 (q, J = 7.3 Hz, 2H), 4.16 - 3.96 (m, 3H), 1.48 - 1.36 (m, 3H). Step 4 - 4-Chloro-5-fluoro-1-methyl-indole-2-carboxylic acid [00285] To a mixture of ethyl 4-chloro-5-fluoro-1-methyl-indole-2-carboxylate (2.60 g, 10.2 mmol) in tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide (1.71 g, 40.7 mmol). Then the mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was concentrated in vacuo. The residue was diluted water (50 mL). The mixture was acidified with 2 M hydrochloric acid to pH = 3 and extracted with ethyl acetate (3 x 50 mL). The organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated to give the title compound. ¹H NMR (400MHz, DMSO-d6) δ = 7.75 - 7.57 (m, 1H), 7.39 (t, J = 9.4 Hz, 1H), 7.19 (s, 1H), 4.05 (s, 3H). 5-Chloro-4-fluoro-1-methyl-indole-2-carboxylic acid (Intermediate F)

Step 1 - Ethyl (2E)-2-[(4-chloro-3-fluoro-phenyl)hydrazono]propanoate [00286] To a solution of 4-chloro-3-fluoro-aniline (8.20 g, 56.3 mmol) in a solvent mixture of ethanol (50 mL) and water (50 mL) was added hydrochloric acid (16 mL) and subsequently a solution of sodium nitrite (4.28 g, 61.9 mmol) in water (50 mL) dropwise during a period of 30 min, during which the temperature of the mixture was maintained -10 °C to -5 °C. A solution of ethyl 2-methyl-3-oxo-butanoate (8.40 g, 58.2 mmol) and sodium acetate (16.1 g, 197 mmol) in ethanol (100 mL) and water (100 mL) was added to the reaction mixture dropwise at -5 °C over 30 min. The mixture was stirred at -5 °C for 2 hours. On completion, the mixture was concentrated in vacuo, and the residue was washed with water (120 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate =40:1) to give the title compound.¹H NMR (400MHz, DMSO-d6) δ = 7.85 (t, J=8.2 Hz, 1H), 7.77 (dd, J=2.0, 9.8 Hz, 1H), 7.68 (dd, J=1.3, 8.5 Hz, 1H), 4.25 - 4.17 (m, 2H), 2.38 (s, 3H), 1.18 (t, J=7.0 Hz, 3H). Step 2– Ethyl -5-Chloro-4-fluoro-1H-indole-2-carboxylate and ethyl 5-chloro-6-fluoro-1H- indole-2-carboxylate [00287] A solution of ethyl (2E)-2-[(4-chloro-3-fluoro-phenyl)hydrazono]propanoate (4.60 g, 17.7 mmol) in trifluoroacetic acid (20 mL) was heated to reflux at 90 °C under a nitrogen atmosphere for 16 hrs. On completion, the mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 40:1) to afford a mixture of the ethyl 5-chloro-4-fluoro-1H-indole-2-carboxylate and ethyl 5-chloro-6-fluoro-1H- indole-2-carboxylate (2.2 g, 40%, yield). ¹H NMR (400MHz, DMSO-d6) δ = 12.44 (br. s., 1H), 7.90 (d, J=7.5 Hz, 1H), 7.33 - 7.30 (m, 1H), 7.19 (d, J=1.5 Hz, 1H), 4.40 - 4.36 (q, 2H), 1.37 - 1.35 (t, 3H); ¹H NMR (400MHz, DMSO-d₆) δ = 12.17 (br. s., 1H), 7.90 (d, J=7.5 Hz, 1H), 7.37 (d, J=9.8 Hz, 1H), 7.15 (d, J=1.3 Hz, 1H), 4.36 - 4.30 (q, 2H), 1.35 - 1.31 (t, 3H). Step 3 - Ethyl 5-chloro-4-fluoro-1-methyl-indole-2-carboxylate and ethyl 5-chloro-6-fluoro-1- methyl-indole-2-carboxylate [00288] To a solution of a mixture of ethyl 5-chloro-4-fluoro-1H-indole-2-carboxylate and ethyl 5-chloro-6-fluoro-1H-indole-2-carboxylate (1.50 g, 6.21 mmol) and potassium carbonate (3.43 g, 24.8 mmol) in N,N-dimethylformamide (10 mL) was added methyl iodide (2.64 g, 18.6 mmol) at 60 °C under a nitrogen atmosphere. The reaction mixture was then stirred at 60 °C for 16 hours. On completion, the mixture was filtered; the filtrate was concentrated in vacuo. The residue was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL), the combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo to afford crude product (1.8 g). The crude product (1 g) was separated by SFC to afford ethyl 5- chloro-4-fluoro-1-methyl-indole-2-carboxylate (230 mg, 14% yield) and ethyl 5-chloro-6-fluoro- 1-methyl-indole-2-carboxylate (450 mg, 28% yield). Ethyl 5-chloro-4-fluoro-1-methyl-indole-2- carboxylate ¹H NMR (400MHz, DMSO-d6) δ = 7.55 - 7.50 (m, 1H), 7.47 - 7.41 (m, 1H), 7.27 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 4.04 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). Ethyl 5-chloro-6-fluoro-1- methyl-indole-2-carboxylate ¹H NMR (400MHz, DMSO-d6) δ = 7.92 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 10.5 Hz, 1H), 7.26 (s, 1H), 4.32 (q, J = 7.0 Hz, 2H), 3.99 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). Step 4 - 5-Chloro-4-fluoro-1-methyl-indole-2-carboxylic acid [00289] To a solution of ethyl 5-chloro-4-fluoro-1-methyl-indole-2-carboxylate (230 mg, 899 µµmol) in a solvent mixture of tetrahydrofuran (4 mL) and water (2.00 mL) was added lithium hydroxide (43.0 mg, 1.80 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 hours. On completion, the mixture was concentrated in vacuo, the residue was diluted with water and extracted with ethyl acetate (3 x 15 mL), the combined organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to afford the title compound.¹H NMR (400MHz, DMSO- d6) δ = 13.32 (br. s., 1H), 7.54 - 7.48 (m, 1H), 7.46 - 7.39 (m, 1H), 7.24 (s, 1H), 4.04 (s, 3H). 2-Oxo-N-pyrimidin-2-yl-oxazolidine-3-sulfonamide (Intermediate H)

[00290] A 250 mL round-bottom flask was charged with dichloromethane (250 mL) and sulfurisocyanatidic chloride (14.9 g, 105 mmol). The flask was cooled in an ice bath for 20 minutes, and then 2-bromoethanol (13.1 g, 105 mmol) was added dropwise. The mixture was stirred for 2.5 hours, then a solution of pyrimidin-2-amine (10 g, 105 mmol) and triethylamine (32 g, 317 mmol) in dichloromethane (150 mL) was added dropwise via an addition funnel over 10 minutes. When the addition was complete, the cooling bath was removed, and the mixture was stirred for 2 days. On completion, to the mixture was added 2N hydrochloric acid, the mixture was filtered and the filter cake was washed with dichloromethane and water. The solid was dried under vacuum to give the title compound.¹H NMR (400MHz, DMSO-d₆) δ = 8.66 (d, J = 5.0 Hz, 2H), 7.30 - 6.99 (m, 1H), 4.52 - 4.35 (m, 2H), 4.33 - 4.15 (m, 2H). (±)-Tert-butyl 3-amino-3-[2-(methylamino)-2-oxo-ethyl]piperidine-1-carboxylate (Intermediate I)

Step 1 - Tert-butyl (3Z)-3-(2-methoxy-2-oxo-ethylidene)piperidine-1-carboxylate [00291] Methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate (41.6 g, 124 mmol) was added to a solution of tert-butyl 3-oxopiperidine-1-carboxylate (20.0 g, 100 mmol) in toluene (100 mL). The resulting reaction mixture was stirred at 120 °C for 16 hours. On completion, the reaction mixture was then cooled to room temperature and concentrated in vacuo. The resulting residue was purified by prep-column chromatography (petroleum ether:ethyl acetate = 30:1 to petroleum ether:ethyl acetate = 3:1) to give the title compound.¹H NMR (400MHz, CDCl3) δ = 5.87 - 5.64 (m, 1H), 4.63 (s, 1H), 4.04 - 3.91 (m, 1H), 3.72 (s, 3H), 3.51 (t, J = 7.3 Hz, 2H), 3.02 - 2.92 (m, 1H), 2.36 (t, J = 6.1 Hz, 1H), 1.73 (td, J = 5.6, 11.6 Hz, 2H), 1.45 (s, 9H). Step 2 - (±)-Tert-butyl 3-amino-3-(2-methoxy-2-oxo-ethyl)piperidine-1-carboxylate [00292] To a mixture of tert-butyl (3Z)-3-(2-methoxy-2-oxo-ethylidene)piperidine-1- carboxylate (17.0 g, 66.0 mmol) in methanol (50 mL) was added ammonia/methanol (200 mL) in an autoclave. Then the mixture was stirred at 80 °C for 16 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-column chromatography (petroleum ether:ethyl acetate = 3:1 to dichloromethane:methanol = 20:1) to give the title compound. LCMS: (ES+) m/z (M-100-16)⁺ = 156.3, tR= 1.262.¹H NMR (400MHz, CDCl₃) δ = 3.71 (s, 3H), 3.58 - 3.29 (m, 3H), 3.21 (br. s., 1H), 2.44 (s, 2H), 1.73 - 1.62 (m, 3H), 1.58 - 1.50 (m, 2H), 1.47 (s, 9H). Step 3 - (±)-Tert-butyl 3-(2-methoxy-2-oxo-ethyl)-3-[(2,2,2-trifluoroacetyl)amino]piperidine-1- carboxylate [00293] To a mixture of (±)-tert-butyl 3-amino-3-(2-methoxy-2-oxo-ethyl)piperidine-1- carboxylate (5.50 g, 20.2 mmol) in dichloromethane (10 mL) was added triethylamine (6.13 g, 60.6 mmol). Then the mixture was stirred at 0 °C for 0.5 hour. A solution of (2,2,2- trifluoroacetyl) 2,2,2-trifluoroacetate (6.36 g, 30.3 mmol) in 5 mL dichloromethane was added to the mixture dropwise at 0 °C. Then the mixture was stirred at 15 °C for 12 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-column chromatography (petroleum ether:ethyl acetate = 10:1 to petroleum ether:ethyl acetate = 3:1) to give the title compound. LCMS: (ES+) m/z (M-56+H)⁺ = 312.9. Step 4 - (±)-Tert-butyl 3-(2-(methylamino)-2-oxoethyl)-3-(2,2,2-trifluoroacetamido)piperidine-1- carboxylate and (±)-tert-butyl 3-amino-3-[2-(methylamino)-2-oxo-ethyl]piperidine-1- carboxylate [00294] A mixture of (±)-tert-butyl 3-(2-methoxy-2-oxo-ethyl)-3-[(2,2,2- trifluoroacetyl)amino]piperidine-1-carboxylate (4.80 g, 13 mmol) in methylamine alcohol solution (15 mL) was stirred at 80 °C for 12 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-column chromatography (dichloromethane:methanol = 100:1 to 10:1) to provide (±)- Tert-butyl 3-(2-(methylamino)-2-oxoethyl)-3-(2,2,2- trifluoroacetamido)piperidine-1-carboxylate (3.10 g, 58% yield) and (±)-tert-butyl 3-amino-3-[2- (methylamino)-2-oxo-ethyl]piperidine-1-carboxylate (1.70 g, 39% yield). (±)- Tert-butyl 3-(2- (methylamino)-2-oxoethyl)-3-(2,2,2-trifluoroacetamido)piperidine-1-carboxylate ¹H NMR (400MHz, CDCl3) δ = 8.04 (s, 1H), 6.52 (br. s., 1H), 4.27 (br. s., 1H), 3.84 - 3.03 (m, 3H), 2.81 (d, J = 4.8 Hz, 3H), 2.68 - 2.46 (m, 2H), 1.76 - 1.52 (m, 4H), 1.49 (s, 9H). (±)-tert-butyl 3- amino-3-[2-(methylamino)-2-oxo-ethyl]piperidine-1-carboxylate ¹H NMR (400MHz, CDCl₃) δ = 8.13 - 7.37 (m, 1H), 3.69 - 3.02 (m, 4H), 2.82 (d, J = 4.8 Hz, 3H), 2.40 - 2.19 (m, 4H), 1.73 - 1.54 (m, 4H), 1.47 (s, 9H).

(±)-Tert-butyl 3-amino-3-(4-(methylamino)-4-oxobutyl)piperidine-1-carboxylate (Intermediate J)

Step 1- (Z/E)-Tert-butyl 3-hydroxyiminopiperidine-1-carboxylate [00295] To a solution of tert-butyl 3-oxopiperidine-1-carboxylate (20.0 g, 100 mmol) and triethylamine (30.4 g, 301 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (20.9 g, 301 mmol) and the reaction mixture was stirred at 90 °C for 1 hr. On completion, the reaction mixture was diluted with 300 mL water and 300 mL ethyl acetate. The aqueous phase was extracted with ethyl acetate (3 x 100 mL). The combined layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1) to give the title compound.¹H NMR (400MHz, CDCl3) δ = 8.46 (br. s., 1H), 4.36 (s, 1H), 4.03 (s, 1H), 3.58 - 3.42 (m, 2H), 2.68 - 2.32 (m, 2H), 1.84 - 1.70 (m, 2H), 1.50 - 1.44 (m, 9H). Step 2 - (±)-Tert-butyl 3-nitropiperidine-1-carboxylate [00296] To a solution of urea-hydrogen peroxide (UHP) (76.8 g, 816 mmol) in acetonitrile (300 mL) was added a solution of trifluoroacetic anhydride (122 g, 583 mmol) in acetonitrile (300 mL) dropwise at 0 °C and the reaction mixture was stirred at 0 °C for 2 hrs. Then the resulting solution was added dropwise to a mixture of tert-butyl (Z/E)-3- hydroxyiminopiperidine-1-carboxylate (50.0 g, 233 mmol) and sodium bicarbonate (98.0 g, 1.17 mol) in acetonitrile (500 mL) at 80 °C and the reaction mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was cooled to 25 °C and 100 mL aqueous sodium sulfite solution (saturated) was added. The resulting mixture was concentrated in vacuo to remove the acetonitrile. Then 200 mL water and 500 mL ethyl acetate was added and the aqueous phase was extracted with ethyl acetate (3 x 200 mL). The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound.¹H NMR (300MHz, CDCl3) δ = 4.42 (tt, J = 4.1, 8.7 Hz, 1H), 4.14 (br. s., 1H), 3.70 (br. s., 2H), 3.13 (br. s., 1H), 2.52 - 2.01 (m, 2H), 1.94 - 1.74 (m, 1H), 1.67 - 1.53 (m, 1H), 1.47 (s, 9H). Step 3 - (±)-Tert-butyl 3-(3-ethoxy-3-oxo-propyl)-3-nitro-piperidine-1-carboxylate [00297] To a mixture of (±)-tert-butyl 3-nitropiperidine-1-carboxylate (10.0 g, 43.4 mmol) and potassium carbonate (18.0 g, 130 mmol) in ethanol (100 mL) was added methyl acrylate (5.61 g, 65.1 mmol) and the reaction mixture was stirred at 15 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo and 200 mL of water was added. The aqueous phase was extracted with ethyl acetate (3 x 200 mL). The combined layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound. ¹H NMR (300MHz, CDCl3) δ = 4.32 (d, J = 14.1 Hz, 1H), 4.15 (q, J = 7.2 Hz, 2H), 3.74 - 3.54 (m, 1H), 3.42 (d, J = 14.1 Hz, 1H), 3.18 (td, J = 6.3, 13.0 Hz, 1H), 2.55 - 2.04 (m, 5H), 1.94 - 1.79 (m, 1H), 1.75 - 1.63 (m, 2H), 1.48 (s, 9H), 1.27 (t, J=7.2 Hz, 3H). Step 4 - (±)-3-(1-Tert-butoxycarbonyl-3-nitro-3-piperidyl)propanoic acid [00298] To a solution of (±)-tert-butyl 3-(3-ethoxy-3-oxo-propyl)-3-nitro-piperidine-1- carboxylate (10.0 g, 28.7 mmol) in a mixture of tetrahydrofuran (30 mL), methanol (30 mL) and water (20 mL) was added lithium hydroxide (4.83 g, 115 mmol) and the reaction mixture was stirred at 15 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo and 200 mL of water was added. The aqueous phase was acidified with 1N hydrochloric acid (40 mL) to pH = 4-5. The aqueous phase was extracted with ethyl acetate (3 x 300 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give the title compound. ¹H NMR (400MHz, CD₃OD) δ = 4.49 (d, J = 11.9 Hz, 1H), 3.77 (d, J = 11.7 Hz, 1H), 3.37 (d, J = 14.7 Hz, 1H), 3.07 (br. s., 1H), 2.50 (d, J = 13.9 Hz, 1H), 2.31 (d, J = 8.2 Hz, 2H), 2.26 - 2.07 (m, 2H), 1.90 (ddd, J = 4.4, 10.5, 14.5 Hz, 1H), 1.76 - 1.64 (m, 1H), 1.64 - 1.53 (m, 1H), 1.48 (s, 9H). Step 5 - (±)-Tert-butyl 3-(3-chloro-3-oxopropyl)-3-nitropiperidine-1-carboxylate [00299] To a solution of (±)-3-(1-tert-butoxycarbonyl-3-nitro-3-piperidyl)propanoic acid (3.00 g, 9.92 mmol) in anhydrous dichloromethane (40 mL) was added anhydrous N,N- dimethylformamide (40 µL) and oxalyl chloride (2.69 g, 21.2 mmol) was added dropwise at 0 °C. The reaction mixture was warm to 15 °C and stirred for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound. The crude product was used to the next step directly. Step 6 - (±)-Tert-butyl 3-(4-diazo-3-oxobutyl)-3-nitropiperidine-1-carboxylate [00300] A solution containing potassium hydroxide (8.40 g, 150 mmol) in water (14 mL) and 2-(2-ethoxyethoxy)ethanol (49.0 g, 365 mmol) were placed in the distillation flask. A solution containing N-4-dimethyl-N-nitroso-benzenesulfonamide (30.0 g, 140 mmol) in ether (160 mL) was placed in the addition funnel, meanwhile the receiving flask was cooled to 0 °C. Heating the distillation flask to 70 °C, the N-4-dimethyl-N-nitroso-benzenesulfonamide (30.0 g, 140 mmol) in ether (160 mL) was added dropwise over 0.5 hr. Diazomethane in ether was distilled from the reaction mixture to give diazomethane (1.97 g, 46.8 mmol) in ether (150 mL) and used to the next step directly without further purification. [00301] To a mixture of (±)-tert-butyl 3-(3-chloro-3-oxo-propyl)-3-nitro-piperidine-1- carboxylate (3.00 g, 9.35 mmol) in anhydrous dichloromethane (30 mL) was added diazomethane (1.97 g, 46.8 mmol) in anhydrous ether (150 mL) at 0 °C. The mixture was stirred at 15 °C for 16 hrs. Dilute acetic acid was added to quench the reaction, then the reaction was basified with sat. sodium bicarbonate (30 mL) to pH = 8, then extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with brine (2 x 30 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give the title compound. LCMS: (ES+) m/z (M+23)⁺ = 349.1, tR = 1.282. ¹H NMR (400 MHz, CDCl3) δ = 5.27 (brs, 1H), 4.38 (brs, 1H), 3.75– 3.06 (m, 3H), 2.42– 2.21 (m, 5H), 1.80 (brs, 1H), 1.66– 1.62 (m, 2H), 1.46 (s, 9H). Step 7 - (±)-4-(1-(tert-butoxycarbonyl)-3-nitropiperidin-3-yl)butanoic acid [00302] To a solution of (±)-tert-butyl 3-(4-diazo-3-oxo-butyl)-3-nitro-piperidine-1- carboxylate (1.70 g, 5.21 mmol) in tetrahydrofuran (20 mL) and water (2 mL) was added triethylamine (1.58 g, 15.6 mmol) and (2,2,2-trifluoroacetyl)oxysilver (115 mg, 521 µmol). The mixture was stirred at 15 °C for 16 hrs. On completion, the mixture was filtered and the filtrate was concentrated. To the mixture was added sat. hydrochloric acid (20 mL) to pH = 8, then extracted with ethyl acetate (3 x 15 mL). The aqueous layer was acidified with hydrochloric acid (2 M, 30 mL) to pH = 1, then extracted with ethyl acetate (3 x 30 mL). The combined organic phase was washed with brine (2 x 40 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound. LCMS: (ES+) m/z (M+23)⁺ = 339.1, tR = 0.544.¹H NMR (300 MHz, DMSO-d₆) δ = 12.15 (brs, 1H), 4.32 (d, J = 13.9 Hz, 1H), 3.62 (d, J = 12.8 Hz, 1H), 3.34 (brs, 1H), 2.98 (brs, 1H), 2.37 (d, J = 14.3 Hz, 1H), 2.21 (t, J = 7.2 Hz, 2H), 1.91 - 1.70 (m, 3H), 1.65 - 1.52 (m, 1H), 1.45 - 1.38 (m, 12H). Step 8 - (±)-Tert-butyl 3-(4-(methylamino)-4-oxobutyl)-3-nitropiperidine-1-carboxylate [00303] To a solution of (±)-4-(1-tert-butoxycarbonyl-3-nitro-3-piperidyl)butanoic acid (1.10 g, 3.48 mmol) in anhydrous dichloromethane (20 mL) was added anhydrous N,N- dimethylformamide (20 µL) and oxalyl chloride (945 mg, 7.45 mmol) dropwise at 0 °C. The reaction mixture was warmed to 15 °C and stirred for 1 hr. On completion, the mixture was concentrated in vacuo to give (±)-tert-butyl 3-(4-chloro-4-oxo-butyl)-3-nitro-piperidine-1- carboxylate. The crude product was used to the next step directly without further purification. To a solution of methylamine hydrochloride salt (333 mg, 4.93 mmol) and triethylamine (1.34 g, 13.2 mmol) in anhydrous dichloromethane (15 mL) was added tert-butyl 3-(4-chloro-4-oxo- butyl)-3- nitro-piperidine-1-carboxylate (1.10 g, crude) in anhydrous dichloromethane (10 mL) at 0 °C. The reaction mixture was warmed to 15 °C and stirred for 16 hrs. On completion, the mixture was concentrated. The residue was purified by silica gel chromatography (ethyl acetate, dichloromethane:methanol = 20:1) to give the title compound. LCMS: (ES+) m/z (M+23)⁺ = 352.2, tR = 1.086. Step 9 - (±)-Tert-butyl 3-amino-3-(4-(methylamino)-4-oxobutyl)piperidine-1-carboxylate [00304] To a solution of (±)-tert-butyl 3-[4-(methylamino)-4-oxo-butyl]-3-nitro-piperidine-1- carboxylate (400 mg, 425 µmol) in ethanol (9 mL) and water (3 mL) was added zinc powder (281 mg, 4.29 mmol) and ammonium chloride (241 mg, 4.50 mmol). The reaction mixture was stirred at 80 °C for 16 hrs. On completion, the mixture was filtered and the filtrate was concentrated to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 300.4, tR = 0.948. (±)-Tert-butyl 3-amino-3-cyano-piperidine-1-carboxylate (Intermediate K)

[00305] To a solution of tert-butyl 3-oxopiperidine-1-carboxylate (5.00 g, 25.1 mmol) in ethanol (30 mL) was added ammonium chloride (2.01 g, 37.6 mmol), potassium cyanide (2.45 g, 37.6 mmol), water (10 mL) and ammonium hydroxide (30 mL) at 15 °C in an autoclave. Then the reaction mixture was stirred at 60 °C for 16 hours. On completion, the reaction mixture was concentrated and the residue was extracted with DCM (3 x 100 mL), washed with brine (200 mL), dried and concentrated. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 2:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ = 4.05 - 3.76 (m, 1H), 2.84 (br. s., 1H), 2.11 (d, J=11.8 Hz, 1H), 1.91 - 1.81 (m, 2H), 1.80 - 1.72 (m, 2H), 1.69 - 1.57 (m, 1H), 1.52 - 1.44 (m, 9H). (±) Tert-butyl 3-(cynomethyl)piperidine-1-carboxylate (Intermediate L) and (±)Tert-butyl 3-(2-acetamidoethyl) -3-aminopiperidine-1-carboxylate (Intermediate M)

Step 1– (±) Tert-butyl 3-(cyanomethylene)piperidine-1-carboxylate [00306] To a three-necked round bottom flask equipped with a thermometer was charged a suspension of sodium hydride (6.79 g, 170 mmol) in tetrahydrofuran (1.00 L) at -10 °C under nitrogen. To the reaction mixture was added 2-diethoxyphosphorylacetonitrile (27.7 g, 157 mmol) dropwise during which the temperature was maintained below -5 °C. The resultant mixture was stirred for 30 min at -5 °C, then a solution of tert-butyl 3-oxopiperidine-1- carboxylate (26.0 g, 130 mmol) in tetrahydrofuran (200 mL) was added in portions. The resulting reaction mixture was warmed to 15 °C with stirring for 16 hrs. On completion, the mixture was quenched with water (200 mL), extracted with ethyl acetate (400 mL), the organic phase was washed with brine (200 mL), dried over sodium sulfate, and concentrated in vacuo to give a crude product. The residue was then purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 10:1 to 5:1) to give the title compound.¹H NMR (300 MHz, CDCl3) δ = 5.24 - 5.17 (m, 1H), 4.24 - 3.98 (m, 2H), 3.51 - 3.50 (m, 2H), 2.64 - 2.39 (m, 2H), 1.76 - 1.70 (m, 2H), 1.48 - 1.45 (m, 9H). Step 2– (±) Tert-butyl 3-amino-3-(cyanomethyl)piperidine-1-carboxylate [00307] To a solution of tert-butyl-3-(cyanomethylene)piperidine-1-carboxylate (3.00 g, 13.5 mmol) in methanol (6.00 mL) was added ammonium hydroxide (18.2 g, 151 mmol, 30% wt in water). Then, the mixture was heated to 80 °C with stirring for 16 hrs in a sealed tube. On completion, the reaction mixture was cooled to 15 °C, concentrated in vacuo to give a brown oil which was purified by column chromatography (eluent: petroleum ether:ethyl acetate = 10:1 to 5:1 to 2:1) to give the title compound. LCMS: (ES⁺) m/z (M-56+H)⁺ = 184.1. Step 3– (±) Tert-butyl 3-(cyanomethyl)-3-(2,2,2-trifluoroacetamino)piperidine-1-carboxylate [00308] To a solution of (±) tert-butyl 3-amino-3-(cyanomethyl)piperidine-1-carboxylate (1.20 g, 5.01 mmol) in dichloromethane (15.0 mL) was added triethylamine (1.52 g, 15.0 mmol). Then the solution was cooled to 0 °C. 2,2,2-Trifluoroacetic anhydride (1.58 g, 7.51 mmol) was added drop-wise at 0 °C and the reaction mixture was stirred at 0 °C for 1 hr. On completion, the reaction mixture was quenched with water (10 mL), and extracted with dichloromethane (10 mL). The organic layer was dried over sodium sulfate, concentrated in vacuo to give a brown oil which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 5:1 to 3:1) to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ = 4.13-4.02 (m, 1H), 3.15-2.86 (m, 3H), 1.67-1.49 (m, 12H). Step 4 – (±)-Tert-butyl 3-(2-acetamidoethyl)-3-(2,2,2-trifluoroacetamino)piperidine-1- carboxylate [00309] To a solution of (±)-tert-butyl 3-(cyanomethyl)-3-[(2,2,2- trifluoroacetyl)amino]piperidine-1-carboxylate (800 mg, 2.39 mmol) in methanol (40.0 mL) was added Raney nickel (1.0 g) under nitrogen. The reaction mixture was stirred under hydrogen gas (50 psi) at 40 °C for 3 hrs. On completion, the mixture was cooled to 15 °C and filtered. The filtrate was concentrated in vacuo, and the residue was extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo to give a crude product which was redissolved in acetic acid and treated with acetic anhydride until analysis showed complete reaction. After removal of all volatiles in vacuo, the crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to give the product (580 mg, 57% yield) as a white solid.¹H NMR (400 MHz, CDCl₃) δ = 7.41 (br. s, 1H), 5.94 (s, 1H), 4.23 (d, J = 14 Hz, 1H), 3.92 (d, J = 13.6 Hz, 1H), 3.48-2.77 (m, 6H), 2.14-1.47 (m, 21H). Step 5– (±)Tert-butyl 3-(2-acetamidoethyl) -3-aminopiperidine-1-carboxylate [00310] To a solution of (±)-tert-butyl 3-(2-acetamidoethyl)-3-[(2,2,2- trifluoroacetyl)amino]piperidine-1-carboxylate (3.00 g, 7.87 mmol) in methanol (29.0 mL) was added a solution of sodium hydroxide (2.32 g, 58.0 mmol) in water (29.0 mL) at 15 °C. The resulting solution was heated to 60 °C with stirring for 16 hrs. On completion, the reaction mixture was cooled to 15 °C and the product was extracted with dichloromethane (2 x 40 mL). The combined dichloromethane phase was washed with brine (50 mL), dried over sodium sulfate, concentrated in vacuo to give a crude product which was purified by column chromatography (dichloromethane:methanol = 20:1 to 10:1) to give the product. ¹H NMR (400 MHz, DMSO-d6) δ = 7.32 (br. s, 1H), 3.44-3.34 (m, 2H), 3.30-3.19 (m, 2H), 3.12 (s, 2H), 1.92 (s, 3H), 1.50-1.44 (m, 8H), 1.39 (s, 9H). (±)-Tert-butyl 3-(3-acetamidopropyl)-3-aminopiperidine-1-carboxylate (Intermediate N)

N Step 1 - (±)-Tert-butyl 3-(2-cyanoethyl)-3-nitropiperidine-1-carboxylate [00311] A mixture of (±)-tert-butyl 3-nitropiperidine-1-carboxylate (12.0 g, 52.1 mmol), acrylonitrile (4.15 g, 78.2 mmol) and potassium carbonate (14.4 g, 104 mmol) in acetone (150 mL) was stirred at 20 °C for 12 hrs. On completion, the mixture was filtered, and the filtrate was concentrated. The residue was purified by chromatography (petroleum ether:ethyl acetate = 4:1 to 2:1) to give the title compound. LCMS: (ES⁺) m/z (M-56)⁺ = 228.1, tR= 0.882. Step 2 - (±)-Tert-butyl 3-(3-aminopropyl)-3-nitropiperidine-1-carboxylate [00312] To the solution of (±) tert-butyl 3-(2-cyanoethyl)-3-nitro-piperidine-1-carboxylate (12.0 g, 42.4 mmol) in dioxane (180 mL) was added borane-tetrahydrofuran complex (1 M, 127 mL). The reaction mixture was stirred at 100 °C for 2 hrs. On completion, the reaction was cooled to 40 °C, and quenched with methanol (10 mL). The resulting mixture was stirred at 100 °C for 1 hr and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL), washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography (dichloromethane:methanol = 20:1 to 5:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 288.2, tR= 1.155. Step 3 - (±)-Tert-butyl 3-(3-acetamidopropyl)-3-nitropiperidine-1-carboxylate [00313] To the solution of (±)-tert-butyl 3-(3-aminopropyl)-3-nitro-piperidine-1-carboxylate (10.0 g, 34.8 mmol) and triethylamine (10.6 g, 104 mmol) in dichloromethane (140 mL) was added acetyl chloride (5.46 g, 69.6 mmol). The reaction mixture was stirred at 20 °C for 12 hrs. On completion, the mixture was quenched with water (50 mL), the organic layer was separated, washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by chromatography (dichloromethane:methanol = 10:1) to give the title compound. LCMS: (ES⁺) m/z (M-100)⁺ = 230.1, tR= 0.830. Step 4 - (±)-Tert-butyl 3-(3-acetamidopropyl)-3-aminopiperidine-1-carboxylate [00314] To the solution of (±) tert-butyl 3-(3-acetamidopropyl)-3-nitro-piperidine-1- carboxylate (10.0 g, 30.4 mmol) in methanol (150 mL) was added palladium dihydroxide on carbon (1.00 g, 10% w/w, Pd(OH)₂/C). The reaction mixture was stirred at 60 °C under hydrogen (50 Psi) for 72 hrs. On completion, the mixture was filtered, and the filtrate was concentrated to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 300.2, tR= 0.995. (±)-Tert-butyl 3-amino-3-[3-(methylamino)-3-oxo-propyl]piperidine-1-carboxylate (Intermediate O)

Step 1 - (±)-Tert-butyl 3-[3-(methylamino)-3-oxo-propyl]-3-nitro-piperidine-1-carboxylate [00315] A solution of (±)-tert-butyl 3-(3-ethoxy-3-oxo-propyl)-3-nitro-piperidine-1- carboxylate (9.40 g, 27.0 mmol, synthesized via Steps 1-3 of Intermediate J) in methylamine / ethanol (100 mL) was stirred at 60 °C for 3 hrs under nitrogen. On completion, the reaction mixture was concentrated in vacuo and 200 mL of water was added. The aqueous phase was extracted with dichloromethane (3 x 200 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give the title compound. ¹HNMR (400MHz, CDCl3) δ = 5.93 - 5.45 (m, 1H), 4.61 - 4.06 (m, 1H), 3.97 - 3.56 (m, 1H), 3.46 (br. s., 1H), 3.28 - 2.91 (m, 1H), 2.81 (d, J = 4.6 Hz, 3H), 2.60 - 2.36 (m, 1H), 2.19 (d, J = 19.1 Hz, 4H), 1.72 - 1.60 (m, 2H), 1.48 (s, 9H). Step 2 - (±)-Tert-butyl 3-amino-3-[3-(methylamino)-3-oxo-propyl]piperidine-1-carboxylate [00316] To a solution of (±)-tert-butyl 3-[3-(methylamino)-3-oxo-propyl]-3-nitro-piperidine- 1-carboxylate (400 mg, 1.27 mmol) in ethyl acetate (30.0 mL) was added Pd(OH)2/C (140 mg, 1.02 mmol) and the reaction mixture was stirred under hydrogen (50 psi) at 60 °C for 16 hrs. On completion, the reaction mixture was filtrated and the filtrate was concentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 286.1, tR= 1.134. Tert-butyl chlorosulfonylcarbamate (Intermediate P)

[00317] A solution of sulfurisocyanatidic chloride (20 g, 141 mmol) in dichloromethane (200 mL) was added dropwise into t-BuOH (13.8 g, 184 mmol) at 0 °C under a nitrogen. The reaction mixture was stirred at 0 °C for 0.5 hr. On completion, the mixture was concentrated in vacuo to give a residue (keeping the temperature below 35 °C as product in unstable under high temperature). The residue was triturated with a solvent mixture of petroleum ether and ethyl acetate (10:1, 50 ml) and dried in vacuo to afford the title compound. ¹H NMR (400MHz, CDCl₃) δ = 8.62 (br. s., 1H), 1.58 (s, 9H). Tert-butyl 4-(3-acetamidopropyl)-4-amino-piperidine-1-carboxylate (Intermediate Q)

Step 1 - (Z/E)-Tert-butyl 4-hydroxyiminopiperidine-1-carboxylate [00318] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100 mmol) and sodium acetate (9.88 g, 120 mmol) in a mixture of ethanol (160 mL) and water (40 mL) was added hydroxylamine hydrochloride (8.37 g, 120 mmol) and the reaction mixture was stirred at 15 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo, and 300 mL water and 300 mL dichloromethane was added. The aqueous phase was extracted with dichloromethane (3 × 100 mL). The combined layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound. ¹H NMR (300MHz, CDCl₃) δ = 8.71 (br. s., 1H), 3.55 (q, J = 6.8 Hz, 4H), 2.63 (t, J = 6.0 Hz, 2H), 2.35 (t, J = 6.0 Hz, 2H), 1.49 (s, 9H). Step 2 - Tert-butyl 4-nitropiperidine-1-carboxylate [00319] To a solution of urea hydrogen peroxide (24.5 g, 261 mmol) in acetonitrile (90 mL) was added a solution of trifluoroacetic anhydride (39.2 g, 186 mmol) in acetonitrile (90 mL) dropwise and the reaction was stirred at 0 °C for 2 hrs. This solution was added dropwise to a mixture of (Z/E)-tert-butyl 4-hydroxyiminopiperidine-1-carboxylate (16.0 g, 74.6 mmol) and saturated sodium bicarbonate (31.3 g, 373 mmol) in acetonitrile (150 mL) with stirring at 70 °C and the reaction mixture was stirred at 70 °C for 0.5 hr. On completion, the reaction mixture was cooled to 25 °C and 50 mL of saturated aqueous solution of sodium sulfite was added. Then the reaction mixture was concentrated in vacuo to remove acetonitrile and 300 mL water and 300 mL ethyl acetate was added. The aqueous phase was extracted with ethyl acetate (3 × 300 mL). The organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound.¹H NMR (400MHz, CDCl3) δ = 4.52 (tt, J = 4.3, 10.1 Hz, 1H), 4.05 (br. s., 2H), 3.01 (t, J = 11.4 Hz, 2H), 2.23 (dd, J = 3.6, 13.0 Hz, 2H), 2.12 - 2.03 (m, 2H), 1.48 (s, 9H). Step 3 - Tert-butyl 4-(2-cyanoethyl)-4-nitro-piperidine-1-carboxylate [00320] To a mixture of tert-butyl 4-nitropiperidine-1-carboxylate (8.00 g, 34.7 mmol) and potassium carbonate (9.60 g, 69.4 mmol) in acetone (100 mL) was added prop-2-enenitrile (3.60 g, 67.8 mmol) and the reaction mixture was stirred at 15 °C for 16 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give light yellow oil, which was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ = 3.96 (br. s., 2H), 2.96 (br. s., 2H), 2.53 (d, J = 13.2 Hz, 2H), 2.41 - 2.34 (m, 2H), 2.30 - 2.21 (m, 2H), 1.86 - 1.72 (m, 2H), 1.47 (s, 9H). Step 4 - Tert-butyl 4-(3-aminopropyl)-4-nitro-piperidine-1-carboxylate [00321] To a solution of tert-butyl 4-(2-cyanoethyl)-4-nitro-piperidine-1-carboxylate (10.0 g, 35.3 mmol) in dioxane (150 mL) was added borane-methylsulfanylmethane (10 M, 10.5 mL) dropwise and the reaction mixture was stirred at 80 °C for 2 hrs. On completion, the reaction mixture was cooled to rt and methanol (10.0 mL) was added dropwise. Then the reaction mixture was warmed to 50 °C and stirred for 20 min. The reaction mixture was concentrated in vacuo to give the title compound. ¹H NMR (400MHz, CDCl₃) δ = 4.02 - 3.82 (m, 2H), 2.95 (br. s., 2H), 2.83 - 2.63 (m, 2H), 2.48 (d, J = 13.9 Hz, 2H), 1.97 - 1.82 (m, 2H), 1.80 - 1.67 (m, 2H), 1.50 - 1.44 (m, 9H), 1.41 (dd, J = 7.7, 16.2 Hz, 2H). Step 5 - Tert-butyl 4-(3-acetamidopropyl)-4-nitro-piperidine-1-carboxylate [00322] To a solution of tert-butyl 4-(3-aminopropyl)-4-nitro-piperidine-1-carboxylate (2.00 g, 6.96 mmol) and triethylamine (2.11 g, 20.8 mmol) in dichloromethane (100 mL) was added acetyl chloride (819 mg, 10.4 mmol) dropwise and the reaction mixture was stirred at 15 °C for 0.5 hr. On completion, the reaction mixture was concentrated in vacuo and 200 mL water was added. The aqueous phase was extracted with dichloromethane (3 × 100 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (dichloromethane:methane = 20:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ = 5.64 - 5.49 (m, 1H), 3.98 - 3.83 (m, 2H), 3.28 - 3.21 (m, 2H), 3.02 - 2.88 (m, 2H), 2.51 - 2.42 (m, 2H), 2.01 - 1.97 (m, 3H), 1.90 - 1.84 (m, 2H), 1.78 - 1.67 (m, 1H), 1.47 (s, 10H). Step 6 - Tert-butyl 4-(3-acetamidopropyl)-4-amino-piperidine-1-carboxylate [00323] To a solution of tert-butyl 4-(3-acetamidopropyl)-4-nitro-piperidine-1-carboxylate (1.50 g, 4.55 mmol) in methanol (50 mL) was added Pd(OH)₂/C (319 mg, 2.28 mmol) and the reaction mixture was stirred under hydrogen (50 psi) at 60 °C for 16 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 300.0, tR= 1.149. Methyl 3-aminocyclohexanecarboxylate (Intermediate R)

[00324] To a solution of 3-aminocyclohexanecarboxylic acid (500 mg, 3.49 mmol) in methanol (20 mL) was added thionyl chloride (984 mg, 8.27 mmol) at 0 °C. The mixture was stirred at 65 °C for 16 hrs. On completion, the mixture was concentrated in vacuo to give the title compound. ¹H NMR (400 MHz, CDCl3-d) δ = 8.33 (brs, 1H), 3.68 (s, 3H), 3.18 (brs, 3H), 2.43 (brs, 2H), 2.21 (brs, 1H), 2.02– 1.93 (m, 2H), 1.72– 1.37 (m, 4H). Methyl 2-(1-aminocyclopentyl)acetate (Intermediate S)

Step 1 - Methyl 2-cyclopentylideneacetate [00325] To a solution of cyclopentanone (1.00 g, 11.9 mmol) in toluene (10 mL) was added methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate (4.37 g, 13.1 mmol) at 15 °C. The mixture was then warmed to 110 °C and stirred for 12 hrs. On completion, the reaction was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 500:1 to 50:1) to give the title compound.¹H NMR (400MHz, CDCl3) δ = 5.74 (br. s., 1H), 3.61 (d, J = 0.9 Hz, 3H), 2.70 (t, J = 7.3 Hz, 2H), 2.37 (t, J = 7.0 Hz, 2H), 1.73 - 1.64 (m, 2H), 1.64 - 1.54 (m, 2H). Step 2 - Methyl 2-(1-aminocyclopentyl)acetate [00326] Methyl 2-cyclopentylideneacetate (400 mg, 2.85 mmol) was added to a solution of ammonia gas in methanol (4M/L, 20 mL) at 15 °C. The reaction was stirred in an autoclave at 100 °C for 3 hrs. On completion, the reaction was concentrated in vacuo to get a residue, and the residue was purified by column chromatography (dichloromethane:methanol=100:1 to 10:1) to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 158.1. Methyl 2-(3-aminotetrahydrofuran-3-yl)acetate (Intermediate T)

Step 1 - Methyl (2E)-2-tetrahydrofuran-3-ylideneacetate [00327] A solution of methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate (3.89 g, 11.62 mmol) and tetrahydrofuran-3-one (1.00 g, 11.62 mmol) in toluene (10.0 mL) was stirred at 100-110 °C for 16 hrs under nitrogen. On completion, the mixture was concentrated to remove the solvent, the residue was diluted with ethyl acetate (30 mL) and filtered, and the filtrate was concentrated to get the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 10:1) to yield the title compound. ¹H NMR (400MHz, CDCl₃) δ = 5.98 - 5.84 (m, 1 H), 4.72 (s, 2 H), 3.88 (t, J = 6.90 Hz, 2 H), 3.70 (s, 3 H), 2.76 - 2.67 (m, 2 H). Step 2 - Methyl 2-(3-aminotetrahydrofuran-3-yl)acetate [00328] A solution of methyl (2E)-2-tetrahydrofuran-3-ylideneacetate (280 mg, 1.97 mmol) in a solution of ammonia in methanol (4M/L, 10.0 mL) was put into a microwave and stirred at 100 °C for 2 hrs. On completion, the mixture was concentrated to remove the solvent and yield the title compound (200 mg, crude) as a yellow oil which was used without further purification. LCMS: (ES⁺) m/z (M+H)⁺ = 160, tR = 0.989. ¹H NMR (300MHz, CDCl3) δ = 4.08 - 3.93 (m, 2H), 3.93 - 3.82 (m, 2H), 3.71 (s, 3H) , 2.63 (d, J = 6.40 Hz, 2H), 1.97 - 1.86 (m, 2H). Methyl 2-(1-aminocyclobutyl)acetate (Intermediate U)

Step 1 - Methyl 2-cyclobutylideneacetate [00329] To a solution of cyclobutanone (2.00 g, 28.5 mmol) in anhydrous toluene (90 mL) was added methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate (9.54 g, 28.5 mmol). The mixture was stirred at 110 °C for 16 hours. On completion, the mixture was concentrated to get a residue. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 20:1) to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 127.3, tR = 0.696. ¹H NMR (400 MHz, CDCl3) δ = 5.65 - 5.53 (m, 1H), 3.68 (s, 3H), 3.13 (t, J = 7.9 Hz, 2H), 2.84 (t, J = 7.9 Hz, 2H), 2.15 - 2.01 (m, 2H). Step 2 - Methyl 2-(1-aminocyclobutyl)acetate [00330] To a solution of methyl 2-cyclobutylideneacetate (1.00 g, 7.93 mmol) in methanol (15 mL) was bubbled excess ammonia gas. The solution was transferred into an autoclave and at the system was warmed to 100 °C and stirred for 16 hrs. On completion, the reaction mixture was concentrated in vacuo to get a residue. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1 to dichloromethane:methanol = 10:1 ) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ = 3.68 (s, 3H), 2.59 (s, 2H), 2.02 - 1.85 (m, 4H), 1.84 - 1.61 (m, 2H). (±)-Tert-butyl 4-amino-3-[tert-butyl(diphenyl)silyl]oxy-piperidine-1-carboxylate (Intermediate V)

Step 1 - (±)-Tert-butyl 3-hydroxy-4,4-dimethoxy-piperidine-1-carboxylate [00331] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.00 g, 30.1 mmol) in methanol (40.0 mL) was added potassium hydroxide (3.72 g, 66.3 mmol) and iodine (8.41 g, 33.1 mmol) in several portions at 0 °C. The reaction was warmed to 15 °C and stirred for 12 hrs. On completion, the reaction was concentrated in vacuo, and the residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give tert-butyl 3-hydroxy-4,4- dimethoxy-piperidine-1-carboxylate. LCMS: (ES+) m/z (M+23)⁺ = 284.2, Step 2 - (±)-Tert-butyl 3-hydroxy-4-oxo-piperidine-1-carboxylate [00332] To a solution of (±)-tert-butyl 3-hydroxy-4,4-dimethoxy-piperidine-1-carboxylate (2.00 g, 7.65 mmol) in acetone (50 mL) was added 4-toluene sulfonic acid (TsOH) (146 mg, 765 µmol), and the reaction was stirred at 15 °C for 5 hrs. On completion, the reaction was concentrated in vacuo to give a residue, which was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give the title compound. LCMS: (ES+) m/z (M- 56+H)⁺ = 160.1. Step 3 - (±)-Tert-butyl 3-[tert-butyl(diphenyl)silyl]oxy-4-oxo-piperidine-1-carboxylate [00333] To a solution of (±)-tert-butyl 3-hydroxy-4-oxo-piperidine-1-carboxylate (1.00 g, 4.65 mmol) in N,N-dimethylformamide (10 mL) was added tert-butyl-chloro-diphenyl-silane (TBDPSCl) (1.53 g, 5.58 mmol) and imidazole (791 mg, 11.6 mmol) in one portion at 15 °C. The reaction was stirred at 15 °C for 12 hrs, and then the reaction was concentrated to give a residue. The residue was diluted with ethyl acetate (20 mL), washed with water (3 x 10 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 200:1 to 1:1) to give the title compound. LCMS: (ES+) m/z (M+23)⁺ = 476.1. Step 4 - (±)-Tert-butyl 4-amino-3-[tert-butyl(diphenyl)silyl]oxy-piperidine-1-carboxylate [00334] To a solution of (±)-tert-butyl 3-[tert-butyl(diphenyl)silyl]oxy-4-oxo-piperidine-1- carboxylate (4.00 g, 8.82 mmol) in ethanol (20 mL) was added sodium cyanoborohydride (1.66 g, 26.5 mmol) and ammonium acetate (2.04 g, 26.5 mmol) in one portion at 15 °C. The solution was stirred at 70 °C for 12 hrs, then the reaction was concentrated in vacuo to give a residue. The residue was purified by column chromatography (dichloromethane/methanol = 500:1 to 100:1) to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 455.3. N-acetylsulfamoyl chloride (Intermediate W)

[00335] To a solution of sulfurisocyanatidic chloride (70.0 g, 495 mmol) in dichloromethane (50 mL) was added acetic acid (29.7 g, 495 mmol) dropwise at 0 °C. The reaction was stirred at 0 °C for 3 hrs. On completion, the reaction was concentrated in vacuo, and the residue was washed with (petroleum ether:ethyl acetate = 10:1, 2 x 500 mL) to give the title compound. ¹H NMR (400MHz, DMSO-d6) δ = 2.11 (s, 3H). (±)4-Amino-1-benzylpiperidine-3-carbonitrile (Intermediate X)

Step 1 - 3-(Benzylamino)propanenitrile [00336] To a solution of phenylmethanamine (18.3 g, 170 mmol) in water (150 mL) was added acrylonitrile (27.2 g, 512 mmol) at 15 °C. The reaction mixture was stirred at 15 °C for 12 hrs. On completion, the reaction mixture was extracted with dichloromethane (3 x 300 mL). The combined organic layers were dried with anhydrous sodium sulfate and concentrated in vacuo. The colorless oil (32.0 g) was purified by silica gel chromatography (dichloromethane: methanol = 100:1) to give the title compound.¹H NMR (400MHz, CDCl₃) δ = 7.44 - 7.28 (m, 5H), 3.86 (s, 2H), 2.95 (t, J = 6.7 Hz, 2H), 2.54 (t, J = 6.7 Hz, 2H). Step 2 - 3,3'-(Benzylazanediyl)dipropanenitrile [00337] To a solution of 3-(benzylamino)propanenitrile (27.0 g, 168 mmol) in water (150 mL) was added prop-2-enenitrile (17.9 g, 337 mmol) at 15 °C. The reaction mixture was stirred at 100 °C for 12 hrs. On completion, the reaction mixture was cooled to 25 °C, and extracted with dichloromethane (3 x 300 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound. ¹H NMR (400MHz, CDCl₃) δ = 7.42 - 7.29 (m, 5H), 3.74 (s, 2H), 2.92 (t, J = 6.8 Hz, 4H), 2.54 - 2.40 (m, 4H). Step 3– 4-Amino-1-benzyl-1,2,5,6-tetrahydropyridine-3-carbonitrile [00338] To a solution of potassium 2-methylpropan-2-olate (1.16 g, 10.3 mmol) in toluene (20 mL) was added dropwise 3-[benzyl(2-cyanoethyl) amino]propanenitrile (2.00 g, 9.38 mmol) at 120 °C under a nitrogen for 0.5 hrs. Then, the mixture was stirred at 120 °C for 3 hrs. On completion, the reaction mixture was concentrated in vacuo, the residue was diluted with dichloromethane (100 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 50:1) to give the title compound. ¹H NMR (400MHz, CDCl3) δ = 7.41 - 7.29 (m, 5H), 4.35 (br. s., 2H), 3.66 - 3.58 (m, 2H), 2.65 (t, J = 5.8 Hz, 2H), 2.30 (t, J = 5.8 Hz, 2H). Step 4– (±)-4-Amino-1-benzylpiperidine-3-carbonitrile [00339] To a solution of 4-amino-1-benzyl-3,6-dihydro-2H-pyridine-5-carbonitrile (400 mg, 1.88 mmol) in ethanol (10 mL) was added sodium cyanotrihydroborate (236 mg, 3.76 mmol) and acetic acid (338 mg, 5.64 mmol, 322 µL) at 25 °C. The reaction mixture was stirred at 50 °C for 12 hrs. On completion, water (10 mL) was added dropwise into the reaction mixture, and the reaction mixture was concentrated in vacuo to remove ethanol. The residual was then extracted with dichloromethane (2 x 10 mL) dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 200:1) to give the title product (300 mg 74% yield).¹H NMR (400MHz, CDCl3) δ = 7.43 - 7.27 (m, 5H), 3.67 - 3.49 (m, 2H), 3.13 - 2.99 (m, 1H), 2.95 - 2.85 (m, 2H), 2.85 - 2.45 (m, 1H), 2.29 - 2.19 (m, 1H), 2.14 (dd, J = 11.8, 2.4 Hz, 1H), 1.91 (qd, J = 13.2, 3.3 Hz, 1H), 1.79 (dd, J = 10.0, 4.0 Hz, 1H), 1.50 - 1.35 (m, 1H). (±)-Tert-butyl 4-amino-3-(2-(tert-butoxy)-2-oxoethyl) piperidine-1-carboxylate (Intermediate Y)

Step 1– (±)-Tert-butyl 3-(2-(tert-butoxy)-2-oxoethyl)-4-oxo piperidine-1-carboxylate [00340] To a solution of diisopropylamine (7.41 g, 73.2 mmol) in dry tetrahydrofuran (150 mL) was added n-BuLi (2.5 M, 16 mL) dropwise at -70 °C under nitrogen. The resultant mixture was warmed to -10 °C and stirred for 30 min. The mixture was cooled to -70 °C, and a solution of tert-butyl 4-oxopiperidine-1-carboxylate (5.00 g, 25.1 mmol) in dry tetrahydrofuran (20.0 mL) was added dropwise and stirred for 30 min. Then, a solution of tert-butyl 2-bromoacetate (4.89 g, 25.1 mmol) in tetrahydrofuran (20.0 mL) was added dropwise, followed by hexamethylphosphoramide (HMPA) (1.80 g, 11.0 mmol). On completion, to the mixture was added water (10 mL), and the solution was extracted with ethyl acetate (3 x 50 mL). The combined ethyl acetate phase was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 0:1 to 100:1) to give the title compound. ¹H NMR (300 MHz, CDCl3) δ = 4.22 - 4.03 (m, 1H), 3.65 (t, J = 6.0 Hz, 2H), 2.83 (s, 1H), 2.57 - 2.33 (m, 4H), 2.32 - 2.06 (m, 1H), 1.43 (s, 9H), 1.38 (s, 9H). Step 2– (±)-Tert-butyl 4-amino-3-(2-(tert-butoxy)-2-oxoethyl) piperidine-1-carboxylate [00341] To a mixture of (±)-tert-butyl 3-(2-tert-butoxy-2-oxo-ethyl)-4-oxo-piperidine-1- carboxylate (2.00 g, 6.38 mmol) in tetrahydrofuran (20.0 mL) was added ammonium acetate (1.48 g, 19.1 mmol), followed by 4A MS (500 mg), and sodium cyanotrihydroborate (1.20 g, 19.1 mmol) in one portion at 20 °C. The mixture was stirred at 20 °C for 16 hrs. On completion, to the mixture was added water (30 mL) and the solution was extracted with dichloromethane (3 x 30 mL). The combined dichloromethane phase was dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to dichloromethane:methanol = 20:1) to give the title compound (crude).¹H NMR (400 MHz, DMSO-d6) δ = 3.90 - 3.72 (m, 2H), 3.41 - 3.31 (m, 1H), 3.08 - 2.74 (m, 3H), 2.37 - 2.24 (m, 1H), 1.87 - 1.84 (m, 1H), 1.63 - 1.39 (m, 19H). (±)-1-(tert-butyl) 3-ethyl 4-aminopiperidine-1,3-dicarboxylate (Intermediate Z)

[00342] A mixture of 1-(tert-butyl) 3-ethyl 4-oxopiperidine-1,3-dicarboxylate (7.00 g, 25.8 mmol, CAS# 98977-34-5), acetic acid (7.10 g, 118 mmol) and ammonium acetate (15.9 g, 206 mmol) in ethanol (20 mL) was stirred at 15 °C for 1 hr. Then sodium cyanoborohydride (6.49 g, 103 mmol) was added and the mixture was stirred at 15 °C for 15 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by chromatography (dichloromethane:methanol = 100:1 to 10:1) to give the title compound. LCMS: (ES+) m/z (M+H)+ = 273.3, tR= 0.648. ¹H NMR (400MHz, CDCl₃) δ = 4.75 - 4.43 (m, 1H), 4.28 (q, J = 7.0 Hz, 2H), 4.19 (d, J = 13.6 Hz, 1H), 3.75 - 3.55 (m, 1H), 3.24 - 3.02 (m, 1H), 3.00 - 2.70 (m, 2H), 2.23 (d, J = 10.5 Hz, 1H), 2.11 - 2.00 (m, 3H), 1.83 - 1.68 (m, 1H), 1.47 (d, J = 12.4 Hz, 9H), 1.33 (t, J= 7.1 Hz, 3H). (±)-Tert-butyl 4-amino-3-(3-tert-butoxy-3-oxo-propyl)piperidine-1-carboxylate (Intermediate AA)

Step 1 - (±)-Tert-butyl 3-(3-tert-butoxy-3-oxo-propyl)-4-oxo-piperidine-1-carboxylate [00343] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.00 g, 30.1 mmol, CAS# 79099-07-3), pyrrolidine (6.42 g, 90.3 mmol) and p-toluenesulfonic acid (518 mg, 3.01 mmol) in toluene (40 mL) was stirred at 110 °C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo to give a black solution (30 mL). Then the resulting solution (15 mL) and tert-butyl prop-2-enoate (3.86 g, 30.1 mmol) were added to toluene (20 mL) and the reaction mixture was stirred at 80 °C for 4 hrs. On completion, the reaction mixture was concentrated in vacuo, and ethyl acetate (200 mL) and 1N hydrochloric acid (100 mL) was added. The organic layer was washed with 1N hydrochloric acid (3 x 50 mL), dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo. The resulting oil was purified by silica gel chromatography (petroleum ether:ethyl acetate = 10:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 328.1, tR = 0.904.¹H NMR (400MHz, CDCl3) δ = 4.09 - 3.98 (m, 1H), 3.48 - 3.26 (m, 1H), 3.10 (br. s., 1H), 2.45 (t, J = 6.3 Hz, 3H), 2.39 - 2.22 (m, 2H), 2.06 - 1.96 (m, 1H), 1.63 - 1.53 (m, 1H), 1.51 (s, 10H), 1.45 (s, 9H). Step 2 - (±)-Tert-butyl 4-amino-3-(3-tert-butoxy-3-oxo-propyl)piperidine-1-carboxylate [00344] To a solution of (±)-tert-butyl 3-(3-tert-butoxy-3-oxo-propyl)-4-oxo-piperidine-1- carboxylate (500 mg, 1.53 mmol), ammonium acetate (353 mg, 4.59 mmol) and 4Å molecular sieves (MS) (1.00 g) in tetrahydrofuran (20 mL) was added sodium cyanoborohydride (288 mg, 4.59 mmol) and the reaction mixture was stirred at 20 °C for 16 hrs. On completion, the reaction mixture was filtrated and the filtrate was concentrated in vacuo. The resulting oil was purified by silica gel chromatography (dichloromethane:methanol = 10:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 329.2, tR = 0.767. (±)-Tert-butyl 4-amino-3-phenyl-piperidine-1-carboxylate (Intermediate AB)

AB [00345] To a solution of (±)-tert-butyl 4-oxo-3-phenyl-piperidine-1-carboxylate (200 mg, 726 µmol, CAS# 632352-56-8) in methanol (8.00 mL) was added ammonium acetate (168 mg, 2.18 mmol). The mixture solution was stirred at 25 °C for 1 hr, and then sodium cyanoborohydride (137 mg, 2.18 mmol) was added. The mixture was stirred at 25 °C for 11 hrs. The reaction mixture was concentrated under reduced pressure to remove methanol. The residue was diluted with water (100 mL) and extracted with dichloromethane (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to dichloromethane : methanol = 10:1) to give the title compound.¹H NMR (400 MHz, CDCl₃) δ = 7.49 - 7.27 (m, 3H), 7.25 - 7.18 (m, 1H), 7.18 - 6.97 (m, 1H), 4.24 (br. s., 1H), 3.91 - 3.74 (m, 1H), 3.39 - 3.19 (m, 1H), 2.97 - 2.80 (m, 1H), 2.43 - 2.26 (m, 1H) , 1.99 - 1.82 (m, 1H), 1.51 - 1.33 (m, 9H), 1.27 - 1.20 (m, 1H). (±)-Tert-butyl 4-amino-2-phenylpiperidine-1-carboxylate (Intermediate AC)

[00346] To a solution of (±)-tert-butyl 4-oxo-2-phenyl-piperidine-1-carboxylate (500 mg, 1.82 mmol) in methanol (20.0 mL) was added ammonium acetate (421 mg, 5.46 mmol), and the mixture was stirred at 10-35 °C for 1 hr. Then sodium cyanoborohydride (343 mg, 5.46 mmol) was added. The mixture was stirred at 10-35 °C for 2 hrs. On completion, the mixture was concentrated to get the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 1:1) to get the title compound. ¹H NMR (400 MHz, CD3OD) δ = 7.41 - 7.13 (m, 5H), 5.04 - 4.90 (m, 1H), 4.82 - 4.74 (m, 1H), 4.18 - 3.94 (m, 1H), 3.59 - 3.32 (m, 2H), 3.02 - 2.60 (m, 1H), 2.38 - 2.12 (m, 1H), 1.89 (s, 9 H), 1.65 - 1.49 (m, 1H). (±)-Tert-butyl 4-amino-4-(3-(methylsulfonamido)propyl)piperidine-1-carboxylate (Intermediate AD)

Step 1 - Tert-butyl 4-(3-(methylsulfonamido)propyl)-4-nitropiperidine-1-carboxylate [00347] To a solution of tert-butyl 4-(3-aminopropyl)-4-nitro-piperidine-1-carboxylate (1.00 g, 3.48 mmol, synthesized via Steps 1-4 of Intermediate Q) in dichloromethane (20 mL) was added triethylamine (1.06 g, 10.4 mmol) and methanesulfonyl chloride (439 mg, 3.83 mmol) at 0 °C under a nitrogen. Then, the reaction mixture was stirred at 15 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 50:1) to give the title compound (1.00 g, 79% yield). ¹H NMR (400MHz, CDCl3) δ = 4.51 (br. s., 1H), 3.89 (br. s., 2H), 3.17 - 3.07 (m, 2H), 3.00 - 2.89 (m, 5H), 2.46 (d, J = 13.8 Hz, 2H), 1.98 - 1.88 (m, 2H), 1.79 - 1.68 (m, 2H), 1.58 - 1.49 (m, 2H), 1.47 - 1.44 (m, 9H). Step 2 - Tert-butyl 4-amino-4-(3-(methylsulfonamido)propyl)piperidine-1-carboxylate [00348] To a solution of tert-butyl 4-[3-(methanesulfonamido)propyl]-4-nitro-piperidine-1- carboxylate (400 mg, 1.09 mmol) in ethyl acetate (5 mL) was added Raney Nickel (93.7 mg, 1.09 mmol) under a nitrogen. The suspension was degassed under vacuum and purged with hydrogen atmosphere several times. The mixture was stirred under hydrogen atmosphere (50 psi) at 40 °C for 16 hours. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title compound, which was used directly for the next step. LCMS: (ES⁺) m/z (M+H) ⁺ = 336.2, tR= 0.790. Tert-butyl 3-hydroxy-4-oxo-piperidine-1-carboxylate (Intermediate AE)

Step 1 - Tert-butyl 4-[3-(benzyloxycarbonylamino)propyl]-4-nitro-piperidine-1-carboxylate [00349] To a solution of tert-butyl 4-(3-aminopropyl)-4-nitro-piperidine-1-carboxylate (1.70 g, 5.92 mmol, synthesized via Steps 1-4 of Intermediate Q) in dichloromethane (20 mL) was added triethylamine (1.80 g, 17.8 mmol) and benzyl carbonochloridate (CbzCl) (1.51 g, 8.9 mmol) in turn at 0 °C and the reaction mixture was stirred at 40 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 10:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 454, tR= 1.066. Step 2 - Tert-butyl 3-hydroxy-4-oxo-piperidine-1-carboxylate [00350] To a solution of tert-butyl 4-[3-(benzyloxycarbonylamino)propyl]-4-nitro-piperidine- 1-carboxylate (900 mg, 2.14 mmol) and ammonium chloride (457 mg, 8.54 mmol) in a mixture of ethanol (20 mL) and water (5 mL) was added iron powder (477 mg, 8.54 mmol) in one portion and the reaction mixture was stirred at 70 °C for 3 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 392.2. Tert-butyl 4-amino-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (Intermediate AF)

Step 1 - Tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate [00351] To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (8.00 g, 40.2 mmol) in anhydrous toluene (90.0 mL) was added methyl 2-(triphenyl-λ⁵-phosphanylidene)acetate (13.4 g, 40.2 mmol). The mixture was stirred at 110 °C for 16 hours. On completion, the mixture was concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20:1) to give the title compound. LCMS: (ES+) m/z (M+H-100)⁺ = 156.1, tR = 0.811. ¹H NMR (400 MHz, CDCl₃) δ 5.72 (s, 1H), 3.70 (s, 3H), 3.49 (td, J = 5.7, 11.2 Hz, 4H), 2.93 (t, J = 5.6 Hz, 2H), 2.28 (t, J = 5.5 Hz, 2H), 1.47 (s, 9H). Step 2 - Tert-butyl 4-amino-4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate [00352] To tert-butyl 4-(2-methoxy-2-oxo-ethylidene)piperidine-1-carboxylate (1.00 g, 3.92 mmol) was added a solution of ammonia in methanol (4 M/L, 30.0 mL). The mixture was stirred at 100 °C for 16 hours under autoclave. On completion, the mixture was concentrated. The residue was purified by silica gel chromatography (petroleum ether /ethyl acetate = 10:1, dichloromethane / methanol = 10:1) to give the title compound. ¹H NMR (400 MHz, CDCl3) δ = 3.69 (s, 3H), 3.61 (brs, 2H), 3.39 - 3.21 (m, 2H), 2.42 (s, 2H), 1.62 - 1.50 (m, 4H), 1.45 (s, 9H). (±)-Tert-butyl 3-cyano-4-((2,4-dimethoxybenzyl)amino)-3-methylpiperidine-1-carboxylate (Intermediate AG)

Step 1 - (±)-Tert-butyl 3-cyano-3-methyl-4-oxo-piperidine-1-carboxylate [00353] To a solution of (±)-tert-butyl 3-cyano-4-oxo-piperidine-1-carboxylate (200 mg, 892 µmol, CAS# 914988-10-6) in acetone (50 mL) was added potassium carbonate (370 mg, 2.68 mmol) and methyl iodide (380 mg, 2.68 mmol) in one portion. The reaction was stirred at 30 °C for 12 hrs. On completion, 20 mL water was added to the solution. Then the solution was extracted with ethyl acetate (3 x 30 mL), washed with water (100 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title compound. ¹H NMR (400MHz, CDCl3) δ = 4.25 (s, 2H), 2.85 - 2.80 (m, 2H), 2.50 - 2.45 (m, 2H), 1.40 (s, 3H), 1.39 (s, 9H). Step 2 - (±)-Tert-butyl 3-cyano-4-((2,4-dimethoxybenzyl)amino)-3-methylpiperidine-1- carboxylate [00354] To a solution of (±)-tert-butyl 3-cyano-3-methyl-4-oxo-piperidine-1-carboxylate (2.00 g, 8.39 mmol) in tetraisopropoxytitanium (23.9 g, 83.9 mmol, 24.8 mL) was added (2,4- dimethoxyphenyl)methanamine (2.81 g, 16.8 mmol) in one portion at 30 °C. The reaction was stirred at 30 °C for 1 hr, then sodium borohydride (95.3 mg, 2.52 mmol) in methanol (20 mL) was added to the solution in one portion. The reaction was stirred at 30 °C for 12 hrs. On completion, 30 mL water was added into the solution, and the solution was extracted with ethyl acetate (3 x 50 mL), washed with water (3 x 30 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 50:1) to give the title compound. LCMS: (ES⁺) m/z (M+Na-56)⁺ = 353.1. (±)-Tert-butyl 3-cyano-4-((2,4-dimethoxybenzyl)amino)-3-ethylpiperidine-1-carboxylate (Intermediate AH)

Step 1 - (±)-Tert-butyl 3-cyano-3-ethyl-4-oxo-piperidine-1-carboxylate [00355] To a solution of (±)-tert-butyl 3-cyano-4-oxo-piperidine-1-carboxylate (3.00 g, 13.3 mmol, CAS# 914988-10-6) in acetone (25 mL) was added potassium carbonate (3.70 g, 26.7 mmol) and iodoethane (4.17 g, 26.7 mmol). The mixture was stirred at 25 °C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with ice water (20 mL) and extracted with dichloromethane (3 × 20 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, which was used in the next step directly without further purification. ¹H NMR (400MHz, CDCl3) δ = 3.84 - 3.71 (m, 3H), 3.57 (t, J = 5.7 Hz, 1H), 2.79 - 2.72 (m, 1H), 2.60 - 2.50 (m, 1H), 2.36 (br. s., 1H), 2.07 - 1.99 (m, 1H), 1.53 (s, 9H), 1.12 (t, J = 7.5 Hz, 3H).

carboxylate [00356] A mixture of (±)-tert-butyl 3-cyano-3-ethyl-4-oxo-piperidine-1-carboxylate (2.90 g, 11.4 mmol), (2,4-dimethoxyphenyl)methanamine (1.92 g, 11.4 mmol) and Ti(Oi-Pr)4 (9.80 g, 34.4 mmol, 10.2 mL) was stirred at 25 °C for 5 hrs. Then, 30 mL of anhydrous methanol was added followed by sodium borohydride (1.30 g, 34.4 mmol) in portions. The resultant reaction mixture was stirred at 25 °C for an additional 15 hrs. On completion, the reaction mixture was concentrated in vacuo to afford a residue which was diluted with 30 mL of ice water, then extracted with dichloromethane (3 × 30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 15:1) to give the title product.¹H NMR (400MHz, CDCl₃) δ = 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 6.48 - 6.41 (m, 2H), 3.88 - 3.68 (m, 9H), 3.34 - 3.10 (m, 1H), 2.95 - 2.63 (m, 1H), 2.41 - 2.11 (m, 1H), 1.89 - 1.68 (m, 2H), 1.67 - 1.52 (m, 3H), 1.49 - 1.45 (m, 9H), 1.13 - 1.03 (m, 3H).

Examples 1-6 (Method 1) 4,5-Dichloro-1-methyl-N-[3-[2-(methylamino)-2-oxo-ethyl]-1- (pyrimidin-2-ylsulfamoyl)-3- piperidyl]indole-2-carboxamide (Example 1)

Step 1 - (±)-Tert-butyl 3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3-[2-(methylamino)- 2-oxo-ethyl] piperidine-1-carboxylate [00357] To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (400 mg, 1.64 mmol) in dichloromethane (10 mL) was added N,N-dimethylformamide (100 µL). The mixture was stirred at 0 °C for 0.5 hour. Then oxalyl dichloride (312 mg, 2.46 mmol) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 1 hour. On completion, the mixture was concentrated to give the title compound 4,5-dichloro-1-methyl-indole-2- carbonylchloride (420 mg, crude) as light yellow solid. [00358] To a solution of (±)-tert-butyl 3-amino-3-[2-(methylamino)-2-oxo-ethyl]piperidine-1- carboxylate (434 mg, 1.60 mmol) in dichloromethane (10 mL) was added triethylamine (485 mg, 4.80 mmol). The mixture was stirred at 0 °C for 0.5 hour. Then a solution of 4,5-dichloro-1- methyl-indole-2-carbonyl chloride (420 mg, 1.60 mmol) in dichloromethane (10 mL) was added to the reaction mixture. The reaction mixture was stirred at 20 °C for 2 hours. On completion, the mixture was concentrated to afford a residue. The residue was purified by silica gel chromatography eluted with petroleum ether:ethyl acetate = 3:1 - 1:1 to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 497.2, tR= 0.813. Step 2 - (±)-4,5-Dichloro-1-methyl-N-[3-[2-(methylamino)-2-oxo-ethyl]-3-piperidyl]indole -2- carboxamide [00359] To a solution of (±)-tert-butyl 3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3- [2-(methylamino)-2-oxo-ethyl]piperidine-1-carboxylate (600 mg, 1.21 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (4.69 g, 41.1 mmol). The mixture was stirred at 20 °C for 1.5 hours. On completion, the mixture was concentrated to get the crude product. The crude product was used directly for the next step without purification. LCMS: (ES⁺) m/z (M+H)⁺ = 397.1, tR= 0.586. Step 3 - (±)-4,5-Dichloro-1-methyl-N-[3-[2-(methylamino)-2-oxo-ethyl]-1-(pyrimidin-2- ylsulfamoyl)-3-piperidyl]indole-2-carboxamide

[^00360] To a solution of (±)-4,5-dichloro-1-methyl-N-[3-[2-(methylamino)-2-oxo-ethyl]-3- piperidyl]indole-2-carboxamide (150 mg, 377 µmol) in acetonitrile (3 mL) was added triethylamine acid (382 mg, 3.78 mmol), and the mixture was stirred at 20 °C for 0.5 hr. Then 2- oxo-N-pyrimidin-2-yl-oxazolidine-3-sulfonamide (70.6 mg, 289 µmol) was added into the mixture. The reaction mixture was transferred into a microwave tube and heated at 130 °C for 2.5 hrs under microwave (150 psi, 120 w). On completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was purified by prep-HPLC [Instrument: GX-I; Column: Phenomenex Synergi C18150*30mm*4µm; Condition: 0.1% trifluoroacetic acid-acetonitrile] to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 554.2, tR= 0.791. Method 1 Table: Compounds Synthesized via Method 1 using the appropriate acids and amines

aHCl in MeOH (4 M) was used for the deprotection (25 °C for 10 mins) instead of TFA in Step 2. ^bStep 2: reaction was performed using DCM as the solvent with HCl in MeOH (4 M) for the deprotection (25 °C for 12 hrs) instead of TFA in Step 2. Example 7 - (±)-N-[1-(acetylsulfamoyl)-3-[2-(methylamino)-2-oxo-ethyl]-3-piperidyl]-4,5- dichloro-1-methyl-indole-2-carboxamide

Step 1 - (±)-Tert-butyl ((3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-3-(2- (methylamino)-2-oxoethyl)piperidin-1-yl)sulfonyl)carbamate [00361] To a solution of (±)-4,5-dichloro-1-methyl-N-[3-[2-(methylamino)-2-oxo-ethyl]-3- piperidyl] indole-2-carboxamide (640 mg, 1.61 mmol, synthesized via Method 1, Steps 1-2 as seen above in Example 1) in dichloromethane (10 mL) was added triethylamine (1.63 g, 16.1 mmol). The mixture was stirred at 0 °C for 0.5 hour. Then tert-butyl N-chlorosulfonylcarbamate (521 mg, 2.42 mmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 3 hours. On completion, the mixture was concentrated to a residue. The residue was purified by silica gel chromatography eluted with petroleum ether :ethyl acetate = 3: 1 - 1: 1 to give the title compound (220 mg, 20% yield) as light yellow liquid. LCMS: (ES⁺) m/z (M+H)⁺ = 576.1, tR= 0.780. Step 2 - (±)-4,5-Dichloro-1-methyl-N-[3-[2-(methylamino)-2-oxo-ethyl]-1-sulfamoyl-3- piperidyl] indole-2-carboxamide [00362] To a solution of (±)-Tert-butyl ((3-(4,5-dichloro-1-methyl-1H-indole-2- carboxamido)-3-(2-(methylamino)-2-oxoethyl)piperidin-1-yl)sulfonyl)carbamate (650 mg, 1.13 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (4.51 g, 39.5 mmol). The mixture was stirred at 20℃ for 2 hours. On completion, the mixture was concentrated to a residue. The residue was extracted with dichloromethane (2 x 3 mL), dried with anhydrous sodium sulfate, filtered and concentrated to give the title compound (326 mg, 49% yield) as yellow solid. LCMS: (ES⁺) m/z (M+H)⁺ = 476.0, tR= 0.681. Step 3 - (±)-N-[1-(acetylsulfamoyl)-3-[2-(methylamino)-2-oxo-ethyl]-3-piperidyl]-4,5-dichloro- 1-methyl-indole-2-carboxamide [00363] To a solution of (±)-4,5-dichloro-1-methyl-N-[3-[2-(methylamino)-2-oxo-ethyl]-1- sulfamoyl-3-piperidyl]indole-2-carboxamide (30 mg, 62.9 µmol) in dichloromethane (2 mL) was added triethylamine (63.7 mg, 629 µmol). The mixture was stirred at 0 °C for 0.5 hr. Then acetyl chloride (14.8 mg, 188 µmol) was added to the reaction mixture. The reaction mixture was stirred at 0 °C for 2 hours. On completion, the mixture was concentrated to a residue. The residue was purified by prep-HPLC (Instrument: GX-B; Xtimate C18 150*25mm*5µm; 0.1% trifluoroacetic acid - acetonitrile) to give the title compound (20.0 mg, 60% yield) as white solid. LCMS: (ES⁺) m/z (M+H)⁺ = 518.2, tR= 0.789. ¹H NMR (400MHz, CDCl3) δ = 9.55 - 9.26 (m, 1H), 7.36 ( s, 1H), 7.22 - 7.17 (m, 1H), 7.16 - 7.10 (m, 2H), 6.27 (d, J = 4.5 Hz, 1H), 4.28 (d, J = 13.1 Hz, 1H), 3.99 (s, 3H), 3.84 (d, J = 13.7 Hz, 1H), 3.30 (t, J = 9.7 Hz, 1H), 3.21 (d, J = 13.3 Hz, 1H), 3.06 (d, J = 13.3 Hz, 1H), 2.91 (d, J = 13.8 Hz, 1H), 2.84 - 2.71 (m, 3H), 2.65 - 2.55 (m, 1H), 2.16 (s, 3H), 1.87 - 1.72 (m, 2H), 1.60 - 1.47 (m, 1H). Example 8 - N-(1-(N-acetylsulfamoyl)piperidin-4-yl)-4-chloro-1,5-dimethyl-1H-indole-2- carboxamide

Step 1 - 4-Chloro-1,5-dimethyl-N-(piperidin-4-yl)-1H-indole-2-carboxamide [00364] To a solution of tert-butyl 4-[(4-chloro-1,5-dimethyl-indole-2- carbonyl)amino]piperidine-1-carboxylate (999 mg, 2.46 mmol, synthesized via Step 1 of Method 1 with acid Intermediate C and tert-butyl 4-aminopiperidine-1-carboxylate) in dichloromethane (10 mL) was added the solution of hydrochloride in methanol (10 mL, 4 M) at 15 °C, and the reaction mixture was stirred for 2 hrs. On completion, the reaction mixture was concentrated in vacuo. The title compound was used in next step directly as a hydrochloride acid salt (0.7 g, 83% yield) as yellow solid. LCMS: (ES⁺) m/z (M+H)⁺ = 306.1. Step 2 - Tert-butyl (4-(4-chloro-1,5-dimethyl-1H-indole-2-carboxamido)piperidin-1-yl)sulfonyl- carbamate [00365] To a solution of 4-chloro-1,5-dimethyl-N-(piperidin-4-yl)-1H-indole-2-carboxamide (0.7 g, HCl salt) and triethylamine (1.20 g, 11.5 mmol) in dichloromethane (5 mL) was added tert-butyl N-chlorosulfonylcarbamate (494 mg, 2.29 mmol) dropwise at 15 °C. The reaction mixture was stirred at 15 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give a crude solid which was triturated with the solvent (petroleum ether:ethyl acetate = 1:1) for 30 min. The mixture was filtered, and the filtrate was concentrated in vacuo to give a white solid (400 mg, yield 36%) as the product.¹H NMR (400 MHz, DMSO-d₆) δ = 8.54 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.23 (d, J =8.4 Hz, 1H), 7.13 (s, 1H), 3.91~4.04 (m, 4H), 3.65 (d, J = 12.4 Hz, 2H), 2.92 (t, J = 11.2 Hz, 2H), 2.42 (s, 3H), 1.91 (d, J = 10.4 Hz, 2H), 1.59~1.62 (m, 2H), 1.45 (s, 9H). Step 3 - 4-Chloro-1,5-dimethyl-N-(1-sulfamoylpiperidin-4-yl)-1H-indole-2-carboxamide [00366] To a solution of tert-butyl-N-[[4-[(4-chloro-1,5-dimethyl-indole-2-carbonyl)amino]- 1-piperidyl] sulfonyl]carbamate (350 mg, 722 µmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1.53 g, 13.4 mmol) dropwise at 15 °C. The reaction mixture was stirred for 16 hrs. On completion, the mixture was concentrated in vacuo to give the title compound (243 mg, 87% yield) which was directly used in next step. LCMS: (ES⁺) m/z (M+H)⁺ = 385.1, tR= 0.983. ¹H NMR (400 MHz, DMSO-d₆) δ = 8.54 (d, J = 7.2 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.15 (s, 1H), 6.79 (br. s, 2H), 3.98(s, 3H), 3.84 (m, 1H), 3.49~3.52 (m, 2H), 2.64 (t, J = 11.2 Hz, 2H), 2.42 (s, 3H), 1.91~1.94 (m, 2H), 1.63~1.66 (m, 2H). Step 4 - N-(1-(N-acetylsulfamoyl)piperidin-4-yl)-4-chloro-1,5-dimethyl-1H-indole-2- carboxamide [00367] To a mixture of 4-chloro-1,5-dimethyl-N-(1-sulfamoyl-4-piperidyl)indole-2- carboxamide (170 mg, 442 µmol), triethylamine (447 mg, 4.42 mmol), and DMAP (5.40 mg, 44.2 µmol) in dichloromethane (6.00 mL) was added acetyl chloride (52 mg, 663 µmol). The mixture was stirred at 15 °C for 16 hrs. On completion, the mixture was concentrated in vacuo to give a yellow suspension. To the suspension was added ethyl acetate (20 mL), and stirred for 30 min. Then, the mixture was filtered, and the filtrate was concentrated in vacuo to give a crude which was purified by prep-HPLC (condition: 0.1% TFA-ACN; column: Welch Ultimate AQ- C18 150*30mm*5µm) to give the title compound (38 mg, yield 20%) as a white solid. LCMS: (ES⁺) m/z (M+H)⁺ = 427.1, tR= 1.0.¹H NMR (400 MHz, DMSO-d6) δ = 11.47 (br. s, 1H), 8.55 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.8 Hz,, 1H), 7.15 (s, 1H), 3.98 (s, 3H), 3.89~3.91 (m, 1H), 3.67 (d, J = 12 Hz, 1H), 2.98 (t, J = 12 Hz, 2H), 2.42 (s, 3H), 1.99 (s, 3H), 1.88~1.91 (m, 2H), 1.55~1.63 (m, 2H). Example 9 (Method 2) - (±)-4-chloro-1,5-dimethyl-N-(3-(4-(methylamino)-4-oxobutyl)-1-(N- (methylcarbamoyl)sulfamoyl)piperidin-3-yl)-1H-indole-2-carboxamide

Step 1 - (±)-Tert-butyl 3-(4-chloro-1,5-dimethyl-1H-indole-2-carboxamido)-3-(4-(methylamino)- 4-oxobutyl)piperidine-1-carboxylate [00368] To a solution of 4-chloro-1,5-dimethyl-indole-2-carboxylic acid (653 mg, 2.92 mmol), hydroxybenzotriazole (HOBt) (474 mg, 3.50 mmol), EDCI (672 mg, 3.50 mmol) and triethylamine (709 mg, 7.01 mmol) in dichloromethane (20 mL) was added (±)-tert-butyl 3- amino-3-(4-(methylamino)-4-oxobutyl)piperidine-1-carboxylate (875 mg, 2.92 mmol) at 15 °C under nitrogen. The mixture was stirred at 15 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate= 1:1 to dichloromethane:methanol = 20:1) to give the title compound (512 mg, 33% yield). LCMS: (ES⁺) m/z (M+H)⁺ = 505.3, tR= 0.906. Step 2 - (±)-4-chloro-1,5-dimethyl-N-(3-(4-(methylamino)-4-oxobutyl)piperidin-3-yl)-1H- indole-2-carboxamide [00369] To a solution of (±)-tert-butyl 3-(4-chloro-1,5-dimethyl-1H-indole-2-carboxamido)-3- (4-(methylamino)-4-oxobutyl)piperidine-1-carboxylate (570 mg, 1.13 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (129 mg, 1.13 mmol) at 15 °C under nitrogen. The reaction mixture was stirred at 15 °C for 1 hr. On completion, the reaction mixture was concentrated in vacuo to give the title compound (1.10 g, 50% purity, 100% yield). The crude product was used to the next step directly without further purification. LCMS: (ES⁺) m/z (M+H)⁺ = 405.2, tR= 0.664. Step 3 – (±)-Tert-butyl ((3-(4-chloro-1,5-dimethyl-1H-indole-2-carboxamido)-3-(4- (methylamino)-4-oxobutyl)piperidin-1-yl)sulfonyl)carbamate [00370] To a solution of (±)-4-chloro-1,5-dimethyl-N-(3-(4-(methylamino)-4- oxobutyl)piperidin-3-yl)-1H-indole-2-carboxamide (770 mg, 1.48 mmol) in dichloromethane (5 mL) was added triethylamine (1.50 g, 14.8 mmol) at 15 °C. Then tert-butyl N- chlorosulfonylcarbamate (479 mg, 2.22 mmol) was added at 0 °C under nitrogen. The reaction mixture was stirred at 15 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 1:1 to dichloromethane:methanol = 20:1) to give the title compound (593 mg, 58% yield). LCMS: (ES⁺) m/z (M+H)⁺ = 584.3, tR= 0.831. Step 4 – (±)-4-chloro-1,5-dimethyl-N-(3-(4-(methylamino)-4-oxobutyl)-1-(N- (methylcarbamoyl)sulfamoyl)piperidin-3-yl)-1H-indole-2-carboxamide [00371] To a solution of tert-butyl ((3-(4-chloro-1,5-dimethyl-1H-indole-2-carboxamido)-3- (4-(methylamino)-4-oxobutyl)piperidin-1-yl)sulfonyl)carbamate (100 mg, 171 µmol) in toluene (4 mL) was added methylamine alcohol solution (5.32 mg, 171 µmol) at 15 °C under nitrogen. The reaction mixture was stirred at 130 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (Instrument: GX-I; Column: Xtimate C18 150*25mm*5µm; Condition: 10 mM aq. NH4HCO3-acetonitrile) to give the title compound (26.0 mg, 28% yield). LCMS: (ES⁺) m/z (M+H)⁺ = 541.3, tR= 1.829. ¹H NMR (400MHz, CD₃OD) δ = 7.32 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.06 (s, 1H), 4.12 (d, J = 12.5 Hz, 1H), 3.96 (s, 3H), 3.63 (d, J = 12.0 Hz, 1H), 3.09 (d, J = 12.5 Hz, 2H), 2.72 (s, 3H), 2.62 (s, 3H), 2.46 (s, 3H), 2.37 (d, J = 13.6 Hz, 1H), 2.22 (t, J = 7.3 Hz, 2H), 1.97 (t, J = 7.4 Hz, 2H), 1.85 (d, J = 14.3 Hz, 1H), 1.78 - 1.64 (m, 3H), 1.59 - 1.48 (m, 1H). Example 10 - (±)-4-Chloro-5-fluoro-1-methyl-N-[3-[4-(methylamino)-4-oxo-butyl]-1- (methylcarbamoylsulfamoyl)-3-piperidyl]indole-2-carboxamide

[00372] (±)-4-Chloro-5-fluoro-1-methyl-N-[3-[4-(methylamino)-4-oxo-butyl]-1- (methylcarbamoylsulfamoyl)-3-piperidyl]indole-2-carboxamide was synthesized via Method 2 with intermediate acid E and amine J. The title compound (23.0 mg, 31% yield) was isolated as a yellow solid. LCMS: (ES⁺) m/z (M+H)⁺ = 545.2, tR = 0.998. ¹H NMR (400MHz, CDCl3) δ = 8.27 (br. s., 1H), 7.23 - 7.17 (m, 1H), 7.16 - 7.08 (m, 2H), 6.95 (s, 1H), 6.21 (br. s., 1H), 5.75 (br. s., 1H), 4.01 (s, 3H), 3.97 (s, 1H), 3.66 (d, J = 11.9 Hz, 1H), 3.13 - 2.94 (m, 2H), 2.83 (d, J = 4.9 Hz, 3H), 2.79 (d, J = 4.6 Hz, 3H), 2.63 (d, J = 14.6 Hz, 1H), 2.26 (d, J = 4.8 Hz, 3H), 1.87 - 1.66 (m, 5H), 1.46 (t, J = 11.0 Hz, 1H).

Examples 11-17 (Method 3) (±)-N-(3-(2-acetamidoethyl)-1-(N-(methylcarbamoyl)sulfamoyl)piperidin-3-yl)-4-chloro- 1,5-dimethyl-1H-indole-2-carboxamide (Example 11)

Step 1 – (±)-Tert-butyl 3-(2-acetamidoethyl)-3-(4-chloro-1,5-dimethyl-1H-indole-2- carboxamido) piperidine-1-carboxylate [00373] To a suspension of 4-chloro-1,5-dimethyl-indole-2-carboxylic acid (1.30 g, 5.81 mmol) in dichloromethane (15.0 mL) was added N,N-dimethylformamide (42.5 mg, 581 µmol) followed by the addition of oxalyl dichloride (885 mg, 6.97 mmol) dropwise at 15 °C. The resulting suspension was heated to 40 °C with stirring for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the crude product as a yellow solid (1.5 g, 90% purity, 95% yield). [00374] To a solution of (±) tert-butyl 3-(2-acetamidoethyl)-3-amino-piperidine-1-carboxylate (1.50 g, 5.26 mmol) and triethylamine (2.66 g, 26.3 mmol) in dry dichloromethane (13.0 mL) was added 4-chloro-1,5-dimethyl-indole-2-carbonyl chloride (1.40 g, 5.79 mmol) in portions at 0 °C. The resulting mixture was warmed to 15 °C with stirring for 16 hrs. On completion, to the reaction mixture was added water (20 mL), the product was extracted with dichloromethane (3 x 40 mL), the combined dichloromethane phase was washed with brine (50 mL), dried over sodium sulfate, and concentrated in vacuo to give a crude product which was purified by column chromatography (petroleum ether:ethyl acetate = 1:1 to 0:1 to dichloromethane:methanol = 20:1) to give the product (1.80 g, 69% yield) as a yellow solid.¹H NMR (400 MHz, CDCl3) δ = 7.18 (s, 2H), 6.94 (br. s, 1H), 4.36-4.31 (m, 2H), 4.04~4.02 (m, 4H), 3.32~3.29 (m, 1H), 3.50-3.46 (m, 1H), 2.90-2.85 (m, 3H), 2.47 (s, 3H), 2.33 (s, 1H), 1.93 (s, 4H), 1.61-1.45 (m, 13H). Step 2 – (±)-N-(3-(2-acetamidoethyl)piperidin-3-yl)-4-chloro-1,5-dimethyl-1H-indole-2- carboxamide [00375] To a solution of (±)-tert-butyl 3-(2-acetamidoethyl)-3-[(4-chloro-1,5-dimethyl-indole- 2-carbonyl) amino]piperidine-1-carboxylate (1.80 g, 3.67 mmol) in dichloromethane (18.0 mL) was added trifluoroacetic acid (1.53 g, 13.4 mmol) dropwise at 0 °C, and the reaction mixture was warmed to 15 °C and stirred for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the title compound (3.20 g, 52.8% purity, 94% yield) as brown oil. LCMS: (ES⁺) m/z (M+H)⁺ = 391.2, tR= 0.799. Step 3 – (±)-Tert-butyl (3-(2-acetamidoethyl)-3-(4-chloro-1,5-dimethyl-1H-indole-2- carboxamido)piperidin-1-yl)sulfonylcarbamate [00376] To a solution of (±)-N-[3-(2-acetamidoethyl)-3-piperidyl]-4-chloro-1,5-dimethyl- indole-2-carboxamide (3.20 g, 6.34 mmol) and triethylamine (1.90 g, 18.8 mmol) in dichloromethane (20.0 mL) was added tert-butyl-N-chlorosulfonylcarbamate (1.03 g, 4.78 mmol) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 20 min. On completion, the reaction mixture was quenched with citric acid (30 mL). The dichloromethane phase was separated, washed with brine (30 mL), dried over sodium sulfate, concentrated in vacuo to give a crude product which was purified by column chromatography (dichloromethane:methanol = 100:1 to 50:1 to 20:1) to give the title compound (1.60 g, 44% yield) as a yellow solid.¹H NMR (300 MHz, DMSO-d6) δ = 10.96 (br. s, 1H), 7.79~7.85 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 3.92 (s, 3H), 3.79 (d, J = 12.3 Hz, 1H), 3.41-2.97 (m, 5H), 2.42-2.22 (m, 5H), 2.04-1.97 (m, 1H), 1.85-1.59 (m, 6H), 1.38 (s, 9H). Step 4 – (±)-N-(3-(2-acetamidoethyl)-1-(N-(methylcarbamoyl)sulfamoyl)piperidin-3-yl)-4- chloro- 1,5-dimethyl-1H-indole-2-carboxamide [00377] To a mixture of (±) tert-butyl N-[[3-(2-acetamidoethyl)-3-[(4-chloro-1,5-dimethyl- indole-2-carbonyl)amino]-1-piperidyl]sulfonyl]carbamate (100 mg, 175 µmol) in toluene (1.00 mL) was added methanamine ethanol solution (175 µmol) in one portion at 15 °C. The mixture was heated to 110 °C and stirred for 3 hrs. On completion, the reaction mixture was concentrated and the residue was purified with prep-HPLC (condition: 0.1%TFA-ACN; column: Phenomenex Synergi C18 150*30mm*4µm) to give the title compound (16 mg, 17% yield) as a white solid. LCMS: (ES⁺) m/z (M+H)⁺ = 527.1, tR= 0.983.¹H NMR (400 MHz, DMSO-d6) δ = 10.14 (br. s, 1H), 7.84 (t, J = 4.8 Hz, 1H), 7.80 (s, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.11 (s, 1H), 8.25-8.24 (m, 1H), 3.92 (s, 3H), 3.80-3.77 (m, 1H), 3.33-3.28 (m, 2H), 3.18-3.00 (m, 3H), 2.54 (d, J = 4.4 Hz, 3H), 2.42 (s, 3H), 2.25-2.18 (m, 1H), 2.04-2.03 (m, 1H), 1.90-1.82 (m, 1H), 1.75-1.62 (m, 6H). Method 3 Table: Compounds Synthesized via Method 3 using the appropriate acids and amines

Example 18 - (±)-N-[3-(3-acetamidopropyl)-1-(methylcarbamoylsulfamoyl)-3-piperidyl]- 4,5-dichloro-1-methyl-indole-2-carboxamide

Step 1 - (±)-N-[3-(3-acetamidopropyl)-3-piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamide [00378] To a solution of (±)-tert-butyl 3-(3-acetamidopropyl)-3-[(4,5-dichloro-1-methyl- indole-2-carbonyl)amino]piperidine-1-carboxylate (600 mg, 1.14 mmol, synthesized via Method 3, Step 1 with acid A and amine N) in methanol (20 mL) was added hydrochloride/methanol (4 M, 10 mL). The reaction mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuo to give the title compound. ¹H NMR (400MHz, methanol-d4) δ = 7.51 - 7.45 (m, 1H), 7.44 - 7.38 (m, 1H), 7.35 (s, 1H), 4.42 (d, J = 13.2 Hz, 1H), 4.03 (s, 3H), 3.39 (br. s., 1H), 3.25 (d, J = 4.0 Hz, 2H), 3.12 - 3.01 (m, 2H), 2.35 (d, J = 14.2 Hz, 1H), 2.25 - 2.14 (m, 1H), 2.12 - 2.02 (m, 1H), 2.01 (br. s., 4H), 1.96 - 1.85 (m, 1H), 1.74 - 1.52 (m, 4H). Step 2 - (±)-tert-butyl N-[[3-(3-acetamidopropyl)-3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]-1-piperidyl]sulfonyl]carbamate [00379] To a solution of (±)-N-[3-(3-acetamidopropyl)-3-piperidyl]-4,5-dichloro-1-methyl- indole-2-carboxamide (450 mg, 974 µmol) and triethylamine (493 mg, 4.87 mmol) in dichloromethane (30 mL) was added tert-butyl N-chlorosulfonylcarbamate (315 mg, 1.46 mmol). The reaction mixture was stirred at 25 °C for 0.5 h. On completion, the mixture was concentrated in vacuo. The residue was purified by chromatography (dichloromethane:methanol = 50:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 604.0, tR= 0.945. ¹H NMR (400MHz, DMSO-d6) δ = 8.63 (s, 2H), 7.92 - 7.82 (m, 2H), 7.60 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.16 (s, 1H), 5.77 (s, 1H), 3.94 (s, 3H), 3.86 (d, J = 12.2 Hz, 1H), 3.22 (d, J = 7.3 Hz, 2H), 2.98 - 2.94 (m, 2H), 2.87 (q, J = 7.2 Hz, 1H), 2.15 - 1.90 (m, 2H), 1.76 (s, 3H), 1.69 (br. s., 2H), 1.63 - 1.41 (m, 4H), 1.33 (s, 9H). Step 3 - (±)-N-[3-(3-acetamidopropyl)-1-sulfamoyl-3-piperidyl]-4,5-dichloro-1-methyl-indole-2- carboxamide [00380] To a solution of (±)-tert-butyl N-[[3-(3-acetamidopropyl)-3-[(4,5-dichloro-1-methyl- indole-2-carbonyl) amino]-1-piperidyl]sulfonyl]carbamate (200 mg, 338 µmol) in methanol (10 mL) was added hydrochloride/methanol (4 M, 10 mL). The reaction mixture was stirred 25 °C for 0.5 h. On completion, the reaction mixture was concentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 504.0, tR= 0.774. ¹H NMR (400MHz, DMSO-d6) δ = 7.85 (t, J = 5.5 Hz, 1H), 7.79 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 6.72 (s, 2H), 5.76 (s, 1H), 3.94 (s, 3H), 3.62 (d, J = 11.5 Hz, 1H), 3.14 - 2.93 (m, 4H), 2.86 (d, J = 8.3 Hz, 1H), 2.09 - 1.95 (m, 2H), 1.76 (s, 3H), 1.69 - 1.33 (m, 6H). Step 4 - (±)-N-[3-(3-acetamidopropyl)-1-(methylcarbamoylsulfamoyl)-3-piperidyl]-4,5-dichloro- 1- methyl-indole-2-carboxamide [00381] To a mixture of (±)-N-[3-(3-acetamidopropyl)-1-sulfamoyl-3-piperidyl]-4,5-dichloro- 1-methyl-indole-2-carboxamide (130 mg, 257 µmol) and cuprous chloride (12.7 mg, 128 µmol) in N,N-dimethylformamide (5 mL) was added isocyanatomethane (5 mL toluene solution, 876 µmol). The reaction mixture was stirred at 40 °C for 9 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep-HPLC (water (0.05% ammonium hydroxide v/v)-ACN, Phenomenex Gemini C18 250*50mm*10 um) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 561.1, tR= 0.969. ¹H NMR (400MHz, DMSO-d6) δ = 9.65 - 9.54 (br. s, 1H), 7.89 (s, 1H), 7.83 (t, J = 5.6 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 6.18 (d, J = 4.4 Hz, 1H), 3.94 (s, 3H), 3.89 (d, J = 12.4 Hz, 1H), 3.11 - 2.89 (m, 4H), 2.53 (s., 3H), 2.11 (d, J = 13.8 Hz, 1H), 2.00 - 1.88 (m, 1H), 1.76 (s, 3H), 1.75 - 1.65 (m, 2H), 1.58 (dd, J = 5.0, 9.9 Hz, 1H), 1.42 - 1.38 (m, 3H). Example 19 - (±)-N-[3-(3-acetamidopropyl)-1-[(2-hydroxy-2-methyl-propanoyl)sulfamoyl] - 3-piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamide

Step 1 - (±)-[2-[[3-(3-acetamidopropyl)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1- piperidyl]sulfonylamino]-1,1-dimethyl-2-oxo-ethyl] acetate [00382] To a solution of (±)-N-[3-(3-acetamidopropyl)-1-sulfamoyl-3-piperidyl]-4,5-dichloro- 1-methyl-indole-2-carboxamide (90.0 mg, 178 µmol, synthesized via Method 3 as seen above for Example 18), N,N-dimethylpyridin-4-amine (21.8 mg, 178 µmol) and triethylamine (72.2 mg, 713 µmol) in dichloromethane (5 mL) was added (2-chloro-1,1-dimethyl-2-oxo-ethyl) acetate (29.3 mg, 178 µmol, CAS# 40635-66-3). The reaction mixture was stirred at 25 °C for 0.5 h. On completion, the reaction was quenched with water (30 mL), and the aqueous phase was extracted with dichloromethane (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 632.2, tR= 0.848. Step 2 - (±)-N-[3-(3-acetamidopropyl)-1-[(2-hydroxy-2-methyl-propanoyl)sulfamoyl]-3- piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamide [00383] To a solution of (±)-[2-[[3-(3-acetamidopropyl)-3-[(4,5-dichloro-1-methyl- indole-2- carbonyl)amino]-1-piperidyl]sulfonylamino]-1,1-dimethyl-2-oxo-ethyl] acetate (150 mg, 237 µmol) in a mixture of tetrahydrofuran (5 mL), methanol (5 mL) and water (3 mL) was added lithium hydroxide (39.8 mg, 948 µmol). The reaction mixture was stirred at 15 °C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by prep- HPLC (Column: Phenomenex Gemini C18 250*50mm*10 um; Condition: 0.1% TFA-ACN) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 590.2, tR= 0.852. ¹H NMR (400MHz, methanol-d4) δ = 7.71 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.13 (s, 1H), 4.23 - 4.15 (m, 1H), 3.98 (s, 3H), 3.71 - 3.63 (m, 1H), 3.24 - 3.17 (m, 1H), 3.14 - 3.06 (m, 1H), 2.41 - 2.32 (m, 1H), 2.10 - 1.94 (m, 1H), 1.93 (s, 3H), 1.86 - 1.68 (m, 1H), 1.66 - 1.49 (m, 1H), 1.35 (s, 3H), 1.30 (s, 3H). Example 20 - N-(3-(3-acetamidopropyl)-1-(N-(isopropylcarbamoyl)sulfamoyl)piperidin-3- yl)-4-chloro-1,5-dimethyl-1H-indole-2-carboxamide

[00384] A mixture of tert-butyl N-[[3-(3-acetamidopropyl)-3-[(4-chloro-1,5-dimethyl-indole- 2-carbonyl) amino]-1-piperidyl]sulfonyl]carbamate (100 mg, 171 µmol, synthesized via Method 3, Steps 1-3 starting with acid C and amine N) and propan-2-amine (20.2 mg, 342 µmol) in toluene (4 mL) was stirred at 110 °C for 2 hrs. On completion, the mixture was concentrated. The residue was purified by Prep-HPLC [Instrument: GX-D; Column: Boston Green ODS 150*30 5u; Mobile phase: 45-75% acetonitrile in water (add 0.225 % formic acid)] to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 569.2, tR= 0.823.¹H NMR (400MHz, CDCl3) δ= 8.60 (br. s., 1H), 7.16 (s, 2H), 7.01 (s, 1H), 6.70 (s, 1H), 6.11 - 5.98 (m, 2H), 3.98 (s, 3H), 3.95 - 3.84 (m, 2H), 3.72 (d, J = 12.0 Hz, 1H), 3.33 (dd, J = 6.4, 13.2 Hz, 1H), 3.24 - 3.12 (m, 1H), 3.04 - 2.88 (m, 2H), 2.54 (d, J = 13.8 Hz, 1H), 2.47 (s, 3H), 2.42 - 2.29 (m, 1H), 1.98 (s, 2H), 1.82 (d, J = 10.5 Hz, 1H), 1.65 - 1.50 (m, 3H), 1.47 - 1.35 (m, 1H), 1.13 (d, J = 6.5 Hz, 3H), 1.07 (d, J = 6.5 Hz, 3H). Example 21 - (±)-N-(3-(2-acetamidoethyl)-1-(N-(methylcarbamoyl)sulfamoyl)piperidin-3- yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

Step 1– (±) Tert-butyl 3-(2-aminoethyl)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino] piperidine-1-carboxylate [00385] To a solution of (±)-tert-butyl 3-(cyanomethyl)-3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]-piperidine-1-carboxylate (800 mg, 1.72 mmol, synthesized via Method 3, Step 1 with acid A and amine L) in methanol (10 mL) and ammonium hydroxide (10 mL) was added Raney nickel (1.60 g, 18.7 mmol) at 15 °C under nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen gas (40 psi) at 15 °C for 16 hrs. On completion, the reaction was concentrated in vacuo to give the title compound. LCMS (ES⁺): 469.1 m/z (M+H)⁺, tR= 1.570 min. Step 2 – (±)-Tert-butyl 3-(2-acetamidoethyl)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl) amino]piperidine-1-carboxylate [00386] To a solution of (±)-tert-butyl 3-(2-aminoethyl)-3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]piperidine-1-carboxylate (1.60 g, 3.41 mmol) in dichloromethane (50.0 mL) was added triethylamine (1.04 g, 10.3 mmol) in one portion at 15 °C under nitrogen. Then acetyl chloride (401 mg, 5.12 mmol) was added to the reaction mixture at 0 °C. The reaction was stirred at 15 °C for 16 hrs. On completion, the reaction was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/methanol=100:1 to 50:1) to give the title compound.¹H NMR (300MHz, CDCl₃): δ = 12.01 (br. s., 2H), 7.23-7.30 (m, 1H), 7.10-7.17 (m, 1H), 6.89 (br. s., 1H), 5.78 (br. s., 1H), 4.23 (d, J = 12.4 Hz, 1H), 3.96 (s, 3H), 3.85-3.93 (m, 1H), 3.32-3.48 (m, 1H), 3.13-3.30 (m, 1H), 2.63-2.89 (m, 3H), 2.24 (br. s., 1H), 1.85 (s, 3H), 1.48-1.72 (m, 3H), 1.42 ppm (s, 9H) Step 3 – (±)-N-(3-(2-acetamidoethyl)piperidin-3-yl)-4,5-dichloro-1-methyl-1H-indole-2- carboxamide [00387] To a solution of (±)-tert-butyl 3-(2-acetamidoethyl)-3-[(4,5-dichloro-1-methyl-indole- 2-carbonyl)amino]piperidine-1-carboxylate (450 mg, 880 µmol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (3.06 g, 26.8 mmol) at 15 °C under nitrogen. The reaction solution was stirred at 15 °C for 1 hr. On completion, the reaction was concentrated in vacuo. The residue was basified with sodium bicarbonate solution (15 mL) to pH = 7-8, and the aqueous was extracted with dichloromethane (5 x 15 mL). The combined the organic layer and washed with brine, dried over sodium sulfate, concentrated in vacuo to give the title compound. LCMS (ES⁺): 411.1 m/z (M+H)⁺, tR= 0.988 min. Step 4 – (±)-Tert-butyl N-[[3-(2-acetamidoethyl)-3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]-1-piperidyl]sulfonyl]carbamate [00388] To a solution of (±)-N-[3-(2-acetamidoethyl)-3-piperidyl]- 4,5-dichloro-1-methyl- indole-2-carboxamide (480 mg, 1.17 mmol) and triethylamine (354 mg, 3.50 mmol) in dichloromethane (15.0 mL), was added a solution of tert-butyl N-chlorosulfonylcarbamate (377 mg, 1.75 mmol) in dichloromethane dropwise at 0 °C under nitrogen. The reaction solution was stirred at 0~5 °C for 0.5 hrs. On completion, water (10 mL) was added to the reaction and the aqueous was extracted with dichloromethane (3 x 20 mL). The combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol = 100:1 to 20:1) to give the title compound. LCMS (ES⁺): 589.1 m/z (M+H)⁺, tR= 0.853 min. Step 5– (±)-N-[3-(2-acetamidoethyl)-1-sulfamoyl-3-piperidyl]-4,5-dichloro-1-methyl-indole-2- carboxamide [00389] To a solution of (±)-tert-butyl N-[[3-(2-acetamidoethyl)-3-[(4,5-dichloro-1-methyl- indole-2-carbonyl)-amino]-1-piperidyl]-sulfonyl]-carbamate (70.0 mg, 62.8 µmol) in dichloromethane (1.50 mL) was added trifluoroacetic acid (459 mg, 4.03 mmol) at 15 °C under nitrogen. The reaction solution was stirred at 15 °C for 3 hrs. On completion, the reaction was concentrated in vacuo. The residue was purified by prep-HPLC (condition: 0.1% TFA-ACN; Phenomenex Synergi C18 100*21.2mm*4µm) to give the title compound. LCMS (ES⁺): 512.0 m/z (M+Na)⁺, tR= 0.788 min.¹H NMR (400 MHz, MeOD-d₄) δ = 7.67 (s, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 9.2 Hz, 1H), 7.09 (s, 1H), 3.96 (s, 3H), 3.84 (d, J = 12.0 Hz, 1H), 3.31-3.30 (m, 2H), 3.01 (d, J = 12.0 Hz, 2H), 2.20-2.18 (m, 3H), 1.89 (s, 3H), 1.75-1.60 (m, 3 H). Step 6 – (±)-N-(3-(2-acetamidoethyl)-1-(N-(methylcarbamoyl)sulfamoyl)piperidin-3-yl)-4,5- dichloro -1-methyl-1H-indole-2-carboxamide [00390] To a solution of (±)-N-[3-(2-acetamidoethyl)-1-sulfamoyl-3-piperidyl]-4,5-dichloro- 1-methyl -indole-2-carboxamide (80.0 mg, 163 µmol) and methylimino(oxo)methane (9.31 mg, 163 µmol) in N,N-dimethylformamide (3.00 mL) was added copper (I) chloride (3.23 mg, 32.6 µmol) at 15 °C under nitrogen. The mixture was stirred at 40 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-HPLC (condition: 0.1% TFA-ACN; Phenomenex Synergi C18 100*21.2mm*4µm) to give the title compound. LCMS (ES⁺): 547.1 m/z (M+H)⁺, tR= 0.803 min. ¹H NMR (400 MHz, DMSO-d6) δ = 8.11-7.97 (m, 2H), 7.60 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1 H), 7.18-7.13 (m, 1H), 6.74 (s, 1H), 6.24 (d, J = 4.39 Hz, 1 H), 3.94 (s, 3H), 3.81 (d, J = 12.30 Hz, 1 H), 3.27 (d, J = 12.1 Hz, 2H), 3.19- 2.97(m, 4H), 2.28-2.14 (m, 1H), 2.01 (br. s., 1H), 1.90-1.79 (m, 1H), 1.74 (s, 4H), 1.61 (d, J = 6.5 Hz, 2H). Example 22 - (±)-N-(3-(2-acetamidoethyl)-1-(N-(isopropylcarbamoyl)sulfamoyl) piperidin- 3-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

[00391] To a solution of (±)-N-[3-(2-acetamidoethyl)-1-sulfamoyl-3-piperidyl]-4,5-dichloro- 1-methyl-indole-2-carboxamide (70.0 mg, 143 µmol, synthesized via Method 3 as seen above in Example 21) and cesium carbonate (140 mg, 428 µmol) in N-methyl-pyrrolidone (NMP) (3.00 mL) was added 2-isocyanatopropane (24.3 mg, 285 µmol) at 15 °C. Then the reaction solution was heated to 80 °C and stirred for 4 hrs. On completion, the residue was concentrated in vacuo. The residue was purified by prep-HPLC (condition: 0.1% TFA-ACN; Phenomenex Synergi C18 100*21.2mm*4µm) to give the title compound. LCMS (ES⁺): 575.2 m/z (M+H)⁺, tR= 1.049 min. ¹H NMR (400 MHz, DMSO-d6) δ = 9.79 (s, 1 H), 7.90 (s, 1H), 7.86-7.80 (m, 1 H), 7.60 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 6.15 (d, J = 6.9 Hz, 1H), 3.97-3.91 (m, 3H), 3.79 (d, J = 12.0 Hz, 1H), 3.61 (dd, J = 13.6, 6.8Hz, 1H), 3.18-2.98 (m, 4 H), 2.24-2.13(m, 1 H), 2.05 (d, J = 13.8 Hz, 1H), 1.93-1.80 (m, 1H), 1.74 (s, 4H), 1.62 (d, J = 8.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 1H), 0.99 (dd, J = 6.6, 3.8 Hz, 6H). Example 23 - (±)-N-[[1-(4,5-dichloro-1-methyl-indole-2-carbonyl)pyrrolidin-3- yl]sulfamoyl]-acetamide

Step 1 - (±)-4,5-Dichloro-1-methyl-N-(1-sulfamoylpyrrolidin-3-yl)indole-2-carboxamide [00392] Tert-butyl N-[3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]pyrrolidin-1- yl]sulfonyl-carbamate (256 mg, 520 µmol, synthesized via Method 3, Steps 1-2 with acid A and tert-butyl 3-aminopyrrolidine-1-carboxylate (CAS# 186550-13-0) as starting materials) was dissolved in 4 M hydrogen chloride methanol solution (10 mL). The mixture was stirred at 15 °C for 30 mins. On completion, the reaction mixture was concentrated in vacuo to give the title compound as a hydrochloride. The crude product was used directly in the next step without further purification. Step 2 - (±)-N-[[1-(4,5-dichloro-1-methyl-indole-2-carbonyl)pyrrolidin-3- yl]sulfamoyl]acetamide [00393] To a solution of 4,5-dichloro-1-methyl-N-(1-sulfamoylpyrrolidin-3-yl)indole-2- carboxamide (210 mg, 536 µmol) in anhydrous dichloromethane (10 mL) was added triethylamine (135 mg, 1.34 mmol) and acetyl chloride (50.5 mg, 644 µmol). The mixture was stirred at 15 °C for 10 mins. On completion, the reaction mixture was washed with brine (10 mL) and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by prep-HPLC (Condition: 0.1% TFA-ACN; Column: YMC-Actus ODS-AQ 100*30 mm; Particle size: 5 µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 433.0, tR = 0.827. ¹H NMR (400 MHz, DMSO-d6) δ = 11.47 (s, 1H), 8.73 (d, J = 6.4 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.25 (s, 1H), 4.47-4.43 (m, 1H), 4.01 (s, 3H),, 3.69 (dd, J = 6.5, 9.9 Hz, 1H), 3.64 - 3.56 (m, 1H), 3.50 - 3.42 (m, 1H), 3.36 (d, J = 5.3 Hz, 1H), 2.20 - 2.10 (m, 1H), 2.06 - 1.98 (m, 1H), 1.96 (s, 3H).

Example 24 - N-[1-(acetylsulfamoyl)azetidin-3-yl]-4,5-dichloro-1-methyl-indole-2- carboxamide

Step 1 - 4,5-Dichloro-1-methyl-N-(1-sulfamoylazetidin-3-yl)indole-2-carboxamide [00394] To a solution of tert-butyl N-[3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]azetidin-1-yl]sulfonylcarbamate (135 mg, 283 µmol, synthesized via Method 3, Steps 1-2 with acid Intermediate A and tert-butyl 3-aminoazetidine-1-carboxylate) in dichloromethane (10 mL) was added 4 M of hydrogen chloride methanol solution (707 µL) in one portion. The mixture was stirred at 15 °C for 1 hour. On completion, the mixture was concentrated in vacuo, and to the residue was added water (20 mL), which was then extracted with dichloromethane (3 × 30 mL). The combined organic phase was washed with brine (3 × 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 398.0. Step 2 - N-[1-(acetylsulfamoyl)azetidin-3-yl]-4,5-dichloro-1-methyl-indole-2-carboxamide [00395] To a solution of 4,5-dichloro-1-methyl-N-(1-sulfamoylazetidin-3-yl)indole-2- carboxamide (100 mg, 265 µmol) in dichloromethane (10 mL) was added triethylamine (134 mg, 1.33 mmol) and acetyl chloride (25 mg, 318 µmol). The reaction was stirred at 0 °C for 3 hrs. On completion, the reaction mixture was concentrated in vacuo, and the residue was purified by prep-HPLC (water (0.05% ammonium hydroxide v/v)-ACN, Phenomenex Gemini 150*25mm; Particle size: 10 µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 419, tR = 1.019. ¹H NMR (400MHz, CDCl3) δ = 7.65 (d, J = 8.9 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.02 (s, 1H), 4.54 - 4.46 (m, 1H), 4.44 - 4.38 (m, 1H), 4.27 - 4.20 (m, 1H), 4.12 (s, 3H), 3.17 - 2.96 (m, 2H), 1.87 (s, 3H). Example 25 - (±)-3-[[4-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]- 1-piperidyl]- sulfonylcarbamoyl amino]butanoic acid

[00396] To a solution of tert-butyl-N-[[4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]- 1-piperidyl]sulfonyl]carbamate (100 mg, 198 µmol, synthesized via Method 3, Steps 1-3 with acid A and tert-butyl 4-aminopiperidine-1-carboxylate, CAS# 87120-72-7, as starting materials) and triethylamine (100 mg, 989 µmol) in a mixture of DMA (1.00 mL) and toluene (5 mL) was added (±)-3-aminobutanoic acid (31 mg, 297 µmol) in one portion at 30 °C. The reaction mixture was stirred at 120 °C for 12 hrs. On completion, the reaction was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% trifluoroacetic acid-ACN, Welch Ultimate AQ- C18 150*30mm*5µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 534, tR= 1.173. ¹H NMR (400MHz, DMSO-d₆) δ = 8.61 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.21 (s, 1H), 6.44 (d, J = 8.2 Hz, 1H), 4.01 (s, 3H), 3.97 (d, J=7.3 Hz, 2H), 3.64 (d, J=10.7 Hz, 2H), 2.95 (t, J=12.2 Hz, 2H), 2.45 - 2.29 (m, 2H), 1.92 (d, J = 10.7 Hz, 2H), 1.70 - 1.53 (m, 2H), 1.14 (d, J = 6.7 Hz, 3H). Example 26 - 3-[[4-[(4,5-Dichloro-1-methyl-indole-2-carbonyl)amino]-1-piperidyl]- sulfonylcarbamoyl amino]propanoic acid

[00397] To a solution of tert-butyl-N-[[4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]- 1-piperidyl]sulfonyl]carbamate (100 mg, 198 µmol, synthesized via Method 3, Steps 1-3 with acid A and tert-butyl 4-aminopiperidine-1-carboxylate, CAS# 87120-72-7, as starting materials) and triethylamine (100 mg, 989 µmol) in a mixture of N,N-dimethyl acetamide (1 mL) and toluene (5 mL) was added 3-aminopropanoic acid (26 mg, 297 µmol) in one portion at 30 °C. The reaction mixture was stirred at 120 °C for 12 hrs. On completion, the reaction was concentrated in vacuo. The residue was purified by prep-HPLC (0.1% trifluoroacetic acid-ACN, Welch Ultimate AQ-C18 150*30mm*5µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 520, tR= 1.165.¹H NMR (400MHz, DMSO-d6) δ = 8.61 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.21 (s, 1H), 6.50 (t, J = 5.6 Hz, 1H), 4.01 (s, 3H), 3.90 (d, J = 6.5 Hz, 1H), 3.64 (d, J = 12.2 Hz, 2H), 3.27 (d, J = 6.1 Hz, 3H), 2.95 (t, J = 11.3 Hz, 2H), 2.43 - 2.40 (m, 1H), 1.91 (d, J = 9.2 Hz, 2H), 1.70 - 1.51 (m, 2H). Example 27 (Method 4) - (±)-N-(6-carbamoyl-6-azaspiro[3.4]octan-3-yl)-4,5-dichloro-1- methyl-indole-2-carboxamide

Step 1 - (±)-Tert-butyl 3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)-amino]-6-azaspiro-[3.4]- octane-6-carboxylate [00398] To a mixture of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (140 mg, 574 µmol) in dichloromethane (20.0 mL) and N,N-dimethyl formamide (839 µg, 11.5 µmol) was added oxalyl chloride (328 mg, 2.58 mmol) dropwise at 0 °C under nitrogen. The reaction mixture was stirred at 15 °C for 2 hours. The reaction solution was concentrated in vacuo to give 4,5- dichloro-1-methyl-indole-2-carbonyl chloride (155 mg, crude) as a yellow solid. [00399] To a solution of tert-butyl 3-amino-6-azaspiro[3.4]-octane-6-carboxylate (CAS# 1251010-30-6, 100 mg, 443 µmol) and triethylamine (134 mg, 1.33 mmol) in dichloromethane (10.0 mL) was added a solution of 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (150 mg, 572 µmol) in dichloromethane (5 mL) dropwise at 0 °C over a period of 30 min under nitrogen. The reaction solution was stirred at 15 °C for 15.5 hrs. On completion, the reaction was concentrated in vacuo to give the title compound. LCMS (ES⁺) m/z (M-56)⁺ = 396.0. Step 2 - (±)-N-(6-azaspiro-[3.4]-octan-3-yl)-4,5-dichloro-1-methyl-indole-2-carboxamide [00400] To a mixture of tert-butyl-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)-amino]-6- azaspiro-[3.4]-octane-6-carboxylate (200 mg, 442 µmol) in dichloromethane (1.50 mL) was added trifluoroacetic acid (459 mg, 4.03 mmol) in one portion at 15 °C under nitrogen. The mixture was stirred at 15 °C for 0.5 hour. On completion, the reaction was concentration in vacuo. The residue was purified by prep-HPLC (condition: 0.1% TFA-ACN; Phenomenex Synergi C18 100*21.2mm*4µm) to give the title compound. LCMS (ES⁺) m/z (M+H)⁺ = 352.0, tR = 0.631 min.¹H NMR (400 MHz, DMSO-d6) δ = 8.96 (d, J = 6.8 Hz, 1H), 8.91 - 8.61 (m, 2H), 7.63 (d, J = 7.2 Hz, 1H), 7.47 (dd, J1 = 2.0 Hz, J2 = 8.8 Hz, 1H), 7.29 (d, J = 5.6 Hz, 1H), 4.46 - 4.40 (m, 1H), 3.99 (s, 3H), 3.35 - 3.13 (m, 4H), 2.17-1.77 (m, 6H). Step 3 - (±)-N-(6-carbamoyl-6-azaspiro[3.4]octan-3-yl)-4,5-dichloro-1-methyl-indole-2- carboxamide [00401] To a mixture of N-(6-azaspiro-[3.4]-octan-3-yl)-4,5-dichloro-1-methyl-indole-2- carboxamide (50.0 mg, 142) and triethylamine (43.1 mg, 426 µmol) in dichloromethane (2.0 mL) was added isocyanato(trimethyl)silane (TMSNCO) (19.6 mg, 170 µmol) dropwise at 15 °C under N2. The mixture was stirred at 15 °C for 2 hours. On completion, the reaction was washed with water (5.0 mL), extracted with dichloromethane (2 x 10 mL), and concentrated in vacuo. The residue was purified by prep-HPLC (condition: 0.05% ammonia-ACN; column: Phenomenex Gemini C18 250*50*10µm) to give the title compound. LCMS (ES⁺) m/z (M+H)⁺ = 395.0, tR = 1.338 min.¹H NMR (400 MHz, DMSO-d₆) δ = 8.80 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 4.4 Hz, 1H),7.24 (s, 1H), 5.61 (s, 2H), 4.46 - 4.40 (m, 1H), 3.97 (s, 3H), 3.17 - 3.15 (m, 3H), 2.32 - 2.08 (m, 4H), 1.72-1.70 (m, 3H). Example 28 - (±)-N-(2-carbamoyl-2-azaspiro[3.3]heptan-7-yl)-4,5-dichloro-1-methyl-indole- 2-carboxamide

[00402] N-(2-carbamoyl-2-azaspiro[3.3]heptan-7-yl)-4,5-dichloro-1-methyl-indole-2- carboxamide was synthesized via Method 4 with acid Intermediate A and (±)-tert-butyl 7-amino- 2-azaspiro[3.3]heptane-2-carboxylate (CAS# 1330765-13-3) as starting materials. In Step 3, the reaction was run for 16 hrs at 15 °C (not 2 hrs). LCMS: (ES+) m/z (M+H)+ = 381.0, tR= 0.668. ¹H NMR (400MHz, DMSO-d6) δ = 9.00 - 8.79 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.31 (s, 1H), 5.75 (s, 2H), 4.42 (q, J = 8.2 Hz, 1H), 4.05 - 3.96 (m, 4H), 3.90 (d, J = 8.3 Hz, 1H), 3.65 (d, J = 8.3 Hz, 1H), 3.62 - 3.57 (m, 1H), 2.07 - 1.90 (m, 4H). Example 29 - (±)-4,5-Dichloro-1-methyl-N-[2-(methylcarbamoyl)-2-azaspiro[3.3]heptan-7- yl]indole-2- carboxamide

[00403] To a solution of (±)-N-(2-azaspiro[3.3]heptan-7-yl)-4,5-dichloro-1-methyl-indole-2- carboxamide (130 mg, 287 µmol, synthesized via Steps 1-2 of Method 4 with acid A and (±)- tert-butyl (7-amino-2-azaspiro[3.3]heptane-2-carboxylate) (CAS# 1330765-13-3) and N- methylcarbamoyl chloride (26.9 mg, 207 µmol) in N,N-dimethylformamide (5 mL) was added triethylamine (365 mg, 3.61 mmol) at 15 °C. Then the reaction mixture was stirred at 15 °C for 16 hrs. On completion, the reaction mixture was concentrated in vacuo, and the residue was purified by prep-HPLC (Column: Welch Ultimate AQ-C18 150*30mm*5µm; Condition: 0.1% TFA-ACN) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 395.1, tR= 0.694.¹H NMR (400MHz, CD3OD) δ = 8.80 (d, J=6.9 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.41 - 7.37 (m, 1H), 7.22 (s, 1H), 4.58 - 4.46 (m, 1H), 4.18 (d, J=8.7 Hz, 2H), 4.02 (s, 3H), 3.86 - 3.73 (m, 2H), 2.67 (s, 3H), 2.33 - 2.17 (m, 1H), 2.13 - 1.91 (m, 4H) Example 30 - (±)-N-[2-(acetylsulfamoyl)-2-azaspiro[3.3]heptan-7-yl]-4,5-dichloro-1-methyl- indole-2-carboxamide

Step 1 - (±)-Tert-butyl-N-[[7-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-2- azaspiro[3.3]-heptan-2-yl]sulfonyl]carbamate [00404] To a mixture of N-(2-azaspiro[3.3]heptan-7-yl)-4,5-dichloro-1-methyl-indole-2- carboxamide (200 mg, 442 µmol, synthesized via Steps 1-2 of Method 4 with acid A and (±)- tert-butyl (7-amino-2-azaspiro[3.3]heptane-2-carboxylate) (CAS# 1330765-13-3) in dichloromethane (10 mL) was added triethylamine (223 mg, 2.21 mmol). Then tert-butyl N- chlorosulfonylcarbamate (124 mg, 574 µmol) was added to the mixture. The reaction mixture was stirred at 15 °C for 12 hours. On completion, water (10 mL) was added to the mixture. The reaction mixture was extracted with dichloromethane (3 x 10 mL). The organic layer was dried over anhydrous sodium sulfate and filtrated to give the title compound. The crude product was used to the next step directly without further purification. LCMS: (ES⁺) m/z (M+H)⁺ = 517.1, tR = 0.917. Step 2 - (±)-4,5-Dichloro-1-methyl-N-(2-sulfamoyl-2-azaspiro[3.3]heptan-5-yl)-1H-indole-2- carboxamide [00405] To a mixture of tert-butyl N-[[7-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino] - 2-azaspiro[3.3]heptan-2-yl]sulfonyl]carbamate (150 mg, 289 µmol) in dichloromethane (10 mL) was added trifluoroacetic acid (2 mL). Then the mixture was stirred at 15 °C for 1 hour. On completion, the mixture was concentrated in vacuo to give the title compound (150 mg, 86% purity, 90% yield) which was used to the next step directly without further purification. LCMS: (ES⁺) m/z (M+H)⁺ = 417.1, tR = 0.904. Step 3 - (±)-N-[2-(acetylsulfamoyl)-2-azaspiro[3.3]heptan-7-yl]-4,5-dichloro-1-methyl-indole-2- carboxamide [00406] To a mixture of 4,5-dichloro-1-methyl-N-(2-sulfamoyl-2-azaspiro[3.3]heptan-7-yl) indole-2-carboxamide (120 mg, 287 µmol) in dichloromethane (4 mL) was added triethylamine (87.3 mg, 862 µmol). Then acetyl chloride (33.8 mg, 431 µmol) was added to the mixture dropwise at 0 °C. The mixture was stirred at 15 °C for 0.5 hour. LCMS showed the 2-acetyl addition by-product had formed. The reaction mixture was concentrated and to the residue was added 2 M sodium hydroxide (2 mL) and methanol (5 mL). The mixture was then stirred at 15 °C for 10 hours. On completion, the mixture was concentrated in vacuo. The residue was purified by prep-TLC (petroleum ether:ethyl acetate = 1:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 459.1, tR = 0.870. ¹H NMR (400MHz, CD₃OD) δ = 7.51 - 7.45 (m, 1H), 7.42 - 7.38 (m, 1H), 7.28 (s, 1H), 4.56 - 4.49 (m, 1H), 4.45 (d, J = 8.3 Hz, 1H), 4.33 - 4.25 (m, 1H), 4.06 (s, 3H), 3.91 (t, J = 8.0 Hz, 2H), 2.26 - 2.16 (m, 1H), 2.13 - 1.99 (m, 3H), 1.87 (s, 3H). Example 31 (Method 5) - (±)-3-(4,5-Dichloro-1-methyl-1H-indole-2- carboxamido)cyclohexanecarboxylic acid

Step 1 - (±)-Methyl 3-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)cyclohexanecarboxylate [00407] To a solution of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (700 mg, 2.87 mmol) in anhydrous dichloromethane (10 mL) was added anhydrous N,N-dimethylformamide (20 µL) and oxalyl chloride (1.45 g, 11.4 mmol) dropwise at 0 °C. The reaction mixture was warmed to 15 °C and stirred for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound (700 mg, crude) as a white solid. The crude product was used in the next step directly. [00408] To a solution of methyl 3-aminocyclohexanecarboxylate (652 mg, 3.36 mmol, HCl salt) and triethylamine (1.62 g, 16.0 mmol) in anhydrous dichloromethane (15.0 mL) was added 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (700 mg, crude) at 0 °C. The reaction mixture was warm to 15 °C and stirred for 1 hr. On completion, the mixture was concentrated in vacuo and the residue was triturated with petroleum ether (15 mL), water (3 mL) and methanol (1 mL) to give the title compound. LCMS: (ES+) m/z (M+H)+ = 383.1, tR = 0.929.¹H NMR (400 MHz, DMSO-d₆) δ = 8.56 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 4.00 (s, 3H), 3.87– 3.79 (m, 1H), 3.60 (s, 3H), 2.48– 2.45 (m, 1H), 2.06– 1.78 (m, 4H), 1.43– 1.23 (m, 4H). Step 2 - (±)-3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)cyclohexanecarboxylic acid [00409] To methyl 3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]cyclohexanecarboxylate (900 mg, 2.35 mmol) in tetrahydrofuran (12.00 mL) and water (4.00 mL) was added lithium hydroxide (300 mg, 7.14 mmol). The mixture was stirred at 60 °C for 2 hrs. On completion, the mixture was acidified to pH = 3 with hydrochloric acid (1 M), during which a fine white precipitate was formed. Then, the filter cake was collected and dried in vacuo to give the title compound. LCMS: (ES+) m/z (M+H)+ = 369.0, tR = 0.969. ¹H NMR (400 MHz, DMSO-d₆) δ = 12.14 (brs, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 4.00 (s, 3H), 3.86– 3.81 (m, 1H), 2.33 (t, J = 12.4 Hz, 1H), 2.07 (d, J = 14.0 Hz, 1H), 1.87– 1.79 (m, 3H), 1.42– 1.23 (m, 4H).

Example 32 - (±)-2-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)cyclohexyl)acetic acid

Step 1 - (±)-3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)cyclohexanecarbonyl chloride [00410] To a solution of 3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]cyclohexanecarboxylic acid (400 mg, 1.08 mmol, Example 31) in anhydrous dichloromethane (10 mL) was added anhydrous N,N-dimethylformamide (20 µL) and oxalyl chloride (435 mg, 3.42 mmol) dropwise at 0 °C. The reaction mixture was warm to 15 °C and stirred for 1 hr. On completion, the mixture was concentrated in vacuo to give the title compound. The crude product was used in the next step directly. Step 2 - (±)-4,5-Dichloro-N-(3-(2-diazoacetyl)cyclohexyl)-1-methyl-1H-indole-2-carboxamide [00411] A solution containing potassium hydroxide (1.12 g, 19.9 mmol) in water (3 mL) and 2-(2-ethoxyethoxy) ethanol (6.54 g, 48.7 mmol) were placed in a distillation flask. A solution containing N, 4-dimethyl-N-nitroso-benzenesulfonamide (4.00 g, 18.7 mmol) in ether (30 mL) was placed in the addition funnel, meanwhile the receiving flask was cooled to 0 °C. Heating the distillation flask to 70 °C, the solution placed in the addition funnel was added dropwise over 30 mins. Diazomethane in ether was distilled from the reaction mixture and used directly in the next step. To 3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]cyclohexanecarbonyl chloride (400 mg, 1.03 mmol) in anhydrous dichloromethane (10 mL) was added diazomethane (433 mg, 10.3 mmol) in anhydrous ether (30 mL) at 0 °C. The mixture was stirred at 15 °C for 16 hrs. On completion, diluted acetic acid was added to quench the reaction, followed by basification with saturated sodium bicarbonate (30 mL) to pH = 8. The mixture was then extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate = 5:1 to 3:1) to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 415.0, tR = 0.897. Step 3 - 2-(3-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)cyclohexyl)acetic acid [00412] To 4,5-dichloro-N-[3-(2-diazoacetyl)cyclohexyl]-1-methyl-indole-2-carboxamide (70.0 mg, 148 µmol) in tetrahydrofuran (4 mL) and water (400 uL) was added triethylamine (44.9 mg, 443 µmol) and (2,2,2-trifluoroacetyl)oxysilver (3.26 mg, 14.8 µmol). The mixture was stirred at 15 °C for 4 hrs. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by prep-HPLC (Instrument: GX-I; Column: Xtimate C18 150*25mm; Particle size: 5 µm; Mobile phase: 0.1% trifluoroacetic acid- acetonitrile) to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 383.0, tR = 0.897. ¹H NMR (400 MHz, DMSO-d₆) δ = 12.08 (brs, 1H), 8.52 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 9.2 Hz, 1H), 7.44 (d, J = 4.0 Hz, 1H), 7.20 (s, 1H), 4.00 (s, 3H), 3.99– 3.33 (m, 1H), 2.22– 2.10 (m, 2H), 1.92– 1.69 (m, 5H), 1.33 - 0.82 (m, 4H). Example 33 - (±)-2-((1R,4R)-4-(4-chloro-1,5-dimethyl-1H-indole-2- carboxamido)cyclohexyl)-acetic acid

[00413] 2-((1R,4R)-4-(4-chloro-1,5-dimethyl-1H-indole-2-carboxamido)cyclohexyl)-acetic acid was synthesized via Method 5 with acid C and 2-(trans-4-aminocyclohexyl)acetic acid (CAS# 2952-00-3). LCMS: (ES⁺) m/z (M+H)⁺ = 363.1, tR= 0.866. ¹H NMR (400MHz, DMSO- d6) δ = 12.06 (br. s., 1H), 8.41 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.12 (s, 1H), 3.97 (s, 3H), 3.78 - 3.67 (m, 1H), 2.42 (s, 3H), 2.14 (d, J = 7.0 Hz, 2H), 1.86 (d, J = 10.5 Hz, 2H), 1.81 - 1.73 (m, 3H), 1.62 (dd, J = 3.6, 10.9 Hz, 1H), 1.45 - 1.30 (m, 2H), 1.15 - 1.02 (m, 2H). Example 34 - 4,5-Dichloro-1-methyl-N-[4-(methylsulfonylcarbamoyl)cyclohexyl]indole-2- carboxamide

[00414] A mixture of 4-[(4,5-dichloro-1-methyl-indole-2-carbonyl) amino]cyclohexanecarboxylic acid (150 mg, 406 µmol, synthesized via Method 5 with acid A and 4-aminocyclohexane-1-carboxylic acid), methanesulfonamide (38.6 mg, 406 µmol), EDCI (233 mg, 1.22 mmol), N,N-dimethylpyridin-4-amine (198 mg, 1.62 mmol) in N,N- dimethylformamide (10 mL) was degassed and purged with nitrogen gas 3 times. The mixture was stirred at 15 °C for 16 hrs under nitrogen gas atmosphere. On completion, the reaction mixture was concentrated in vacuo and the residue was purified by prep-HPLC (Condition: 0.1% TFA-ACN; Column: Welch Ultimate AQ-C₁₈ 150*30 mm; Particle size: 5 µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 446.1, tR= 0.843. ¹H NMR (400 MHz, DMSO-d6) δ = 11.64 (br. s., 1H), 8.51 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.20 (s, 1H), 4.00 (s, 3H), 3.76 (d, J = 7.7 Hz, 1H), 3.24 (s, 3H), 2.27 (t, J = 11.5 Hz, 1H), 1.91 (t, J = 12.4 Hz, 4H), 1.51 - 1.30 (m, 4H). Example 35 - (±)-N-[1-(2-amino-2-oxo-ethyl)cyclopentyl]-4,5-dichloro-1-methyl-indole-2- carboxamide

[00415] To a solution of 2-[1-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]cyclopentyl]acetic acid (90.0 mg, 243 µmol, synthesized via Method 5 with acid A and amine S) in N,N-dimethylformamide (3.00 mL) was added (1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate) (HATU) (185 mg, 487 µmol), triethylamine (74.0 mg, 731 µmol) and ammonium chloride (13.0 mg, 243 µmol) at 15 °C. The solution was stirred at 15 °C for 12 hrs. On completion, 10 mL water was added to the reaction, and the suspension was extracted with ethyl acetate (3 × 20 mL). The organic phase was collected, washed with 1 M hydrochloric acid (10 mL), dried over anhydrous sodium sulfate, concentrated in vacuo to get a residue which was purified by prep-HPLC (0.1% TFA-ACN, Welch Ultimate AQ-C18 150*30mm; Particle size: 5 µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 368, tR = 1.021. ¹H NMR (400MHz, DMSO-d₆) δ = 8.32 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.29 (br. s., 1H), 7.10 (s, 1H), 6.86 (br. s., 1H), 3.97 (s, 3H), 2.66 (s, 2H), 2.37 - 2.22 (m, 2H), 1.78 - 1.55 (m, 6H). Example 36 - (±)-N-[3-(2-amino-2-oxo-ethyl)tetrahydrofuran-3-yl]-4,5-dichloro-1-methyl- indole-2-carboxamide

[00416] To a solution of 2-[3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]tetrahydrofuran-3-yl]acetic acid (80.0 mg, 215.51 µmol, synthesized via Method 5 with acid A and amine T) and triethylamine (43.62 mg, 431.02 µmol) in dimethyl formamide (5.00 mL) was added ammonium chloride (57.64 mg, 1.08 mmol) and HATU (163.89 mg, 431.02 µmol). The reaction mixture was stirred at 50-60 °C for 3 hrs. On completion, to the mixture was added dichloromethane (10 mL) and was then adjusted to pH to 6-7 with 1 M hydrochloric acid. Then ammonium hydroxide was added to adjust the pH to 8-9. The organic phase was washed with water (2 x 10 mL) and concentrated to get the crude product. The crude was dissolved with methanol (4 mL) and purified by prep-HPLC (Condition: water (0.05% ammonium hydroxide v/v)-ACN Column: Phenomenex Gemini 150*25mm*10µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 370.1, tR = 1.21.¹H NMR (400 MHz, DMSO-d6) δ = 8.60 (s, 1 H), 7.60 (d, J = 8.78 Hz, 1 H), 7.44 (d, J = 8.78 Hz, 1 H), 7.33 (br. s., 1H), 7.20 (s, 1H), 6.86 (br. s., 1H), 4.13 (d, J = 9.16 Hz, 1H), 3.97 (s, 3H), 3.71 - 3.85 (m, 3H), 2.84 - 2.71 (m, 2H), 2.58 - 2.52 (m, 1H).2.10 (dt, J = 13.02, 7.92 Hz, 1H). Example 37 - N-(1-(2-Amino-2-oxoethyl)cyclobutyl)-4,5-dichloro-1-methyl-1H-indole-2- carboxamide

[00417] To a solution of 2-[1-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]cyclobutyl]acetic acid (120 mg, 338 µmol, synthesized via Method 5 with acid A and amine U) in N,N-dimethylformamide (4 mL) was added triethylamine (103 mg, 1.01 mmol) and HATU (257 mg, 676 µmol). After stirring for 30 mins, ammonium chloride (36.1 mg, 676 µmol) was added. Then the mixture was stirred at 15 °C for 15.5 hours. On completion, water (15 mL) was added and the solution was extracted with ethyl acetate (2 × 20 mL). The combined organic phase was washed with brine (2 × 20 mL), dried with anhydrous sodium sulfate, filtered and concentrated in vacuo to get a residue. The residue was purified by prep- HPLC [Instrument: GX-I; Column: Xtimate C18 150*25mm*5µm; Mobile phase: 0.1% trifluoroacetic acid-acetonitrile] and lyophilized to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 354.1, tR = 0.806. ¹H NMR (400 MHz, DMSO-d6) δ = 8.70 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.31 (brs, 1H), 7.20 (s, 1H), 6.85 (brs, 1H), 3.99 (s, 3H), 2.73 (s, 2H), 2.46 - 2.37 (m, 2H), 2.28 - 2.18 (m, 2H), 1.90 - 1.77 (m, 2H). Example 38 - N-(4-(2-amino-2-oxoethyl)-1-(N-(pyrazin-2-yl)sulfamoyl)piperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide

Step 1 - tert-butyl 4-(2-amino-2-oxoethyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)- piperidine-1-carboxylate [00418] To a solution of 2-[1-tert-butoxycarbonyl-4-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]-4-piperidyl]acetic acid (400 mg, 826 µmol, synthesized via Method 5 with acid A and amine AF) in N,N-dimethylformamide (4.00 mL) was added triethylamine (251 mg, 2.48 mmol) and HATU (628 mg, 1.65 mmol). After stirring for 30 mins, ammonium chloride (88.4 mg, 1.65 mmol) was added. Then the mixture was stirred at 15 °C for 16 hours. On completion, to the mixture was added water (15 mL), then the solution was extracted with ethyl acetate (20 mL × 2). The combined organic phase was washed with brine (20 mL × 2), dried with anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1:1, 0/1) to give the title compound. LCMS: (ES+) m/z (M+23)⁺ = 505.1, tR = 0.879. ¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.91 (s, 1H), 6.52 (s, 1H), 5.84 - 5.56 (m, 2H), 3.96 (s, 3H), 3.80 (brs, 2H), 3.21 (t, J = 11.5 Hz, 2H), 2.84 (s, 2H), 2.48 (d, J = 13.8 Hz, 2H), 1.83 - 1.67 (m, 2H), 1.47 (s, 9H). Step 2 - N-(4-(2-amino-2-oxoethyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2- carboxamide [00419] To a solution of tert-butyl 4-(2-amino-2-oxo-ethyl)-4-[(4,5-dichloro-1-methyl-indole- 2- carbonyl)amino]piperidine-1-carboxylate (300 mg, 620 µmol) was added hydrochloric acid / methanol (4 M, 10.0 mL). The mixture was stirred at 15℃ for 16 hours. On completion, the mixture was concentrated to give the title compound (0.26 g, 97% purity, 96% yield) as white solid. LCMS: (ES+) m/z (M+H)+ = 383.1, tR = 0.668. Step 3 - N-(4-(2-amino-2-oxoethyl)-1-(N-(pyrazin-2-yl)sulfamoyl)piperidin-4-yl)-4,5-dichloro- 1-methyl-1H-indole-2-carboxamide [00420] To a solution of N-[4-(2-amino-2-oxo-ethyl)-4-piperidyl]-4,5-dichloro-1-methyl - indole-2-carboxamide (30.0 mg, 71.4 µmol, hydrochloride salt) and 2-oxo-N-pyrazin-2-yl- oxazolidine-3-sulfonamide (34.9 mg, 143 µmol) in acetonitrile (2.00 mL) was added triethylamine (72.3 mg, 715 µmol). The sealed tube was heated at 130 °C for 3 hours under microwave. On completion, the mixture was filtered and the filtrate was concentrated. The residue was purified by prep-HPLC (Instrument: GX-I; Column: Xtimate C18150*25mm*5µm; Mobile phase: 0.1% trifluoroacetic acid– acetonitrile) and lyophilized to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 540.1, tR = 0.766. ¹H NMR (400 MHz, DMSO-d6) δ = 10.94 (brs, 1H), 8.37 (s, 1H), 8.25 (d, J = 14.3 Hz, 2H), 8.12 (s, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 7.27 (br. s., 1H), 6.97 (s, 1H), 6.85 (s, 1H), 3.90 (s, 3H), 3.14 (t, J = 11.5 Hz, 2H), 2.59 (brs, 6H), 1.62 (t, J = 10.9 Hz, 2H). Examples 39-45 (Method 6) (±)-2-(1-(N-Acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin- 3-yl) acetic acid (Example 39)

Step 1– (±)-Tert-butyl 3-(2-(tert-butoxy)-2-oxoethyl)-4-(4,5-dichloro-1-methyl-1H-indole-2- carboxamido)piperidine-1-carboxylate [00421] To a mixture of 4,5-dichloro-1-methyl-indole-2-carboxylic acid (1.78 g, 7.29 mmol) in dichloromethane (6.00 mL) was added DMF (53.3 mg, 729 µmol), followed by oxalyl dichloride (1.85 g, 14.6 mmol) in one portion at 15 °C. The mixture was heated to 40 °C and stirred for 30 min. On completion, the mixture was concentrated in vacuo to give a crude which was not purified further (1.9 g, crude). To a mixture of (±)-tert-butyl 4-amino-3-(2-tert-butoxy- 2-oxo-ethyl)piperidine-1-carboxylate (400 mg, 1.27 mmol) and triethylamine (386 mg, 3.81 mmol) in dichloromethane (5.00 mL) was added 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (333 mg, 1.27 mmol) in three portions at 20 °C. The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was concentrated in vacuo to give a crude which was purified by column chromatography (petroleum ether:ethyl acetate = 5:1 to 1:1) to give the title compound. ¹H NMR (400 MHz, DMSO-d₆) δ = 8.55 - 8.47 (br. s., 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 11.2 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 4.21 - 3.94 (m, 4H), 3.81 - 3.72 (m, 2H), 3.22- 3.18 (m, 1H), 2.45 - 1.33 (m, 23H). Step 2 – (±)-Methyl 2-(4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-3- yl)acetate hydrochloride [00422] To a mixture of (±)-tert-butyl 3-(2-tert-butoxy-2-oxo-ethyl)-4-[(4,5-dichloro-1- methyl-indole-2-carbonyl)amino]piperidine-1-carboxylate (300 mg, 555 µmol) in methanol (2.00 mL) was added hydrochloride/methanol (4 M, 5.00 mL) in one portion at 20 °C. The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was concentrated in vacuo directly to give a crude product. LCMS (ESI⁺) m/z 398 (M+1), tR= 0.852. Step 3 - (±)-Methyl 2-(1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2- carboxamido)piperidin-3-yl)acetate [00423] To a mixture of (±)-methyl 2-[4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3- piperidyl]acetate hydrochloride (241 mg, 554 µmol) and triethylamine (280 mg, 2.77 mmol) in dry dichloromethane (5.00 mL) was added N-acetylsulfamoyl chloride (87.4 mg, 554 µmol) in three portions at 20 °C. The mixture was stirred at 20 °C for 3 hrs. On completion, to the mixture was added citric acid solution (20 mL), and the solution was extracted with dichloromethane (3 x 30 mL). The combined dichloromethane phase was dried over sodium sulfate, and concentrated in vacuo to give a crude product which was purified by column chromatography (dichloromethane:methanol = 50:1 to 20:1) to give the title compound. LCMS (ESI⁺) m/z 519 (M+1), tR = 1.021. Step 4 – (±)-2-(1-(N-Acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido) piperidin-3-yl) acetic acid [00424] To a solution of (±)-methyl 2-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole- 2-carbonyl) amino]-3-piperidyl]acetate (60.0 mg, 116 µmol) in tetrahydrofuran (1.00 mL) was added a solution of lithium hydroxide hydrate (9.7 mg, 231 µmol) in water (1.00 mL) dropwise at 20 °C. The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was extracted with ethyl acetate (3 x 20 mL). To the aqueous phase was added hydrochloric acid (2 M, 1 mL) until the pH was 4-5, whereupon a white solid precipitated out. The mixture was extracted with dichloromethane (3 x 50 mL). The combined dichloromethane phase was dried over sodium sulfate and concentrated in vacuo to give a crude solid, which was purified by prep-HPLC (condition: 0.1%TFA-ACN; column: Welch Ultimate AQ-C18150*30mm*5µm) to give the title compound. LCMS (ESI⁺) m/z 505 (M+1), tR = 0.970. ¹H NMR (400 MHz, DMSO-d₆) δ = 12.22 (br. s., 1H), 11.47 (br. s., 1H), 8.62 - 8.56 (m, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 3.99 (d, J = 8.8 Hz, 3H), 3.77 - 3.68 (m, 3H), 2.95 - 2.68 (m, 3H), 2.46 - 1.68 (m, 7H). Method 6 Table: Compounds Synthesized via Method 6 using the appropriate acids and amines

used instead of HCl/MeOH for the deprotection. The reaction was run at 30 °C for 12 hrs and concentrated directly to form the product. Example 46, 47, 48, and 49 ((3S,4S)-1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1–methyl-1H-indole-2- carboxamido)piperidin-3-yl)acetic acid and ((3R,4R)-(N-acetylsulfamoyl)-4-(4,5-dichloro-1- methyl-1H-indole-2-carboxamido) piperidin-3-yl)acetic acid (Examples 46 and 49); ((3S,4R)-1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2- carboxamido)piperidin-3-yl)acetic acid and ((3R,4S)-1-(N-acetylsulfamoyl)-4-(4,5-dichloro- 1-methyl-1H-indole-2-carboxamido)piperidin-3-yl)acetic acid (Examples 47 and 48)

[00425] 450 mg of (±)-2-(1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H-indole-2- carboxamido) piperidin-3-yl)acetic acid (Example 39) was separated by SFC (condition: Base- MeOH; column: IC (250mm*30mm*10µm); Gradient Time (min): 4.7 minutes, 360 minutes; condition: Base-MeOH; column: AD (250mm*30mm*10µm); Gradient Time (min): 5.5 minutes, 180 min) to give four isomers. [00426] Example 46 (peak 1): ((3S,4S)-1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1–methyl-1H- indole-2-carboxamido)piperidin-3-yl)acetic acid or ((3R,4R)-1-(N-acetylsulfamoyl)-4-(4,5- dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-3-yl)acetic acid was obtained as white solid (100 mg, ee: 85%). LCMS: (ES⁺) m/z (M+H)⁺ = 505.0, tR= 0.966. cSFC analytical tR = 3.155 min. ¹H NMR (400 MHz, DMSO-d₆) δ = 8.67 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 4.06 (s, 3H), 3.83 - 3.65 (m, 3H), 2.86 (t, J = 8.7 Hz, 1H), 2.63 (d, J = 11.2 Hz, 1H), 2.50 (d, J = 13.2 Hz, 1H), 2.14 - 2.07 (m, 2H), 1.95 - 1.90 (m, 4H), 1.71 - 1.68 (m, 1H). [00427] Example 49 (peak 3): ((3R,4R)-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H- indole-2-carboxamido)piperidin-3-yl)acetic acid or ((3S,4S)-1-(N-acetylsulfamoyl)-4-(4,5- dichloro-1–methyl-1H-indole-2-carboxamido)piperidin-3-yl)acetic acid was obtained as white solid (66 mg, ee: 100%). LCMS: (ES⁺) m/z (M+H)⁺ = 505.0, tR= 0.975. cSFC analytical tR = 3.652 min. ¹H NMR (400 MHz, DMSO-d6) δ = 8.61 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 4.00 (s, 3H), 3.84 - 3.67 (m, 2H), 2.94 (t, J = 12.0 Hz, 1H), 2.71 (t, J = 11.2 Hz, 1H), 2.49 - 2.46 (m, 1H), 2.13 - 2.04 (m, 2H), 1.99 (s, 3H), 1.89 (d, J = 9.2 Hz, 1H), 1.70 - 1.62 (m, 1H). [00428] Example 47 (peak 2): ((3S,4R)-1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H- indole-2-carboxamido)piperidin-3-yl)acetic acid or ((3R,4S)-1-(N-acetylsulfamoyl)-4-(4,5- dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-3-yl)acetic acid was obtained as white solid (11 mg ee: 95%). LCMS: (ES⁺) m/z (M+H)⁺ = 505.0, tR= 0.956. cSFC analytical tR = 3.298 min.¹H NMR (400 MHz, DMSO-d₆) δ = 12.17 (br. s, 1H), 11.50 (br. s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 4.16 (s, 1H), 3.98 (s, 3H), 3.60 - 3.57 (m, 1H), 3.51 (dd, J = 12.8, 3.6 Hz, 1H), 3.17 (d, J = 12.8 Hz, 1H), 3.12 (t, J = 9.2 Hz, 1H), 2.46 - 2.43 (m, 1H), 2.39 - 2.30 (m, 2H), 1.99 (s, 3H), 1.84 - 1.70 (m, 2H). [00429] Example 48 (peak 4): ((3R,4S)-1-(N-acetylsulfamoyl)-4-(4,5-dichloro-1-methyl-1H- indole-2-carboxamido)piperidin-3-yl)acetic acid or ((3S,4R)-1-(N-acetylsulfamoyl)-4-(4,5- dichloro-1-methyl-1H-indole-2-carboxamido)piperidin-3-yl)acetic acid was obtained as white solid (12 mg, ee: 97%). LCMS: (ES⁺) m/z (M+H)⁺ = 505.0, tR= 0.967. cSFC analytical tR = 3.684 min.¹H NMR (400 MHz, DMSO-d6) δ = 11.48 (br. s., 1H), 8.58 (d, J = 7.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.23 (s, 1H), 4.16 (s, 1H), 3.98 (s, 3H), 3.60 - 3.57 (m, 1H), 3.51 (dd, J = 12.8, 4.8 Hz, 2H), 3.17 (d, J = 12.8 Hz, 1H), 3.11 (t, J = 9.6 Hz, 1H), 2.47 - 2.42 (m, 1H), 2.38 - 2.32 (m, 2H), 1.99 (s, 3H), 1.84 - 1.70 (m, 2H). Example 50 - (±)-N-(1-(N-Acetylsulfamoyl)-3-(2-(methylamino)-2-oxoethyl)piperidin-4-yl)- 4,5-dichloro-1-methyl-1H-indole-2-carboxamide

[00430] To a mixture of (±)-2-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2- carbonyl) amino]-3-piperidyl]acetic acid (60.0 mg, 119 µmol, Example 39) and methanamine hydrochloride (40.1 mg, 594 µmol) in N,N-dimethylformamide (1.00 mL) was added triethylamine (72.1 mg, 712 µmol) in one portion at 30 °C. Then, HATU (67.7 mg, 178 µmol) was added. The mixture was stirred at 30 °C for 16 hrs. On completion, to the mixture was added water (5 mL) and the solution was extracted with dichloromethane (3 x 10 mL). The combined organic phase was dried over sodium sulfate, concentrated in vacuo to give a crude which was purified by prep-HPLC (condition: water (0.1%TFA)-ACN; column: Welch Ultimate AQ-C18 150*30mm*5µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 518.2, tR= 0.777.¹H NMR (400 MHz, DMSO-d₆) δ = 11.44 (br. s, 1H), 8.61 (q, J = 5.6 Hz, 1H), 7.81~7.80 (m, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 3.6 Hz, 1H), 4.15 - 4.13 (m, 3H), 3.99 (d, J = 9.6 Hz, 3H), 3.78 - 3.67 (m, 1H), 3.53 - 3.50 (m, 1H), 3.17 (d, J = 10.0 Hz, 2H), 2.55 - 2.54 (m, 4H), 2.37 - 2.16 (m, 2H), 1.99 (s, 3H), 1.91 - 1.64 (m, 2H). Example 51 - (±)-2-(4-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)-1-(N-(pyrazin-2- yl)sulfamoyl)piperidin-3-yl)acetic acid

Step 1 - (±)-Methyl 2-(4-(4,5-dichloro-1-methyl-1H-indole-2-carboxamido)-1-(N -(pyrazin-2-yl) sulfamoyl)piperidin-3-yl)acetate [00431] To a mixture of (±)-methyl 2-[4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-3- piperidyl]acetate hydrochloride (100 mg, 230 µmol, synthesized via Method 6, Steps 1-2 with acid A and amine Y) and 2-oxo-N-pyrazin-2-yl-oxazolidine-3-sulfonamide (84.3 mg, 345 µmol) in acetonitrile (5.00 mL) was added triethylamine (233 mg, 2.30 mmol) in one portion at 30 °C. The mixture was heated to 130 °C and stirred for 3 hrs under microwave irradiation. On completion, the mixture was cooled to room temperature, concentrated in vacuo to give a residue which was purified by column chromatography (dichloromethane:methanol = 20:1 to 10:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 555.2, tR= 0.891. Step 2 - (±)-2-(4-(4,5-Dichloro-1-methyl-1H-indole-2-carboxamido)-1-(N-(pyrazin-2-yl) sulfamoyl)-piperidin-3-yl)acetic acid [00432] To a mixture of (±)-methyl 2-[4-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]-1- (pyrazin-2-ylsulfamoyl)-3-piperidyl]acetate (100 mg, 180 µmol) in tetrahydrofuran (5.00 mL) and water (5.00 mL) was added lithium hydroxide hydrate (37.8 mg, 900 µmol) in one portion at 30 °C. The mixture was stirred at 30 °C for 16 hrs. On completion, to the reaction mixture was added ethyl acetate (2 x 10 mL). To the aqueous phase was added hydrochloride solution (2N, 0.3 mL) to adjust the pH to 4-5. The product was extracted with dichloromethane (3 x 10 mL). The combined dichloromethane phase was concentrated in vacuo to give a crude product which was purified by prep-HPLC (condition: water (0.1% TFA)-ACN; column: Welch Ultimate AQ- C18 150*30mm*5µm) to give the title product. LCMS: (ES⁺) m/z (M+H)⁺ = 541.1, tR= 0.984. ¹H NMR (400 MHz, DMSO-d₆) δ = 12.16 (br.s., 1H), 11.04 (br, s, 1H), 8.59 - 8.52 (m, 1H), 8.34 (d, J = 5.2 Hz, 2H), 8.28 (s, 1H), 7.61 (d, J = 10.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 3.2 Hz, 1H), 3.98 (d, J = 8.8 Hz, 3H), 3.77 - 3.54 (m, 3H), 3.22 - 3.11 (m, 2H), 3.00 - 2.68 (m, 1H), 2.32 - 1.76 (m, 4H). Examples 52 and 53– N-((3S,4R and 3R,4S)-1-(N-acetylsulfamoyl)-3- (hydroxymethyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide and N- ((3S,4S and 3R,4R)-1-(N-acetylsulfamoyl)-3-(hydroxymethyl)piperidin-4-yl)-4,5-dichloro-1- methyl-1H-indole-2-carboxamide

[00433] To a mixture of (±)-ethyl 1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino] piperidine-3-carboxylate (192 mg, 370 µmol, synthesized via Steps 1-3 of Method 6 with acid A and amine Z as starting materials) in anhydrous tetrahydrofuran (10 mL) was added lithium borohydride (32.2 mg, 1.48 mmol). The mixture was stirred at 20 °C for 16 hrs. On completion, the mixture was concentrated in vacuo. The residue was purified by prep- HPLC (Condition: 0.225% FA-ACN; Column: Boston Green ODS 150*30 5µ) to give N- ((3S,4R and 3R,4S)-1-(N-acetylsulfamoyl)-3-(hydroxymethyl)piperidin-4-yl)-4,5-dichloro-1- methyl-1H-indole-2-carboxamide (14.3 mg, 8.2% yield) and N-((3S,4S and 3R,4R)-1-(N- acetylsulfamoyl)-3-(hydroxymethyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2- carboxamide (24.7 mg, 14% yield) as white solids, both as a mixture of enantiomers. [00434] N-((3S,4R and 3R,4S)-1-(N-acetylsulfamoyl)-3-(hydroxymethyl)piperidin-4-yl)-4,5- dichloro -1-methyl-1H-indole-2-carboxamide (Example 52): LCMS: (ES+) m/z (M+H)⁺ = 477.2, tR= 0.836. ¹H NMR (400MHz, DMSO-d6) δ = 8.56 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.17 (s, 1H), 4.67 (br. s., 1H), 4.21 (td, J = 3.8, 7.8 Hz, 1H), 3.98 (s, 3H), 3.57 (dd, J = 5.1, 10.5 Hz, 1H), 3.51 - 3.46 (m, 2H), 3.28 - 3.16 (m, 3H), 2.10 - 2.02 (m, 1H), 1.97 (s, 3H), 1.86 - 1.76 (m, 1H), 1.76 - 1.65 (m, 1H). [00435] N-((3S,4S and 3R,4R)-1-(N-acetylsulfamoyl)-3-(hydroxymethyl)piperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide (Example 53): LCMS: (ES+) m/z (M+H)⁺ = 477.1, tR= 0.848. ¹H NMR (400MHz, DMSO-d6) δ = 11.87 - 10.98 (m, 1H), 8.62 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.21 (s, 1H), 4.64 (br. s., 1H), 4.00 (s, 3H), 3.88 (d, J = 10.4 Hz, 1H), 3.80 - 3.72 (m, 1H), 3.72 - 3.64 (m, 1H), 3.56 (d, J = 10.8 Hz, 1H), 2.95 - 2.85 (m, 1H), 2.68 (t, J = 12.0 Hz, 1H), 2.53 (br. s., 1H), 1.98 (s, 3H), 1.93 - 1.86 (m, 1H), 1.86 - 1.78 (m, 1H), 1.62 (dq, J = 4.4, 12.3 Hz, 1H). Example 54 - N-((2R,4R and 2S,4S)-1-(N-acetylsulfamoyl)-2-phenylpiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide

[00436] N-((2R,4R and 2S,4S)-1-(N-acetylsulfamoyl)-2-phenylpiperidin-4-yl)-4,5- dichloro- 1-methyl-1H-indole-2-carboxamide was synthesized via Steps 1-3 of Method 6, with acid A and amine AC as the starting materials. After Step 1, the diastereomers were separated by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 1:0 to 5:1). N-((2R,4R and 2S,4S)-1-(N-acetylsulfamoyl)-2-phenylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2- carboxamide were isolated as a white solid, as a mixture of enantiomers. LCMS: (ES⁺) m/z (M+H)⁺ = 523.1, tR = 0.813.¹H NMR (400 MHz, DMSO-d₆) δ = 8.67 (d, J=7.65 Hz, 1H), 7.59 (d, J=8.78 Hz, 1H), 7.41 - 7.48 (m, 5H), 7.28 - 7.33 (m, 1H), 7.26 (s, 1H), 5.29 (d, J=4.14 Hz, 1H), 3.98 (s, 3H), 3.83 (d, J=14.93 Hz, 2H), 3.04 (t, J=12.23 Hz, 1H) , 2.53 - 2.58 (m, 1H), 1.98 - 2.07 (m, 4H), 1.68 - 1.78 (m, 1 H), 1.54 - 1.67 (m, 1 H). Example 55 - N-((2S,4R and 2R4S)-1-(N-acetylsulfamoyl)-2-phenylpiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide

[00437] N-((2S,4R and 2R,4S)-1-(N-acetylsulfamoyl)-2-phenylpiperidin-4-yl)-4,5-dichloro-1- methyl-1H-indole-2-carboxamide was synthesized via Steps 1-3 of Method 6, with acid A and amine AC as the starting materials. After Step 1, the diastereomers were separated by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 1:0 to 5:1). N-((2S,4R and 2R,4S)-1-(N-acetylsulfamoyl)-2-phenylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2- carboxamide (27.6 mg, 52.0 µmol, 23% yield) were isolated as a white solid, as a mixture of enantiomers. LCMS: (ES⁺) m/z (M+H)⁺ = 523.2, 525.2. tR = 0.903. ¹H NMR (400 MHz, DMSO-d6) δ = 8.02 (d, J=6.40 Hz, 1H), 7.55 (d, J=8.78 Hz, 1H), 7.40 (d, J=8.78 Hz, 1H), 7.37 - 7.29 (m, 4H), 7.21 - 7.12 (m, 1H), 6.38 (s, 1H), 5.00 (t, J=6.27 Hz, 1H), 4.08 (s., 1H), 3.90 (s, 3H), 3.62 - 3.78 (m, 2H), 2.36 - 2.46 (m, 1H), 2.12 (dt, J=9.19, 4.75 Hz, 1H), 2.04 - 1.86 (m, 4H), 1.74 - 1.62 (m, 1H). Example 56 - N-[1-(acetylsulfamoyl)-4-[3-(sulfamoylamino)propyl]-4-piperidyl]-4,5- dichloro-1-methyl-indole-2-carboxamide

Step 1 - N-[1-(acetylsulfamoyl)-3-(3-aminopropyl)-3-piperidyl]-4,5-dichloro-1-methyl-indole-2- carboxamide [00438] To a solution of benzyl N-[3-[1-(acetylsulfamoyl)-3-[(4,5 -dichloro-1-methyl-indole- 2-carbonyl)amino]-3-piperidyl]propyl]carbamate (20 mg, 31.3 µmol, synthesized via Method 6, Steps 1-3 with acid A and amine AE) and hydrochloric acid (1 M, 0.2 mL) in methanol (20 mL) was added Pd/C (5.0 mg, 50%) at 30 °C and the reaction mixture was stirred under hydrogen (15 psi) at 30 °C for 1 hr. On completion, the reaction was concentrated in vacuo to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 504.2. Step 2 - Tert-butyl N-[3-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]-4-piperidyl]propylsulfamoyl]carbamate [00439] To a solution of N-[1-(acetylsulfamoyl)-4-(3-aminopropyl)-4-piperidyl]-4,5-dichloro- 1-methyl-indole-2-carboxamide (70 mg, 138 µmol) and triethylamine (42 mg, 416 µmol) in dichloromethane (20 mL) was added tert-butyl N-chlorosulfonylcarbamate (45 mg, 208 µmol) in one portion at 0 °C. The reaction mixture was stirred at 0 °C for 1 hr. On completion, 20 mL water was added into the solution. The aqueous phase was extracted with dichloromethane (2 x 20 mL). The combined organic layer was washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 100:1 to 1:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 527.2, tR= 1.159. Step 3 - N-[1-(acetylsulfamoyl)-4-[3-(sulfamoylamino)propyl]-4-piperidyl]-4,5-dichloro-1- methyl-indole-2-carboxamide [00440] To a solution of tert-butyl N-[3-[1-(acetylsulfamoyl)-4-[(4,5-dichloro-1-methyl- indole-2-carbonyl)amino]-4-piperidyl]propylsulfamoyl]carbamate (50 mg, 73 µmol) in dichloromethane (20 mL) was added trifluoroacetic acid (167 mg, 1.46 mmol) in one portion at 0 °C and the reaction mixture was stirred at 0 °C for 12 hrs. On completion, 20 mL water was added to the solution. The mixture was adjusted to pH = 3 with aqueous saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane (2 x 20 mL), washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtrated and concentrated in vacuo. The resulting solid was purified by prep-HPLC (0.05% ammonium hydroxide v/v)- ACN, Phenomenex Gemini C18 250mm*50mm*10µm) to give the title compound. LCMS: (ES+) m/z (M+H)⁺ = 583.2, tR= 1.281.¹H NMR (400MHz, DMSO-d₆) δ = 7.92 (s, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.43 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H), 6.44 (s, 2H), 3.93 (s, 3H), 2.88 (s, 4H), 2.84 - 2.77 (m, 3H), 2.42 - 2.41 (m, 1H), 1.83 (s, 3H), 1.75 (br. s., 2H), 1.46 (d, J = 9.7 Hz, 4H). Example 57 - (±)-N-[3-(acetamidomethyl)-1-(pyrimidin-2-ylsulfamoyl)-3-piperidyl]-4,5- dichloro-1-methyl -indole-2-carboxamide

Step 1 - (±)-Tert-butyl 3-cyano-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino]piperidine- 1- carboxylate [00441] To a solution of (±)-tert-butyl 3-amino-3-cyano-piperidine-1-carboxylate (461 mg, 2.05 mmol) in 10 mL anhydrous dichloromethane was added triethylamine (622 mg, 6.15 mmol). Then 4,5-dichloro-1-methyl-indole-2-carbonyl chloride (538 mg, 2.05 mmol) dissolved in 15 mL anhydrous dichloromethane was added dropwise. The mixture was stirred at 18 °C for 16 hours. On completion, the reaction mixture was partitioned between ice water (20 mL) and dichloromethane (20 mL). The organic phase was separated, washed with brine (3 x 15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (petroleum ether:ethyl acetate = 8:1 to 3:1) to give the title compound. LCMS: (ES⁺) m/z (M-56)⁺ = 395.1, tR= 1.061. Step 2 - (±)-Tert-butyl 3-(aminomethyl)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino] piperidine-1-carboxylate [00442] To a solution of (±)-tert-butyl 3-cyano-3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino] piperidine-1-carboxylate (400 mg, 886 µmol) in methanol (10 mL) was added Raney nickel (400 mg, 4.67 mmol) under nitrogen. The suspension was degassed under vacuum and purged with hydrogen gas several times. The mixture was stirred under hydrogen gas (15 psi) at 18 °C for 48 hours. On completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane:methanol = 20:1 to 5:1) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 455.2, tR= 1.529. Step 3 - (±)-Tert-butyl 3-(acetamidomethyl)-3-[(4,5-dichloro-1-methyl-indole-2-carbonyl)amino] piperidine-1-carboxylate [00443] To a solution of (±)-tert-butyl 3-(aminomethyl)-3-[(4,5-dichloro-1-methyl-indole-2- carbonyl)amino]piperidine-1-carboxylate (150 mg, 329 µmol) in anhydrous dichloromethane (5 mL) was added triethylamine (83.3 mg, 823 µmol) at 0 °C. Then acetyl chloride (28.4 mg, 362 µmol) was added dropwise. Afterwards, the mixture was warmed to 18 °C and stirred for 0.5 hour. On completion, the reaction mixture was washed with ice water (3 x 5 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound. The crude product was used to the next step directly without further purification.¹H NMR (400MHz, CDCl₃) δ = 7.76 (br. s., 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 7.05 (br. s., 1H), 6.92 (br. s., 1H), 4.12 (d, J = 13.8 Hz, 1H), 4.05 (s, 3H), 3.87 - 3.75 (m, 1H), 3.58 - 3.32 (m, 3H), 3.23 (br. s., 1H), 2.92 (br. s., 1H), 2.10 (s, 3H), 1.71 - 1.54 (m, 3H), 1.52 (s, 9H). Step 4 - (±)-N-[3-(acetamidomethyl)-3-piperidyl]-4,5-dichloro-1-methyl-indole-2-carboxamide [00444] To a solution of (±)-tert-butyl 3-(acetamidomethyl)-3-[(4,5-dichloro-1-methyl-indole- 2-carbonyl)amino]piperidine-1-carboxylate (150 mg, 301 µmol) in dichloromethane (5 mL) was added trifluoroacetic acid (3.06 g, 26.8 mmol) at 18 °C. After addition, the mixture was stirred at 18 °C for 0.5 hour. On completion, the reaction mixture was concentrated in vacuo to give the title compound. The crude product was used to the next step directly without further purification. LCMS: (ES⁺) m/z (M+H)⁺ = 397.1, tR= 1.705. Step 5 - (±)-N-[3-(acetamidomethyl)-1-(pyrimidin-2-ylsulfamoyl)-3-piperidyl]-4,5-dichloro-1- methyl -indole-2-carboxamide [00445] To a solution of (±)-N-[3-(acetamidomethyl)-3-piperidyl]-4,5-dichloro-1-methyl- indole-2-carboxamide (130 mg, 229 µmol) in acetonitrile (5 mL) was added triethylamine (231 mg, 2.29 mmol). The mixture was stirred at 18 °C for 0.5 hour. Then 2-oxo-N-pyrimidin-2-yl- oxazolidine-3-sulfonamide (83.9 mg, 343 µmol) was added and the mixture was transferred to a microwave tube. The sealed tube was heated at 130 °C for 3 hours under microwave. On completion, the reaction mixture was purified by prep-HPLC (Condition: 0.05% HCl-ACN; Column: Phenomenex Synergi C18 150 x 30 mm x 4 µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 554.1, tR= 0.799.¹H NMR (400MHz, CDCl₃) δ = 8.44 (d, J = 4.9 Hz, 2H), 7.46 - 7.43 (m, 1H), 7.40 - 7.37 (m, 1H), 7.00 (s, 1H), 6.91 (t, J = 4.9 Hz, 1H), 4.18 (d, J = 12 Hz, 1H), 4.00 (s, 3H), 3.76 (s, 3H), 3.30 (d, J = 13.4 Hz, 1H), 3.27 - 3.19 (m, 1H), 2.42 - 2.33 (m, 1H), 2.02 (s, 3H), 1.89 - 1.75 (m, 2H), 1.60 (ddd, J = 4.1, 10.3, 14.0 Hz, 1H). Example 58 - (±)-N-[1-(acetylsulfamoyl)-3-hydroxy-4-piperidyl]-4,5-dichloro-1-methyl- indole- 2-carboxamide

Step 1 - (±)-4,5-dichloro-N-(3-hydroxypiperidin-4-yl)-1-methyl-1H-indole-2-carboxamide [00446] To a solution of (±)-tert-butyl-3-[tert-butyl(diphenyl)silyl]oxy-4-[(4,5-dichloro-1- methyl-indole-2-carbonyl)amino]piperidine-1-carboxylate (100 mg, 147 µmol, synthesized via Step 1 of Method 3 with acid A and amine V) in methanol (10 mL) was added HCl/methanol (4 M, 1 mL) in one portion at 15 °C, and the reaction was stirred at 15 °C for 1 hr. On completion, the reaction was concentrated in vacuo to afford the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 342.1 Step 2 - (±)-N-[1-(acetylsulfamoyl)-3-hydroxy-4-piperidyl]-4,5-dichloro-1-methyl-indole-2- carboxamide [00447] To a solution of (±)-4,5-dichloro-N-(3-hydroxypiperidin-4-yl)-1-methyl-1H-indole-2- carboxamide (80 mg, 138 µmol) in dichloromethane (10 mL) was added triethylamine (42 mg, 413 µmol) and N-acetylsulfamoyl chloride (22 mg, 138 µmol) in one portion, and the reaction was stirred at 15 °C for 1 hr. On completion, the reaction was concentrated in vacuo to give a residue, the residue was purified by prep-HPLC (10 mM NH4HCO3-methanol, Welch Ultimate AQ-C18 150*30mm*5µm) to give the title compound. LCMS: (ES⁺) m/z (M+H)⁺ = 463, tR= 1.312.¹H NMR (400MHz, DMSO-d6) δ = 11.51 (br. s., 1H), 8.55 (d, J = 8.3 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.23 (s, 1H), 5.27 (d, J = 4.9 Hz, 1H), 4.01 (s, 3H), 3.75 (d, J = 7.3 Hz, 2H), 3.66 - 3.51 (m, 2H), 2.98 - 2.84 (m, 1H), 2.68 - 2.65 (m, 1H), 1.99 (s, 3H), 1.91 (d, J = 9.7 Hz, 1H), 1.64 - 1.49 (m, 1H). Example 59 - (±)-N-(1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5-dichloro-1-methyl- 1H-indole-2-carboxamide

Step 1 (±)-N-(1-benzyl-3-cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide [00448] To a solution of (±)-4-amino-1-benzyl-piperidine-3-carbonitrile (300 mg, 1.39 mmol) and 4,5-dichloro-1-methyl-indole-2-carboxylic acid (374 mg, 1.53 mmol) in N,N- dimethylformamide (5 mL) was added HATU (1.06 g, 2.79 mmol) and triethylamine (423 mg, 4.18 mmol) at 25 °C under a nitrogen. The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo to remove N,N-dimethylformamide, and the residue was diluted with dichloromethane (200 mL), and washed with water (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 200:1) to give the title product. LCMS: (ES⁺) m/z (M+H)⁺ = 441.2, tR = 0.766. Step 2– (±)-4,5-Dichloro-N-(3-cyanopiperidin-4-yl)-1-methyl-1H-indole-2-carboxamide [00449] To a solution of (±)-N-(1-benzyl-3-cyano-4-piperidyl)-4,5-dichloro-1-methyl-indole- 2-carboxamide (300 mg, 680 µmol) in 1,2-dichloroethane (15 mL) was added 1-chloroethyl carbonochloridate (194 mg, 1.36 mmol) at 25 °C. The reaction mixture was heated at 85 °C for 8 hrs. Then the reaction mixture was concentrated in vacuo. To the residue was added methanol (10 mL) and the mixture was heated to 70 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane: methanol = 50:1 to 20:1) to give the title compound. LCMS: (ES⁺) m/z (M+H) ⁺ = 351.1, tR =0.708. Step 3 - (±)-N-(1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole- 2-carboxamide [00450] To a solution of (±)-4,5-dichloro-N-(3-cyano-4-piperidyl)-1-methyl-indole-2- carboxamide (120 mg, 260 µmol) in dichloromethane (5.00 mL) was added triethylamine (78.8 mg, 779 µmol) and N-acetylsulfamoyl chloride (61.4 mg, 390 µmol) at 25 °C under nitrogen. Then, the reaction mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was concentrated in vacuo. The residual was purified by prep-HPLC [Instrument: GX-A; Column: Phenomenex Gemini C18 250mm*50mm*10µm; Condition: water (0.05% ammonia hydroxide v/v)-ACN] to give the title compound. LCMS: (ES-) m/z (M-H)- =470.0, tR = 1.013. ¹H NMR (400MHz, DMSO-d6) δ = 8.92 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 4.28 (d, J = 10.8 Hz, 1H), 4.02 (s, 3H), 3.95 (d, J = 10.0 Hz, 1H), 3.64 (d, J = 12.6 Hz, 1H), 3.19 - 3.03 (m, 3H), 1.98 (br. s., 3H), 1.93 (br. s., 1H), 1.65 - 1.54 (m, 1H). Examples 60, 61, 62, and 63 - N-((3R,4R)-1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide, N-((3S,4S)-1-(N-acetylsulfamoyl)-3- cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide, N-((3R,4S)-1-(N- acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide, and N-((3S,4R)-1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H- indole-2-carboxamide

[00451] (±)-N-[1-(acetylsulfamoyl)-3-cyano-4-piperidyl]-4,5-dichloro-1-methyl-indole-2- carboxamide (105 mg, 222 µmol, Example 59) was separated by chiral SFC (Instrument: SFC-A; Column: OJ (250mm*30mm*10µm); Condition: Base-methanol), to give the four isomers. [00452] Example 60 (Peak 1): N-((3R,4R)-1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide or N-((3S,4S)-1-(N-acetylsulfamoyl)-3- cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide (25 mg, ee: 100%) was obtained as a white solid. LCMS: (ES-) m/z (M-H)- = 470.0, tR = 0.977. cSFC analytical tR = 2.870 min.¹H NMR (400MHz, DMSO-d₆) δ = 8.92 (d, J = 8.6 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.21 (s, 1H), 4.32 - 4.22 (m, 1H), 4.02 (s, 3H), 3.95 (d, J = 10.3 Hz, 1H), 3.64 (d, J =13.1 Hz, 1H), 3.14 (dt, J = 10.6, 3.6 Hz, 1H), 3.10 - 3.04 (m, 1H), 1.98 (s, 3H), 1.96 - 1.89 (m, 1H), 1.67 - 1.55 (m, 1H). [00453] Example 61 (Peak 2): N-((3S,4S)-1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide or N-((3R,4R)-1-(N-acetylsulfamoyl)-3- cyanopiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide (23 mg, ee: 97%) was obtained as white solid. LCMS: (ES-) m/z (M-H)- = 470.0, tR = 0.980. cSFC analytical tR = 3.277 min.¹H NMR (400MHz, DMSO-d6) δ = 8.92 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 9.0 Hz, 1H), 7.21 (s, 1H), 4.25 (d, J =12.0 Hz, 1H), 4.02 (s, 3H), 3.94 (d, J = 10.2 Hz, 1H), 3.63 (d, J = 12.8 Hz, 1H), 3.25 (br. s., 1H), 3.14 (dt, J = 10.4, 3.6 Hz, 1H), 3.04 (t, J = 11.4 Hz, 1H), 1.95 (s, 3H), 1.92 (br. s., 1H), 1.66 - 1.54 (m, 1H). [00454] Example 62 (peak 3): N-((3R,4S)-1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide or N-((3S,4R)-1-(N-acetylsulfamoyl)-3- cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide (2 mg, ee: 87%) was obtained as white solid. LCMS: (ES-) m/z (M-H)- = 470.0, tR = 0.984. cSFC analytical tR = 3.595 min.¹H NMR (400MHz, DMSO-d₆) δ = 9.05 (d, J = 6.4 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.35 (s, 1H), 4.01 (s, 3H), 4.00 - 3.95 (m, 1H), 3.84 (d, J = 12.8 Hz, 1H), 3.68 (d, J = 3.8 Hz, 2H), 3.07 (d, J = 11.6 Hz, 1H), 2.84 (t, J = 11.2 Hz, 1H), 1.97 (dd, J = 12.6, 3.8 Hz, 1H), 1.93 - 1.88 (m, 3H), 1.85 (br. s., 1H). [00455] Example 63 (peak 4): N-((3S,4R)-1-(N-acetylsulfamoyl)-3-cyanopiperidin-4-yl)-4,5- dichloro-1-methyl-1H-indole-2-carboxamide or N-((3R,4S)-1-(N-acetylsulfamoyl)-3- cyanopiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide (2 mg, ee: 95%) was obtained as white solid. LCMS: (ES-) m/z (M-H)- = 470.0, tR = 0.985. cSFC analytical tR = 4.102 min.¹H NMR (400MHz, DMSO-d₆) δ = 9.06 (d, J = 6.2 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.34 (s, 1H), 4.08 - 4.02 (m, 1H), 4.00 (s, 3H), 3.86 (d, J = 13.2 Hz, 1H), 3.75 - 3.68 (m, 2H), 3.12 (br. s., 1H), 2.96 - 2.87 (m, 1H), 2.00 - 1.94 (m, 1H), 1.92 (s, 3H), 1.90 - 1.83 (m, 1H).

Examples 64 and 65 - (±)-N-((3S,4S and 3R,4R)-1-(N-acetylsulfamoyl)-3- carbamoylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide and (±)-N- ((3R,4S and 3S,4R)-1-(N-acetylsulfamoyl)-3-carbamoylpiperidin-4-yl)-4,5-dichloro-1- methyl-1H-indole-2-carboxamide

[00456] To a solution of (±)-N-[1-(acetylsulfamoyl)-3-cyano-4-piperidyl]-4,5-dichloro-1- methyl-indole-2-carboxamide (100 mg, 212 µmol, Example 59) in DMSO (2 mL) was added anhydrous potassium carbonate (11.7 mg, 84.7 µmol) and hydrogen peroxide (590 mg, 17.3 mmol, 30% wt, 0.5 mL) at 25 °C. Then, the reaction was stirred at 60 °C for 3 hrs. On completion, the reaction mixture was filtered. The residue was purified by prep-HPLC [Instrument: GX-I; Column: Innoval DB C18 150*25mm*10µm; Condition: 0.1%TFA-ACN] to give each diastereomer as mixture of the enantiomers. [00457] Example 64 (peak 1): N-((3S,4S and 3R,4R)-1-(N-acetylsulfamoyl)-3- carbamoylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide (8.00 mg, 7.3% yield) LCMS: (ES⁺) m/z (M+H) ⁺ =490.1, tR = 0.745.¹H NMR (400MHz, DMSO-d₆) δ = 11.53 (br. s., 1H), 8.53 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.37 (br. s., 1H), 7.14 (s, 1H), 7.10 (br. s., 1H), 4.10 (d, J = 11.6 Hz, 1H), 4.02 - 3.95 (m, 3H), 3.74 (d, J = 10.2 Hz, 1H), 3.67 (d, J = 12.4 Hz, 1H), 3.03 - 2.87 (m, 2H), 2.68 - 2.60 (m, 1H), 2.00 (s, 3H), 1.95 (br. s., 1H), 1.63 - 1.51 (m, 1H). [00458] Example 65 (peak 2): N-((3R,4S and 3S,4R)-1-(N-acetylsulfamoyl)-3- carbamoylpiperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide (4.00 mg, 3.5% yield) LCMS: (ES⁺) m/z (M+H) ⁺ = 490.1, tR = 0.757.¹H NMR (400MHz, DMSO-d6) δ = 11.48 (br. s., 1H), 8.49 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz,1H), 7.49 (br. s., 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.10 (s, 1H), 7.06 (br. s., 1H), 4.52 (d, J = 3.6 Hz, 1H), 3.95 (s, 3H), 3.68 (dd, J = 13.2, 9.8 Hz, 2H), 3.59 - 3.52 (m, 2H), 2.82 - 2.75 (m, 1H), 2.06 - 2.01 (m, 1H), 1.99 (s, 3H), 1.79 - 1.70 (m, 1H). Example 66 and 67 - N-((3S,4S or 3R,4R)-1-(N-acetylsulfamoyl)-3- (methylsulfonamidomethyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide and N-((3S,4R or 3S,4R)-1-(N-acetylsulfamoyl)-3-(methylsulfonamidomethyl)piperidin-4- yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide

Step 1 - (±)-N-(1-(N-Acetylsulfamoyl)-3-(aminomethyl)piperidin-4-yl)-4,5-dichloro-1-methyl- 1H-indole-2-carboxamide [00459] To a solution of (±)-N-[1-(acetylsulfamoyl)-3-cyano-4-piperidyl]-4,5-dichloro-1- methyl-indole-2-carboxamide (200 mg, 423 µmol, Example 59) and ammonium hydroxide (910 mg, 25.9 mmol) in a solvent mixture of tetrahydrofuran (5 mL) and methanol (5 mL) was added Raney nickel (100 mg, 423 µmol) at 25 °C under hydrogen. The reaction mixture was stirred at 25 °C for 12 hrs. On completion, the reaction mixture was filtered and concentrated in vacuo to give the title product (180 mg, 80% yield) which was used directly in the next step. LCMS: (ES⁺) m/z (M+H) ⁺ = 476.1, tR = 0.699. Step 2 - N-((3S,4S or 3R,4R)-1-(N-acetylsulfamoyl)-3-(methylsulfonamidomethyl)piperidin-4- yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide and N-((3S,4R or 3S,4R)-1-(N- acetylsulfamoyl)-3-(methylsulfonamidomethyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole- 2-carboxamide [00460] To a solution of (±)-N-[1-(acetylsulfamoyl)-3-(aminomethyl)-4-piperidyl]-4,5- dichloro-1-methyl-indole-2-carboxamide (180 mg, 378 µmol) in dichloromethane (20 mL) was added triethylamine (115 mg, 1.13 mmol) and methanesulfonyl chloride (43.3 mg, 378 µmol) at 25 °C under nitrogen. Then, the reaction mixture was stirred at 25 °C for 2 hrs. On completion, the reaction mixture was concentrated in vacuo to give the residue. The residue was purified by prep-HPLC [Instrument: GX-I; Column: YMC-Actus ODS-AQ 150 mm*30 5µm; Conditions: water (0.1%TFA)-ACN] to give each diastereomer as mixture of the enantiomers. [00461] Example 66 (peak 2): N-((3S,4S and 3R,4R)-1-(N-acetylsulfamoyl)-3- (methylsulfonamidomethyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide (42.7 mg, 39% yield). LCMS: (ES⁺) m/z (M+H)⁺ = 554.1, tR = 1.081. ¹H NMR (400MHz, DMSO-d6) δ = 11.49 (s, 1H), 8.65 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 7.08 (t, J = 6.4 Hz, 1H), 3.99 (s, 3H), 3.88 (d, J = 10.8 Hz, 1H), 3.77 (d, J = 9.6 Hz, 1H), 3.68 (d, J = 12.0 Hz, 1H), 3.15 (d, J = 11.2 Hz, 1H), 2.95 (t, J = 11.8 Hz, 1H), 2.85 (s, 3H), 2.83 - 2.77 (m, 1H), 2.76 - 2.69 (m, 1H), 1.98 (s, 3H), 1.88 (d, J = 10.2 Hz, 1H), 1.72 - 1.58 (m, 1H). [00462] Example 67 (peak 1): N-((3S,4R and 3R,4S)-1-(N-acetylsulfamoyl)-3- (methylsulfonamidomethyl)piperidin-4-yl)-4,5-dichloro-1-methyl-1H-indole-2-carboxamide (8.00 mg, 8.2% yield). LCMS: (ES⁺) m/z (M+H) ⁺ = 554.2, tR = 1.051. ¹H NMR (400MHz, DMSO-d6) δ = 8.57 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.23 (s, 1H), 7.00 (t, J = 5.6 Hz, 1H), 4.22 (br. s., 1H), 3.98 (s, 3H), 3.47 - 3.39 (m, 2H), 3.19 (d, J = 13.6 Hz, 2H), 3.09 - 3.00 (m, 2H), 2.88 (s, 3H), 2.13 (br. s., 1H), 1.92 (s, 3H), 1.80 (br. s., 1H), 1.70 (d, J = 3.8 Hz, 1H). Example 68 - (±)-4,5-dichloro-N-(3-cyano-1-(N-(pyrazin-2-yl)sulfamoyl)piperidin-4-yl)- 1- methyl-1H-indole-2-carboxamide

[00463] To a solution of 4,5-dichloro-N-(3-cyano-4-piperidyl)-1-methyl-indole-2- carboxamide (500 mg, 1.42 mmol, synthesized via Steps 1-2 of Example 59) in acetonitrile (5.0 mL) was added triethylamine (432 mg, 4.27 mmol) at 15 °C under nitrogen. Then, 2-oxo-N- pyrazin-2-yl-oxazolidine-3-sulfonamide (521 mg, 2.14 mmol) was added. The reaction mixture was transferred into a microwave tube and the sealed tube was heated at 130 °C for 3 hrs. On completion, the reaction mixture was concentrated in vacuo to give the residue. The residual was purified by prep-HPLC [Instrument: GX-H; Column: YMC-Actus ODS-AQ 100*30 5 µm; Conditions: 0.1% TFA-ACN] to give the title product (215 mg, 30% yield). LCMS: (ES⁺) m/z (M+H) ⁺ = 508.0, tR = 0.832.¹H NMR (400MHz, DMSO-d6) δ = 11.20 (br. s., 1H), 9.05 (d, J = 6.4 Hz, 0.3H), 8.87 (d, J = 8.4 Hz, 0.7H), 8.35 (s, 1.76H), 8.30 (d, J = 2.0 Hz, 1H), 8.27 (br. s., 0.3H), 7.62 (d, J = 9.0 Hz, 1H), 7.46 (d, J = 9.0 Hz, 1H), 7.32 (s, 0.3H), 7.17 (s, 0.7H), 4.37 - 4.24 (m, 0.85H), 4.04 (d, J = 10.8 Hz, 1.15H), 4.00 (s, 3H), 3.95 (d, J = 5.2 Hz, 0.3H), 3.82 (d, J = 13.6 Hz, 0.36H), 3.76 - 3.67 (m, 1H), 3.26 (d, J = 13.2 Hz, 0.8H), 3.18 - 3.08 (m, 1.7H), 3.04 - 2.93 (m, 0.5H), 1.97 - 1.88 (m, 1H), 1.65 - 1.53 (m, 1H). Example 69, 70, 71, and 72 - 4,5-dichloro-N-((3S,4S)-3-cyano-1-(N-(pyrazin-2- yl)sulfamoyl)piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide, 4,5-dichloro-N-((3R,4R)- 3-cyano-1-(N-(pyrazin-2-yl)sulfamoyl)piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide, 4,5-dichloro-N-((3S,4R)-3-cyano-1-(N-(pyrazin-2-yl)sulfamoyl) piperidin-4-yl)-1-methyl- 1H-indole-2-carboxamide, and 4,5-dichloro-N-((3R,4S)-3-cyano-1-(N-(pyrazin-2- yl)sulfamoyl) piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide

[00464] (±)-4,5-dichloro-N-[3-cyano-1-(pyrazin-2-ylsulfamoyl)-4-piperidyl]-1-methyl-indole- 2-carboxamide (200 mg, Example 68) was separated by chiral SFC (Instrument: SFC-A; Column: OJ (250mm*30mm*10µm); Condition: Base-methanol) to give four isomers. [00465] Example 69 (peak 1): 4,5-dichloro-N-((3S,4S)-3-cyano-1-(N-(pyrazin-2- yl)sulfamoyl)piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide or 4,5-dichloro-N-((3R,4R)-3- cyano-1-(pyrazin-2-ylsulfamoyl)-4-piperidyl]-1-methyl-indole-2-carboxamide (41.7 mg, 83% yield). LCMS: (ES-) m/z (M-H)- =470.0, tR = 0.977. cSFC analytical tR = 1.595 min. ¹H NMR (400MHz, DMSO-d₆) δ = 8.89 (d, J = 8.8 Hz, 1H), 8.34 - 8.25 (m, 2H), 8.19 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 4.33 - 4.22 (m, 1H), 4.06 - 3.97 (m, 4H), 3.71 (d, J = 12.8 Hz, 1H), 3.19 - 3.11 (m, 2H), 3.06 (t, J = 11.2 Hz, 1H), 1.92 (dd, J = 12.8, 3.4, Hz, 1H), 1.68 - 1.55 (m, 1H). [00466] Example 70 (peak 2): 4,5-dichloro-N-((3R,4R)-3-cyano-1-(pyrazin-2-ylsulfamoyl)-4- piperidyl]-1-methyl-indole-2-carboxamide or 4,5-dichloro-N-((3S,4S)-3-cyano-1-(N-(pyrazin-2- yl)sulfamoyl)piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide (47.1 mg, 92% yield). LCMS: (ES-) m/z (M-H)- = 470.0, tR = 0.977. cSFC analytical tR = 2.192 min. ¹H NMR (400MHz, DMSO-d₆) δ = 8.88 (d, J = 8.4 Hz, 1H), 8.34 - 8.30 (m, 2H), 8.23 (d, J = 2.4 Hz, 1H), 7.62 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.18 (s, 1H), 4.34 - 4.23 (m, 1H), 4.05 (br. s., 1H), 4.00 (s, 3H), 3.72 (d, J = 12.8 Hz, 1H), 3.15 (dt, J = 10.4, 3.6, Hz, 2H), 3.10 - 3.04 (m, 1H), 1.93 (d, J = 10.0 Hz, 1H), 1.61 (q, J = 10.8 Hz, 1H). [00467] Example 71 (peak 3): 4,5-dichloro-N-((3S,4R)-3-cyano-1-(N-(pyrazin-2- yl)sulfamoyl)piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide or 4,5-dichloro-N-((3R,4S)-3- cyano-1-(N-(pyrazin-2-yl)sulfamoyl)piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide (20.8 mg, 41% yield). LCMS: (ES-) m/z (M-H)- =470.0, tR = 0.977. cSFC analytical tR = 4.005 min. ¹H NMR (400MHz, DMSO-d6) δ = 9.05 (d, J =6.0 Hz, 1H), 8.46 - 7.90 (m, 3H), 7.62 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 4.01 (s, 4H), 3.90 (d, J = 12.0 Hz, 1H), 3.75 (d, J = 10.5 Hz, 1H), 3.68 (br. s., 1H), 3.09 (d, J = 11.8 Hz, 1H), 2.86 (br. s., 1H), 2.02 - 1.92 (m, 1H), 1.88 (br. s., 1H). [00468] Example 72 (peak 4): 4,5-dichloro-N-((3R,4S)-3-cyano-1-(N-(pyrazin-2- yl)sulfamoyl) piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide or 4,5-dichloro-N-((3S,4R)-3- cyano-1-(N-(pyrazin-2-yl)sulfamoyl)piperidin-4-yl)-1-methyl-1H-indole-2-carboxamide (20.8 mg, 41% yield) LCMS: (ES-) m/z (M-H)- =470.0, tR = 0.977. cSFC analytical tR = 7.092 min. ¹H NMR (400MHz, DMSO-d₆) δ = 9.13 - 8.94 (m, 1H), 8.45 - 7.90 (m, 3H), 7.62 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H), 7.33 (s, 1H), 4.01 (s, 4H), 3.90 (d, J = 11.2 Hz, 1H), 3.73 (br. s., 1H), 3.68 (br. s., 1H), 3.06 (d, J = 8.8 Hz, 1H), 2.85 (br. s., 1H), 2.02 - 1.92 (m, 1H), 1.89 (d, J = 11.2 Hz, 1H). Example 73: Full length (FL) 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorase coupled assay (500 µM NAD)

[00469] PHGDH activity was determined by detecting the NADH produced during the reaction. Diaphorase was used to catalyze the oxidation of NADH with the concomitant reduction of resazurin to the fluorescent product resorufin. Resorufin fluorescence quantitatively reflected the production of NADH by the PHGDH reaction. To drive the forward reaction, two enzymes in the serine synthesis pathway subsequent to PHGDH, Phosphoserine aminotransferase (PSAT1) and phosphoserine phosphatase (PSPH) were also added to the reaction.

[00470] Briefly, serial dilutions of compounds were incubated in a volume of 20 µL in 384 well plates with the assay mixture containing 5 nM PHGDH, 500 nM PSAT1, 500 nM PSPH, 500 µM NAD⁺, 80 µM 3-phosphoglycerate, 1 mM glutamate, 57 µM Resazurin and 0.2 mg/mL Diaphorase in assay buffer containing 50 mM Trisethanoloamine (TEA) pH 8.0, 10 mM MgCl2, 0.01% Tween-20 and 0.05% Bovine Serum Albumin (BSA). The plate was then incubated at 30 ^oC for 60 minutes and resorufin fluorescence was measured at emission wavelength 598 nm following excitation at 525 nm. The positive control consisted of the complete reaction mixture with 4% DMSO and was set to 0% inhibition. The negative control consisted of the reaction mix lacking PHGDH with 4% DMSO and was set to 100% inhibition. Percent inhibition with the compounds was then calculated by normalizing the fluorescence observed at a given compound concentration to the positive and negative controls. IC50 was calculated by plotting the % inhibition versus concentration and using hyperbolic fit to determine compound concentration corresponding to 50% inhibition.

Example 74: Full length (FL) 3-Phosphoglycerate Dehydrogenase (PHGDH) Diaphorase coupled assay (20 µM NAD)

[00471] Serial dilutions of compounds were incubated in a volume of 20 µL in 384 well plates with the assay mixture containing 10 nM PHGDH, 500 nM PSAT1, 500 nM PSPH, 20 µM NAD⁺, 80 µM 3-phosphoglycerate, 1 mM glutamate, 57 µM Resazurin and 0.2 mg/mL Diaphorase in assay buffer containing 50 mM Trisethanoloamine (TEA) pH 8.0, 10 mM MgCl2, 0.01% Tween-20 and 0.05% Bovine Serum Albumin (BSA). The plate was then incubated at 30 ^oC for 60 minutes and resorufin fluorescence was measured at emission wavelength 598 nm following excitation at 525 nm. The positive control consisted of the complete reaction mixture with 4% DMSO and was set to 0% inhibition. The negative control consisted of the reaction mix lacking PHGDH with 4% DMSO and was set to 100% inhibition. Percent inhibition with the compounds was then calculated by normalizing the fluorescence observed at a given compound concentration to the positive and negative controls. IC50 was calculated by plotting the % inhibition versus concentration and using hyperbolic fit to determine compound concentration corresponding to 50% inhibition. Results of Assays

[00472] Table 2 shows the activity of selected compounds of this invention in the PHGDH activity inhibition assay. The compound numbers correspond to the compound numbers in Table 1. Compounds having an activity designated as“A” provided an IC50 of 0.01 to <1.5 μM; compounds having an activity designated as“B” provided an IC50 of 1.5 to <5 μM; and compounds having an activity designated as“C” provided an IC₅₀ of 5 µM or greater. Table 2

[00473] While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims

We claim: 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is hydrogen or C_1-4 alkyl;

each of R² and R³ is independently halogen, -OR, -CN, C_1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’; or R² and R³ are optionally taken together with the carbon atoms to which they are attached and any intervening atoms to form a 5-8 membered partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, an 8-10 membered bicyclic aromatic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each L is independently a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, -C(O)N(R)-, -(R)NC(O)-, -N(R)-, - N(R)C(O)N(R)-, -S-, -SO-, or -SO₂-;

each R’ is independently hydrogen, C1-6 aliphatic, or an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R⁴ is hydrogen, halogen, -OR⁵, -CN, C1-6 aliphatic optionally substituted with 1, 2, or 3 halogens, or -L-R’;

R⁵ is hydrogen, -(CH₂)_m-phenyl, or C_1-6 alkyl optionally substituted with 1, 2, or 3 halogens; m is 0, 1, 2, 3, or 4;

R⁶ is hydrogen or C1-4 alkyl;

Ring A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-12 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-12 membered saturated or partially unsaturated bicyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L¹ is a covalent bond or a C1-8 bivalent straight or branched hydrocarbon chain wherein 1-5 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, - C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-;

each -Cy- is independently a bivalent 6-membered arylene ring containing 0-2 nitrogen atoms, a bivalent 5-membered heteroarylene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a bivalent partially unsaturated 8-10 membered bicyclic heterocyclene ring with 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein -Cy- is optionally substituted with 1 or 2 substituents independently selected from C1-4 alkyl or -OR;

each R⁸ is independently hydrogen, -CO₂R, or C_1-6 optionally substituted aliphatic;

R⁹ is hydrogen, halogen, C1-4 alkyl, C1-4 alkyl substituted with an optionally substituted phenyl, optionally substituted phenyl, -CN, -OR, or L²-R⁸;

each L² is independently a C_1-8 bivalent straight or branched hydrocarbon chain wherein 1-4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, - C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, -OC(O)N(R)-, -(R)NC(O)O-, - N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, -C(S)O-, -OC(S)-, - C(S)N(R)-, -(R)NC(S)-, or -(R)NC(S)N(R)-; and

n is 0, 1, 2, 3, 4, or 5.

2. The compound according to claim 1, wherein the compound is represented by Formulae II-a, II-b, or II-c:

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1, wherein the compound is represented by Formula III:

or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, wherein the compound is represented by Formulae IV-a, IV-b, IV-c, IV-d, IV-e, IV-f, IV-g, IV-h, IV-i, IV-j, or IV-k:

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, wherein the compound is represented by Formulae V-a, V-b, V-c, V-d, V-e, or V-f:

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, wherein the compound is represented by Formulae VI-a, VI-b, VI-c, or VI-d:

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1, wherein the compound is represented by Formulae VII-a or VII-b:

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, wherein the compound is represented by Formulae VIII-a, VIII-b, VIII-c, or VIII-d:

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1, wherein the compound is represented by Formulae IX-a or IX-b:

or a pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1-4, wherein R⁶ is hydrogen or methyl.

11. The compound according to any one of claims 1-10, wherein R¹ is methyl.

12. The compound according to any one of claims 1-11, wherein each R⁸ is independently hydrogen, methyl, -CO₂H, or -C(O)CH₃.

13. The compound according to any one of claims 1-12, wherein R² and R³ are each independently selected from halogen, C_1-4 alkyl, -OH, -OCH₃, -OCF₃, or -CN.

14. The compound according to any one of claims 1 or 3-9, wherein R⁴ is selected from hydrogen, halogen, C1-4 alkyl, -OH, -OCH3, -OCF3, or -CN.

15. The compound according to claim 14, wherein R⁴ is hydrogen.

16. The compound according to any one of claims 1-15, wherein R² and R³ are each independently methyl, F, or Cl.

17. The compound according to claim 16, wherein R² and R³ are each Cl.

18. The compound according to any one of claims 1-17, wherein L¹ is a C1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, or 3 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -N(R)-, -C(O)N(R)-, -(R)NC(O)-, - OC(O)N(R)-, -(R)NC(O)O-, -N(R)C(O)N(R)-, -S-, -SO-, -SO2-, -SO2N(R)-, -(R)NSO2-, -C(S)-, - C(S)O-, -OC(S)-, -C(S)N(R)-, -(R)NC(S)-, -(R)NC(S)N(R)-, or -Cy-, wherein each R is independently hydrogen, -CH₂-phenyl, phenyl, -CH₃, -CH₂CH₃, cyclopentyl, cyclohexyl, -CH₂F, -CHF2, -CF3, -CH2CHF2, or -CH2CF3.

19. The compound according to claim 18, wherein L¹ is a C_1-6 bivalent straight or branched hydrocarbon chain wherein 1, 2, 3, or 4 methylene units of the chain are independently and optionally replaced with -O-, -C(O)-, -C(O)O-, -OC(O)-, -NH-, -C(O)NH-, -NHC(O)-, - NHC(O)NH-, -SO₂-, or -Cy-.

20. The compound according to claim 18, wherein L¹ is

wherein each -Cy- is

independently phenylene, pyridinylene, pyrimidinylene, pyrazinylene,

21. The compound according to claim 1, wherein the compound is selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising a compound according to any one of claims 1- 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier, or vehicle.

23. A method for treating a PHGDH-mediated disorder in a patient in need thereof, comprising administering to said patient the compound of any one of claims 1-21 or a pharmaceutical composition thereof.

24. A method for treating cancer in a patient in need thereof, comprising administering to said patient the compound of any one of claims 1-21.

25. The method of claim 24, wherein the cancer is melanoma or breast cancer.

26. A method for treating a tumor in a patient in need thereof, comprising administering to said patient the compound of any one of claims 1-21.

27. The method of claim 26, wherein the tumor comprises a melanoma, breast, or lung cancer.

28. The method of claim 26, wherein the tumor comprises a small cell lung cancer (SCLC) or a non-small cell lung cancer (NSCLC).