WO2011050284A1 - Pyrazolylpyridine antiviral agents - Google Patents

Pyrazolylpyridine antiviral agents Download PDF

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Publication number
WO2011050284A1
WO2011050284A1 PCT/US2010/053789 US2010053789W WO2011050284A1 WO 2011050284 A1 WO2011050284 A1 WO 2011050284A1 US 2010053789 W US2010053789 W US 2010053789W WO 2011050284 A1 WO2011050284 A1 WO 2011050284A1
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WIPO (PCT)
Prior art keywords
pyrazolo
piperazinone
chloro
cyclopropyl
pyridin
Prior art date
Application number
PCT/US2010/053789
Other languages
French (fr)
Inventor
Anna Banka
John G. Catalano
Pek Yoke Chong
Jing Fang
Dulce Maria Garrido
Andy Maynard
John Miller
Dan Patterson
Andrew James Peat
Jeremiah Powers
Daniel J. Price
Chris Roberts
Vincent Tai
Michael Youngman
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Glaxosmithkline Llc
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Publication of WO2011050284A1 publication Critical patent/WO2011050284A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of pharmaceuticals.
  • HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans.
  • the genome is a single ⁇ 9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of ⁇ 3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR).
  • the polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles.
  • HCV polyprotein The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.
  • HCV is major causative agent for post-transfusion and for sporadic hepatitis. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. An estimated 70 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et ai, Pathoi.OncoI.Res. 2003, 9:215-221 , and Hoofnagle JH, Hepatology 1997, 26:15S-20S. In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV-related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.
  • the standard treatment for chronic HCV is interferon alpha (IFN- alpha) in combination with ribavirin and this requires at least six months of treatment.
  • IFN- alpha interferon alpha
  • IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.
  • Ribavirin an inhibitor of inosine 5'-monophosphate dehydrogenase (I PDH), enhances the efficacy of IFN-alpha in the treatment of HCV.
  • IPN interferon-alpha
  • ribavirin an inhibitor of inosine 5'-monophosphate dehydrogenase
  • ribavirin an inhibitor of inosine 5'-monophosphate dehydrogenase (I PDH)
  • IPN interferon-alpha
  • ribavirin standard therapy of chronic hepatitis C has been changed to the combination of pegylated IFN-alpha plus ribavirin.
  • Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clear need for more effective antiviral therapy of HCV infection.
  • a number of approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection.
  • the viral targets the NS3/4a protease/helicase and the NS5b RNA- dependent RNA polymerase are considered the most promising viral targets for new drugs.
  • compounds said to be useful for treating HCV infections are disclosed, for example, in WO2005/051318 (Chunduru, ef a/.) and WO2009/023179 (Schmitz, ef a/.). These references disclose methods for preparing the compounds, compositions comprising the compounds, compositions comprising the compounds and additional compounds, and methods of treating HCV.
  • antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication.
  • antiviral activity can be achieved by inhibiting host cell cyclophilins.
  • a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans.
  • Flaviviridae family of viruses and further in view of the limited treatment options, there is a strong need for new effective drugs for treating infections cause by these viruses.
  • Z is optionally a bond or (C C 3 )alkylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, halo, (Ci-C 6 )alkyl, (C
  • R is selected from the group consisting of hydrogen, halo, cyano, hydroxy!, (Cr Ce)alkyl, (C r C 6 )alkoxy, (C r C 6 )alkenyl, (C C 6 )alkynyl, -C(0)N(R 6 ) 2 , -R 9 R 6 , -SOsN ⁇ 6 , -S0 2 R 6 , (C 3 -C 14 )cycloalkyl, aryl, (C 2 -C B )heterocyclic having 1- 3 heteroatoms selected from S, N and O, and (C2-Ce)heteroaryl having 1 -3 heteroatoms selected from S, N, and O; wherein said alkyl, aikoxy, alkenyl, alkynyl, cycloaikyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R 11 ;
  • R 2 is independently selected from the group consisting of hydrogen, hydroxy), oxo, (Ci-Ce)alkyl, (C 3 -C 4 )cycloalkyl, -alkylR 6 , and aryl, or optionally two R 2 alky[ groups, together with any intervening atoms, form a spiro or fused (C 3 - Ci 4 )cycioalkyl ring;
  • R 3 is selected from the group consisting of hydrogen, (C r C 6 )alkyl, (C 3 - Ci 4 )cycloalkyi, halo, -alkylR 8 , and cyano;
  • R 4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (C C 6 )alkyl, (C C 6 )alkoxy, (C C 6 )alkenyl, (Ci-C 6 )alkynyl, (C 3 -C 14 )cycloalkyl, aryl, -OR 6 (R 5 ) m , -R 6 (R 5 ) m , -alky!(R 5 ) m R e , -alkylR 9 R 6 , -NR 6 R 6 , - NR 6 C(0)NR 6 R 6 , -S0 2 NR 6 R 6 , -C(0)NR 6 R 6 , -OR 7 , -R 6 R 7 , -S0 2 R 6 , - NR 6 C(S)NR 6 R 6 , -NR 6 S(0) 2 R 6 , -a!kylR 9 R 6 , -NR e C(0)
  • R 5 is independently selected from the group consisting of hydrogen and halo
  • R 6 is independently selected from the group consisting of hydrogen and (C
  • R 7 is (C 3 -C 14 )cycloalkyl
  • R 8 is hydroxyl
  • R 9 is carboxyl
  • R 10 is independently selected from the group consisting of (C r C 6 )alkyl, (C
  • R 11 is independently selected from the group consisting of (C C 6 )alkyl, (C
  • C 14 cycloalkyl, aryl, (C 2 -C 6 )heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C 2 -C 6 )heteroaryl having 1-3 heteroatoms selected from S, N, and O; or optionally two R 1 groups, together with any intervening atoms, form a fused (C 3 -C 14 )cycloa[kyl ring or a fused (C 2 - C 6 )heterocyclic ring having 1 -3 heteroatoms selected from S, N and 0; wherein said fused cycloalkyl or heterocyclic ring is optionally substituted with one to three R 12 ;
  • R 12 is independently selected from the group consisting of (C-
  • n is an integer from 1 to 3;
  • n is zero or an integer from 1 to 4.
  • composition comprising a
  • a method for treating a virai infection in a patient mediated at least in part by a virus in the Flaviviridae family of viruses comprising administering to said patient a composition comprising a compound Formula (I), or a pharmaceutically acceptable salt or solvate thereof.
  • the viral infection is mediated by hepatitis C virus.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C x- Cy)alkyl refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH3CH2-), n-propyl (CH 3 CH Z CH 2 ⁇ ), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), f-butyl ( ⁇ CH 3 ) 3 C-), n-penty! (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • Alkylidene or alkylene refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
  • (C u-V )alkylene refers to alkylene groups having from u to v carbon atoms.
  • the alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups.
  • (C 1-6 )alkylene is meant to include methylene, ethylene, propylene, 2- methypropylene, pentylene, and so forth.
  • (C x - C y )alkenyl refers to aikenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1 ,3-butadienyl, and the like.
  • Alkynyl refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond.
  • alkynyl is also meant to include those hydrocarbyl groups having one triple bond and one double bond.
  • (C 2 -C 6 )alkyn l is meant to include ethynyl, propynyl, and the like.
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, / butoxy, f-butoxy, sec-butoxy, and n-pentoxy.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-,
  • alkynyl-C(O)- alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-.
  • Acyl includes the "acetyl" group CH 3 C(0)-.
  • Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)cycloalkyl,
  • R 20 is hydrogen or alkyl
  • Acyloxy refers to the groups alkyl-C(0)0-, alkenyl-C(0)0-,
  • Amino refers to the group -NR 21 R 22 where R 21 and R 22 are independently selected from hydrogen, alkyl, aikenyl, alkynyl, aryl, cyc!oalkyl, heteroaryl, heterocyclic, -S0 2 -alkyl, -S0 2 -alkenyl, -S0 2 -cycloalkyl, -S0 2 -aryl, -S0 2 -heteroaryl, and
  • R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • R 2 is hydrogen and R 22 is alkyl
  • the amino group is sometimes referred to herein as alkylamino.
  • R 21 and R 22 are alkyl, the amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R 21 or R 22 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 2 nor R 22 are hydrogen.
  • Hydroxyamino refers to the group -NHOH.
  • Alkoxyamino refers to the group -NHO-alkyl wherein alkyl is defined herein.
  • Aminocarbonyl refers to the group -C(0)NR 6 R 27 where R 26 and R 27 are independently selected from hydrogen, aikyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R 26 and R 27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
  • Aryl or “Ar” refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl).
  • Aryl or “Ar” applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
  • Cycloalkyl refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,- tetrahydronaphthalene-5-yl).
  • Cycloalkyl includes cycloaikenyl groups, such as cyclohexenyl.
  • cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and
  • cyclohexenyl examples include multiple ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such cycloalkyl multiple ring structures are exemplified and named below:
  • (C u- C v )cycloalkyl refers to cycloalkyl groups having u to v carbon atoms.
  • Spiro cycloalkyl refers to a 3 to 1 0 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkyiene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the group shown here attached to bonds marked with wavy lines is substituted with a spiro cycloalkyl group:
  • Fused cycloalkyl refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyl grou :
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Haloalkoxy refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
  • Heteroaryi refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl).
  • single ring e.g. imidazolyl
  • multiple ring systems e.g. benzimidazol-2-yl and benzimidazol-6-yl.
  • the term “heteroaryi” applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaryi group are optionally oxidized to provide for the N-oxide (N ⁇ 0), sulfinyl, or suifonyl moieties.
  • heteroaryi includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyi, pyrroiyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl,
  • Heterocyclic or “heterocycle” or “heterocycloalkyl” or “heterocyclyl” refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems.
  • heterocyclic For multiple ring systems having aromatic and/or non-aromatic rings, the terms “heterocyclic”, “heterocycle”, “heterocycloalkyl”, or “heterocyclyl” apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g. 1 ,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and
  • the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties.
  • the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon- 1-yl, morpholinyl, and pyrrolidiny!.
  • a prefix indicating the number of carbon atoms (e.g., C 3 - Cio) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
  • heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 , 2, 3, 4-tetrahydr
  • fused heterocyclic refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:
  • Compound refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgenerlc formulae, Including the racemates, stereoisomers, and tautomers of the compound or compounds.
  • Oxazolidinone refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms "connected by a carbonyl” and 2 carbons, as exemplified by the following structure wherein the oxazolidinone group shown here is bonded to a parent molecule, which is indicated by a wavy line in the bond:
  • Racemates refers to a mixture of enantiomers.
  • the compounds of Formula I, or pharmaceutically acceptable salts thereof are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration.
  • reference to an enantiomerically enriched compound or salt is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
  • Solvate or “solvates” of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvates of a compound includes solvates of all forms of the compound.
  • solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraa!kylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahi, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002. [0046] "Patient” refers to mammals and includes humans and non-human mammals.
  • Treating" or “treatment” of a disease in a patient refers to 1 ) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent "arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-0-C(0)-.
  • C(R X ) 2 it should be understood that the two R x groups can be the same, or they can be different if R x is defined as having more than one possible identity.
  • certain substituents are drawn as -R x R y , where the "-" indicates a bond adjacent to the parent molecule and R y being the terminal portion of the functionality.
  • impermissible substitution patterns ⁇ e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
  • Z is optionally a bond or (C C 3 )alkylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, halo, (C C 6 )alky[, (C
  • R 6 -alky!R 9 R 6 , -NR 6 C(0)OR 6 , -NR 6 C(0)R 6 , (C 2 -C 6 )heteroaryl having 1-3 heteroatoms selected from S, N, and O, (C 2 -C 6 )heterocyclic having 1 -3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R 10 ;
  • R 1 is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (d-
  • R 2 is independently selected from the group consisting of hydrogen, hydroxyl, oxo, (C r C 6 )alkyl, (C 3 -C 4 )cycloa!kyl, -alkylR 8 , and aryl, or optionally two R 2 alkyl groups, together with any intervening atoms, form a spiro or fused (C 3 - Ci )cycloalkyl ring;
  • R 3 is selected from the group consisting of hydrogen, (C r C 6 )alkyl, (C 3 -
  • Ci 4 cycloaikyl, halo, -alkylR 8 , and cyano
  • R 4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (d- Cejalkyl, (C C 6 )alkoxy, (C r C 6 )alkeny!, (d-Ce)alkynyl, (d ⁇ d4)cycloa!kyl, aryl, -OR 6 (R 5 ) m , -R 6 (R 5 ) m , -alkyl(R 5 ) m R 6 , -alkylR 3 R 6 , -NR 6 R 6 , -
  • R 5 is independently selected from the group consisting of hydrogen and halo
  • R 6 is independently selected from the group consisting of hydrogen and (d- C 6 )alkyi
  • R 7 is (C 3 -d )cycloa!kyl
  • R 8 is hydroxyl
  • R 9 is carboxyl
  • R 10 is independently selected from the group consisting of (d-Ce)alkyl, (d-
  • R 11 is independently selected from the group consisting of (C C 6 )alkyl, (C-p
  • R 12 is independently selected from the group consisting of (C C 6 )alkyl, (C
  • n is an integer from 1 to 3;
  • n is zero or an integer from 1 to 4.
  • A is selected from the group consisting of hydrogen, ⁇ C-i-C 6 )alkyl, halo, hydroxyl, (C C 6 )aikoxy, -OR 7 , -alkoxy(R 5 ) m , (C 3 -C 14 )cycloalkyl, -R 6 (C 3 - C 1 )cycloalkyl, (C 2 -C 6 )heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C 2 -C 6 )heteroaryl having 1-3 heteroatoms selected from S, N, and O.
  • A is selected from the group consisting of hydrogen, hydroxyl, bromo, fluoro, chloro, iodo, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropylmethyl, cydopropyloxy, methoxy, ethoxy, propoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl.
  • R 1 is selected from the group consisting of hydrogen, (C r C 6 )alkyl, ⁇ C 3 -C 4 )cycloalkyl, aryl, (C 2 -C 6 )heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C 2 -C 6 )heteroaryl having 1 -3 heteroatoms selected from S, N, and O.
  • R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, acetate, thiazo!yl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyc!opentenyl, cyclohexenyi, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl,
  • R is selected from the group consisting of oxazolidinone, cyciopentyl, cyclobutyl, and cyclohexyl.
  • R 3 is selected from the group consisting of hydrogen, (C C 6 )alkyl, halo, cyano, -afkylR 8 , and (C 3 -C 14 )cycloa!kyl.
  • R 3 is selected from the group consisting of hydrogen, methyl, ethyl, chioro, bromo, cyano, hydroxymethyl, and cyclopropyl.
  • R 3 is selected from the group consisting of hydrogen, chioro, bromo, and cyano.
  • R 4 is selected from the group consisting of hydrogen, (C-
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, dimethylamino, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, chioro, fluoro, bromo, difluoroethyl, and trifluoromethyl.
  • R 11 is selected from the group consisting of hydroxyl, oxo, -OC(0)R 6 , -alkylR 8 , -R 6 (R 6 ) m , halo, ⁇ C C 6 )a!kyf, and (C C 6 )a!koxy.
  • R 11 is selected from the group consisting of hydroxyl, oxo, hydroxymethyl, acyloxy, fluoro, trifluoromethyl, methoxy, and methyl.
  • R 11 is selected from the group consisting of methyl, hydroxy], and oxo.
  • Z is optionally a bond or methylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, bromo, fluoro, chloro, iodo, methyi, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropyloxy, methoxy, ethoxy, propoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl;
  • R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, acetate, thiazolyl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyc!ohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl, wherein R 1 is optionally substituted with one to two R 11 ;
  • R 2 is independently selected from the group consisting of hydrogen, oxo, methyl, ethyl, cyciopropyl, hydroxymethyl, and phenyl, or optionally two R 2 groups, together with any intervening atoms, form a spiro or fused cycloalkyl ring;
  • R 3 is selected from the group consisting of hydrogen, chloro, bromo, fluoro, and cyano;
  • R 4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, dimethylamino, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, chloro, fluoro, bromo, difluoroethyl, and trifluoromethyl;
  • R 5 is independently selected from the group consisting of hydrogen and halo; R 1 is independently selected from the group consisting of hydroxyl, oxo,
  • n is zero or an integer from 1 to 4.
  • Z is optionally a bond or methylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, (C r C 6 )alkoxy, hydroxyl, and
  • R is selected from the group consisting of (Cs-C-uJcycloalkyl and (C 2 -
  • R is optionally substituted with one to two R 11 ;
  • R 2 is oxo
  • R 3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano;
  • R 4 is trifluoromethyl;
  • R 5 is independently selected from the group consisting of hydrogen and halo;
  • R 1 is independently selected from the group consisting of methyl, hydroxyl, and oxo;
  • n is zero or an integer from 1 to 4.
  • Z is optionally a bond or methylene
  • W is selected from CH or N;
  • A is selected from the group consisting of methoxy, hydroxyl, and cyclopropyl
  • R 1 is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyi, and cyclohexyl, wherein R is optionally substituted with one to two R 1 ;
  • R 2 is oxo
  • R 3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano;
  • R 4 is trifluoromethyl;
  • R 5 is independently selected from the group consisting of hydrogen and chloro;
  • R 1 is independently selected from the group consisting of methyl, hydroxyl, and oxo;
  • n is zero or an integer from 1 to 4.
  • R 1 or a pharmaceutically acceptable salt thereof, wherein:
  • Z is optionally a bond or methylene
  • W is selected from CH or N;
  • A is selected from the group consisting of methoxy, hydroxy], and cyclopropyl
  • R 1 is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyl, and cyclohexyl, wherein R is optionally substituted with one to two R 11 ;
  • R 2 is hydrogen
  • R 3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano;
  • R 4 is trifluoromethyl;
  • R 5 is independently selected from the group consisting of hydrogen and chloro
  • R 11 is independently selected from the group consisting of methyl, hydroxyl, and oxo
  • n is zero or an integer from 1 to 4.
  • Z is optionally a bond or (Ci-C 3 )alkylene
  • W is selected from CH or N;
  • A is selected from the group consisting of hydrogen, halo, (C r )
  • R is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (d- C 6 )alky!, (C r C 6 )a[koxy, (C C 6 )alkenyl, (C r C 6 )alkynyl, -C(0)N(R 6 ) 2 , -R 9 R 6 , -S0 2 NR 6 R 6 , -S0 2 R
  • R 3 is selected from the group consisting of hydrogen, (CrC 6 )alkyl, (C 3 - Ci 4 )cycloalkyl, halo, -alkylR 8 , and cyano;
  • R 4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (C
  • C 6 heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R 1Q ;
  • R 5 is independently selected from the group consisting of hydrogen and halo;
  • R 6 is independently selected from the group consisting of hydrogen and (C
  • R 7 is (C 3 -Ci 4 )cycloalkyl
  • R 8 is hydroxyl
  • R 9 is carboxyl
  • R 10 is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C r )
  • R 1 is independently selected from the group consisting of (C 1 -C 6 )alkyl, (C
  • R 2 is independently selected from the group consisting of (d-CeJalkyl, (C r )
  • n is an integer from 1 to 3.
  • the compound of the present invention is 4- ⁇ [3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]p.yridin-2-yl]carbonyi ⁇ -1 -(4- hydroxycyclohexyl)-2-piperazinone, or a pharmaceutically acceptable salt thereof.
  • the compound of the present invention is 4- ⁇ [3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony[ ⁇ -1 -(trans-4- hydroxycyciohexyl)-2-piperazinone, or a pharmaceutically acceptable salt thereof.
  • Formula (I), wherein the compound or salt of the compound is used in the manufacture of a medicament for use in the treatment of a viral infection in a human.
  • a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in a compound of Formula (I).
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been
  • compound of Formula (I) further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV rep!icase, HCV NS5A protein, or inosine 5'-
  • a method for treating a virai infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae 35 family of viruses which method comprises administering to a mammal, that has been
  • a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.
  • the compound of the present invention is chosen from the compounds set forth in Table 1.
  • the compound of the present invention is chosen from the compounds set forth in Table 2.
  • the compounds of Table 2 may be synthesized according to the following synthetic methods, schemes, and the Examples.
  • the compound(s) of the present invention is chosen from the compounds set forth in Table 1 and/or Table 2.
  • the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For exam le, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
  • the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well- known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. ( ilwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA).
  • reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -78 °C to about 1 10 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like.
  • solvent solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like.
  • THF tetrahydrofuranyl
  • DMF dimethylformamide
  • the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • Substituted pyridines can be converted to the corresponding 1 -aminopyridinium salts 1.1 by treatment with a number of aminating agents (O-acyl, O-aryl-, O-phosphinyl- and O- sulfonylhydroxylamines) such as O-mesitylenesulfonylhydroxylamine (MSH) and hydroxylamine-O-sulfonic acid (HOSA).
  • Aminating agents O-acyl, O-aryl-, O-phosphinyl- and O- sulfonylhydroxylamines
  • MSH O-mesitylenesulfonylhydroxylamine
  • HOSA hydroxylamine-O-sulfonic acid
  • halogens can be introduced to the carboxylic acids 1.6.
  • Intermediates 1.4 can also undergo metal-catalyzed or metal-mediated cross coupling reactions to provide methyl esters 1.5, which can be saponified to carboxylic acids 1.7.
  • Esters 1.3 and 1.4 where A CI, Br, I, OTf, B(OH) 2 , for example, can undergo metal-catalyzed or metal-mediated cross coupling reactions (including, but not limited to, Suzuki, Stille, Sonogashira, Negishi, and Buchwald-Hartwig reactions) to introduce new groups at position A (intermediate 1.8) and subsequent saponification can yield the substituted acids 1.9.
  • metal-catalyzed or metal-mediated cross coupling reactions including, but not limited to, Suzuki, Stille, Sonogashira, Negishi, and Buchwald-Hartwig reactions
  • A Aryl, Heteroaryl, Alkyl,
  • N-Hoteroaryl N-Alkyl, etc.
  • DME Duibeco's Modified Eagle's Medium
  • HCV hepatitus C virus
  • IC 50 inhibitory concentration at 50% inhibition
  • nm nanomolar
  • lodomethane (0.48 ml_, 7.7 mmol) was added to a solution of 2- (trifluoromethyl)-4-pyridino! (0.58 g, 3.5 mmol, prepared according to reference: Tyvorskii, V. I.; Bobrov, D. N. Chemistry of Heterocyclic Compounds. 1997, 33, 995.) and potassium carbonate (0.59 g, 4.3 mmol) in DMF (7 ml_). The reaction mixture was heated at 65 °C for 2 hours, diluted with water, and extracted with 9:1 hexanes:CH 2 CI 2 .
  • N-Bromosuccinimide (0.019 g, 0.1 1 mmol) was added to a solution of 3-(1- ⁇ [5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin ⁇ 2-yl]carbonyl ⁇ -4-piperi
  • N-Chlorosuccinimide (0.018 g, 0.13 mmol) was added to a solution of 3-(1- ⁇ [5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl ⁇ -4-piperidinyl)-1 , ⁇ oxazolidin-2-one (0.045 g, 0.11 mmol) in DMF (1.1 mL).
  • the reaction mixture was heated at 50 °C overnight and 57 °C for 6 hours, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.011 g, 22%) as a white solid.
  • N-phenyltrifluoromethanesulfonimide (0.080 g, 0.22 mmol) was added to a
  • N-Bromosucctnimide (0.005 g, 0.03 mmol) was added to a solution of 3-(1- ⁇ [5-cyclopropyl-7-(trifluoromethyl)py ⁇
  • N-Chlorosuccinimide (0.015 g, 0.1 1 mmol) was added to a solution of 3-(1- ⁇ [5-cyclopropyl-7-(trifluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl ⁇ -4-piperidinyl)-1 , ⁇ oxazo!idin-2-one (0.043 g, 0.10 mmol) in DMF (1 mL). The reaction mixture was heated at 50 °C for 5 hours and 55 °C overnight.
  • N-phenyltrifluoromethanesuifonimide (0.55 g, 1.53 mmol) was added to a solution of methyl 5-hydroxy-7-(trifluoromethyI)pyrazoio[1 ,5-a]pyridine-2-carboxylate (0.31 g, 1.18 mmol) and DIPEA (0.41 ml, 2.35 mmol) in dichloromethane (1 1.8 ml).
  • the reaction mixture was stirred at room temperature for 3 hours, an additional portion of N- phenyltrifluoromethanesulfonimide (0.30 g, 0.84 mmol) was added, and stirring was continued for another 7 hours.
  • reaction mixture was concentrated and purified by silica gel chromatography (0-10% MeOH in CH 2 Cl 2 ) followed by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.0072 g, 16%) as a white solid.
  • N-Chlorosuccinimide (0.014 g, 0.11 mmoi) was added to a solution of 3-(1- ⁇ [5-cyclopropyl-7-(trifluoromethyl)pyrazolo[ ⁇ ⁇
  • N-Bromosuccinimide (0.042 g, 0.10 mmol) was added to a solution of 1- cyclopentyl-4- ⁇ [5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ) 5-a]pyridin-2-yl]carbonyl ⁇ -2- piperazinone (0.042 g, 0.12 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature overnight, concentrated and purified by reverse phase HPLC
  • N-Chlorosuccinimide (0.032 g, 0.24 mmol) was added to a solution of 1 - cycIopentyl-4- ⁇ [5-cyclopropyl-7-(trifluoromethy!)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl ⁇ -2- piperazinone (0.067 g, 0.16 mmoi) in DMF (1.6 mL).
  • the reaction mixture was heated at 55 °C overnight, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.042 g, 58%) as a white solid.
  • N-Bromosuccinimide (0.021 g, 0.12 mmol) was added to a solution of 1- cyclobutyl-4- ⁇ [5-cyclopropyl-7-(trifluoromethyl)pyrazo!o[1 ,5-a]pyridin-2-yl]carbonyl ⁇ -2- piperazinone (0.041 g, 0.10 mmol) in DMF (1 ml_).
  • the reaction mixture was stirred at room temperature for 30 minutes, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.012 g, 24%) as a white solid.
  • N-Chlorosuccinimide (0.032 g, 0.24 mmol) was added to a solution of 1 - cyclobutyl-4- ⁇ [5-cyclopropyl-7-(trif[uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl ⁇ -2- piperazinone (0.065 g, 0.16 mmol) in D F (1 .6 mL). The reaction mixture was heated at 55 °C overnight, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.063 g, 90%) as a white solid.
  • HATU (7.32 g, 19.24 mmol) was added to a mixture of N-[(4- nitrophenyl)sulfonyl]glycine (4.17 g, 16.04 mmol), (3-methylcyclobutyl)amine hydrochloride (1.95 g, 16.04 mmol) and DIPEA (8.40 mL, 48.1 mmol) in DMF (50 mL).
  • the mixture was stirred at RT overnight then EtOAc and water were added.
  • the organic layer was washed with water and brine and dried over sodium sulfate.
  • the solvent was evaporated to give the title compound (5.10 g, 97%) as a pink solid that was used without further purification.
  • N-Chlorosuccinimide (0.027 g, 0.20 mmoi) was added to a solution of 4- ⁇ [5- cyclo pro py l-7-(trif lu o rom eth yl )pyra zo
  • N-Chlorosuccinimide (1.02 g, 7.6 mmol) was added to a solution of methyl 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (1.44 g, 5.1 mmol) in DMF (17 mL).
  • the reaction mixture was heated at 60 °C for 1 hour, concentrated and purified by silica gel chromatography (15-30% EtOAc in hexanes) to afford the title compound (1.47 g, 91%) as a white solid.
  • 1 H N R 400 MHz, CHLOROFORM-d
  • DIPEA (2.3 ml, 13.1 mmol) was added dropwise to a solution of 3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (1 .00 g, 3.3 mmol) and 1-(ira 7s-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (1.16 g, 4.9 mmol) in DMF (8.9 ml). The reaction mixture was stirred at room temperature for 30 minutes, cooled to 0 °C and 1 -propanephosphoric acid cyclic anhydride (2.93 ml of a 50% wt % in EtOAc, 4.9 mmol) was added dropwise.
  • N-Bromosuccinimide (0.101 g, 0.57 mmol) was added to a solution of 4- ⁇ [5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyndin-2-yl]carbonyl ⁇ -1 -(ira/is-4- hydroxycyclohexyl)-2-piperazinone (0.21 g, 0.47 mmol) in DMF (4.7 mL).
  • the reaction mixture was stirred at room temperature for 30 minutes, concentrated and purified by silica gel chromatography (0-10% MeOH in CH 2 CI 2 ) to afford the title compound (0.17 g, 67%) as a white foam.
  • the reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc and washed with 5% LiCl (3x), saturated NaHC0 3) brine, dried (MgSO ⁇ ), filtered, and concentrated.
  • the crude residue was purified by silica gel chromatography (0-5% MeOHT>CM) to give the product which was farther purified by reverse phase chromatography (5-95% ACN/Water + 0.1% formic acid) to give the title compound (0.048 g, 18%).

Abstract

Provided are compounds of Formula (I) and/or Formula (II) and pharmaceutically acceptable salts thereof, their pharmaceutical compositions, their methods of preparation, and their use for treating viral infections mediated by a member of the Flaviviridae family of viruses such as hepatitis C virus (HCV).

Description

PYR AZO LYLPYRIDINE ANTIVIRAL AGENTS
CROSS REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS
[0001] This application is a Patent Cooperation Treaty application and claims the priority benefit of U.S. Provisional Patent Application No. 61/254,372, filed October 23, 2009, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of pharmaceuticals. Provided herein are compounds and compositions, methods for their preparation, and methods for their use in treating viral infections in patients mediated, at least in part, by a virus in the Flaviviridae family of viruses. BACKGROUND OF THE INVENTION
[0003] Chronic infection with HCV is a major health problem associated with chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver failure. HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans. The genome is a single ~9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of ~3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR). The polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles. The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.
[0004] HCV is major causative agent for post-transfusion and for sporadic hepatitis. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. An estimated 70 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et ai, Pathoi.OncoI.Res. 2003, 9:215-221 , and Hoofnagle JH, Hepatology 1997, 26:15S-20S. In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV-related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years. [0005] At present, the standard treatment for chronic HCV is interferon alpha (IFN- alpha) in combination with ribavirin and this requires at least six months of treatment.
IFN-alpha belongs to a family of naturally occurring small proteins with characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities that are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction. Ribavirin, an inhibitor of inosine 5'-monophosphate dehydrogenase (I PDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and ribavirin. By now, standard therapy of chronic hepatitis C has been changed to the combination of pegylated IFN-alpha plus ribavirin. However, a number of patients still have significant side effects, primarily related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic. Even with recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clear need for more effective antiviral therapy of HCV infection.
[0006] A number of approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. Among the viral targets, the NS3/4a protease/helicase and the NS5b RNA- dependent RNA polymerase are considered the most promising viral targets for new drugs. Indeed, compounds said to be useful for treating HCV infections are disclosed, for example, in WO2005/051318 (Chunduru, ef a/.) and WO2009/023179 (Schmitz, ef a/.). These references disclose methods for preparing the compounds, compositions comprising the compounds, compositions comprising the compounds and additional compounds, and methods of treating HCV.
[0007] Besides targeting viral genes and their transcription and translation products, antiviral activity can also be achieved by targeting host cell proteins that are necessary for viral replication. For example, antiviral activity can be achieved by inhibiting host cell cyclophilins. Alternatively, a potent TLR7 agonist has been shown to reduce HCV plasma levels in humans. [0008] In view of the worldwide epidemic level of HCV and other members of the
Flaviviridae family of viruses, and further in view of the limited treatment options, there is a strong need for new effective drugs for treating infections cause by these viruses.
SUMMARY OF THE INVENTION
[0009] In accordance with one embodiment of the present invention, provided is a compound of Formula (I):
(I)
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (C C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo, (Ci-C6)alkyl, (C
C6)alkoxy, (CrC6)alkenyl, (Ci-C6)alkynyl, (C3-Ci4)cycloalkyl, aryl, hydroxy!, -NR6R6, -NRaC{0)NR6R6, -OR6(R5)m, -R6(R6)m, -S02NR6R6, -
C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C{0)R6, (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O, (C2-C6)heierocyclic having 1 -3 heteroatoms selected from S, N and O; wherein said a!kyl, aikoxy, alkenyl, alkynyl, cycloaikyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R10;
R is selected from the group consisting of hydrogen, halo, cyano, hydroxy!, (Cr Ce)alkyl, (CrC6)alkoxy, (CrC6)alkenyl, (C C6)alkynyl, -C(0)N(R6)2, -R9R6, -SOsN ^6, -S02R6, (C3-C14)cycloalkyl, aryl, (C2-CB)heterocyclic having 1- 3 heteroatoms selected from S, N and O, and (C2-Ce)heteroaryl having 1 -3 heteroatoms selected from S, N, and O; wherein said alkyl, aikoxy, alkenyl, alkynyl, cycloaikyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R11;
R2 is independently selected from the group consisting of hydrogen, hydroxy), oxo, (Ci-Ce)alkyl, (C3-C 4)cycloalkyl, -alkylR6, and aryl, or optionally two R2 alky[ groups, together with any intervening atoms, form a spiro or fused (C3- Ci4)cycioalkyl ring;
R3 is selected from the group consisting of hydrogen, (CrC6)alkyl, (C3- Ci4)cycloalkyi, halo, -alkylR8, and cyano;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (C C6)alkyl, (C C6)alkoxy, (C C6)alkenyl, (Ci-C6)alkynyl, (C3-C14)cycloalkyl, aryl, -OR6(R5)m, -R6(R5)m, -alky!(R5)mRe, -alkylR9R6, -NR6R6, - NR6C(0)NR6R6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02R6, - NR6C(S)NR6R6, -NR6S(0)2R6, -a!kylR9R6, -NReC(0)ORe, -NR6C{0)R6,
(C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and 0, (C2- Ce)heterocyclic having 1 -3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkeny!, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R10;
R5 is independently selected from the group consisting of hydrogen and halo;
R6 is independently selected from the group consisting of hydrogen and (C
C6)alkyl;
R7 is (C3-C14)cycloalkyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of (CrC6)alkyl, (C
C6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, hydroxyl, oxo, carboxyl, cyano, halo, -C(0)NH2, -S02NH2, -SR6, -S(0)R6, -S(0)2R6, -
S{0)2NR6R6, -NR6R6, -NR6C(0)NR6R6, -NR6C(S)NR6R6, - NR¾(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NReRe, -C(0)NR6R6, -
C(0)OR6, -C(0)R6, {C3-C14)cycloaikyl, aryl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2~C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O;
R11 is independently selected from the group consisting of (C C6)alkyl, (C
C6)alkoxy, (d-CeJalkenyl, (C C6)alkynyl, oxo, hydroxyl, -NR6R6 -
NR6C(0)R6, -OC(0)R6, -OR6(R5)m, -R6{R5)m, halo, -C(0)NR6 R6,
-S02NR6R6, -S02R6, -alkylR8, -alkylR9, -alkylR9R6, (C3-
C14)cycloalkyl, aryl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; or optionally two R 1 groups, together with any intervening atoms, form a fused (C3-C14)cycloa[kyl ring or a fused (C2- C6)heterocyclic ring having 1 -3 heteroatoms selected from S, N and 0; wherein said fused cycloalkyl or heterocyclic ring is optionally substituted with one to three R12;
R12 is independently selected from the group consisting of (C-|-C6)alkyl, (C
C6)alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -R6(R5)m, and -
NR6R6;
m is an integer from 1 to 3; and
n is zero or an integer from 1 to 4.
[0010] Also provided is a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Formula (l) or a pharmaceutically acceptable salt or solvate thereof.
[0011] Also provided are synthetic intermediates, methods for preparing the compounds of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and compositions thereof and for their therapeutic uses. In some embodiments, provided is a method for treating a virai infection in a patient mediated at least in part by a virus in the Flaviviridae family of viruses, comprising administering to said patient a composition comprising a compound Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the viral infection is mediated by hepatitis C virus. Those and other embodiments are further described in the text that follows.
DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS
[0012] Throughout this application, references are made to various embodiments relating to compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present invention.
[0013] it is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.
[0014] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 14 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms.
"(Cx-Cy)alkyl" refers to alkyl groups having from x to y carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CHZCH2~), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), f-butyl ({CH3)3C-), n-penty! (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
[0015] "Alkylidene" or "alkylene" refers to divalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and, in some embodiments, from 1 to 6 carbon atoms. "(Cu-V)alkylene" refers to alkylene groups having from u to v carbon atoms. The alkylidene and alkylene groups include branched and straight chain hydrocarbyl groups. For example "(C1-6)alkylene" is meant to include methylene, ethylene, propylene, 2- methypropylene, pentylene, and so forth.
[0016] "Aikenyl" refers to a linear or branched hydrocarbyl group having from 2 to 0 carbon atoms and in some embodiments from 2 to 6 carbon atoms or 2 to 4 carbon atoms and having at least 1 site of vinyl unsaturation (>C=C<). For example, (Cx- Cy)alkenyl refers to aikenyl groups having from x to y carbon atoms and is meant to include for example, ethenyl, propenyl, isopropylene, 1 ,3-butadienyl, and the like.
[0017] "Alkynyl" refers to a linear monovalent hydrocarbon radical or a branched monovalent hydrocarbon radical containing at least one triple bond. The term "alkynyl" is also meant to include those hydrocarbyl groups having one triple bond and one double bond. For example, (C2-C6)alkyn l is meant to include ethynyl, propynyl, and the like.
[0018] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, / butoxy, f-butoxy, sec-butoxy, and n-pentoxy.
[0019] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-,
alkynyl-C(O)-, cycloalkyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)-, and heterocyclic-C(O)-. Acyl includes the "acetyl" group CH3C(0)-.
[0020] "Acylamino" refers to the groups -NR20C(O)alkyl, -NR20C(O)cycloalkyl,
-NR20C(O)alkenyl, -NRZ0C(O)alkynyl, -NR20C(O)aryl, -NR20C(0)heteroaryl, and
-NR20C(O)heterocyclic, wherein R20 is hydrogen or alkyl.
[0021] "Acyloxy" refers to the groups alkyl-C(0)0-, alkenyl-C(0)0-,
alkynyl-C{0)0-, aryl-C(0)O~, cycloalkyl-C(0)0-, heteroaryl-C(0)0-, and
heterocyclic-C(0)0-.
[0022] "Amino" refers to the group -NR21R22 where R21 and R22 are independently selected from hydrogen, alkyl, aikenyl, alkynyl, aryl, cyc!oalkyl, heteroaryl, heterocyclic, -S02-alkyl, -S02-alkenyl, -S02-cycloalkyl, -S02-aryl, -S02-heteroaryl, and
-S02-heterocyclic, and wherein R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group. When R2 is hydrogen and R22 is alkyl, the amino group is sometimes referred to herein as alkylamino. When R21 and R22 are alkyl, the amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R21 or R22 is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R2 nor R22 are hydrogen.
[0023] "Hydroxyamino" refers to the group -NHOH.
[0024] "Alkoxyamino" refers to the group -NHO-alkyl wherein alkyl is defined herein.
[0025] "Aminocarbonyl" refers to the group -C(0)NR 6R27 where R26 and R27 are independently selected from hydrogen, aikyl, alkenyl, alkynyl, aryl, cycloalkyl, heteroaryl, heterocyclic, hydroxy, alkoxy, amino, and acylamino, and where R26 and R27 are optionally joined together with the nitrogen bound thereto to form a heterocyclic group.
[0026] "Aryl" or "Ar" refers to an aromatic group of from 6 to 14 carbon atoms and no ring heteroatoms and having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "Aryl" or "Ar" applies when the point of attachment is at an aromatic carbon atom (e.g., 5,6,7,8 tetrahydronaphthalene-2-yl is an aryl group as its point of attachment is at the 2-position of the aromatic phenyl ring).
[0027] "Cyano" or "carbonitri!e" refers to the group -CN.
[0028] "Cycloalkyl" refers to a saturated or partially saturated cyclic group of from 3 to 14 carbon atoms and no ring heteroatoms and having a single ring or multiple rings including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and non-aromatic rings that have no ring heteroatoms, the term "cycloalkyl" applies when the point of attachment is at a non-aromatic carbon atom (e.g. 5,6,7,8,- tetrahydronaphthalene-5-yl). The term "Cycloalkyl" includes cycloaikenyl groups, such as cyclohexenyl. Examples of cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and
cyclohexenyl. Examples of cycloalkyl groups that include multiple ring systems are bicyclohexyl, bicyclopentyl, bicyclooctyl, and the like. Two such cycloalkyl multiple ring structures are exemplified and named below:
Figure imgf000009_0001
bicyclohexyl, and bicyclohexyl.
[0029] "(Cu-Cv)cycloalkyl" refers to cycloalkyl groups having u to v carbon atoms.
[0030] "Spiro cycloalkyl" refers to a 3 to 1 0 member cyclic substituent formed by replacement of two hydrogen atoms at a common carbon atom in a cyclic ring structure or in an alkyiene group having 2 to 9 carbon atoms, as exemplified by the following structure wherein the group shown here attached to bonds marked with wavy lines is substituted with a spiro cycloalkyl group:
Figure imgf000010_0001
[0031] "Fused cycloalkyl" refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused cycloalkyl grou :
Figure imgf000010_0002
[0032] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[0033] "Haloalkoxy" refers to substitution of alkoxy groups with 1 to 5 (e.g. when the alkoxy group has at least 2 carbon atoms) or in some embodiments 1 to 3 halo groups (e.g. trifluoromethoxy).
[0034] "Hydroxy" or "hydroxyl" refers to the group -OH,
[0035] "Heteroaryi" refers to an aromatic group of from 1 to 14 carbon atoms and 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur and includes single ring (e.g. imidazolyl) and multiple ring systems (e.g. benzimidazol-2-yl and benzimidazol-6-yl). For multiple ring systems, including fused, bridged, and spiro ring systems having aromatic and non-aromatic rings, the term "heteroaryi" applies if there is at least one ring heteroatom and the point of attachment is at an atom of an aromatic ring (e.g. 1 ,2,3,4- tetrahydroquinolin-6-yl and 5,6,7,8-tetrahydroquinolin-3-yl). In some embodiments, the nitrogen and/or the sulfur ring atom(s) of the heteroaryi group are optionally oxidized to provide for the N-oxide (N→0), sulfinyl, or suifonyl moieties. More specifically the term heteroaryi includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, imidazolinyl, isoxazolyi, pyrroiyl, pyrazolyl, pyridazinyl, pyrimidinyl, purinyl, phthalazyl, naphthylpryidyl, benzofuranyl, tetrahydrobenzofuranyl,
isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazoly!, indoly!, isoindolyl, indolizinyl, dihydroindoiy!, indazolyl, indolinyl, benzoxazolyl, quinolyl, isoquinolyl, quinolizyl, quianazolyl, quinoxalyl, tetrahydroquinolinyl, isoquinolyl, quinazolinonyl, benzimidazoly!, benzisoxazolyl, benzothienyl, benzopyridazinyl, pteridinyl, carbazo!yl, carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenoxazinyl, phenothiazinyl, and phthalimidyl. [0036] Heterocyclic" or "heterocycle" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated cyclic group having from 1 to 14 carbon atoms and from 1 to 6 heteroatoms selected from nitrogen, sulfur, phosphorus or oxygen and includes single ring and multiple ring systems including fused, bridged, and spiro ring systems. For multiple ring systems having aromatic and/or non-aromatic rings, the terms "heterocyclic", "heterocycle", "heterocycloalkyl", or "heterocyclyl" apply when there is at least one ring heteroatom and the point of attachment is at an atom of a non-aromatic ring (e.g. 1 ,2,3,4-tetrahydroquinoline-3-yl, 5,6,7,8-tetrahydroquinoline-6-yl, and
decahydroquinolin-6-yl). In one embodiment, the nitrogen, phosphorus and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, phosphinane oxide, sulfinyl, sulfonyl moieties. More specifically the heterocyclyl includes, but is not limited to, tetrahydropyranyl, piperidinyl, piperazinyl, 3-pyrrolidinyl, 2-pyrrolidon- 1-yl, morpholinyl, and pyrrolidiny!. A prefix indicating the number of carbon atoms (e.g., C3- Cio) refers to the total number of carbon atoms in the portion of the heterocyclyl group exclusive of the number of heteroatoms.
[0037] Examples of heterocycle and heteroaryl groups include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, pyridone, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1 , 2, 3, 4-tetrahydro isoquinoline,
4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholine, thiomorpholine (also referred to as thiamorpholine), piperidine, pyrrolidine, and tetrahydrofuranyl.
[0038] "Fused heterocyclic" refers to a 3 to 10 member cyclic substituent formed by the replacement of two hydrogen atoms at different carbon atoms in a cycloalkyl ring structure, as exemplified by the following structure wherein the cycloalkyl group shown here contains bonds marked with wavy lines which are bonded to carbon atoms that are substituted with a fused heterocyclic group:
Figure imgf000011_0001
[0039] Compound", "compounds", "chemical entity", and "chemical entities" as used herein refers to a compound encompassed by the generic formulae disclosed herein, any subgenus of those generic formulae, and any forms of the compounds within the generic and subgenerlc formulae, Including the racemates, stereoisomers, and tautomers of the compound or compounds.
[0040] "Oxazolidinone" refers to a 5-membered heterocyclic ring containing one nitrogen and one oxygen as heteroatoms "connected by a carbonyl" and 2 carbons, as exemplified by the following structure wherein the oxazolidinone group shown here is bonded to a parent molecule, which is indicated by a wavy line in the bond:
Figure imgf000012_0001
[0041] "Racemates" refers to a mixture of enantiomers. In an embodiment of the invention, the compounds of Formula I, or pharmaceutically acceptable salts thereof, are enantiomerically enriched with one enantiomer wherein all of the chiral carbons referred to are in one configuration. In general, reference to an enantiomerically enriched compound or salt, is meant to indicate that the specified enantiomer will comprise more than 50% by weight of the total weight of all enantiomers of the compound or salt.
[0042] "Solvate" or "solvates" of a compound refer to those compounds, as defined above, which are bound to a stoichiometric or non-stoichiometric amount of a solvent. Solvates of a compound includes solvates of all forms of the compound. In certain embodiments, solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. Suitable solvates include water.
[0043] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
[0044] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.
[0045] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, and tetraa!kylammonium, and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, and oxalate. Suitable salts include those described in P. Heinrich Stahi, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002. [0046] "Patient" refers to mammals and includes humans and non-human mammals.
[0047] "Treating" or "treatment" of a disease in a patient refers to 1 ) preventing the disease from occurring in a patient that is predisposed or does not yet display symptoms of the disease; 2) inhibiting the disease or arresting its development; or 3) ameliorating or causing regression of the disease.
[0048] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-0-C(0)-. In a term such as "C(RX)2". it should be understood that the two Rx groups can be the same, or they can be different if Rx is defined as having more than one possible identity. In addition, certain substituents are drawn as -RxRy, where the "-" indicates a bond adjacent to the parent molecule and Ry being the terminal portion of the functionality. Similarly, it is understood that the above definitions are not intended to include impermissible substitution patterns {e.g., methyl substituted with 5 fluoro groups). Such impermissible substitution patterns are well known to the skilled artisan.
[0049] In one embodiment of the invention, there is provided a compound of
Formula (I):
(I)
Figure imgf000013_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (C C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo, (C C6)alky[, (C
C6)alkoxy, (Ci-C6)alkenyl, (C C6)alkynyl, (C3-C14)cycloa!ky[, aryl, hydroxyl, -NR6R6, -NR6C(0)NR6R6, -OR6(R5)m, -R6(R5)m, -S02NR6R6, -
C(0)NR6R6, -OR7, -ReR7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6,
-alky!R9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R10;
R1 is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (d-
C6)a[kyl, (CrC6)alkoxy, (CrC6)alkenyl, (d-Ce)alkynyl, -C(0)N(R6)2, -R9R6, -S02NR6R6, -S02R6, (C3-C14)cycloalkyl, aryl, (C2-C6)heterocyclic having 1 - 3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R11;
R2 is independently selected from the group consisting of hydrogen, hydroxyl, oxo, (CrC6)alkyl, (C3-C 4)cycloa!kyl, -alkylR8, and aryl, or optionally two R2 alkyl groups, together with any intervening atoms, form a spiro or fused (C3- Ci )cycloalkyl ring;
R3 is selected from the group consisting of hydrogen, (CrC6)alkyl, (C3-
Ci4)cycloaikyl, halo, -alkylR8, and cyano;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (d- Cejalkyl, (C C6)alkoxy, (CrC6)alkeny!, (d-Ce)alkynyl, (d~d4)cycloa!kyl, aryl, -OR6(R5)m, -R6(R5)m, -alkyl(R5)mR6, -alkylR3R6, -NR6R6, -
NR6C(0)NR6R6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02Re, - NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C{0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O, (C2- C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R10;
R5 is independently selected from the group consisting of hydrogen and halo; R6 is independently selected from the group consisting of hydrogen and (d- C6)alkyi;
R7 is (C3-d )cycloa!kyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of (d-Ce)alkyl, (d-
C6)alkoxy, (d-C6)alkenyl, (d-C6)alkynyl, hydroxy!, oxo, carboxyl, cyano, halo, -C(0)NH2| -S02NH2, -SR6, -S(0)R6, -S(0)2R6, -
S(0)2NR6R6, -NR6R6, -NR6C(0)NR6R6, -NR6C(S)NR6R6, - NR6S(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NR6R6, -C(0)NR6R6,.- C(0)OR6, -C(0)R6, (C3-C14)cycloalkyl, aryl, (C2-C6)heterocyciic having 1 -3 heteroatoms selected from S, N and 0, and (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O;
R11 is independently selected from the group consisting of (C C6)alkyl, (C-p
C6)alkoxy, (CrC6)alkenyl, (CrC6)alkynyl, oxo, hydroxyl, -NR6R6 - NR6C(0)R6, -OC(0)R6, -OR6(R )mi -R6(R5)m, halo, -C(0)NR6 R6,
-S02NR6R6, -S02R6, -alkylR8, -alkylR9, -alkylR9R6, (C3-
C1 )cycloaIkyl, aryl, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O; or optionally two R1 groups, together with any
intervening atoms, form a fused (C3-Ct )cycloalkyl ring or a fused (C2- C6)heterocyciic ring having 1 -3 heteroatoms selected from S, N and O; wherein said fused cycloalkyl or heterocyclic ring is optionally substituted with one to three R12;
R12 is independently selected from the group consisting of (C C6)alkyl, (C
C6)alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -R6(R5)mi and - NR6R6;
m is an integer from 1 to 3; and
n is zero or an integer from 1 to 4.
[0050] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein Z is a bond.
[0051] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein W is N.
[0052] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein W is CH.
[0053] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of hydrogen, {C-i-C6)alkyl, halo, hydroxyl, (C C6)aikoxy, -OR7, -alkoxy(R5)m, (C3-C14)cycloalkyl, -R6(C3- C1 )cycloalkyl, (C2-C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O.
[0054] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of hydrogen, hydroxyl, bromo, fluoro, chloro, iodo, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropylmethyl, cydopropyloxy, methoxy, ethoxy, propoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl. [0055] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein A is selected from the group consisting of methoxy, ethoxy, hydroxyl, cyclopropyl, methyl, ethyl, isobuty!, bromo, chloro, furanyl, and difluoromethoxy.
[0056] In another embodiment of the invention, there is provided a compound of Formula (I), wherein A is selected from the group consisting of methoxy, hydroxyl, and cyclopropyl.
[0057] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein A is cyclopropyl.
[0058] In another embodiment of the invention, there is provided a compound of Formula (l), wherein R1 is selected from the group consisting of hydrogen, (CrC6)alkyl, {C3-C 4)cycloalkyl, aryl, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O.
[0059] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, acetate, thiazo!yl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyc!opentenyl, cyclohexenyi, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl,
tetrahydrothiopyranyl, and thienyl.
[0060] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R is selected from the group consisting of oxazolidinone, cyciopentyl, cyclobutyl, and cyclohexyl.
[0061] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R is cyclohexyl.
[0062] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R is substituted with one or two R11.
[0063] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R is substituted with one R11.
[0064] In another embodiment of the invention, there is provided a compound of Formula (I), wherein R2 is selected from the group consisting of hydrogen, oxo, and methyl.
[0065] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R2 is hydrogen.
[0066] In another embodiment of the invention, there is provided a compound of Formula (I), wherein R2 is oxo. [0067] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R3 is selected from the group consisting of hydrogen, (C C6)alkyl, halo, cyano, -afkylR8, and (C3-C14)cycloa!kyl.
[0068] In another embodiment of the invention, there is provided a compound of Formula (I), wherein R3 is selected from the group consisting of hydrogen, methyl, ethyl, chioro, bromo, cyano, hydroxymethyl, and cyclopropyl.
[0069] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R3 is selected from the group consisting of hydrogen, chioro, bromo, and cyano.
[0070] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R3 is chioro.
[0071] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R4 is selected from the group consisting of hydrogen, (C-|-C6)alkyl, (C C6)alkenyl, -OR6(R5)m, -R6(R5)m, -alkyl(R5)mR6.
[0072] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, dimethylamino, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, chioro, fluoro, bromo, difluoroethyl, and trifluoromethyl.
[0073] In another embodiment of the invention, there is provided a compound of Formula (I), wherein R4 is selected from the group consisting of trifluoromethyl, ethyl, and isopropylene.
[0074] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R4 is trifluoromethyl.
[0075] In another embodiment of the invention, there is provided a compound of Formula (I), wherein R11 is selected from the group consisting of hydroxyl, oxo, -OC(0)R6, -alkylR8, -R6(R6)m, halo, {C C6)a!kyf, and (C C6)a!koxy.
[0076] in another embodiment of the invention, there is provided a compound of
Formula (I), wherein R11 is selected from the group consisting of hydroxyl, oxo, hydroxymethyl, acyloxy, fluoro, trifluoromethyl, methoxy, and methyl.
[0077] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R11 is selected from the group consisting of methyl, hydroxy], and oxo.
[0078] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R11 is oxo.
[0079] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R11 is hydroxyl. [0080] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein R11 is absent.
[0081] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein m is three.
[0082] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein m is two.
[0083] In another embodiment of the invention, there is provided a compound of
Formula (I), wherein n is one.
[0084] In another embodiment of the invention, there is provided a compound of
Formula (I):
(I)
Figure imgf000018_0001
R1
a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, bromo, fluoro, chloro, iodo, methyi, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropyloxy, methoxy, ethoxy, propoxy, difluoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazolyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl;
R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, acetate, thiazolyl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyc!ohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl, wherein R1 is optionally substituted with one to two R11;
R2 is independently selected from the group consisting of hydrogen, oxo, methyl, ethyl, cyciopropyl, hydroxymethyl, and phenyl, or optionally two R2 groups, together with any intervening atoms, form a spiro or fused cycloalkyl ring; R3 is selected from the group consisting of hydrogen, chloro, bromo, fluoro, and cyano;
R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, dimethylamino, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, chloro, fluoro, bromo, difluoroethyl, and trifluoromethyl;
R5 is independently selected from the group consisting of hydrogen and halo; R1 is independently selected from the group consisting of hydroxyl, oxo,
hydroxymethyl, acyloxy, fluoro, trifluoromethyl, methoxy, and methyl; and n is zero or an integer from 1 to 4.
[0085] In another embodiment of the invention, there is provided a compound of
Formula (I):
(l)
Figure imgf000019_0001
pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, (CrC6)alkoxy, hydroxyl, and
(C3-C-|4)cycloalkyl;
R is selected from the group consisting of (Cs-C-uJcycloalkyl and (C2-
C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, wherein
R is optionally substituted with one to two R11;
R2 is oxo;
R3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano; R4 is trifluoromethyl;
R5 is independently selected from the group consisting of hydrogen and halo; R1 is independently selected from the group consisting of methyl, hydroxyl, and oxo; and
n is zero or an integer from 1 to 4. [0086] In another embodiment of the invention, there is provided a compound of
Formula (I):
(I)
Figure imgf000020_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of methoxy, hydroxyl, and cyclopropyl; R1 is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyi, and cyclohexyl, wherein R is optionally substituted with one to two R1 ;
R2 is oxo;
R3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano; R4 is trifluoromethyl;
R5 is independently selected from the group consisting of hydrogen and chloro; R 1 is independently selected from the group consisting of methyl, hydroxyl, and oxo; and
n is zero or an integer from 1 to 4.
[0087] In another embodiment of the invention, there is provided a compound of
Formula (I):
Figure imgf000020_0002
R1 or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of methoxy, hydroxy], and cyclopropyl; R1 is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyl, and cyclohexyl, wherein R is optionally substituted with one to two R11;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano; R4 is trifluoromethyl;
R5 is independently selected from the group consisting of hydrogen and chloro; R11 is independently selected from the group consisting of methyl, hydroxyl, and oxo; and
n is zero or an integer from 1 to 4.
[0088] !n another embodiment of the invention, there is provided a compound of
Formula (II):
(11)
Figure imgf000021_0001
pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (Ci-C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo,
Figure imgf000021_0002
(Cr
C6)alkoxy, (CrC6)alkenyl, (C1-C6)aikynyl, {C3-C14)cycloalkyi, aryl, hydroxyl, -NR6R6, -NR6C(0)NR6R6, -OR6(R5)m, -R6(R5)m, ~S02NR6R6, -
C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NReS(0)2R6,
-alkylR R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and 0; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R 0; R is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (d- C6)alky!, (CrC6)a[koxy, (C C6)alkenyl, (CrC6)alkynyl, -C(0)N(R6)2, -R9R6, -S02NR6R6, -S02R6, (C3-C14)cyc[oalkyl, aryl, (C2-C6)heterocyc!ic having 1- 3 heteroatoims selected from S, N and 0, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroary!, or heterocyclic is optionally substituted with one to three R11;
R3 is selected from the group consisting of hydrogen, (CrC6)alkyl, (C3- Ci4)cycloalkyl, halo, -alkylR8, and cyano;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (C
C6)alkyl, {CrC6)alkoxy, (C C6)alkenyl, (C C6)alkynyl, (C3-C14)cycloalkyl, aryl, -OR6(R5)m, -R6(R5)m, -alkyl(R5)mR6, -alkylR9R6, -NR6R6, - NR6C(0)NR6R6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02R6, - NR6C(S)NR6R6, -NR6S(0)2R6, -alky!R9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O, (C2-
C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R1Q;
R5 is independently selected from the group consisting of hydrogen and halo; R6 is independently selected from the group consisting of hydrogen and (C
C6)alkyl;
R7 is (C3-Ci4)cycloalkyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of (C1-C6)alkyl, (Cr
C6)alkoxy, (d-CeJalkenyl, (CrC6)alkynyl, hydroxyl, oxo, carboxyl, cyano, halo, -C(0)NH2, -S02NH2l -SR6, -S(0)R6, -S(0)2R6, -
S(0)2NReR6, -NR6R6, -NR6C(0)NR6R6, -NReC(S)NR6R6, -
NR6S(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NR6R6, -C(0)NR6R6, - C(0)OR6, -C(0)Re, {C3-C14)cycloalkyl, aryl, {C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-C6)heteroary! having 1-3 heteroatoms selected from S, N, and O;
R1 is independently selected from the group consisting of (C1-C6)alkyl, (C
C6)alkoxy, (d-CeJalkenyl, (C C6)alkynyl, oxo, hydroxyl, -NR6R6 - NR6C(0)R6, -OC(0)R6, -OR6(R )m, -R6(R5)m, halo, -C{0)NR6 R6,
-S02NR6R6, -S02R6, -alkylR8, -alkylR9, -alkylR9R6, (C3- Cnjcycloalkyl, aryl, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O; or optionally two R11 groups, together with any intervening atoms, form a fused (Cs-C^cycloalkyl ring or a fused (C2- C6)heterocyciic ring having 1 -3 heteroatoms selected from S, N and O; wherein said fused cycloalkyl or heterocyclic ring is optionally substituted with one to three R 2;
R 2 is independently selected from the group consisting of (d-CeJalkyl, (Cr
C6)alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -R6(R5)m, and - NR8R6; and
m is an integer from 1 to 3.
[0089] In another embodiment of the invention, there is provided a compound selected from the group consisting of:
3-(1-{[5-(methyloxy)-7-(trifluoro
1 ,3-oxazolidin-2-one,
3-(1-{[3-bromo-5-(methyloxy)-7-(trifluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3"(1 [5-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4-piperidinyl)-1 I3- oxazolidin-2-one,
3-(1-{[3-chloro-5-(methyloxy)-7-(trif[uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- pi perid inyl )- 1 , 3-oxazo I id i n-2-one,
3-(1-{[3l4-dichloro-5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3-(1-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidin-2-one,
3-(1 -{[3-bromo-5-cyclopropyl-7-(trif luoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinylJ-I .S-oxazolidin^-one,
3-(1-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3-(1-{[5-cyclopropyl-7-(tnfluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyi}-4-piperidinyl^ 1 ,3-oxazolidine-2,4-dione,
3- (1 -{[3-chIoro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 J5-a]pyridin-2-yl]carbonyl}-4- piperidiny])-1 ,3-oxazolidine-2,4-dione,
1-cyclopentyl-4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony[}-2- piperazinone,
4- {[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 J5-a]pyridin-2-yl]carbonyl}-1 - cyc!opentyl-2-piperazinone,
2-[(4-cyclopentyl-3-oxo-1 -piperazinyl)carbonyl]-5-cyclopropyl-7- (trifluoromethy pyrazolofl ^^pyridine-S-carbonitrile,
4-{[3-chloro-5-cyclopropyl-7-(trifluorom
cyclopentyl-2-piperazinone,
1-cyclobutyl-4-{[5-cyc!opropyl-7-(trffl^
piperazinone,
4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyI}-1 - cyclobuty!-2-piperazinone,
4-{[3-chloro-5-cyclopropyi-7-(M
cyclobutyl-2-piperazinone,
4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 !5-a]pyridin-2-yl]carbonyl}-1 -(3- methylcyclobutyl)-2-piperazinone,
4- {[3-bromo-5~cyc!opropyl-7-(trifluoro^
methy[cyclobutyl)-2-piperazinone,
5- cyclopropyl-2-{[4-(3-methylcyclobutyl)-3-oxo-1-piperazinyl]carbonyl}-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-3-carbonitrile,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- methylcyclobutyl)-2-piperazinone,
4-{[5-cyclopropyl-7-(trifluoromeihyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(4- hyd roxycyclo hexyl)-2-p i pe razi none,
4-{[5-cyclopropyl-7-(trifluoromethy!)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyc!opropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(4- hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trif!uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-{trans- 4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-bromo-5-cycloprOpyl-7-(trifluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(4- hydroxycyclohexyl)-2-piperazinone,
4-{[3-bromo-5-cyclopropyl-7-(trifluoroiTiethyi)pyrazolo[1 ,5-a]pyndin--2-yl]carbonyl}-1-(trans-
4- hydroxycyclohexyl)-2-piperazinone,
5- cyclopropyl-2-{[4-(4-hydroxycyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-3-carbonitnle,
5-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1 -piperazinyl]carbonyl}-7- (trifluorom ethyl )pyrazolo[1 ,5-a]pyridine-3-carbonitrile, 4-{[3-chloro-5-cyclopropyi-7-(trif!uorom
[(1S,3S)-3-hydroxycyclopentyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- t(1 ,3R)-3-hydroxycyclopentyl]-2-piperazinone,
4-{[3-chIoro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - [(1R,3S,4S)-3-ethyl-4-hydroxycyclopentyl]-2-piperazinone,
4-{[3-chIoro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}-1- [(1 R,3S,4S)-3-ethyl-4-hydroxycyclopen†y[]-2-piperazinone (Isomer 1 ),
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 l5-a]pyridin-2-yi]carbonyl}-1- [(1 R.SS^S^S-ethyl^-hydroxycyclopentylj^-piperazinone (Isomer 2),
4-{[3-ch!oro-5-cyc[opropyl-7-(tnfluoromethy])pyrazolo[1 ,5-a]pyndin-2-yl]carbonyl}~1- [(1 R^S^SJ-S-ethyW-hydroxycyclopentyil^-piperazinone (isomer 3),
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin--2-yl]carboriyl}-1 -(3- methylcyclopentyl)-2-piperazinone,
4-{[5-(ethyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-4- hyd roxycy o hexy [)-2- p i pe razi n o n e ,
4-{[3-chloro-5-(ethyloxy)-7-(trifluor^^
hydroxycyclohexy ^-piperazinone,
1-[(1R,5S,6r)-bicyclo[3.1.0]hex-6-yl]-4-{[3-chloro-5-cyclopropyl-7- (trifluorornethyl)pyrazolo[1 ,5-a]pyndin-2-yl]carbonyl}-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y!]carbonyl}-1-^
3- (hydroxymethyl)cyclobutyl]-2-piperazinone,
4- [(3-chloro-5,7-dicyclopropylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1-(trans-4- hyd roxycy clo h exy I )-2- p i pe razi no n e ,
4-{[3-chloro-5-(1-methylethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - (trans~4-hydroxycyclohexyl)-2-piperazinone,
1-(trans-4"hydroxycyclohexyl)-4-{[5-(1-methylethyl)-7-(trifluoromethyl)pyrazolo[1 J5- a]pyridin-2-yl]carbonyl}-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(methyloxy)p^^
hyd roxycyclohexyl )-2-p i perazi no n e ,
4-[(7-bromo-3-chloro-5-cyclopropylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1-(trans-4- hyd roxycyclohexyl )-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(1-methylethenyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (trans^-hydroxycyclohexyi^-piperazinone,
4-[(3-chloro-5-cyclopropyl-7-iodopyrazolo[1 ,5-a]pyridin-2-yl)carbony!]-1-(trans-4- hydroxycyclohexyl )-2-p i perazi no ne , 4-[(3-chloro-5-cyclopropyl-7-ethylpyrazolo[1 ,5-a]pyridin-2-y!)carbonyl]-1-{trans-4- hydroxycyc!ohexyl)-2-piperazinone,
4-[(3-chloro-5-cyclopropyl-7-phenyipyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1-(trans-4- hyd roxycyclohexy! )-2-pi perazi none,
4-{[3-chloro-5-cyclopropyl-7-(2-furanyl)pyrazolo[1 (5-a]pyridin-2-yl]carbonyI}-1 -(trans-4- hyd roxycyclohexyl )-2-pi perazi none,
4-{[3-chioro-5-cyclopropyi-7-(3-furanyl)pyrazolo[1 ,5-a]pyridin-2-y]]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[3,5-dichloro-7-(trtfluoromethy[)pyrazolo[1 ,5-a]pyridin-2-yl]carbony]}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyi-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(3- cyclopenten-1-yl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}^ hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl^
[(1R,2R,3R,5R)-2-hydroxybicyc[o[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyc!opropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}-1-
[(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yI]-2-piperazinone,
4-{[5-cyclopropyl-3-methyl-7-(trifluorome^
4-hydroxycyclohexyl)-2-piperazinone,
4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyi)pyrazolo[1 J5-a]pyridin-2-yl]carbonyl}-1-
[(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yI]-2-piperazinone,
4-{[3-chloro-5-cyciopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans- 4-hyd roxycyclohexyl )-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(IS^S.SS^S^-hydroxybicyclop. .Olhex-S-yll^-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trif[uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyi}-1-(ci hyd roxycyclohexyl )-2-piperazinone,
1-(trans-4-aminocyclohexyl)-4-{[3-chloro-5-cycIopropy!-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-2-piperazinone,
4-{[3-chloro-5-cyclopropyi-7-(trifluoromethyl)pyrazolo[1 !5-a]pyridin-2-yl]carbonyl}-1-(4,4- dimethylcyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyi-7-(trifluorom
4-methylcyciohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropy[-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(2- fluoro-4-methylphenyl)-2-piperazinone, 4-{[3-chloro-5-cyclopropyl-7-(trif luoromethyl)pyrazoio[1 ,5-a]pyridin-2-yl]carbonyi}-1 -(1 - methyl- H-imidazol-5-yi)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(triffuoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony!}-1 -{2- chlorophenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethy[)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[2- chloro^methyloxyjphenylj^-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifl^^
chloro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyi-7-(trifluoromethyI)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- fluorophenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(3- f I uo ro-2-pyri dinyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trffl^
hydroxyethyl)cyclobutyl]-2-piperazinone,
4 [3-chloro-5-cyclopropyl-7-(irifluoromethyl)pyrazolo[1 J5-a]pyridin-2"y]]carbonyl}-1-
[(1 R,2S,3R,5R)-2-hydroxybicycio[3.1 .0]hex-3-yl]-2-piperazinone,
4-{[3-chloro~5^yclopropyl-7-(trif[uorom
[(1 S>2R,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoro
[(1 S,2S,3R,5S)-2-hydroxybicyclo[3.1 .0]hex-3-yl]~2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
[(1 R,2R,3S,5R)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4 [3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
[(1 R,3R,5R)-2-oxobicyclo[3.1.Ojhex-S-yll^-piperazinone,
4-{[3-chloro-5-cyc]opropy[-7-(trif!uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -
[{1S,3S,5S)-2-oxobicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(tr^ hyd roxycyclo hexy I )-2-piperazinone,
4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 l5-a]pyridin-2-yl]carbonyl}-1 - [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3,5-dichloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[3carbonyl}-1-[(1^
hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone>
4-{[3-chloro-5-cyclopropyl"7"(1 ,3-oxazo!-5-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony!}-1 -{trans- 4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(1 ,3-oxazol-5-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - t(1 S,2S,3Sl5S)~2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone, 4-{[5-chloro-3-methyl-7-(trifl^
[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(3-thienyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
-{[3-Chloro-5-cyclopropyl-7-(3-thienyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}-1- [(1 S,2S,3S,5S)-2-hydraxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(1 H-pyrrol-2-yl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}-1-(trans- 4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(1 ,3-thiazol-4-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony[}-1 -{trans- 4-hydroxycyclohexyl)-2-piperazinone ,
1-[(trans)-bicyclo[3.1 ]hex-3~yl]-4-{[3-cN^
a] pyrid i n-2-yl] carbonyl}-2-piperazi none ,
4-{[3-chloro-5-cyc!opropyl-7-(3-furanyl)pyrazoio[1 !5-a]pyridin-2-yl]carbony!}-1- [{ 1 S , 2S, 3S , 5S)-2-hyd roxyb i cycl o [3.1.0] hex-3-yi]-2-pi pe razi none ,
4-{[5-cyclopropyl-3-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone,
1-cyclobutyl-4-{[5-cyclopropyl-3-{methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yi]carbonyl}~2~piperazinone,
1- cyclobutyl-4-{[5-cyclopropyl-3-hydroxy-7-(tnfluoromethyl)pyrazolo[1 ,5-a]pyridin-2" yl]carbonyl}-2-piperazinone,
4-{[5-cyclopropyl-3-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 J5-a]pyridin-2-yl]carbonyl}-1-[2- fluoro-4-(methyloxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-{trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}-1 -[3- fluoro-4-(methy!oxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(tnfluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[4- (methyloxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[2,3- difluoro-4-(methyloxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}^ difluoro-4-(methyloxy)pheny[]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony]}-1 -(2- fluoro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chloro-5-cyciopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -
2- piperazinone, 4-{[3-ch loro-5-cyclo propyl-7-(trffl ^
fluoro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chioro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(2,3- difluoro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -{4- hydroxyphenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyndin-2-yl]carbonyl}-1 -(2,5- difluoro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(4- cyc!opropyI-2-fluorophenyl)-2-piperazinone,
[4-(4-{[3-chloro-5-cyclopropyl-7-(W^^
oxo-1 -piperazinyl)-3-fluorophenyl]boronic acid,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 i5-a]pyridin-2-yl]carbonyl}-1 -(3- hydroxyphenyl)-2-piperazinoner
4-{[3-chloro-5-cyclopropy[-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(4- hydroxyphenyl)-3-methyl-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trif!uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[(5R)-
2- hydroxy-1 ,2-oxaborinan-5-yl]-2-piperazinone,
4-{[3-chioro-5-cycIopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[^^ hydroxy-1 ,2-oxaborinan-5-yl]-2-piperazinone,
3- chloro-N,5-dicyclopropyl-2-{[4-(trans-4-hydroxycycSohexyi)-3-oxo-1 - piperazinyl]carbonyl}pyrazolo[1 ,5-a]pyridine-7-carboxamide,
3- chloro-5-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1-piperaziny!]carbonyl}-N- methylpyrazolo[1 ,5-a]pyndine-7-carboxamide,
3-chloro-5-cyclopropyl-2-{[4-(trans-4-hydroxycyc!ohexyl)-3-oxo-1-piperazinyl]carbonyl}- N,N-dimethyipyrazolo[1 ,5-a]pyridine-7-carboxamide,
(Trans)-4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}" 1-(3-oxabicyclo[3.1.0]hex-6-yl)-2-piperazinone,
4- {[3-chloro-5-cyclopropyl-7-(irifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - [(1 R.SRJ-S-ihydroxymethy cyclopentyl^-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(5-oxo-
3- pyrrolidinyl)-2-piperazinone,
4- {[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(6- oxabicyclo[3.1.0]hex-3-yl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoro
difluorobicyclo[3.1.0]hex-3-yl)-2-piperazinone (Isomer 1 ), 4-{[3-chloro-5-cyclopropyl-7-{trifluorom
difluorobicycIo[3.1.0]hex-3-yl)-2-piperazinone (Isomer 2),
4-{[3-chIoro-5-[(difluoromethyl)oxy]^
1-(trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-[(difiuoromethyl)o^
1 - [(1 S,2S,3S,5S>-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5~(difluoromethyl)-7-(trifluoromethyl)pyrazolo[1 )5-a]pyridin-2-yl]carbo
(trans-4-hyd roxycyclo hexyl )-2-p i perazi none ,
4-{[3-chloro-5-(difluoromethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y
[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-y!]-2-piperazinone,
(+/-)-4-{[3-Chloro-5-(2-hydroxy-1 -methylethy[)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyri yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2~piperazinone,
4-{[3-chloro-5-(2-hydroxy-1 -methylethyl)-7-(irifiuoromethyl)pyrazolo[1 ,5-a]pyridin-2- y[]carbonyl}-1-[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-y[]-2-piperazinone,
4-{[5-Acetyl-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-4- hyd roxycyclohexy I )-2-piperazinone,
4-{[3-Chloro-5-(1 -difluoroethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-2-piperazinone,
(+/-)-4-{[3-Chloro-5-(2,2-difluorocyclopropyl)-7-(trifluoromethyl)pyrazolot1 ,5-a]pyridin-2- yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}~1- (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(4-isothiazolyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans- 4-hydroxycyclohexyl)-2-piperazinone,
4-[(3-Chloro-5-cyclopropyl-7-phenylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1 -[{1 S,2S,3S,5S)-
2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(I RS.SRS.SRS^^-difiuorobicydop.l .Ojhex-S-yll^-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethy])pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(1 S,3S,5S)-2-f!uorobicyclo[3.1.0]hex-3-yl]-2-piperazinone, and
4-{[3-chloro-5-[(difluoromethyl)oxy]-7-(trifiuoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-
1 -[(1S,3S,5S)-2-oxobicyclo[3.1.0]hex-3-yl]-2-piperazinone,
or a pharmaceutically acceptable salt thereof.
[0090] In certain embodiments, the compound of the present invention is 4-{[3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]p.yridin-2-yl]carbonyi}-1 -(4- hydroxycyclohexyl)-2-piperazinone, or a pharmaceutically acceptable salt thereof. [0091] In other embodiments, the compound of the present invention is 4-{[3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony[}-1 -(trans-4- hydroxycyciohexyl)-2-piperazinone, or a pharmaceutically acceptable salt thereof.
[0092] In another embodiment of the invention, there is provided a compound having the structure:
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof.
[0093] In another embodiment of the invention, there is provided a compound having the structure:
Figure imgf000031_0002
H
or a pharmaceutically acceptable salt thereof.
[0094] in another embodiment of the invention, there is provided a compound of
Formula (I), wherein the compound or salt of the compound is used in the manufacture of a medicament for use in the treatment of a viral infection in a human.
[0095] In another embodiment of the invention, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in a compound of Formula (I). [0096] fn another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
5 compound of Formula (I).
[0097] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
10 compound of Formula (I), wherein said virus is hepatitis C virus.
[0098] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
15 compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus,
[0099] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been
20 diagnosed with said viral infection or is at risk of developing said viral infection, a
compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV rep!icase, HCV NS5A protein, or inosine 5'-
25 monophosphate dehydrogenase.
[00100] In another embodiment of the invention, there is provided a method for treating a virai infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a
30 compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon.
[00101] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae 35 family of viruses which method comprises administering to a mammal, that has been
diagnosed with said viral infection or is at risk of developing said viral infection, a
SVCA_258875.1 30 compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is ribavirin.
[00102] In another embodiment of the invention, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of Formula (I), further comprising administration of a therapeutically effective amount of one or more agents active against hepatitis C virus, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.
[00103] In yet further embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1.
Tab!e 1
Compound Structure Name
Number
1 3-(1-{[5-(methyloxy)-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3~oxazolidin-2-one
3-(1 -{[3-bromo-5-(methyloxy)-7- (trifluoromethyl)pyrazolo[ ,5- a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
Figure imgf000033_0001
3-(1 -{[5- ydroxy-7- (trifluoromethy[)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
3-{1-{[3-chloro-5-(methyloxy)-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
3-(1 -{[3,4-dichloro~5~{methyloxy)-
7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- p i perid i nyl )- 1 , 3-oxazo I id i n-2-one
3-(1 -{[5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
Figure imgf000034_0001
3-(1 -{[3-bromo-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
3-(1-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- piperidiny -l
Figure imgf000035_0001
3-(1 -{[5-cyclopropyl-7~
(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidine-2,4~ dione
3-(1-{[3-chloro-5-cyclopropyl-7-
(trifluoromethyl)pyrazolo[1 ,5- a]pyridin~2-yl]carbony[}-4- p iperid i n y I )~ 1 , 3 -oxazo! id i ne-2 , 4- dione 11 1-cyclopentyl-4-{[5-cyclopropyl-7- (trifluoromethyl)pyrazolo[ ,5- a]pyridin-2-yl3carbonyl}-2- piperazinone
12 4-{[3-bromo-5-cyciopropyl-7- {trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 - cycIopentyl-2-piperazinone
13 2-[(4-cyclopentyl-3-oxo-1 - piperazinyl)carbonyl]-5- cyclopropy[-7-
(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-3-carbonitrile
14 4-{[3-chioro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 - cyclopentyl-2-piperazinone
Figure imgf000036_0001
1 -cyclobutyl-4-{[5-cyclopropyl-7- (trif!uoromethyl)pyrazo!o[1 ,5- a] py ri d i n -2-y I] ca rbo n y l}-2- piperazinone
4-{[3-bromo-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[ ,5- a]pyridin-2-y[]carbonyl}-1 - cyclobutyl-2-piperazinone
4-{[3-ch!oro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 - cyclobutyl-2-piperazinone
8 4-{[5-cyclopropyl-7- (trifluoromethyl)pyrazo[o[1 ,5- a]pyridin-2-y[]carbonyl}-1 -(3- methy!cyclobutyl)-2-piperazinone
9 4-{[3-bromo-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(3- methylcyclobutyl)-2-piperazinone
(a) 5-cyclopropyl-2-{[4-(3- methylcyclobutyi)-3-oxo-1 - piperazinyI]carbonyl}-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridine-3-carbonitrile
Figure imgf000038_0001
(b) 5-cyclopropyl-2-{[4-(3- methylcyclobutyl)-3-oxo-1 - piperazinyl]carbonyl}-7- (trifluoromethy])pyrazolo[1 ,5- a]pyridine-3-carbonitrile
Figure imgf000039_0001
,
1 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-y[]carbonyi}-1 -(3- methylcyclobutyl)-2-piperazinone
(a) 4-{[5-cyclopropy!-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2~yl]carbonyl}-1 -(4- hydroxycyclohexyl)-2- piperazinone
Figure imgf000039_0002
Figure imgf000040_0001
(a) 4-{[3-bromo-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(4- h yd roxy cycio h exy ί )-2- piperazinone
(b) 4-{[3-bromo-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(trans- 4-hydroxycyclohexyl)-2- piperazinone
(a) 5-cyclopropyl-2-{[4-(4- hydroxycyclohexyl)-3-oxo-1 - piperaziny[]carbonyl}-7- (trifluoromethyi)pyrazolo[1 ,5- a] pyri d i ne-3-carbo n itri le
Figure imgf000041_0001
5-cyclopropyl-2-{[4-(trans-4- hydroxycyclohexyl)-3-oxo-1 - piperazinyl]carbonyl}-7- (trifluoromethyl)pyrazoio[1 ,5- a]pyridine-3-carbonitrile
4-{[3-ch!oro-5-cyciopropyl-7- (trifluoromethyl)pyrazo!o[1 ,5- a]pyridin-2-yl]carbonyl}-1 - [(1S,3S)-3-hydroxycyclopentyl]-2- piperazinone
4-{[3-chloro-5-cyclopropyl-7-
(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -
[( 1 R,3R)-3-hydroxycyciopentyl]-2- piperazinone
4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 - [(1 R,3S,4S)-3-ethyl-4- h yd roxycycl o pe nty l]-2- piperazinone 29 Isomer 1 :
4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 - [(1 R,3S,4S)-3-ethyl-4- hyd roxycyclopentyl]-2- piperazinone
Figure imgf000043_0001
30 isomer 2:
4-{[3-chloro-5-cyclopropyl-7- {trifluoromethyl)pyrazolo[1 ,5- a]pyridi n -2-yl]ca rbonyl}- - [(1 R,3S,4S)-3-ethyl-4- hydroxycyclopentyl]-2- piperazinone
Figure imgf000043_0002
31 Isomer 3;
4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 - [(1 R,3S,4S)-3-ethyl-4- hydroxycyclopen†yl]-2-
Figure imgf000043_0003
piperazinone
32 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(3- methylcyclopentyl)-2- piperazinone
Figure imgf000043_0004
33 4-{[5-{ethyloxy)-7- (trifluorornethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-(trans- 4- h yd roxycy cl o h exy I )-2- piperazinone
Figure imgf000044_0001
34 4-{[3-ch1oro-5-(ethyloxy)-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(trans- 4-hyd roxycyclo hexyl )-2- piperazinone
Figure imgf000044_0002
35 1 -[( 1 R,5S,6r)~bicyclo[3.1.0]hex-6- yl]-4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-2- piperazinone
Figure imgf000044_0003
36 4-{[3-chIoro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-[trans- 3-(hydroxymethyl)cyc!obutyl]-2- piperazinone
Figure imgf000044_0004
37 4-[(3-chloro-5,7- dicyclopropylpyrazolo[1 ,5- a]pyridin-2-yl)carbonyl]-1 -(trans- 4-h d roxycyclo hexyl )-2- piperazinone
38 4-{[3-ch!oro-5-(1 -methylethyl)-7- (trifluoromethyl)pyrazolo[1 ,5- a] py ri d i n-2 -y I ] ca rbo ny I }- 1 -(tra ns- 4-hyd roxycycl o hexyi )-2- piperazinone
Figure imgf000045_0001
39 1 -(tra ns-4-hyd roxycyclo hexyl )-4- {[5-{1-methylethyl)-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-y[]carbonyl}-2- piperazinone
Figure imgf000045_0002
40 4-{[3-chloro-5-cyclopropyl-7- (methyloxy)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-(trans- 4-hyd roxycycl o h exy I )-2- piperazinone
Figure imgf000045_0003
4-[(7-bromo-3-chloro-5- cycl o pro py I pyra zolo [ 1 , 5-a] pyri d i n -
2-yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2- piperazinone
Figure imgf000046_0001
4-{[3-chloro-5-cyclopropyl-7-(1 - methylethenyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(trans- 4-hydroxycyclohexyl)-2- piperazinone
Figure imgf000046_0002
4-[(3-chloro-5-cyclopropy!-7- iodopyrazolo[1 ,5-a]pyridin-2- yl)carbonyl]-1 -(trans-4- hyd roxycy cl o h exy I )-2 - piperazinone
Figure imgf000046_0003
4-[{3-chIoro-5-cyclopropyl-7- ethylpyrazolo[1 ,5-a]pyridin-2- yl)carbonyl]-1 -(trans-4- h yd roxycycl o h exy I )-2- piperazinone
Figure imgf000046_0004
4-[(3-ch lo ro-5-cyclo pro pyl-7- phenylpyrazolo[1 , 5-a] pyrid in -2- yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2- piperazinone
Figure imgf000047_0001
4-{[3-chloro-5-cyclopropyl-7-(2- furanyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1 -(trans-4- hyd roxycyclohexyl )-2- piperazinone
4-{[3-chloro-5-cyclopropyl-7-(3- f ura nyl )pyrazo lo [1 , 5-a] pyrid i n-2- y!]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2- piperazinone
4-{[3,5-dichloro~7- (trifluoromeihyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(trans- 4-hydroxycyclohexyl)-2- piperazinone
Figure imgf000047_0002
i]-2-
Figure imgf000048_0001
Figure imgf000049_0001
7 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -{cis-4- ydroxycyclohexyl)-2- piperazinone
Figure imgf000050_0001
8 1 -(trans-4-aminocyclohexyl)-4- {[3-chloro-5-cyc!opropyl-7- (trif I uo rom ethyl )pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-2- piperazinone
Figure imgf000050_0002
0
OH (b) 1 -(trans-4-aminocyclohexyl)-4- {[3-ch!oro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyrid in-2-yl] ca rbonyl}-2- piperazinone
Figure imgf000050_0003
9 F F 4-{[3-chloro-5-cyclopropyl-7- Y 0 (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(4,4- dimethy!cyclohexyl)-2- piperazinone 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1~(trans- 4- m eth y I cycl o h exy I )-2- piperazinone
Figure imgf000051_0001
4-{[3-chloro-5-cyclopropyl-7-
Λ x (trif[uoromethyl)pyrazolo[1 ,5- a]pyridin-2-yi]carbonyl}-1 -(2- fluoro-4-methylphenyl)-2- piperazinone
4-{[3-chloro-5-cyclopropyl-7- (trifiuoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -( 1 - methyl-1 H-imidazol-5-yl)-2- piperazinone
Figure imgf000051_0002
4-{[3-chloro-5-cyclopropyl-7- (trifluoromet yl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(2- chlorophenyl)-2-piperazinone
Figure imgf000051_0003
4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a] py ri d i n-2-y I] ca rbo ny I}- 1 - [2 - chloro-4-(methyloxy)phenyl]-2- piperazinone
Figure imgf000052_0001
4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yi]carbonyl}-1 -(2- chloro-4-hydroxypheny[)-2- piperazinone
Figure imgf000052_0002
4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyi}-1 -(2- fluorophenyl)-2-piperazinone
4-{[3-c loro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(3- fluoro-2-pyridiny])-2-piperazinone
Figure imgf000052_0003
1 -
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
84 4-{[3-Chloro-5-cyclopropyl-7-(1 ,3- thiazol-4-yl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-(trans- 4-hyd roxycyclohexyl )-2- piperazinone
Figure imgf000057_0001
85 1 -[(trans)-bicyclo[3.1.0]hex-3-yi]- 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-2- piperazinone
86 4-{ [3-ch!o ro-5-cy cl o pro py I -7-( 3- f u rany I ) pyrazoio [ 1 , 5-a] pyrid i n -2- yl]carbonyl}-1-[(1S,2S,3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yi]-2- piperazinone
87 4-{[5-cyclopropyl-3-(methyloxy)-
7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-(trans-
4-hydroxycyclohexyl)-2- piperazinone
Figure imgf000057_0002
88 1-cyclobutyl-4-{[5-cyclopropyl-3- (methyloxy)-7- {trifluoromethyl)pyrazoio[1 ,5- a]pyridin-2-y[]carbonyl}-2- piperazinone
Figure imgf000058_0001
89 1-cyclobutyl-4-{[5-cyclopropyl-3- hydroxy-7-
(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-2- piperazinone
Figure imgf000058_0002
90 4-{[5-cyclopropyl-3-hydroxy-7- (trif[uoromethyl)pyrazolo[1 ,5- a]pyrid i n-2-yi] carbo nyl}- 1 -( trans- 4-hydroxycyclohexyl)-2- piperazinone
91 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin~2~yl]carbonyl}-1 -[2- fluoro-4-(methyloxy)phenyl]-2- piperazinone
Figure imgf000058_0003
92 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-y[]carbonyl}-1 -[3- fluoro-4-(methyloxy)phenyl]-2- piperazinone
Figure imgf000059_0001
93 4-{[3-chioro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -[4- (methyloxy)pheny!]-2- piperazinone
Figure imgf000059_0002
94 4-{[3-chloro-5-cyc!opropy[-7- (trifluoromethyl)pyrazolo[1 ,5- a] py ri d i n-2-y l] carb o n y I}- 1 - [2 , 3~ difluoro-4-(methy[oxy)phenyl]-2- piperazinone
Figure imgf000059_0003
95 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethy])pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -[2,5- difluoro~4-(methyloxy)phenyl]-2- piperazinone
Figure imgf000059_0004
96 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[ ,5- a]pyridin-2-yl]carbonyl}-1-(2- fluoro-4-hydroxyphenyl)-2- piperazinone
97 4-{[3-chloro-5-cycfopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-phenyl- 2-piperazinone
Figure imgf000060_0001
98 4-{[3-chloro-5-cyc!opropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(3- fluoro-4-hydroxyphenyl)-2- piperazinone
99 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethy])pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-(2,3- difluoro-4-hydroxyphenyl)-2- piperazinone
Figure imgf000060_0002
100 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yi]carbonyl}-1 -(4- hydroxypheny[)-2-piperazinone
Figure imgf000061_0001
101 4-{[3-ch!oro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a] py rid i n -2-y I] ca rbo ny I }- 1 -(2 , 5- difluoro-4- ydroxyp enyl)-2- piperazinone
02 4-{[3-ch!oro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(4- cyclopropyl-2-fluorophenyl)-2- piperazinone
Figure imgf000061_0002
103 [4-(4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-y[]carbonyl}-2~oxo-1- piperazinyl)-3- fluorophenyl]boronic acid
Figure imgf000061_0003
104 4-{[3-ch!oro-5-cyclopropyl-7- (trifiuoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -(3- hydroxyphenyl)-2-piperazinone
105 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbony]}-1 -(4- hydroxyphenyl)-3-methyl-2- piperazinone
106 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -[(5R)-2- hydroxy-1 ,2-oxaborinan-5-yl]-2- piperazinone
Figure imgf000062_0001
107 4-{[3-chloro-5-cyc!opropy[-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -[(5S)-2- hydroxy-1 ,2-oxaborinan-5-yl]-2- piperazinone
Figure imgf000062_0002
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
124 4-{[3-Chloro-5-(1 , 1-difluoroethyl)
7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -{trans-
4-hydroxycyclohexyl)-2- piperazinone
Figure imgf000067_0001
125 (+/-)-4-{[3-Chloro-5-{2,2- difluorocyclopropy[)-7- (trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyi}-1-(trans- 4- hyd roxy cy cl o he xy I )-2- piperazinone
Figure imgf000067_0002
126 4-{[3-Chloro-5-cyclopropyl-7-(1 H" pyrazol-4-yl)pyrazolo[ ,5- a]pyridin-2-yI]carbonyl}-1-(trans- 4-hydroxycyclohexyl)-2- piperazinone H
127 4-{[3-Chioro-5-cyclopropyl-7-(4- isothiazolyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-(trans- 4-hyd roxycycl o hexyt )-2- piperazinone
Figure imgf000067_0003
Figure imgf000068_0001
[00104] The compounds of Table 1 were synthesized according to the Synthetic Methods, General Schemes, and the Examples described below,
[00105] In other embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 2.
Table 2
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001

Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
72
Figure imgf000075_0001
73
Figure imgf000076_0001
74
Figure imgf000077_0001
Figure imgf000078_0001
76
Figure imgf000079_0001
77
Figure imgf000080_0001

Figure imgf000081_0001
79
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Figure imgf000089_0001
Figure imgf000090_0001
[00106] The compounds of Table 2 may be synthesized according to the following synthetic methods, schemes, and the Examples.
[00107] In certain embodiments, the compound(s) of the present invention, or a pharmaceutically acceptable salt thereof, is chosen from the compounds set forth in Table 1 and/or Table 2.
Synthetic Methods
[00108] The methods of synthesis for the provided chemical entities employ readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
[00109] Additionally, the methods of this invention may employ protecting groups which prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For exam le, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.
[00110] Furthermore, the provided chemical entities may contain one or more chiral centers and such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this specification, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well- known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
[00111] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. ( ilwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Ernka-Chemce or Sigma (St. Louis, Missouri, USA). Others may be prepared by procedures, or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1 -15 (John Wiley and Sons, 1991 ), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplemental (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991 ), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).
[00112] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -78 °C to 200 °C. Further, except as employed in the Examples or as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about -78 °C to about 1 10 °C over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
[00113] The terms "solvent," "organic solvent," and "inert solvent" each mean a solvent inert under the conditions of the reaction being described in conjunction therewith, including, for example, benzene, toluene, acetonitrile, tetrahydrofuranyl ("THF"), dimethylformamide ("DMF"), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone ("NMP"), pyridine and the like.
[001 ] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column
chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.
[00115] When desired, the (R)- and (S)-isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid
chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.
[001161 Scheme 1 shows a representative general synthesis of certain
pyrazolo[1 ,5-a]pyridine-2-carboxylic acids (see, for example, WO09023179A2).
Substituted pyridines can be converted to the corresponding 1 -aminopyridinium salts 1.1 by treatment with a number of aminating agents (O-acyl, O-aryl-, O-phosphinyl- and O- sulfonylhydroxylamines) such as O-mesitylenesulfonylhydroxylamine (MSH) and hydroxylamine-O-sulfonic acid (HOSA). 1-aminopyridinium salts 1.1 undergo cycloaddition with alkynes (such as dimethylacetylene dicaboxylate) to afford the substituted pyrazolo[1 ,5-a]py dines.
[00117] Treatment of dimethyl pyrazolo[1 ,5-a]pyridine-2,3-dicarboxy!ates, 1.2, with sulfuric acid effects a regioselective decarboxylation that provides the carboxylic acid 1.6 or the methyl ester 1.3 after re-esterification. Halogens (such as CI, Br, !) can be introduced at R3 by treating intermediate 1.3 with halogenating agents (such as NBS, NCS, or NIS) to yield compounds such as 1.4, which upon saponification of the ester can give the corresponding carboxylic acids, 1.7.
[00118] Alternatively, halogens can be introduced to the carboxylic acids 1.6. Intermediates 1.4 can also undergo metal-catalyzed or metal-mediated cross coupling reactions to provide methyl esters 1.5, which can be saponified to carboxylic acids 1.7.
[00119] Esters 1.3 and 1.4 where A = CI, Br, I, OTf, B(OH)2, for example, can undergo metal-catalyzed or metal-mediated cross coupling reactions (including, but not limited to, Suzuki, Stille, Sonogashira, Negishi, and Buchwald-Hartwig reactions) to introduce new groups at position A (intermediate 1.8) and subsequent saponification can yield the substituted acids 1.9. Scheme 1
Figure imgf000093_0001
1.8 1.9 3 = H, CI, Br R3 = H, CI, Br
A = Aryl, Heteroaryl, Alkyl,
Alkenyl, Alkynyl, etc and N-Aryl,
N-Hoteroaryl, N-Alkyl, etc.
[00120] Additional synthetic protocols useful in making the synthetic intermediates for compounds according to Formula (I) may be found in PCT Published Application No. WO2009/023179 filed on August 8, 2008 and entitled "Certain Nitrogen Containing
Bicyclic Chemical Entities for Treating Viral Infections."
EXAMPLES
[00121] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes. In the examples below and the synthetic schemes above, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.
aq. = aqueous
μΙ_ = microliters
μΜ = micromoiar
NMR = nuclear magnetic resonance
boc = tert-butoxycarbonyl
br = broad Cbz = benzyloxycarbortyl
d = doublet
δ = chemical shift
°C = degrees celcius
DCM = dichloromethane
dd = doublet of doublets
DME = Duibeco's Modified Eagle's Medium
DMF = N,N-dimethylformamide
DMSO = dimethylsulfoxide
EtOAc = ethyl acetate
g = gram
h or hr = hours
HCV = hepatitus C virus
HPLC = high performance liquid chromatography
Hz = hertz
IU = International Units
IC50 = inhibitory concentration at 50% inhibition
J = coupling constant (given in Hz unless otherwise indicated)
m = multiplet
M = molar
M+H+ = parent mass spectrum peak plus H+ mg = milligram
mL = milliliter
mM = millimolar
mmol = millimole
MS = mass spectrum
nm = nanomolar
ppm = parts per million
q.s. = sufficient amount
s = singlet
sat. = saturated
t = triplet
TFA = trifluoroacetic acid EXAMPLE 1
3-(1-{[5-{methyloxy)-7-(trifluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
(Compound 1)
Figure imgf000095_0001
Step A
4-(methyloxy)-2-(trifluoromethyl)pyridine
[00122] lodomethane (0.48 ml_, 7.7 mmol) was added to a solution of 2- (trifluoromethyl)-4-pyridino! (0.58 g, 3.5 mmol, prepared according to reference: Tyvorskii, V. I.; Bobrov, D. N. Chemistry of Heterocyclic Compounds. 1997, 33, 995.) and potassium carbonate (0.59 g, 4.3 mmol) in DMF (7 ml_). The reaction mixture was heated at 65 °C for 2 hours, diluted with water, and extracted with 9:1 hexanes:CH2CI2. The combined organic layers were dried over sodium sulfate and the solvent was evaporated to afford the title compound as a yellow oil, 1H NMR (400 MHz, CHLOROFORM- /) 5 ppm 8.55 (d, J=5.7 Hz, 1 H), 7.20 (d, J=2.3 Hz, 1 H), 6.98 (dd, J=5.7, 2.3 Hz, 1 H), 3.93 (s, 3 H). ES-LCMS m/z: 178 (M+1 ).
Step B
1-amino-4-(methyioxy)-2-(triftuoromethyl)pyridinium 2,4,6-trimethylbenzenesulfonate
[00123] A solution of 4-(methyloxy)-2-(trifluoromethyl)pyridine (2.65 g, 15.0 mmol) and O-mesityienesulfonylhydroxylamine (3.87 g, 18.0 mmol, prepared according to reference: Mendiola, J.; Rincon, J. A.; Mateos, C; Francisco Soriano, J.; de Frutos, O.; Niemeier, J.; Davis, E. M. Organic Process Research & Development, 2009, 13, 263) in methylene chloride (35 ml_) was stirred at room temperature overnight. The solvent was evaporated and the solid was suspended in diethyl ether, filtered and dried to afford the title compound (3.64 g, 62%) as a yellow solid. 1 H NMR (400 MHz, DMSO-<¾) δ ppm 8.98 (d, J=7.3 Hz, 1 H), 8.10 (d, J=3.2 Hz, 1 H), 7,82 (dd, J=7.2, 3.2 Hz, 1 H), 7.60 (s, 2 H), 4.19 (s, 3 H), 2.49 (s, 6 H), 2.17 (s, 3 H). Step C
dimethyl 5-(methyloxy)-7-(trifiuoromethyi)pyrazolo[ 1, 5-a]pyridine-2, 3-dicarboxylate [00124] Dimethyl acetylenedicarboxylate ( 2.29 mL, 18.5 mmol) was added to a 0 °C solution of 1-amino-4-(methyloxy)-2-(trifluoromethyl)pyridinium 2,4,6- trimethylbenzenesulfonate (3.64 g, 9.25 mmol) and potassium carbonate (2.56 g, 8.5 mmol) in DMF (31 mL). The reaction mixture was stirred at room temperature overnight. Water (40 mL) was added and the solid was collected by vacuum filtration. The filtrate was extracted with 9:1 hexanes:CH2CI2 and the organic phase was dried over sodium sulfate. The solvent was evaporated and the resulting residue was combined with the above filtered solid. Purification by silica gel chromatography (0-50% EtOAc in hexanes) afforded the title compound (1.49 g, 49%) as a light yellow solid. 1 H NMR (400 MHz, CHLOROFORM-cf) δ ppm 7.62 (d, J=2.6 Hz, 1 H), 7.15 (d, J=2.Q Hz, 1 H), 4.02 (s, 3 H), 3.99 (s, 3 H), 3.92 (s, 3 H). ES-LCMS m/z: 333 (M+1 ).
Step D
5-(methyloxy)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid
[00125] A solution of dimethyl 5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2,3-dicarboxyiate (0.085 g, 0.26 mmol) in concentrated sulfuric acid (1 mL, 19 mmol) and water (0.2 mL) was heated at 90 °C for 40 hours. Water was added and the white solid precipitate was collected by vacuum filtration. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The residue was combined with the above solid and stirred in a mixture of 1 N aqueous NaOH (1 .5 mL, 1.5 mmol) and methanol (1 .5 mL) at 45 °C for 1 hour. 1 HCI (3 mL, 3 mmol) was added and the mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate and the solvent was evaporated to afford the title compound (0.066 g, 99%) as a white solid. ES-LCMS m/z: 261(M+1 ).
Step E
3-(1-{[5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2^
1 , 3-oxazolidin-2-on e
[00126] A mixture of 5-(methyloxy)-7~(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.066 g, 0.26 mmol), 3-(4-piperidiny!)-1 ,3-oxazolidin-2-one (0.043 g, 0.26 mmol), DIPEA (0.18 mL, 1.0 mmol) and HATU (0.116 g, 0.31 mmol) in DMF (2.6 mL) was stirred at room temperature for 2 hours. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.094 g, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.43 (d, J=2.3 Hz, 1 H), 7.34 (d, J=2A Hz, 1 H), 6.84 (s, 1 H), 4.61 (d, J=13.2 Hz, 1 H), 4.38 (d, J=13.3 Hz, 1 H), 4.25 (t, J=8.0 Hz, 2 H), 3.89 (s, 3 H), 3,76 - 3.87 (m, 1 H), 3.44 - 3.58 (m, 2 H), 3.14 - 3.25 (m, 1 H), 2.81 - 2.94 (m, 1 H), 1.54 - 1.84 (m, 4 H). ES-LCMS m/z: 413 ( +1 ). EXAMPLE 2
3-(1-{[3-bromo-5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-4-piperidinyl)-1,3-oxazolidin-2-one
(Compound 2)
Figure imgf000097_0001
100127] N-Bromosuccinimide (0.019 g, 0.1 1 mmol) was added to a solution of 3-(1- {[5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin~2-yl]carbonyl}-4-piperi
oxazolidin-2-one (0.0374 g, 0.091 mmol) in DMF (0.9 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.023 g, 52%) as a white solid. 1H NMR (400 MHz, DMSO-i/6) δ ppm 7.43 (d, J=2.4 Hz, 1 H), 7.16 (d, J=2.4 Hz, 1 H), 4.61 (d, J=13.3 Hz, 1 H), 4.25 (t, J=8.0 Hz, 2 H), 3.97 (s, 3 H), 3.75 - 3.88 (m, 1 H), 3.64 (d, J=13.7 Hz, 1 H), 3.42 - 3.59 (m, 2 H), 3.14 - 3.25 (m, 1 H), 2.93 (td, J=12.8, 2.4 Hz, 1 H), 1.52 - 1.87 (m, 4 H). ES-LCMS m/z: 491 (M+1 ). EXAMPLE 3
3-{1-{[5-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one
(Compound 3)
Figure imgf000097_0002
[00128] A mixture of 37% 5-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.161 g, 0.62 mmol), 3-(4-piperidinyl)-1 ,3-oxazolidin-2-one (0.211 g, 1.24 mmol), EDC (0.131 g, 0.68 mmol), HOBT (0.123 g, 0.81 mmol) and DIPEA (0.20 mL, 1.15 mmol) in DMF (6.2 mL) was stirred at room temperature for 2 hours. Additional DIPEA (0.20 mL, 1.15 mmol) was added and the mixture was stirred overnight, diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography (0-10% MeOH (2M NH3) in CH2CI2) to afford the title compound (0.081 g, 33%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.02 (d, J=2.0 Hz, 1 H), 6.93 (d, J=2.0 Hz, 1 H), 6.64 (s, 1 H), 4.82 - 4.98 (m, 2 H), 4.39 (t, J=8.0 Hz, 2 H), 4.00 - 4.13 (m, 1 H), 3.57 (t, J=8.0 Hz, 2 H), 3.11 - 3.24 (m, 1 H), 2.84 - 2.96 (m, 1 H), 1.69 - 2.04 (m, 4 H). ES-LCMS m/z: 399 (M+1 ).
EXAMPLE 4
3-(1-{[3-chloro-5-(methyloxy)-7-(trif|uoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-4-piperidinyl)-1,3-oxazolidin-2-one
(Compound 4)
Figure imgf000098_0001
[00129] N-Chlorosuccinimide (0.018 g, 0.13 mmol) was added to a solution of 3-(1- {[5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4-piperidinyl)-1 ,^ oxazolidin-2-one (0.045 g, 0.11 mmol) in DMF (1.1 mL). The reaction mixture was heated at 50 °C overnight and 57 °C for 6 hours, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.011 g, 22%) as a white solid. 1H NMR (400 MHz, DMSO-dg) δ ppm 7.43 (d, J=2.4 Hz, 1 H), 7.25 <d, J=2A Hz, 1 H), 4.54 - 4.66 (m, 1 H), 4.25 (t, J=8.0 Hz, 2 H), 3.97 (s, 3 H), 3.76 - 3.89 (m, 1 H), 3.67 - 3.76 (m, 1 H), 3.42 - 3.59 (m, 2 H), 3.16 - 3.26 (m, 1 H), 2.93 (td, J=12.9, 2.6 Hz, 1 H), 1.51 - 1.87 (m, 4 H). ES-LCMS m/z: 447 (M+1 ). EXAMPLE 5
3-(1-{[3,4-dichloro-5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- y[]carbonyl}-4-piperidinyl)-1 ,3-oxazolidin-2-one
(Compound 5)
Figure imgf000099_0001
[00130] The title compound (0.018 g, 34%) was isolated from the reaction mixture in Example 4 as a white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.72 (s, 1 H), 4.60 (d, J=13.2 Hz, 1 H), 4.25 (t, J=8.0 Hz, 2 H), 4.09 (s, 3 H), 3.82 (ddd, J= 1.6, 7.8, 4.2 Hz, 1 H), 3.62 (d, J=13.6 Hz, 1 H), 3.43 - 3.58 (m, 2 H), 3.20 (t, J=11.9 Hz, 1 H), 2.90 - 3.01 (m, 1 H), 1.51 - 1.86 (m, 4 H). ES-LCMS m/z: 481 (M+1 ).
EXAMPLE 6
3-(1-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1,3-oxazoiidin-2-one
(Compound 6)
Figure imgf000099_0002
Step A
2-{[4~(2-oxo-1,3-oxazolidin-3-yi)-1^iperidinyl]carbonyi}-7-(triflu
a]pyridin-5-yl trifluoromethanesulfonate
[00131] N-phenyltrifluoromethanesulfonimide (0.080 g, 0.22 mmol) was added to a
0 °C solution of 3-(1-{[5-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one (0.074 g, 0.19 mmol) and DIEA (0.049 ml, 0.28 mmol) in dichloromethane (1.9 mi). Stirring was continued at room temperature for 3 hours and saturated sodium bicarbonate was added. The aqueous phase was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography (50-100% EtOAc in hexanes) to afford the title compound (0.069 g, 69%) as a white foam. 1H NMR (400 MHz, DMSO-de) δ ppm 8.48 (d, J=2.1 Hz, 1 H), 8.06 (d, J=2.3 Hz, 1 H), 7.26 (s, 1 H), 4.56 - 4.69 (m, 1 H), 4.17 - 4.30 (m, 3 H), 3.76 - 3.90 (m, 1 H), 3.41 - 3.59 (m, 2 H), 3.15 - 3.28 (m, 1 H), 2.84 - 2.98 (m, 1 H), 1.54 - 1.85 (m, 4 H). ES-LCMS m/z: 531 (M+1 ).
Step B
3~(1 -{[5-cyclopropyI- 7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-4-piperidinyl)-
1, 3-oxazolidin-2-one
[00132] A degassed solution of 2-{[4-(2-oxo-1 ,3-oxazolidin-3-yl)-1- piperidinyl]carbonyl}-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-5-yl
trifluoromethanesulfonate
(0.069 g, 0.13 mmol), cyclopropyiboronic acid (0.022 g, 0.26 mmol), potassium phosphate (0.083 g, 0.39 mmol), and PdCI2(dppf)-CH2CI2 adduct (5.3 mg, 6.49 pmol) in ,4-dioxane (1.3 ml) was heated at 90 °C for 3 hours. The reaction mixture was filtered through ceiite and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography (40-100% EtOAc in CH2CI2) to afford the title compound (0.054 g, 99%) as a white solid. H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (s, 1 H), 7.00 (s, 1 H), 6.93 (s, 1 H), 4.83 - 5.05 (m, 2 H), 4.36 (t, J=8.0 Hz, 2 H), 4.00 - 4.16 (m, 1 H), 3.55 (t, J=8.0 Hz, 2 H), 3.08 - 3.24 (m, 1 H), 2.86 (td, J=13.0, 2.5 Hz, 1 H), 1.67 - 2.04 (m, 5 H), 1 .08 - 1.16 (m, 2 H), 0.78 - 0.84 (m, 2 H). ES-LCMS m/z: 423 (M+1 ).
EXAMPLE 7
3-{1-{I3-bromo-5-cyc!opropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-4-piperidinyl)-1 ,3-oxazolidin-2-one
{Compound 7)
Figure imgf000100_0001
[00133] N-Bromosucctnimide (0.005 g, 0.03 mmol) was added to a solution of 3-(1- {[5-cyclopropyl-7-(trifluoromethyl)py^
oxazolidin-2-one (0.012 g, 0.03 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.0 3 g, 91 %) as a white solid. 1H NMR (400 MHz, DMSO-c/6) 5 ppm 7.62 (s, 1 H), 7.39 (s, 1 H), 4.61 (d, J=13.1 Hz, 1 H), 4.25 (t, J=8.0 Hz, 2 H), 3.76 - 3.89 (m, 1 H), 3.63 (d, J=13.7 Hz, 1 H), 3.42 - 3.58 (m, 2 H), 3.12 - 3.24 (m, 1 H), 2.93 (td, J=12.8, 2.4 Hz, 1 H), 2.18 - 2.28 (m, 1 H), 1.50 - 1.87 (m, 4 H), 1.04 - 1.13 (m, 2 H), 0.91 - 1.01 (m, 2 H). ES-LCMS m/z: 501 (M+1 ).
EXAMPLE 8
3-(1-{t3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazo!o[1 ,5-a]pyridin-2- yi]carbonyl}-4-piperidinyl)-1 ,3-oxazolidin-2-one
(Compound 8)
Figure imgf000101_0001
[00134] N-Chlorosuccinimide (0.015 g, 0.1 1 mmol) was added to a solution of 3-(1- {[5-cyclopropyl-7-(trifluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4-piperidinyl)-1 ,^ oxazo!idin-2-one (0.043 g, 0.10 mmol) in DMF (1 mL). The reaction mixture was heated at 50 °C for 5 hours and 55 °C overnight. Additional N-chlorosuccinirnide (0.020 g, 0.15 mmol) was added and the reaction mixture was heated at 65 °C for 1 hour, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.036 g, 78%) as a white solid. 1H NMR (400 MHz, DMSO-c/6) $ ppm 7.68 (s, 1 H), 7.41 (s, 1 H), 4.61 (d, J=13.2 Hz, 1 H), 4.25 (t, J=7.9 Hz, 2 H), 3.76 - 3.88 (m, 1 H), 3.72 (d, J=13.5 Hz, 1 H), 3.42 - 3.59 (m, 2 H), 3.14 - 3.26 (m, 1 H), 2.93 (td, J= 2.8, 2.3 Hz, 1 H), 2.16 - 2.28 (m, 1 H), 1.53 - 1.86 (m, 4 H), 1 .04 - 1.14 (m, 2 H), 0.92 - 1.01 (m, 2 H). ES-LCMS m/z: 457 (M+1 ).
EXAMPLE 9
3-(1-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazoIidine-2,4-dione
(Compound 9)
Figure imgf000102_0001
Step A
methyl 5-hydroxy-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
[00135] A solution of dimethyl 5-(methyloxy)-7-{trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2,3-dicarboxylate (2.09 g, 6.3 mmol) in H2S04 (10 ml_, 188 mmol) and water (4.2 ml.) was heated at 90 °C for 16 hours. Water was added and the solid was collected by filtration. The filtrate was extracted with EtOAc. The organic layer was dried over sodium sulfate and the solvent was evaporated. The resulting residue was combined with the above solid and added to a mixture of ethanethiol (7.0 mL, 95 mmol) and aluminum tribromide (5.0 g, 8.9 mmol). The mixture was stirred at room temperature for 2 days, carefully quenched by addition of 0.5 N aqueous HCI, and extracted with EtOAc (3x). The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The residue was dissolved in eOH (6 mL) and cone. H2S04 (3 drops) was added. The solution was heated under reflux for 2 hours. Dilute HCI was added and the mixture was extracted with EtOAc. The organic phase was dried over sodium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography (0-70% EtOAc in hexanes) to afford the title compound (1.20 g, 73%) as a light yellow solid. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.16 (d, J=2.4 Hz, 1 H), 7.09 (d, J=2.3 Hz, 1 H), 6.95 (s, 1 H), 3.95 (s, 3 H). ES-LCMS m/z: 261 (M+1 ).
Step B
methyl 7-(trifluoromethyl)-5~{[(trifluoromethyl)sulfonyl]oxy}pym^
carboxylate
[00136] N-phenyltrifluoromethanesuifonimide (0.55 g, 1.53 mmol) was added to a solution of methyl 5-hydroxy-7-(trifluoromethyI)pyrazoio[1 ,5-a]pyridine-2-carboxylate (0.31 g, 1.18 mmol) and DIPEA (0.41 ml, 2.35 mmol) in dichloromethane (1 1.8 ml). The reaction mixture was stirred at room temperature for 3 hours, an additional portion of N- phenyltrifluoromethanesulfonimide (0.30 g, 0.84 mmol) was added, and stirring was continued for another 7 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (0-40% EtOAc in hexanes) to provide the title compound (0.42 g, 92%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-^) δ ppm 7.79 (d, J=2.5 Hz, 1 H), 7.38 (s, 1 H), 7.29 (d, J-2.5 Hz, 1 H), 4.03 (s, 3 H). ES-LCMS m/z: 393 (M+1 ).
Step C
methyl 5-cyclopropyl-7-(trifluoromethyi)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
[00137] A degassed solution of methyl 7-(trifiuoromethyl)-5- {[(trifluoromethyl)sulfonyl]oxy}pyrazolo[1 ,5-a]pyridine~2-carboxylate (2.37 g, 6.1 mmol), cyc!opropylboronic acid (1 .04 g, 12.1 mmol), potassium phosphate (3.85 g, 18.2 mmol), and PdCI2(dppf)-CH2CI2 adduct (0.25 g, 0.30 mmol) in 1 ,4-dioxane (50 ml) was heated at 90 °C for 4.5 hours. The reaction mixture was filtered through celite and washed with water. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by silica gel chromatography (0-40% EtOAc in hexanes) to afford the title compound (1.44 g, 84%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.46 (s, 1 H), 7.09 (s, 1 H), 7.06 (d, J=1.2 Hz, 1 H), 4.00 (s, 3 H), 1.95 - 2.05 (m, 1 H), 1.08 - 1.17 (m, 2 H), 0.78 - 0.87 (m, 2 H). ES-LCMS m/z: 285 (M+1 ).
Step D
5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5--a]pyndine-2-carboxylic acid
[00138] A solution of methyl 5-cyclopropyi-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine- 2-carboxylate (0.31 g, 1.08 mmol) in 1 N sodium hydroxide (5.4 ml_, 5.4 mmol) and methanol (5.4 ml_) was heated at 50 °C for 1.5 hours. 1 M aqueous HCI (10 mL) was added and the mixture was extracted with EtOAc. The combined organic layers were dried over sodium sulfate and the solvent was evaporated to provide the title compound (0.28 g, 96%) as a white solid. ES-LCMS m/z: 271 (M+1 ). Step E
3-(1~{[5-cyclopropyl-7~(trifiuoromethyl)pyrazolo[1,5-a]pyrM^
1, 3-oxazoIidine-2, 4-dione
[00139] A mixture of 5-cyciopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.027 g, 0.10 mmol), 3-(4-pipendinyl)-1 ,3-oxazolidine-2, 4-dione hydrochloride salt (0.022 g, 0.10 mmol), DIPEA (0.070 mL, 0.4 mmol) and HATU (0.057 g, 0.15 mmol) in DMF (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel chromatography (0-10% MeOH in CH2Cl2) followed by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.0072 g, 16%) as a white solid. H NMR (400 MHz, DMSO-c 6) δ ppm 7.76 (s, 1 H), 7.37 (s, 1 H), 6.91 (s, 1 H), 4.76 (s, 2 H), 4.63 (d, J=13.1 Hz, 1 H), 4.42 (d, J=13.4 Hz, 1 H), 4.09 - 4.21 (m, J=12.1 , 12.1 , 4.0, 3.9 Hz, 1 H), 3.14 - 3.24 (m, 1 H), 2.83 - 2.95 (m, 1 H), 2.04 - 2.24 (m, 3 H), 1.65 - 1.88 (m, 2 H), 1.02 - 1.10 (m, 2 H), 0.85 - 0.93 (m, 2 H). ES-LCMS m/z: 437 (M+1 ).
EXAMPLE 10
3-(1-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-4-piperidinyl)-1 ,3-oxazolidine-2,4-dione
(Compound 10)
Figure imgf000104_0001
[00140] N-Chlorosuccinimide (0.014 g, 0.11 mmoi) was added to a solution of 3-(1- {[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[^ ^
oxazolidine-2,4-dione (0.031 g, 0.07 mmoi) in DMF (0.7 ml_). The reaction mixture was heated at 55 °C overnight, concentrated and purified by reverse phase HPLC
(acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.031 g, 93%) as a white solid. 1H NMR (400 MHz, DMSO- /6) δ ppm 7.68 (s, 1 H), 7.41 (s, 1 H), 4.76 (s, 2 H), 4.63 (d, J=13.2 Hz, 1 H), 4.14 (tt, J=12.1 , 3.9 Hz, 1 H), 3.74 (d, J=13.7 Hz, 1 H), 3.20 (t, J=12.2 Hz, 1 H), 2.87 - 2.99 (m, 1 H), 2.05 - 2,26 (m, 3 H), 1.84 (d, J=11.4 Hz, 1 H), 1.68 (d, J=11.1 Hz, 1 H), 1.04 - 1.14 (m, 2 H), 0.93 - 1.01 (m, 2 H). ES-LCMS m/z: 471 (M+1 ). EXAMPLE 1
1-cyclopentyl-4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-2-piperazinone
(Compound 11)
Figure imgf000104_0002
Step A
1, 1-dlmethylethyl [2-(cyclopentylamino)ethyl]carbamate
[00141] A mixture of 151 -dimet y[ethyl (2-bromoethyl)carbamate (1.32 g, 5.87 mmol), cyclopentylamine (0.58 mL, 5,87 mmol) and potassium carbonate (1.62 g, 1 1.74 mmol) in DMF (10 mL) was heated at 60 °C for 30 minutes. The reaction mixture was diluted with EtOAc and water was added. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated to a yellow oil. The crude product was carried on to the next step without further purification. Step B
1, 1-dimethylethyl {2-[(bromoacetyl) ( cyclopentyl) amino]ethy!}carbamate
[00142] To a cooled solution of bromoacetyl bromide (0.38 mL, 4.39 mmol) in dichloromethane (8 mL) was added a solution of 1 , 1 -dimethylethyl [2- (cyclopentylamino)ethyl]carbamate (0.91 1 g, 3.99 mmol) and triethyiamine (0.61 mL, 4.39 mmol) in dichloromethane (6 mL). The mixture was stirred while cooling in an ice bath for 30 min. The solvent was evaporated and EtOAc and water were added to the residue. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography (EtOAc:hexane) gave the title compound (0.706 g, 51 %). ES-LCMS m/z: 349 (M+1).
Step C
1 -cyclop en tyl-2-pip erazin on e
[00143] TFA (2 mL, 26.0 mmol) was added to a solution of 1 , 1 -dimethylethyl {2- [(bromoacetyl)(cyclopentyl)amino]ethyl}carbamate (0.680 g, 1.947 mmol) in
dichloromethane (10 mL). The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated to give a colorless oil which was dissolved in ethanol (10 mL). Potassium carbonate (807 mg, 5.84 mmol) was added and the mixture was heated at reflux for 30 minutes. The solvent was evaporated and the residue was taken up in DCM and water. The aqueous layer was back-extracted with DCM. The combined organic layers were dried over sodium sulfate and concentrated. Purification by silica gel chromatography (MeOH:DCM) afforded the title compound (0.1 12 g, 34%) as a colorless oil. H NMR (400 MHz, chloroform-cf) δ ppm 4.76 - 4.96 (m, 1 H) 3.43 (s, 2 H) 3.08 - 3.17 (m, 2 H) 2.90 - 3.03 (m, 2 H) 1.90 (br. s., 1 H) 1.65 - 1.77 (m, 2 H) 1.54 - 1.65 (m, 2 H) 1.46 - 1.54 (m, 2 H) 1.34 - 1.45 (m, 2 H). Step D
1-cyclopentyl-4-{[5 ycIopropy 7-(trifluoromethyl)pyrazolo[1,5-a]py
piperazinone
[00144] A mixture of 5-cyclopropyi-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.081 g, 0.30 mmol), 1-cyc!opentyl-2-piperazinone hydrochloride salt (0.061 g, 0.30 mmol), DIPEA (0.21 mL, 1.2 mmol) and HATU (0.17 g, 0.45 mmol) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) followed by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.010 g, 8%) as a white solid. 1H NMR (400 MHz, DMSO- /6) δ ppm 7.78 (br. s., 1 H), 7.39 (s, 1 H), 6.98 (s, 1 H), 4.68 - 4.85 (m, 1 H), 4.51 (s, 1 H), 4.21 (s, 1 H), 4.05 (t, J=5.1 Hz, 1 H), 3.85 (t, J=5.3 Hz, 1 H), 3.34 - 3.41 (m, 2 H), 2.10 - 2.19 (m, 1 H), 1.44 - 1.79 (m, 8 H), 1 .03 - 1.1 1 (m, 2 H), 0.85 - 0.95 (m, 2 H). ES-LCMS m/z: 421 (M+1 ). EXAMPLE 12
4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- cyclopentyl-2-piperazinone
(Compound 12)
Figure imgf000106_0001
[00145] N-Bromosuccinimide (0.042 g, 0.10 mmol) was added to a solution of 1- cyclopentyl-4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 )5-a]pyridin-2-yl]carbonyl}-2- piperazinone (0.042 g, 0.12 mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature overnight, concentrated and purified by reverse phase HPLC
(acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.035 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.62 - 7.67 (m, 1 H), 7.42 (d, J=1.3 Hz, 1 H), 4.67 - 4.86 (m, 1 H), 4.24 (s, 1.2 H), 4.09 (s, 0.8 H), 3.87 (t, J=5.4 Hz, 0.8 H), 3.68 (t, J=5.2 Hz, .2 H), 3.37 - 3.43 (m, 0.8 H), 3.27 - 3.32 (m, 1 .2 H), 2.18 - 2.28 (m, 1 H), 1.41 - 1.78 (m, 8 H), 1.04 - 1.14 (m, 2 H), 0.91 - 1 .02 (m, 2 H). ES-LCMS m/z: 499 (M+1 ). EXAMPLE 13
2-[(4-cyclopentyl-3-oxo-1-piperazinyl)carbonyl]-5-cyclopropyl-7- {trifluoromethy[)pyrazolo[1,5-a]pyridine-3-carbonitrile
(Compound 13)
Figure imgf000107_0001
[00146] A mixture of 4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-cyclopentyl-2-piperazinone (0.031 g, 0.06 mmol), copper(l) cyanide (0.022 g, 0.25 mmol) in DMF (0.6 mL) was heated in a microwave oven at 135 °C for 20 minutes and 160 °C for 45 minutes. Upon cooling to room temperature, the mixture was diluted with EtOAc, filtered through a pad of Celite, concentrated and purified by reverse phase HPLC (acetonitriie/water with 0.1 % formic acid) to afford the title compound (0.022 g, 81 %) as a white solid. H NMR (400 MHz, DMSO-d6) δ ppm 7,95 - 8.00 (m, 1 H), 7.60 - 7.66 (m, 1 H), 4.65 - 4.86 (m, 1 H), 4.45 (s, 1 H), 4.25 (s, 1 H), 3.82 - 4.06 (m, 2 H), 3.34 - 3.43 (m, 2 H), 2.23 - 2.36 (m, 1 H), 1.45 - 1.77 (m, 8 H), 1.16 (d, J-7.9 Hz, 2 H), 1.07 (d, J=3.4 Hz, 2 H). ES-LCMS m/z: 446 (M+1 ).
EXAMPLE 14
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony[}-1 cyclopentyl-2-piperazinone
{Compound 14)
Figure imgf000107_0002
[00147] N-Chlorosuccinimide (0.032 g, 0.24 mmol) was added to a solution of 1 - cycIopentyl-4-{[5-cyclopropyl-7-(trifluoromethy!)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}-2- piperazinone (0.067 g, 0.16 mmoi) in DMF (1.6 mL). The reaction mixture was heated at 55 °C overnight, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.042 g, 58%) as a white solid. 1H NMR (400 MHz, DMSO-c(6) δ ppm 7.67 - 7.73 (m, 1 H), 7.42 - 7.46 (m, 1 H), 4.66 - 4.85 (m, 1 H), 4.23 (s, 1.2 H)( 4.15 (s, 0.8 H), 3.87 (t, J=5.4 Hz, 0.8 H), 3.73 (t, J=5.2 Hz, 1.2 H), 3.38 - 3.43 (m, 0.8 H), 3.27 - 3.31 (m, 1.2 H), 2.17 - 2.28 (m, 1 H), 1.59 - 1.77 (m, 4 H), 1.41 - 1 .59 (m, 4 H), 1.05 - 1.16 (m, 2 H), 0.93 - 1.02 (m, 2 H). ES-LCMS m/z: 455 (M+1 ).
EXAMPLE 15
1-cyclobutyl-4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazo[o[1 ,5-a]pyridin-2- yl]carbonyl}-2-piperazinone
(Compound 15)
Figure imgf000108_0001
Step A
1 -cyclob utyl-2-pip erazinone
[00148] 1-Cyclobutyl-2-piperazinone (0.108 g, 14% over 3 steps) was prepared from cyclobutylamine (0.350 g, 4.92 mmol) by the procedure described for Example 1 1. 1H NMR (400 MHz, chloroform-d) δ ppm 4.77 - 5.20 (m, 1 H) 3.49 (s, 2 H) 3.31 (t, J=5.46 Hz, 2 H) 3.07 (t, J=5A6 Hz, 2 H) 2.03 - 2.19 (m, 3 H) 1.59 - 1.74 (m, 3 H).
Step B
1-cyclobutyl-4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazo
piperazinone
[00149] A mixture of 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.081 g, 0.30 mmol), 1-cyclobuty!-2-piperazinone trifluoroacetic acid salt (0.080 g, 0.30 mmol), DIPEA (0.21 mL, 1.2 mmol) and HATU (0.17 g, 0.45 mmol) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) followed by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.012 g, 10%) as a white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.78 (s, 1 H), 7.40 (br. s., 1 H), 6.98 (s, 1 H), 4.83 (dt, J=16.6, 8.2 Hz, 1 H), 4.50 (s, 1 H), 4.20 (s, 1 H), 4.09 (t, J=5.2 Hz, 1 H), 3.88 (t, J=5.3 Hz, 1 H), 3.43 - 3.54 (m, 2 H), 2.07 - 2.25 (m, 3 H), .90 - 2.05 (m, 2 H), 1.54 - 1.69 (im, 2 H), 1.00 - 1.12 (m, 2 H), 0.85 - 0.95 (m, 2 H). ES-LCMS m/z: 407 (M+1 ).
EXAMPLE 16
4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1- cyclobutyl-2-piperazinone
(Compound 16)
Figure imgf000109_0001
[00150] N-Bromosuccinimide (0.021 g, 0.12 mmol) was added to a solution of 1- cyclobutyl-4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazo!o[1 ,5-a]pyridin-2-yl]carbonyl}-2- piperazinone (0.041 g, 0.10 mmol) in DMF (1 ml_). The reaction mixture was stirred at room temperature for 30 minutes, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.012 g, 24%) as a white solid. H NMR (400 MHz, DMSO-c/6) δ ppm 7.61 - 7.69 (m, 1 H), 7.39 - 7.45 (m, 1 H), 4.74 - 4.92 (m, 1 H), 4.22 (s, .2 H), 4.08 (s, 0.8 H), 3.90 (t, 7=5.4 Hz, 0.8 H), 3.71 (t, J=5.2 Hz, 1.2 H), 3.50 (t, J=5A Hz, 0.8 H), 3.41 (t, J=5.2 Hz, 1 .2 H), 2.06 - 2,29 (m, 3 H), 1.93 - 2.04 (m, 2 H), 1.55 - 1.68 (m, 2 H), 1.05 - 1 .16 (m, 2 H), 0.93 - 1.00 (m, 2 H). ES- LCMS m/z: 485 (M+1 ).
EXAMPLE 17
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- cyclobutyl-2-piperazinone
(Compound 17)
Figure imgf000109_0002
[00151] N-Chlorosuccinimide (0.032 g, 0.24 mmol) was added to a solution of 1 - cyclobutyl-4-{[5-cyclopropyl-7-(trif[uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-2- piperazinone (0.065 g, 0.16 mmol) in D F (1 .6 mL). The reaction mixture was heated at 55 °C overnight, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.063 g, 90%) as a white solid. 1H NMR (400 MHz, DMSO-de) δ ppm 7.67 - 7.73 (m, 1 H), 7.41 - 7.48 (m, 1 H), 4.76 - 4.90 (m, 1 H), 4.22 (s, 1.2 H), 4.14 (s, 0.8 H), 3.90 (t, J=5.4 Hz, 0.8 H), 3.76 (t, J=5.3 Hz, 1.2 H), 3.50 (t, J=5.5 Hz, 0.8 H), 3.41 (t, J=5.3 Hz, 1.2 H), 2.08 - 2.29 (m, 3 H), .92 - 2.04 (m, 2 H), 1.53 - 1.72 (m, 2 H), 1.06 - 1.16 (m, 2 H), 0.94 - 1.02 (m, 2 H). ES-LCMS m/z: 441 (M+1 ).
EXAMPLE 18
4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbony[}-1-(3- methylcyclobutyl)-2-piperazinone
(Compound 18)
Figure imgf000110_0001
Step A
N~[(4-nitrophenyl)sutfonyl]glycine
[00152] To a solution of glycine (10 g, 133 mmol) in 1 N sodium hydroxide (140 mL, 140 mmol) at 0 °C was added 4-nitrobenzenesulfonyl chloride (29.5 g, 133 mmol) to give a suspension. After 30 minutes, the cooling bath was removed and 1 N sodium hydroxide solution was added to maintain the pH>9. After 2 hours, the mixture was diluted with 1 N sodium hydroxide and water and extracted with EtOAc (250 mL). The insoluble material was filtered off, and the aqueous phase was separated and further extracted with EtOAc (250 mL, 00 mL). The aqueous phase was then acidified with 6N HCI to pH1 to precipitate the product. The precipitate was filtered and dried under high vacuum to afford the title compound (20.88 g, 60.2 %) as a white solid. ES-LCMS m/z: 259 (M-1 ) Step B
(3-methyleyclobutyl) amine hydrochloride
[00153] A solution of 3-methylcyclobutanecarboxylic acid (6.60 g, 57.8 mmol), diphenylphosphoryl azide (18.74 ml_, 87 mmol) and triethylamine (16.12 mL, 1 16 mmol) in tert-butanol ( 00 mL) was heated at reflux overnight. Saturated aqueous sodium bicarbonate was added followed by evaporation of most of the tBuOH under reduced pressure. The resulting suspension was extracted with diethyl ether. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 10.6 g of 1 , 1 - dimethylethyl (3-methylcyclobutyl)carbamate. A mixture of ,1-dimethylethyl (3- methylcyclobutyl)carbamate (10.56 g, 57 mmol) and HCI (4N in dioxane) (100 mL, 400 mmol) was stirred at RT. The solvent was evaporated to give the desired product as a white solid (4.00 g, 58%) (N12179-48-1 ).
Step C
N 1-(3-methylcyclob utyl)~N2-[(4-nitrophenyl) sulfonyljglycinamide
[00154] HATU (7.32 g, 19.24 mmol) was added to a mixture of N-[(4- nitrophenyl)sulfonyl]glycine (4.17 g, 16.04 mmol), (3-methylcyclobutyl)amine hydrochloride (1.95 g, 16.04 mmol) and DIPEA (8.40 mL, 48.1 mmol) in DMF (50 mL). The mixture was stirred at RT overnight then EtOAc and water were added. The organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated to give the title compound (5.10 g, 97%) as a pink solid that was used without further purification.
Step D
1-(3-methylcyclobutyl)-4-[(4-nitrophenyl)sulfonyl]-2 iperazinone
[00155] A mixture of N1-(3-methylcyclobutyl)-N2-[(4- nitrophenyl)suifonyl]glycinamide (5.09 g, 15.55 mmol) and potassium carbonate (10.74 g, 78 mmol) in DMF (8 mL) was heated at 60 °C for 30 minutes. 1 ,2-dibromoethane (6.70 mL, 78 mmol) was added and heating was continued overnight. EtOAc and water were added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated to give the title compound as an oil that was used without further purification. Step E
1 -(3-methylcyclobutyl)-2-piperazinone hydrochloride [00156] Thiophenol (3,24 mL, 31.5 mmol) was added to a suspension of potassium carbonate (6.09 g, 44.1 mmo!) in acetonitrile (30 mL) at 50 °C. After 30 minutes, 1-(3- methy!cyclobutyi)-4-[(4-nitrophenyl)sulfonyl]-2-piperazinone (4.45 g, 12.59 mmol) in acetonitrile (10 mL) was added dropwise. The mixture was heated at 50 °C overnight then was cooled to RT and filtered through Celite. The solvent was evaporated under reduced pressure and the residue was purified on silica gel (0-10% MeOH:DCM) to give the title compound as a dark brown oil. The oil was dissolved in DCM and 4N HCI in dioxane (10 mL, 40.0 mmol) was added. The solvent was evaporated and the residue was triturated with diethyl ether and dried under vacuum overnight to give the titie compound (1.27 g, 60%) as a white solid.
Step F
4-{[5-cyclopropyl- 7- ( trifluorom ethyl)pyrazolo[ 1,5-a ]pyridin-2-yI]carbonyl}- 1-(3~
methylcyclobutyl)-2-piperazinone
[00157] A mixture of 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.081 g, 0.30 mmol), 1-(3-methylcyclobutyl)-2-piperazinone hydrochloride salt (0.061 g, 0.30 mmol), DIPEA (0.21 mL, 1 .2 mmol) and HATU (0.17 g, 0.45 mmol) in DMF (3 mL) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) followed by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.0052g, 4%) as a white solid. 1H NMR (400 MHz, DMSO~cf6) δ ppm 7.78 (s, 1 H), 7.40 (br. s., 1 H), 6.98 (s, 1 H), 4.99 - 5.16 (m, 0.5 H), 4.56 - 4.73 (m, 0.5 H), 4.50 (s, 1 H), 4.20 (d, J=2.3 Hz, 1 H), 4.03 - 4.14 (m, 1 H), 3.88 (br. s., 1 H), 3.40 - 3.53 (m, 2 H), 1.92 - 2.44 (m, 4 H), 1.63 - 1.79 (m, 2 H), 1.00 - 1.18 (m, 5 H), 0.84 - 0.94 (m, 2 H). ES-LCMS m/z: 421 (M+1 ).
EXAMPLE 19
4-{[3-bromo-5-cyclopropyl-7-(trifluoro
(3-methylcyclobutyl)-2-piperazinone
(Compound 19)
Figure imgf000112_0001
[001581 N-Bromosuccinimide (0.029 g, 0.16 mmol) was added to a solution of 4-{[5- cyclopropy!-7-(trifluoromethyl)pyr
2-piperazinone (0.057 g, 0.14 mmol) in DMF (1.4 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.034 g, 51 %) as a white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.60 - 7.68 (m, 1 H), 7.39 - 7.46 (m, 1 H), 4.99 - 5.14 (m, 0.6 H), 4.57 - 4.71 (m, 0.4 H), 4.23 (d, J=2.0 Hz, 1.2 H), 4.08 (d, J=1.4 Hz, 0.8 H), 3.91 (br. s„ 0.8 H), 3.68 - 3.75 (m, 1.2 H), 3.36 - 3.56 (m, 2 H), 1.94 - 2.42 (m, 4 H), 1.63 - .81 (m, 2 H), 0.92 - 1.20 (m, 7 H). ES-LCMS m/z: 499 (M+1 ).
EXAMPLE 20
5-cyclopropyl-2-{[4-(3-methylcyclobutyl)-3-oxo-1-piperazinyl]carbony[}-7- (trifluoromethyl)pyrazolo[1,5-a]pyridine-3-carbonitrile
(Compounds 20a and 20b)
Figure imgf000113_0001
[00159] A mixture of 4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyI}-1-(3-methylcyclobutyl)-2-piperazinone (0.033 g, 0.07 mmoi), copper(l) cyanide (0.024 g, 0.26 mmoi) in DMF (0.7 mL) was heated in a microwave oven at 60°C for 60 minutes. Upon cooling to room temperature, the mixture was diluted with EtOAc, filtered through a pad of Ceiite, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.023 g, 77%) as a white solid. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.97 (d, J=9.9 Hz, 1 H), 7.63 (d, J=10.2 Hz, 1 H), 4.99 - 5.15 (m, 0.5 H), 4.57 - 4.72 (m, 0.5 H), 4.43 (s, 1 H), 4.23 (d, J=2.2 Hz, 1 H), 4.05 (q, J=4.6 Hz, 1 H), 3.91 (br. s., 1 H), 3.40 - 3.55 (m, 2 H), 1.93 - 2.43 (m, 4 H), 1.64 - 1.81 (m, 2 H), 0.99 - 1.21 (m, 7 H). ES-LCMS m/z: 446 (M+1 ).
EXAMPLE 21
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
(3-methylcyciobuty])-2-piperazinone
(Compound 21)
Figure imgf000114_0001
[00160] N-Chlorosuccinimide (0.027 g, 0.20 mmoi) was added to a solution of 4-{[5- cyclo pro py l-7-(trif lu o rom eth yl )pyra zo
2-piperazinone (0.057 g, 0.14 mmol) in DMF (1.4 mL). The reaction mixture was heated at 55 CC overnight, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.026 g, 41 %) as a white solid. 1H NMR (400 MHz, DMSO-ai6) δ ppm 7.67 - 7.74 (m, 1 H), 7.41 - 7.48 (m, 1 H), 5.06 (ddd, J=17.1 , 8.7, 8.6 Hz, 0.4 H), 4.58 - 4.72 (m, 0.6 H), 4.22 (s, 1.2 H), 4.14 (s, 0.8 H), 3.90 (br. s., 0.8 H), 3.72 - 3.80 (m, 1 .2 H), 3.35 - 3.56 (m, 2 H), 1.90 - 2.41 (m, 4 H), 1 .62 - 1.80 (m, 2 H), 0.93 - 1.18 (m, 7 H). ES-LCMS m/z: 455 (M+1 ).
EXAMPLE 22
4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-(frans-4- hydroxycyclohexyl)-2-piperazinone
(Compounds 22a and 22b)
Figure imgf000114_0002
Step A
methyl N-{[( 1, 1 -dimethyle thy!) oxy]carbonyl}-N-2-prop en-1 -ylglycina te
[00161] To a solution of N-(tert-butoxycarbonyl)-glycine methyl ester (39.3 mL, 266 mmol) in DMF (600 mL) at 0 °C was added allyl bromide (28.8 mL, 332 mmol) followed by sodium hydride (60%, 12.76 g, 319 mmol). After 75 minutes, saturated aqueous NH4CI (100 mL) was added and the suspension was stirred for 30 minutes. The white precipitate was filtered off through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (400 mL) and washed with brine (100 mL) The aqueous phase was separated and further extracted with EtOAc (200 mL). The combined organic phase was dried over MgS04, filtered and concentrated to give 55g of crude product as an oil which was purified on silica gel (0-15% EtOAc/ hexanes) to give the title compound (24.89 g, 109 mmol, 40.8 % yield) as a colorless oil. ES-LCMS: m/z 174 (M+1 ).
Step B
methyl N-{[(1, 1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate
[00162] A solution of methyl W-{[(1 ,1 -dimethylethyl)oxy]carbonyI}-/V-2-propen-1 - ylglycinate (12 g, 52.3 mmol) in methanol {374 mL) was cooled to -78 °C before ozone was bubbled into the mixture. Ozone was applied until the reaction mixture turned blue and TLC indicated consumption of the starting material. Nitrogen was bubbled into the reaction mixture until the blue solution became colorless, and then bubbled with nitrogen for 25 more minutes. Dimethyl sulfide (19.36 mL, 262 mmol) was added slowly and the mixture was allowed to slowly come to room temperature as the cold-bath warmed overnight. The mixture was concentrated and the residue was taken up in ethy! acetate (750 mL). The organic phase was washed with water (250 mL), washed with brine (250 mL), dried over sodium sulfate, and concentrated to give the title compound (12.7 g, 99%). H NMR (CHLOROFORM-c/) δ ppm 9.59 - 9.77 (m, 1 H), 4.13 (s, 1 H), 4.05 (s, 1 H), 4.00 (s, 1 H), 3.90 (s, 1 H), 3.72 - 3.80 (m, 3 H), 1.39 - 1.54 (m, 9 H). Spectral data matches that reported previously in the literature: Bioorg. Med. Chem., 2007 (15), 2092-2105. Step C
1, 1-dimethylethyl 4-(trans-4-hydroxycyclohexyl)-3-oxo-1-piperazinecarboxylate
[00163] To a solution of methyl Λ/-{[(1 ,1 -dimethylethyl)oxy]carbonyl}-W-(2- oxoethyl)glycinate (12.7 g, 52.2 mmol) in methanol (200 mL) was added sodium sulfate (46.3 g, 326 mmol) followed by trans-4-aminocyclohexanol hydrochloride (9.49 g, 62.6 mmol) and /V-ethyl-/V-(1 -methylethyl)-2-propanamine {10.93 mL, 62.6 mmol). The mixture was stirred for 60 minutes before sodium borohydride {2.369 g, 62.6 mmol) was added portionwise in order to control effervescence. A mild exotherm was observed. After 2 hours, LC- S showed the uncyclized
amine/ester. Sodium hydride (60% in mineral oil) (3.99 g, 00 mmol) was added portionwise in order to control effervescence. The reaction appeared to be complete after 1 hour. The reaction was stirred for an additional hour and was concentrated. The mixture was quenched with 30% citric acid trisodium salt. 1 N Hydrochloric acid was added until pH~7, and then solid citric acid was added until pH~5. The mixture was extracted three times with ethyl acetate and the combined organic layers were washed with brine. The organic phase was dried over sodium sulfate and concentrated. Solids precipitated while concentrating. Once the volume reached -100-150 mL, hexanes were added (400 mL), Solids were collected by filtration, washed with hexanes, and dried under vacuum to give the title compound (10.65 g, 68%). ES-LCMS: m/z 299 (M+1 ).
Step D
1 -(trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride
[00164] To a solution of 1 ,1-dimethylethyl 4-(trans-4-hydroxycyciohexyl)-3-oxo-1- piperazinecarboxylate (10.65 g, 35.7 mmol) in dich!oromethane (DCM) (100 mL) was added a solution of 4M HCI in 1 ,4-dioxane (89 mL, 357 mmol). After 6 hours, the solvent was removed under reduced pressure to give 1-(trans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride (9,78 g, 36.4 mmol, quantitative) as a white solid. The compound contained -0.23 eq DCM and -0.16 eq of 1 ,4-dioxane. MS (ESI): 199.3 (MH+). Step E
4-{[5-cyclopropyi-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin 2-yl]carbon
hydroxycyclohexyl)-2-piperazinone
[00165] A mixture of 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.286 g, 1.06 mmol), 1-(irans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride salt (0.30 g, 1.27 mmol), DIPEA (0.74 mL, 4.2 mmol) and HATU (0.61 g, 1.59 mmol) in DMF (10.6 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by silica gei chromatography (0-5% MeOH in CH2CI2) to afford the title compound (0.39 g, 82%) as a white foam. A 21 mg sample was purified by reverse phase HPLC (acetonitriie/water with 0.1 % formic acid) to afford the title compound (0.008 g, 38%) as a white solid. H NMR (400 MHz, DMSO-c/6) δ ppm 7.78 (d, J=0.7 Hz, 1 H), 7.39 (s, 1 H), 6.97 (s, 1 H), 4.58 (br. s., 1 H), 4.51 (s, 1 H), 4.09 - 4.26 (m, 2 H), 4.04 (t, J=5.1 Hz, 1 H), 3.82 (t, J=5.2 Hz, 1 H), 3.34 - 3.40 (m, 3 H), 2.08 - 2.20 (m, 1 H), 1.77 - 1.92 (m, 2 H), 1.44 - 1.64 (m, 4 H), 1.14 - 1.32 (m, 2 H), 1 .02 - 1.1 1 (m, 2 H), 0.82 - 0.95 (m, 2 H). ES-LCMS m/z: 451 (M+1 ). EXAMPLE 23
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1- (irans-4-hydroxycyclohexyl)-2-piperazinone
(Compounds 23a and 23b)
Figure imgf000117_0001
Step A
methyl 3-chloro-5-cyclopropyi-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
[00166] N-Chlorosuccinimide (1.02 g, 7.6 mmol) was added to a solution of methyl 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (1.44 g, 5.1 mmol) in DMF (17 mL). The reaction mixture was heated at 60 °C for 1 hour, concentrated and purified by silica gel chromatography (15-30% EtOAc in hexanes) to afford the title compound (1.47 g, 91%) as a white solid. 1H N R (400 MHz, CHLOROFORM-d) δ ppm 7.45 (s, 1 H), 7.11 (br. s., 1 H), 4.02 (s, 3 H), 1.99 - 2.09 (m, 1 H), 1.14 - 1.21 (m, 2 H), 0.83 - 0.90
(m, 2 H). ES-LCMS m/z: 319 ( +1 ).
Step B
3-chloro-5-cyclopropyl~7~(trifluoromethyl)pyrazoto[ 1, 5-a]pyridine-2-carboxytic acid
[00167] A solution of methyl 3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (1.47 g, 4.62 mmol) in 0.5 N sodium hydroxide (47 mL, 23.5 mmol) and methanol (23 mL) was heated at 50 °C for 4 hours. 1 M aqueous HCI (30 mL) was added and the resulting solid was filtered. The aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were dried over sodium sulfate and the solvent was evaporated. The residue was combined with the above filtered solid to provide the title compound (1.41 g, quantitative) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.70 (br. s., 1 H), 7.71 (s, 1 H), 7.47 (br. s„ 1 H), 2.17 - 2.29 (m, 1 H), 1.05 - 1.14 (m, 2 H), 0.94 - 1.03 (m, 2 H). ES-LCMS m/z: 305 (M+1 ). Step C
4^[3~chlorO'5-cyclopropyl-7-(trifluoromethyI)pyrazolo[1,5-a]pyridin^
4-hydroxycyclohexyl) -2-pip erazinone
[00168] DIPEA (2.3 ml, 13.1 mmol) was added dropwise to a solution of 3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (1 .00 g, 3.3 mmol) and 1-(ira 7s-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (1.16 g, 4.9 mmol) in DMF (8.9 ml).The reaction mixture was stirred at room temperature for 30 minutes, cooled to 0 °C and 1 -propanephosphoric acid cyclic anhydride (2.93 ml of a 50% wt % in EtOAc, 4.9 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hours and added to water (100 mL) while stirring. After 45 minutes, the solid was filtered, washed with water and air dried overnight to afford the title compound (1.58 g, 99%) as a white solid. 1H NMR (400 MHz, DMSO-oie) δ ppm 7.68 - 7.72 (m, 1 H), 7.44 (d, J=1.7 Hz, 1 H), 4.58 (d, J=3.8 Hz, 1 H), 4.09 - 4.26 (m, 3 H), 3.66 - 3.90 (m, 2 H), 3.23 - 3.38 (m, 3 H), 2.18 - 2.27 (m, 1 H), 1.86 (d, J=1 1.3 Hz, 2 H), 1.42 - 1.64 (m, 4 H), 1.15 - 1.33 (m, 2 H), 1.05 - 1.14 (m, 2 H), 0.92 - 1.02 (m, 2 H). ES-LCMS m/z: 485 (M+1 ).
EXAMPLE 24
4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-2-piperazinone
(Compounds 24a and 24b)
Figure imgf000118_0001
H
[00169] N-Bromosuccinimide (0.101 g, 0.57 mmol) was added to a solution of 4-{[5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyndin-2-yl]carbonyl}-1 -(ira/is-4- hydroxycyclohexyl)-2-piperazinone (0.21 g, 0.47 mmol) in DMF (4.7 mL). The reaction mixture was stirred at room temperature for 30 minutes, concentrated and purified by silica gel chromatography (0-10% MeOH in CH2CI2) to afford the title compound (0.17 g, 67%) as a white foam. A 13 mg sample was purified by reverse phase HPLC (acetonitrile/water with 0.1% formic acid) to afford the title compound (8.3 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-de) δ ppm 7.61 - 7.67 (m, 1 H), 7.42 (br. s., 1 H), 4.58 (t, J=4.3 Hz, 1 H), 4.03 - 4.26 (m, 3 H), 3.62 - 3.89 (m, 2 H), 3.24 - 3.40 (m, 3 H), 2.19 - 2.29 (m, 1 H), 1.86 (d, 11.8 Hz, 2 H), 1.43 - 1.60 (m, 4 H), 1.14 - 1 .32 (m, 2 H), 1.05 - 1 .13 (m, 2 H), 0.93 - 1 .01 (m, 2 H). ES-LCMS m/z: 529 (M+1 ),
EXAMPLE 25
5-cyclopropyl"2-{[4-{irans-4-hydroxycyclohexyl)-3-oxo-1-piperazinyl]carbonyl}-7- (trif[uoromethyl)pyrazolo[1,5-a]pyridine-3-carbonitrile
(Compounds 25a and 25b)
Figure imgf000119_0001
[00170] A mixture of 4-{[3-bromo-5-cyclopropyl-7-(trif!uoromethyI)pyrazolo[1 ,5- a]pyridin"2-yl]carbonyl}-1-{trans-4-hydroxycyclohexyl)-2-piperazinone (0.055 g, 0.10 mmol), copper(l) cyanide (0.037 g, 0.41 mmol) in D F (1 .0 mL) was heated in a microwave oven at 160°C for 35 minutes. Upon cooling to room temperature, the mixture was diluted with EtOAc, filtered through a pad of Celite, concentrated and purified by reverse phase HPLC (acetonitrile/water with 0.1 % formic acid) to afford the title compound (0.025 g, 52%) as a white solid. H NMR (400 MHz, DMSO-c 6) δ ppm 7,97 (d, J=5.9 Hz, 1 H), 7.59 - 7.65 (m, 1 H), 4.58 (t, J=3.9 Hz, 1 H), 4.44 (s, 1 H), 4.10 - 4.26 (m, 2 H), 3.99 (t, J=5.1 Hz, 1 H), 3.85 (t, J=5,2 Hz, 1 H), 3.33 (s, 3 H), 2.25 - 2.34 (m, 1 H), 1.86 (d, J=11.4 Hz, 2 H), 1.43 - 1.61 (m, 4 H), 1.12 - 1.30 (m, 4 H), 1.01 - 1.1 1 (m, 2 H). ES-LCMS m/z: 476 (M+1 ).
EXAMPLE 26
4-{[3-chloro-5-cyc[opropyl-7-(trifiuoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(1S,3S)-3-hydroxycyciopentyl]-2-piperazinone
(Compound 26)
Figure imgf000120_0001
Step A
1, 1-dimethylethyl 4-[( 1S,3S)-3~hydroxycyclopentyi]-3-oxo-1-piperazinecarboxyIate
[00171] A solution of methyl N-{[(l,l-dimethylethyl)oxy]carbonyl}-N-(2- oxoethyl)glycinate (1.0 g, 4.32 mmol) in MeOH (16.57 ml) was treated with sodiuni sulfate (3.84 g, 27.0 mmol) followed by (lS,3S)-3-aminocyclopentanol (0.525 g, 5.19 mmol). The mixture was stirred for 1.5 hours. The reaction was then treated by the portion-wise addition of NaBH4 (0.1 6 g, 5.19 mmol). After stirring for 1 hour, the reaction was treated by the portion-wise addition of 60% NaH (0.330 g, 8,26 mmol). The reaction was then allowed to stir for 1.25 hours. The reaction was quenched by the addition of 30% citric acid to bring the pH to ~5. The combined organic phases were then concentrated under reduced pressure and the residue was taken up in water and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried Na2SC>4, filtered, and concentrated to an oil. The crude residue was purified by silica gel chromatography (0-5% MeOH/DCM) to give the title compound (0.603 g, 49%) as an oil.
Step B
1-[(1S, 3S) -3-hydroxycyclopentyi]-2-piperazinone
[00172] A solution of 1 , 1-dimethylethyl 4-[(l S,3S)-3-hydroxycyclopentyl]-3-oxo-l - piperazinecarboxylate (0.603 g, 2.121 mmol) in DCM (3.29 ml) was treated by the drop-wise addition of 4N in dioxanes HC1 (2.65 ml, 10.60 mmol). The reaction was stirred at room temperature for 2.5 hours. The reaction was concentrated under reduced pressure and the crude residue was taken up in MeOH and solids were crashed out with Et20 to give the title compound (0.462 g, 99%) as a sticky solid. Step C
4-{[3-ch!oro-5-cyclopropyl-7-(trifIuoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1- [( 1 S, 3S)-3-hydroxycyclopentyl]-2-piperazinone
[00173] A mixture of 1-[(1 S,3S)-3-hydroxycyclopentyl]-2-piperazinone HC1 (0.057 g,
0.256 mmol) and 3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[l,5-a]pyridine-2-carboxylic acid (0.060 g, 0.197 mmol) in DMF (0.534 ml) was treated by the addition of DIPEA (0.138 ml, 0.788 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled to 0 °C. To the mixture was added drop-wise a 50% solution in EtOAc 1 -propanephosphonic acid cyclic anhydride (0.176 ml, 0.295 mmol). The mixture was stirred for 1 hour. The solution was then treated with water (5.34 mL) and stirred for 45 minutes. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with 5% LiCl (2x), saturated NaHC03, brine, dried (MgS04), filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-4% MeOH/DCM) to give the title compound as a white solid. Ή NMR (400 MHz, CDClj) δ ppm 7.42 (d, J=9.77 Hz, 1 H) 7.07 (s, 1 H) 5.08 - 5.27 (m, 1 H) 4.46 (s, 2 H) 4.37 (s, 1 H) 3.96 - 4.07 (m, 2 H) 3.42 (t, J=5.08 Hz, 2 H) 2.00 - 2.18 (m, 3 H) 1.78 - 1.97 (m, 2 H) 1.57 - 1.72 (m, 2 H) 1.12 - 1.22 (m, 2 H) 0.87 (d, 2 H). ES-LCMS m/z: 471.1 (M+l).
EXAMPLE 27
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazo!o[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(1R,3R)-3-hydroxycyclopentyl]-2-piperazinone
(Compound 27)
Figure imgf000121_0001
Step A
1, 1-dimethylethyl 4-l(1R,3R)-3-hydroxycyc pentyl]-3-oxo-1-piperazinecarboxy!ate
[00174] A solution of methyl N-{[(l,l-dimethylethyl)oxy]carbonyl}-N-(2- oxoethyl)glycinate (1.0 g, 4.32 mmol) in MeOH (16,57 ml) was treated with sodium sulfate (3.84 g, 27.0 mmol) followed by (lR,3R)-3-aminocyclopentanol (0.525 g, 5.19 mmol). The reaction mixture was stirred for 1.5 hours. The reaction was then treated by the portion-wise addition of NaBH4 (0.196 g, 5.19 mmol). After stirring for 1.0 hour, the reaction was treated by the portion- wise addition of 60% NaH (0.330 g, 8.26 mmol). The reaction was then allowed to stir for 1.25 hours and quenched by the addition of 30% citric acid to bring the pH to ~5. The organic solvents were then concentrated under reduced pressure and the residue was taken up in water and extracted with EtOAc (3x). The combined organics were washed with brine, dried
Figure imgf000121_0002
filtered, and concentrated to an oil. The crude residue was purified by silica gel chromatography (0-5%
MeOH/DCM) to give the title compound (0.834g, 68%) as an oil. Step B
1-[( 1 R, 3R)-3-hydroxycyclopentyi]-2-piperazinone HCl
[00175] A solution of 1,1-dimethylethyl 4-[(lR}3R)-3-hydroxycyclopentyl]-3-oxo-l- piperazinecarboxylate (.834 g, 2.93 mmol) in DCM (4.55 ml) was treated by the drop-wise addition of 4N HCl in dioxane (3.67 ml, 14.66 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, concentrated under reduced pressure and the crude residue was taken up in MeOH and solids were crashed out with Et20 to give title product (0.639 g, 99%).
Step C
4-{[3-c loro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,^
1(1 R, 3R)-3-hydroxycyclopentyl]-2-piperazinone
[00176] A mixture of l-[(lR,3R)-3-hydroxycyclopentyl]-2-piperazinone HCl (0.057 g,
0.256 mmol) and 3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[li5-a]pyridine-2-carboxylic acid (0.060 g, 0.197 mmol) in DMF (0.220 ml) was treated by the addition of DIPEA (0.138 ml, 0.788 mmol). The reaction mixture was stirred at room temperature for 30 minutes and then cooled to 0 °C. To the mixture was added drop-wise a 50% solution in EtOAc 1 -propanephosphonic acid cyclic anhydride (0.176 ml, 0.295 mmol). The mixture was stirred for 1 hour, treated with water (5.34 mL) and stirred for 45 minutes. The gummy solid was dissolved with EtOAc. The layers were separated. The aqueous layer was extracted with EtOAc and the combined organic phases were washed with 5% LiCl (2x), saturated NaHC03, brine, dried (MgS04), filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-4% MeOH/DCM) to give the title compound as a white solid. ¾ NMR (400 MHz, CDC13) δ ppm 7.39 - 7.48 (m, 1 H) 7.07 (s, 1 H) 5.12 - 5.23 (m, 1 H) 4.46 (s, 2 H) 4.37 (s, 1 H) 3.94 - 4.10 (m, 2 H) 3.42 (t, J=5.18 Hz, 2 H) 1.99 - 2.19 (m, 3 H) 1.76 - 1.98 (m, 2 H) 1.58 - 1.76 (m, 2 H) 1.26 (br. s., 1 H) 1.12 - 1.22 (m, 2 H) 0.76 - 0.93 (m, 2 H). ES-LCMS m/z: 471.1 (M+l).
EXAMPLE 28
4-{[3-chloro-5-cyclopropyl-7-(trifluoro
[(1 R,3S,4S) and (1S,3R,4R)-3-ethyl-4-hydroxycyciopentyl]-2-piperazinone
(Compound 28)
Figure imgf000123_0001
Step A
(3-cyclopenten-1-yloxy)(1 , 1-dimethylethyl)dimethylsilane
[00177] A solution of 3-cyclopenten-l-ol (2.0 g, 23.78 mmol) in DMF (79 ml) was cooled to 0 °C and treated by the addition of imidazole (3.56 g, 52,3 mmol) followed by the addition of TBDMSC1 (4.30 g, 28.5 mmol). The reaction mixture was stirred at room temperature overnight, diluted with EtOAc and washed with 5% LiCl (3 ), brine, dried (Na2S04), Filtered, and
concentrated. The crude residue was purified by silica gel chromatography (0-10%
EtOAc/Hexanes) to give the title product (5.19 g, 100%).
Step B
(1 , l-dimethytethyl) (dimethyl) [( R, 3 R, 5S a nd 1 S , 3S , 5R)-6-oxabicyclo[3.1.0]hex-3- yloxyjsilane
[00178] A solution of (3-cyclopenten-l-yloxy)(l,l-dimethyletl yl)dimethylsilane (4.72 g, 23.79 mmol) in DCM (95 ml) was cooled to 0 °C and treated by the portion-wise addition of m-
CPBA (7.47 g, 33.3 mmol). The reaction was stirred with warming to room temperature overmght. DCM and water were added to the reaction mixture and the organic layer was washed with 10% NaHS03 until peroxides was not detected. The organic layer was washed with saturated NaHC03s water, brine, dried (Na2S04), filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-10% EtOAc/Hexanes) to give the title compound (1.84 g, 36%).
Step C
(1R,2S,4R) and (1S,2R,4S)~4-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}-2- eth enylcyclop entanol
[00179] A suspension of copper© iodide (0.245 g, 1.288 mmol) in dry THE (12.62 ml) was cooled to -30 °C under N2 and was treated by the drop-wise addition of 1M in THE
vinylmagnesium bromide (12,88 ml, 12.88 mmol). The suspension was stirred for an additional 15 minutes and a solution of (lsl-dimethylethyl)(dimethyl)[( 1R,3R;5S and lS„3S,5R)-6- oxabicyclo[3.1.0]hex-3-yloxy]silane (1.841 g, 8.59 mmol) hi THF (6.31 ml) was added drop-wise. The solution was allowed to warm slowly to 0 °C over 30 minutes and stirred for an additional 2 hours. The reaction mixture was quenched by the addition of NH4C1 (200 mL) and extracted with Et20. The combined organic phases were washed with saturated NH4C1, brine, dried (MgS04), filtered, and concentrated to give the title compound (2.26 g, 100%) as a pale yellow oil. Step D
(1, 1-dimethylethyl)({(1R,3R,4R) and (1S,3S,4S)-3-ethenyl-4- [(phenylmethyl)oxy]cyclopentyl}oxy)dimethylsilane
[00180] A solution of (1R,2S,4R) and (lS,2R,4S)-4-{[(l,l- dimethylethyl)(dimethyl)silyl]oxy}-2-methylcyclopentaiiol (2.26 g, 9.32 mmol) i DMF (92 ml) was cooled to 0 °C and treated by the portion-wise addition of 60% NaH (0.429 g, 10.72 mmol).
After stirring for 30 minutes, (bromomethyl)benzene (1 ,218 ml, 10.25 mmol) was added drop-wise. The reaction mixture was allowed to stir with wanning to room temperature overnight and quenched by the addition of water and extracted with EtOAc. The combined organic phases were washed with 5% LiCl (3x), brine, dried (MgS04), filtered, and concentrated. The residue was concentrated from hexanes to give the title compound (3.23 g, 100%).
Step E
(1R,3S,4R) and (1S,3R,4S)-3-ethenyl-4-[(phenylmethyl)oxy]cyclopentanol
[00181] A solution of (1,1 -dimethylethyl)({ (1R,3R,4R) and fiS,3S,4S -3-ethenyl-4- [(phenylmethyl)oxy]cyclopentyl}oxy)dimethylsilane (3.23 g, 9.71 mmol) in THF (36.9 ml) was cooled to 0 °C and treated by the drop-wise addition of 1M in THF TBAF (11.66 ml, 11.66 mmol). The reaction was stirred with wanning to room temperature overnight, concentrated and purified by silica gel chromatography (0-35% EtOAc Hexanes) to give the title product (1.017 g, 48%). Step F
2-{(1R, 3R, 4S) and (1S,3S, 4R)-3-ethenyl-4-[(phenylmethyl)oxy]cyclopentyl}-1H~isoindoIe-
1,3(2H)-dione
[00182] A 0 °C solution of triphenylphosphine (1.820 g, 6.94 mmol) in THF (32.4 ml) was treated by the addition of DIAD (1.349 ml, 6.94 mmol). The mixture was stirred at 0 °C for 30 minutes. A solution of (1R,3S,4R) and fi^^R^S^-S-ethenyl^-ftphenylmethy^oxyJcyclopentanol (1.01 g, 4.63 mmol) in THF (32.4 ml) was added, followed by phthalimide (2.042 g, 13.88 mmol). The mixture was stirred with warming to room temperature for 3 days. The reaction mixture was loaded onto celite and purified by silica gel chromatography (0-40% EtOAc/Hexanes) to give the title compound (1.14 g, 71%). Step G
(1 R, 3R, 4S) and (1S,3S, 4R) -3-ethenyl-4-[(phenylmethyl) oxy]cyclopentanamine
[00183] A solution of 2-{(lR,3R,4S) and ^^^-S-et enyl^-
[(phenylmethyl)oxy]cyclopentyl}-lH-isoindole-l,3(2H)-dione (.683 g, 1.966 mmol) in EtOH (9.64 ml) was treated with hydrazine monohydrate (0.191 ml, 3.93 mmol) and the reaction was heated to refruxed overnight. The reaction was cooled, the solids were filtered off and the solvents were removed under reduced pressure. The residue was treated with saturated NaHCC>3 and extracted with DCM. The combined organic phases were washed with brine, dried (MgS04), filtered and concentrated. The crude residue was purified by silica gel chromatography (3% MeOH/DCM, then 10% MeOH/DCM) to give the title compound (0.328 g, 77%).
Step H
1, 1-dimethylethyl 4-{(1R,3R,4S) and (1S,3S,4R)~3-ethenyl-4- [ (phenyl me thyl) oxyjcyclopentyl} -3-oxo- 1-pip erazin ecarboxylate
[00184] A solution methyl N-{[(l,l-dimetliylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate
(0.52 g, 2.249 mmol) in MeOH (8.62 ml) was treated with sodium sulfate (1.996 g, 14.05 mmol) followed by {(1R,3R,4S) and (1S,3S, ^RJ-3-ethenyl-4-[(phenylmethyl)oxy]cyclopentyl}amine (0.538 g, 2.474 mmol). The mixture was stirred for 2 hours. The reaction was then treated by the portion- wise addition of NaBH4 (0.102 g, 2.70 mmol). After stirring for 1 hour, the reaction was treated by the portion-wise addition of 60% NaH (0.172 g, 4.29 mmol). The reaction was then allowed to stir for 1.25 hours and quenched by the addition of 30% citric acid to bring the pH to -5. The organic phase was then concentrated under reduced pressure and the residue was taken up in water and extracted with EtOAc (3x). The combined organic phases were washed with brine, dried (MgSO^, filtered, and concentrated to obtain an oil. The crude residue was purified by silica gel chromatography (0-5% MeOH DCM) to give the title compound as an oily residue.
Step I
1, 1-dimethylethyl 4-[(1R,3S,4S) and (1S;3R,4R)-3-ethyl-4-hydroxycyclopentyt]-3-oxo-1- piperazinecarboxy!a te
[00185] A solution of 1,1-dimethylethyl A-{(1R,3R,4S) and
Figure imgf000125_0001
[(phenylmethyl)oxy]cyclopentyl}-3-oxo-l-piperazinecarboxylate (0.400 g, 1.00 mmol) in EtOAc (5 ml) was treated with 10% Degussa Pd C (0.106 g, 0.100 mmol) and hydrogenated overnight under a 40 psi hydrogen atmosphere. The catalyst was filtered using a filter disk and the solvents were removed under reduced pressure. The residue was re-subj ected to catalyst, solvent, and hydrogen gas at 40 psi for 48 hours. The catalyst was filtered using a filter disk and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (0-5%
MeOH/DCM) to give the title compound (0,144 g, 46.2%).
Step J
1-[(1R, S, 4S) and (1S, 3R, 4R)-3-ethyl-4-hydroxycyclopentyl]-2-piperazinone HCI
[00186] A solution of 1,1-dimethylethyl A-[(1R,3S,4S) and (IS R^R^-et yl-A- hydroxycyclopentyl]-3-oxo-l-piperazinecarboxylate (.078 g, 0.250 mmol) in DCM (2 mL) was treated with 4N HCI in dioxane (0.5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to give the title compound (0.064 g, 100%) as the HCI salt.
Step K
4-{[3-chloro-5-cyclopropyl~7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1- [(1R,3S,4S) and (1S,3R,4R)-3-ethyl-4-hydroxycyciopentyl]-2-piperazinone
[00187] A solution of 3-chloro-5-cyclopropyl-7-(trifluoiOinethyl)pyrazolo[l,5-a]pyridine-2- carboxylic acid (0.175 g, 0.574 mmol) and \-[((lRs3Ss4S) and (lS,3R,4R)-3-ethy\A- hydroxycyclopentyl]-2-piperazinone HCI (0.111 g, 0.522 mmol) in DMF (2.64 ml) was treated with DIPEA (0.228 ml, 1.306 mmol) and HATU (0.218 g, 0.574 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with EtOAc and washed with 5% LiCl (3x), saturated NaHC03) brine, dried (MgSO^), filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-5% MeOHT>CM) to give the product which was farther purified by reverse phase chromatography (5-95% ACN/Water + 0.1% formic acid) to give the title compound (0.048 g, 18%). Ή NMR (400 MHz, CHLOROFORM-i/) δ ppm 7.42 (d, 7=9.77 Hz, 1 H) 7.06 (s, 1 H) 5.01 - 5.19 (m, 1 H) 4.31 - 4.61 (m, 2 H) 4.01 (d, J=4.10 Hz, 3 H) 3.41 (t, J=5.08 Hz, 2 H) 1.76 - 2.22 (m, 4 H) 1.37 - 1.76 (m, 3 H) 1.10 - 1.37 (m, 4 H) 0.77 - 1.00 (m, 5 H). ES- LCMS m z: 499.2 (M+l).
EXAMPLES 29, 30. 31
4-{[3-ch I oro-5-cycl opropyl-7-(trif to
(3-ethyl-4-hydroxycyclopentyl)-2-piperazinone
isomer 1 , isomer 2, and isomer 3
(Compounds 29, 30, and 31)
Figure imgf000127_0001
Step A
[001881 Separation of 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[l ,5- a]pyridin-2-yl]carbonyl}-l -[(1R,3S,4S) and (1 S,3R,4R 3-ethyl-4-hydroxycyclopentyl]-2- piperazinone (0.042 g) was performed on Phenomenex Hydro-RP 20.2X150mm column with 40% ACN (0.1% formic acid) 60% H20 (0.1% formic acid) isocratic 25 minutes, collection threshold triggered on 235 nm (local lambda max) to afford a first isomer (0.043 g): Ή NMR (400 MHz, CHLOROFORM-i ) δ ppm 7.42 (d, J=8.39 Hz, 1 H) 7.06 (s, 1 H) 5.01 - 5.10 (m,l H) 4.32 - 4.63 (m, 2 H) 3.98 - 4.17 (m, 1 H) 3.91 (dd, J=7.41, 3.90 Hz, 1 H) 3.47 (br. s., 1 H) 3.25 - 3.41 (m, 1 H) 2.65 (s, 2 H) 2.42 (br. s, 1 H) 1.84 - 2.25 (m, 4 H) 1.66 (dt, J=9.37, 4.68 Hz, 1 H) 1.43 (d, J=4.88 Hz, 1 H) 0.98 - 1.32 (m, 5 H) 0.79 - 0.98 (m, 6 H), ES-LCMS m/z: 499.0 (M+l); a second eluting isomer (0.019 g) Ή NMR (400 MHz, CHLOROFORM-J) δ ppm 7.42 (d, J=9.56 Hz, 1 H) 7.06 (s, 1 H) 4.72 - 4.93 (m, 1 H) 4.31 - 4.59 (ms 3 H) 3.84 - 4.14 (m, 2 H) 3.40 (br. s., 2 H) 2.26 - 2.40 (m, 1 H) 1.81 - 2.09 (m, 4 H) 1.58 (br. s., 2 H) 1.24 - 1.43 (m, 2 H) 1.18 (d, J=7.80 Hz, 2 H) 0.76 - 1.00 (m, 5 H), ES-LCMS m/z: 499.0 (M+l)., and a third eluting isomer (0.079 g) Ή NMR (400 MHz, CHLOROFORM-ίί) δ ppm 7.42 (d, J=9.95 Hz, 1 H) 7.06 (br. s., 1 H) 5.02 - 5.21 (m, 1 H) 4.45 (s, 1 H) 4.36 (s, 1 H) 3.88 - 4.08 (m, 3 H) 3.41 (t, J=5.17 Hz, 2 H) 1.78 - 2.21 (m, 5 H) 1.60 - 1.78 (m, 2 H) 1.11 - 1.38 (m, 4 H) 0.96 (t, J=7.32 Hz, 3 H) 0.81 - 0.91 (m, 2 H), ES-LCMS m/z: 499.0 (M+l). Absolute stereochemical assignments were not made.
EXAMPLE 32
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-
(3-methylcyclopentyl)-2-piperazinone
(Compound 32)
Figure imgf000127_0002
Step A
3~methylcyclopentanone oxime
[00189] A solution of 3-methylcylcpentanone (2.0 g, 20.38 mniol), hydroxylamine hydrochloride (3.54 g, 50.9 mmol), and TEA (8.52 ml, 61.1 mmol) in EtOH (29.9 ml) was heated to reflux overnight. The reaction was cooled and the solvents were removed under reduced pressure. The residue was diluted with water and acidified to pH 1 with HCl. The mixture was extracted with EtOAc and the combined organics were washed with water, brine, dried (MgS04), filtered and evaporated to give the title product (2.63 g, 100%) as a pale yellow oil.
Step B
(3-methylcyclopentyl)amine HC!
[00190] A solution of 3-methylcyclopentanone oxime (1.31 g, 11.58 mmol) in Et20 (34.7 ml) was cooled to -78 °C and treated by the addition of 1 M LAH in THF (23.1 ml, 23.15 mmol) . The mixture was stirred with warming to room tem erature overnight, The reaction mixture was cooled to 0 °C and then treated by the drop-wise addition water (.880 mL), 15% NaOH (0.880 mL), and water (2.64 mL). The resulting reaction mixture was stirred for 30 minutes and then filtered, washing with Et20. 2N HCl in Et20 (- 10 mL) was added and the solvents were removed under reduced pressure to give the crude residue as an oil (2.63 g). Due to the excess mass, the residue was taken up in water and Et20 and acidified with IN HCl. The aqueous phase was extracted with Et20 (2x) and the organic phases were set aside. The aqueous phase was basified with IN NaOH and extracted with Et20 (3x). The combined organic phases were washed with brine, dried (MgSOi), filtered and concentrated and the residue was treated with 2M HCl in Et20 and concentrated to give the title compound (0.849 g, 54%) as the HCl salt.
Step C
N1-(3-methyicyclopentyl)-N2'[(4-nitrophenyl)sulfonyl]glycinamide
[00191] A solution of (3-methylcyclopentyl)amine HCl (.849 g, 6.26 mmol) in DMF (28.6 ml) was treated by the addition of DTPEA (2.73 ml, 15.65 mmol), N-[(4- nitrophenyl)sulfonyl] glycine (1.792 g, 6.89 mmol), and HATU (2.62 g, 6.89 mmol). The reaction mixture was stirred at room temperature for 3 days, diluted with water and EtOAc. The combined organic phases were washed with 5% LiCl (3x), saturated NaHC03, and brine, dried (MgS04), filtered and concentrated to give the title compound (1.95 g, 91%) which, was used without further purification. Step D
1-(3-methylcyctopentyt)-4-[(4-nitrophenyl)sulfonyl]-2^ip^
[00192] A solution of Nl -(3-methylcyclopentyl)-N2-[(4-nitrophenyl)sulfonyl]glycinaniide
(1.95 g, 5.71 mmol) inDMF (24.61 ml) was treated by the addition of K2C03 (6.32 g, 45.7 mniol) and 1 ,2-dibromoethane (3.95 ml, 45,7 mmol). The reaction mixture was heated at 60 °C overnight, cooled and diluted with water and EtOAc. The combined organics were washed with 5% LiCl (3x), saturated NaHC03, brine, dried (MgSO^), filtered, and concentrated to give the title compound (0.789 g, 38%) as dark red oily solid which was used without further purification. Step E
1-(3-methylcyclopentyl)-2-piperazinone HCt
[00193] A solution of K2C03 (1.039 g, 7.52 mmol) in ACN (20.35 ml) was heated to 50 °C and treated by the addition of benzenethiol (0.553 ml, 5.37 mmol). The mixture was stirred for 30 minutes and then treated by the drop-wise addition of l-(3-methylcyclopentyl)-4-[(4- nitrophenyl)sulfonyl]-2-piperazinone (.789 g, 2.147 mmol) in DMF (4.07 ml). The reaction was stirred for 90 minutes and cooled to room temperature. The organic salts were filtered through GF/F and the filtrate was concentrated under reduced pressure. The residue was loaded onto celite and was purified by silica gel chromatography (5% MeOH DCM then 5% 2N N¾ in MeOH/DCM) to give a residue which was then taken up in DCM and treated with 2N HC1 in EtiO. The solvents were evaporated to afford the title product (0.225 g, 48%).
Step F
4-{[3-chloro-5~cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyr^^
methytcyclopentyi)-2-piperazinone
[00194] A solution of 3-chloro-5-cyclopropyl-7-(trifluorometliyl)pyrazolo[l ,5-a]pyridine-2~ carboxylic acid (0.092 g, 0.302 mmol) and l-(3-methylcyclopentyl)-2-piperazinone FICl (.060 g, 0.274 mmol) in DMF (3.07 ml) was treated by the addition of HATU (0.115 g, 0.302 mmol) and DIPEA (0.120 ml, 0.686 mmol). The reaction mixture was stirred at room temperature for 2 hours and diluted with EtOAc and water. The combined organic phases were washed with 5% LiCl (3x), saturated NaHC(¾, brine, dried (MgS04), filtered, and concentrated. The cmde residue was purified by silica gel chromatography (0-2% MeOH/DCM) to give the title product (0.101 g, 79%) as a white solid. JH NMR (400 MHz, CHLOROFORM-c δ ppm 7.37 - 7.48 (m, 1 H) 7.06 (br. s., 1 H) 4.87 - 5.21 (m, 1 H) 4.42 - 4.51 (m, 1 H) 4.34 (s, 1 H) 3.90 - 4.12 (m, 2 H) 3.43 (d, J=5.66 Hz, 2 H) 1.79 - 2.19 (m, 5 H) 1.46 - 1.56 (m, 1 H) 1.10 - 1.32 (m, 4 H) 1.04 (ddd, J=12.58, 6.44, 2.24 Hz, 3 H) 0.87 (d, J=5.27 FIz, 2 H). ES-LCMS m/z: 469.3 (M+l). EXAMPLE 33
(Compound 33)
4-{[5-(ethyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(frans-4- hydroxycyciohexyl)-2-piperazinone
Figure imgf000130_0001
0H
Step A
4-(ethyloxy)~2~(trifluoromethyI)pyridine
[00195] 2-(trifluoromethyl)-4-pyridinol (820 mg, 5.03 mmol) was dissolved in N,N- dimethylformamide (15 mL) and cooled to 5 °C in an ice bath. Sodium hydride (60% in mineral oil) (302 mg, 7.54 mmol) was added portion-wise to control frothing. The mixture was stirred for 10 minutes before ethyl iodide (0,61 mL, 7.5 mmol) was added. The mixture was stirred for 1 hour at 5 °C and then was allowed to warm to room temperature. The mixture was stirred for 2 hours and diluted with water before being extracted 2 times with ethyl acetate. The combined organic layers were washed 2 times with brine, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5 % ethyl acete in dichloromethane. Fractions were concentrated to give the title compound (850 mg, 88%). MS (ESI) m z = 192 (MH+).
Step B
1-amino-4-(ethyloxy)-2-(trifluoromethyl)pyridinium 2,4, 6-trimethylbenzenesulfonate
[00196] Trifluoroacetic acid (10 mL) was cooled to 5 °C in an ice bath before 1,1- dimethylethyl {[(2,4,6-trimethylphenyl)sulfonyl]oxy}carbamate (1670 mg, 5.30 mmol) was added. The mixture was stirred for 1 hour before 3 mL of cold water were added. A white precipitate formed and was collected by filtration. The filter cake was washed with cold water and air dried for a few minutes. The solids were added to dichloromethane (35 mL) with stirring anhydrous magnesium sulfate. The mixture was filtered directly mto a second flask containing 4-(ethyloxy)-2- (trifluoromethyl)pyridine (844 mg, 4.42 mmol). The reaction was allowed to stir at room temperature overnight. The mixture was concentrated to give the title compound (2.05 g). MS (ESI) m z: 207 (M+). Step C
dimethyl 5-(ethyloxy)-7-(trifluoromethyl)pyrazolo[1,5~a]pyridine-2,3-dicarboxylate
[00197] l-arnino-4-(ethyloxy)-2-(trifluoromethyl)pyridiniirrn 2,4,6- trimethylbenzenesulfonate (1800 mg, 4.42 mmol) was dissolved in N,N-dimethylfoimamide (20 mL) and cooled to 5 °C. Potassium carbonate (1220 mg, 8.84 mmol) was added and stirred for 10 minutes before dimethyl 2-butynedioate (1260 mg, 8.84 mmol) was added slowly drop-wise. The mixture was allowed to warm to room temperature and stirred over the weekend. The mixture was quenched with water. Solids were collected by filtration, washed with water, and air dried to give the title compound (630 mg, 42% over 2 steps). MS (ESI) m/z; 347 (MH*).
Step D
methyl 5~hydroxy-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
[00198] Dimethyl 5-(ethyloxy)-7-(trifiuoromethyl)pyrazolo[l ,5-a]pyridine-2,3- dicarboxylate (632 mg, 1.82 mmol) was dissolved in sulfuric acid (2920 μΐ, 54.8 mmol) and the mixture heated to 90 °C for 2 hours. Water (0.5 mL) was added and the mixture continued to heat overnight. The mixture was allowed to cool to room temperature and was poured into cold water. The mixture was extracted 2 times with ethyl acetate and the combined organic layers washed with brine, dried over sodium sulfate, and concentrated. The residue was dissolved in methanol (20 mL) before 2 drops of sulfuric acid were added. The mixture was heated to reflux overnight. The mixture was concentrated and the residue dried under vacuum to give the title compound (460 mg, 97%). MS (ESI) m/z: 261 (MH+).
Step E
methyl 5-(ethyloxy)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
[00199] To a mixture of methyl 5-hydroxy-7-(trifluoromethyl)pyrazolo[l ,5-a]pyridine-2- carboxylate (230 mg, 0.707 mmol) and potassium carbonate (391 mg, 2.83 mmol) in N,N- dimethylfonnamide (5 mL) was added ethyl iodide (0.114 mL, 1.41 mmol) . The mixture was stirred overniglit at room tem erature. The mixture was quenched with water and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography and fractions concentrated to give the title compound (170 mg, 83%). MS (ESI) m z: 289 (MH+). Step F
4-{[5-(ethyloxy)-7-(triftuoromethyl)pyrazolo[1,5-a]pyridin^
hydroxycyclohexyi)-2-piperazinone
[002001 To a mixture of methyl 5-(ethyloxy)-7-(trifluoromethyl)pyrazolo[l ,5-a]pyridine-2- carboxylate (83 mg, 0.29 mmol) in tetrahydrofuran (2 mL) and water (2 mL) was added 1M sodium hydroxide (0.58 mL, 0.58 mmol). The mixture was stirred for 2 hours and concentrated. N,N- Dimetbylfonnamide 2mL) was added to the residue, followed by l-(ira¾s-4-hydiOxycyclohexyi)-2- piperazinone hydrochloride (74 mg, 0.32 mmol), N-ethyl-N-(l-methylethyl)-2-propanamine (0.25 mL, 1,4 mmol), and 1 -propanephosphonic acid cyclic anhydride, 50 wt. % solution in ethyl acetate (0.26 mL, 0.43 mmol). The mixture was stirred for 2 hours, diluted with water, and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sullfate, and concentrated. The residue was purified by silica cliromatography eluting with a gradient of 0% to 5% methanol in dichloromethane. Fractions were concentrated to give the title compound (84 mg, 64%). Ή NMR (400 MHz, CHLOROFORM -d) δ ppm 7.02 (s, 1 H), 6.95 (s, 0.5 H), 6.88 - 6.93 (m, 1 H), 6.86 (s, 0.5 H), 4.72 (s, 1 H), 4.33 - 4.55 (m, 4 H), 4.09 (q, 2 H), 3.95 (t, 1 H), 3.52 - 3.64 (m, 1 H), 3.31 - 3.44 (m, 2 H), 1.98 - 2.13 (m, 2 H), 1.65 - 1.82 (m, 4 H), 1.37 - 1.64 (m, 5 H). MS (ESI) m/z: 455 (MH+).
EXAMPLE 34
4-{[3-chloro-5-(ethyloxy)-7-(^
(frans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 34)
Figure imgf000132_0001
OH
[002 1 ] To a solution of 4- { [5 -(ethyloxy)-7-(trifluoromethyl)pyrazolo [ 1 ,5 - ]pyridin-2- yl]carbonyl}-l-(ira«i,-4-hydroxycyclohexyl)-2-piperazinone (79 mg, 0.17 mmol) in N,N- dimethylfon TLamide (2 mL) was added N-chlorosuccinnnide (26 mg, 0.19 mmol). The mixture was heated to 60 °C for 2 hours and cooled to room temperature. The mixture was diluted with water and extracted 2 times with ethyl acetate. The combined organic layers were washed with brine, washed with 5% lithium chloride, dried over sodium sulfate, and concentrated. The residue was purified by silica chromatography eluting with a gradient of 0% to 5% methanol in
dichloromethane. Fractions were concentrated to give the title compound (50 mg, 60%). ]H NMR (400 MHz, DMSO-(/6) δ ppm 7.45 (br. s., 1 H), 7.24 (br. s., 1 H), 4.50 - 4.67 (m, 1 H), 4.08 - 4.33 (m, 5 H)} 3.84 (br. s., 1 H), 3.72 (br. s., 1 H), 3.33 (s, 3 H), 1.84 (br. s., 2 H), 1.51 (br. s„ 4 H), 1.40 (t, 3 H), 1.24 (br. s., 2 H). MS (ESI) m/z: 489, 491 (MH+).
EXAMPLE 35
1-[(1R,5S,6r)-bicyclo[3.1.0]hex-6-yl]-4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-2-piperazinone
(Compound 35)
Figure imgf000133_0001
Step A
1, 5a-bicyclo[3.1.0]hex-2-ene-6fi-carbaldehyde
[00202] mCPBA (20 g, 87 mmol) was added in portions over 2 hours to a 0 °C solution of norbornadiene (11.5 mL, 113 mmol) in CH2C¾ (300 mL). After 3 hours at room temperature, the suspension was filtered. The organic layer was washed with ice cold 5% NaHC(¾ solution and ice cold water, dried (MgSC>4), filtered, and evaporated to provide the endo aldehyde as a clear oil. The oil was taken up in MeOH (100 mL) and NaOMe (7g, 130 mmol) was added. The mixture was heated under reflux for 24 hours, diluted with water (150 mL), and extracted with Et O. The combined organic layers were washed with water, brine, dried (MgS04), filtered through a pad of silica gel, rinsed with Et20, and evaporated to provide the title compound (5,2 g, 55%) as a dark brown oil. 1H NMR (400 MHz, CHLOROFORM-i) δ ppm 9.34 (d, J=4.6 Hz, 1 H), 5.98 (dd, J=5.4, 2.1 Hz, 1 H), 5,59 - 5.64 (m, 1 H), 2.72 - 2.82 (m, 1 H), 2.62 (dt, .7=4.2, 2.1 Hz, 1 H), 2.50 (dd, J=18.9, 2.0 Hz, 1 H), 2.39 (td, J=6.3, 3.1 Hz, 1 H), 1.25 - 1.31 (m, 1 H).
Step B
1,5a-bicyclo[3.1.0]hex-2~ene^-carboxy!ic acid
[00203] A solution of silver nitrate (27.6 g, 162 mmol) in water (70 mL) was added to a solution of l,5ff-bicyclo[3.1 ,0]hex-2-ene-65-carbaldehyde (5.2 g, 48 mmol) in EtOH (30 mL). 2M NaOH solution (128 mL, 256 mmol) was added dropwise to the reaction mixture and the solution was stirred in the dark for 4 hours. The reaction mixture was filtered, washed with water and extracted with Et20. The aqueous layer was acidified to pH 1 with cone. HC1 and extracted with ΕΪ2Ο (3x). The combined organic layers were washed with water, dried (MgSO^, filtered, and evaporated to provide the title compound (4.0 g, 67%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-J) δ ppm 11.09 (br. s., 1 H), 5.91 - 5.98 (m, 1 H), 5.54 - 5.64 (m, 1 H), 2.72 (dd, J=18.4, 6.5 Hz, 1 H), 2.41 - 2.56 (m, 2 H), 2.23 - 2.36 (m, 1 H), 0.90 - 1.05 (m, 1 H).
Step C
1, 1 -dimethylethyi 1, 5 -bicyclo[3.1.0]hex-2-en-6fi-ylcarbamate
[00204] Triethylamine (3.7 mL, 26.6 mmol) and ethyl chloroformate (2.6 mL, 27.1 mmoL) were slowly added to a 0°C solution of l, a-bicyclo[3.1 ,0]hex-2-ene-6p-carboxylic acid (3.0 g, 24.2 mmol) in CH2C12 (60 mL). After 15 mins, the reaction mixture was evaporated to diyness and the residue was taken up in acetone (30 mL) and cooled to 0 °C. A 0 °C solution of sodium azide (3.14 g, 48.3 mmol) in water (16 mL) was added and the solution was stirred for 15 mins, diluted with water and extracted with EtOAc. The combined organic layers were dried (MgS04), filtered, and evaporated to dryness. The dark brown oil was taken up in toluene (60 mL), and tBuOH (9 mL) and the solution was heated under reflux for 24 hours. After evaporation, the residue was purified by silica gel chromatography (0-30% EtOAc/hexs) to provide the title compound (0.8 g, 17%) as an off-white solid. 1H NMR (400 MHz, CHLOROFORM-t ) δ ppm 5.80 - 5.93 (m, 1 H), 5.37 - 5.52 (m, 1 H), 4.72 (br. s., 1 H), 2.55 - 2.67 (m} 1 H); 2.37 - 2.48 (m, lH), 2.02 (d, J=5.9 Hz, 1 H), 1.86 (br. s., 1 H), 1.67 (t, J=6.5 Hz, 1 H), 1.45 (s, 9 H).
Step D
1, 1 -dimethylethyi 4~bicyclo[3.1.0]hex-2-en-6-yl-3-oxo-1-piperazinecarboxylate
[00205] A solution of 1,1 -dimethylethyi l,5a-bicyclo[3.1.0]hex-2-en-6 -ylcarbamate (0.80 g, 4.1 mmol) in TFA (3 mL) and CH2CI2 (6 mL) was stirred at room temperature for 1 hour.
Aqueous NaHC(¾ was added and the solution was extracted with EtOAc. The combined organic phases were dried (Na2S04), filtered and evaporated to provide the amine which was used without further purification. A solution of the amine, methyl N-{ [(1,1 -dimethylethyl)oxy]carbonyl}-N-.(2- oxoethyl)glycinate (0.95 g, 4.1 mmol) and sodium sulfate (4.1 g, 28.7 mmol) in MeOH (11.5 mL) was stirred for 1 hour. NaB¾ (0.17 g, 4.5 mmol) was added and after another 2 hours, NaH (0.26 g, 6.6 mmol) was added and the mixture was stirred for an additional 2 hours before addition of citric acid and EtOAc. The solution was extracted with EtOAc and organic layers were combined, dried (Na2S04), evaporated and the residue was purified by silica gel chromatography (0-60% EtOAc/hexanes) to provide the title compound (0.26 g, 0.94 mmol) as a yellow oil. Step E
1, 1-dimethyiethyl 4-bicyclo[3.1.0]hex-6-yl-3-oxo-1~piperazinecarboxylate
[00206] A solution of 1, 1-dimethyiethyl 4-bicyclo[3.1.0]hex-2-en-6-yl-3-oxo-l- piperazinecarboxylate (0.26 g, 0.94 mmol) and catalytic Ρΐ(¼ in EtOAc (10 mL) was stirred under a 20 psi hydrogen atmosphere for 2 hours 15 mins. The reaction mixture was filtered through celite and evaporated to provide the title compound as a light yellow oil (0,27 g, quant).
Step F
1~bicycio[3 .0]hex-6-yl-4-{[3-chloro-6-cyclopropyl-8-(trifl
2-yl]carbonyl}-2-piperazinone
[00207] A solution of 1 ,1-dimethylethyl (lJ?,5S,6 )-bicyclo[3.1.0]hex-6-ylcarbamate (0.066 g, 0.24 mmoL) and TFA (0.25 mL, 3,2 mmol) in CH2C¾ (0.5 mL) was stirred at room temperature for 1 hour. The mixture was evaporated to dryness to provide the crude amine which was used without further purification. 1-Propanephosphonic acid cyclic anhydride (0.21 mL of a 50% solution in EtOAc, 0.35 mmol) was added to a mixture of 3-chloro-5-cycIopropyl-7-
(trifluoromethyl)pyrazolo[l,5-a]pyridine-2-carboxylic acid (0.066 g, 0.24 mmol), the above amine (0.24 mmol) and DIPEA (0.25 mL, 1.4 mmol) in DMF (1.6 mL). The reaction mixture was stirred at room temperature overnight, diluted with methylene chloride and washed with 0.5 M sodium carbonate. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by reverse phase HPLC (acetonitrile/water with 0,1% formic acid) to afford the title compound (0.031 g, 28%) as a white solid.1H NMR (400 MHz, DMSO-J6) δ ppm 7.67 -
7.73 (m, 1 H), 7.44 (br. s., 1 H), 4.19 (s, 1 H), 4.10 (s, 1 H), 3.86 (t, .7=5.4 Hz, 1 H), 3.70 (t, J=5.1 Hz, 1 H), 3.28 (t, J=5.2 Hz, 2 H), 2.40 (s, 1 H), 2.18 - 2.27 (m; 1 H), 1.74 - 1.83 (m, 2 H), 1.62 -
1.74 (m, 2 H), 1.47 - 1.60 (m, 3 H), 0.93 - 1.35 (m, 5 H). ES-LCMS m z: 467 (M+l).
EXAMPLE 36
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1- [frans-3-(hydroxymethyl)cyclobutyl]-2-piperazinone
(Compound 36)
Figure imgf000136_0001
Step A
( trans-3-aminocyclobutyl)methanol hydrochloride
[00208] To a solution of ier -butyl ir «s-3-hydroxymethylcyclobutylcarbamate ( 94 mg, 4.94 mmol) in DCM (10 mL) was added a solution of 4 M hydrogen chloride in 1,4-dioxane (9.88 mL, 39.5 mmol). After 1 hour, 50 minutes, the solvent was removed under reduced pressure to give (irarcs-3-anunocyclobutyl)methanol hydrochloride (808.2 mg) as white solid. This was used in the next step without further purification. MS(ESI) m/z: 203.1 (2M+1). Ste B
1, 1 -dimethylethyl 4~[trans-3-(hydroxymethyl)cyclobutyl]-3-oxo-1-piperazinecarboxylate
[00209] A solution of methyl N- {[(1 , l-dimethylethyl)oxy]carbonyl} -N-(2- oxoethyl)glycinate (1142 mg, 4.94 mmol), (fra;¾y-3-arrnnocyclobutyl)methanol hydrochloride (0.8 g crude weight from previous step), N,N-diisopropylethylamine (0.863 mL, 4.94 mmol) and sodium sulfate (4210 mg, 29.6 mmol) was stirred in methanol (25 mL). After 40 minutes, sodium borohydride (187 mg, 4.94 mmol) was added. After 50 minutes, sodium hydride (395 mg, 9.88 mmol) was added to the mixture. After 2 horns, 30% citric acid (25 mL) was added to the mixture and the salt filtered through a short pad of Celite, The solvent was removed under reduced pressure. The crude material was extracted with EtOAc (150 mL), and washed with saturated NaHC03 (50 mL), brine (50 mL), dried (Na2S04), filtered and concentrated. The residue was absorbed on silica gel and purified by silica gel chromatography [0-5% MeOH in EtOAc] to give 1 ,1 -dimethylethyl 4-[iram,-3-(hydroxymemyl)cyclobutyl]-3-oxo-l -piperazinecarboxylate (634.4 mg, 2.231 mmol, 45%) as white solid. MS(ESI) m z: 285.2 (MH+).
Step C
4-{[3-chloro-5~cyclopropyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1 -[tans-
3-( hydroxym ethyl) cyclobutyl]~2-piperazinone
[00210] A solution of 1,1 -dimethylethyl 4-[irani,-3-(hydroxymethyl)cyclobutyl]-3-oxo-l- piperazinecarboxylate (0.083 g, 0.29 mmoL) and TFA (0.29 mL, 3.8 mmol) in CH2CI2 (0.5 mL) was stirred at room temperature for 1 hour. The reaction mixture was evaporated to dryness to provide the crude amine which was used without further purification. The title compound (0.12 g, 84%) was obtained as a white solid from 3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[l ,5- a]pyridine-2-carboxylic acid (0.09 g, 0.29 mmol) and the above crude amine using a previously described procedure. 1H NMR (400 MHz, DMSO-J6) δ ppm 7.66 - 7.74 (m, 1 H), 7.42 - 7.47 (m, 1 H)f 4.88 - 5.06 (m, J=16.8, 8.4, 8.4, 8.4, 8.4 Hz, 1 H), 4.64 (t, J=5.2 Hz, 1 H), 4.22 (s, 1 H), 4.14 (s, 1 H), 3.91 (t, J=5.3 Hz, 1 H), 3.77 (t, J=5.1 Hz, 1 H), 3.54 (t, J=5.3 Hz, 1 H), 3.45 (t, .7=5.1 Hz, 3 H), 2.09 - 2.35 (m, 4 H), 1.88 (t, J=9.0 Hz, 2 H), 1.04 - 1.14 (m, 2 H), 0.92 - 1.04 (m, 2 H). ES- LCMS m z: 471 (M+l).
EXAMPLE 37
^[(S-chloro-S^-dicycIopropylpyrazolotl ^-aJpyridin^-y carbonylJ-l-tfrans^- hydroxycyclohexyl)-2-piperazinone
Compound 37)
Figure imgf000137_0001
Step A
Dimethyl 5, 7-bis(4, 4, 5,5~tetramethyi- 1, 3,2~dioxaboroian-2-yl)pyrazolo[ 1, 5-a]pyridine-2, 3- dicarboxytate
[00211] A sealed tube was charged with dimethyl pyrazolo[l ,5-a]pyridine-2,3- dicarboxylate (0.50 g, 2.14 mmol), bis-(pinacolato)diboron (1.36 g, 5.34 mmol), 4,4,-bis(l,l- dimethylethyl 2,2'-bipyridine (0.12 g, 0.43 mmol) , and [Ir(OMe)(COD)] 2 (0.1 g, 0.21 mmol) and purged with nitrogen gas. n-Heptane (10.7 ml) was added and the vessel was sealed and heated at 90 °C overnight. The reaction mixture was diluted with CH CI2, washed with water, dried
(Na2S04), filtered and evaporated to obtain the title compound (assumed quant.) as a brown oil which was used without further purification.
Step B
Dimethyl 5, 7-dibromopyrazolo[ 1, 5-a]pyridine-2,3-dicarboxylate
[00212] A solution of CuBi"2 (0.95 g, 4.3 mol) in water (10 mL) was added to a solution of dimethyl 5 J7-bis(434J5J5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazolo[l ,5-a]pyridme-2t3- dicarboxylate (0.52 g, 1.07 mmol) in MeOH (10 mL) and the reaction mixture was heated at 85 °C for 12 hours. The solution as diluted with EtOAc and water and filtered through celite, The organic layer was isolated and the aqueous layer was extracted with CH2CI2. The combined organic layers were dried (Na2S04), filtered, evaporated and purified by silica gel chromatography (0-40%
EtOAc/hexs) to afford the title compound (0.17 g, 40%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-i δ ppm 8.38 (d, J-2.0 Hz, 1 H), 7.46 (d, J=2.0 Hz, 1 H), 4.03 (s, 3 H), 3.93 (s, 3 H).
Step C
Dimethyl 5, 7~dicyclopropylpyrazolo[ 1, 5-a]pyridine-2, 3-dicarboxylate
[00213] A solution of dimethyl 5,7-dibromopyrazolo[l ,5-a]pyridine-2,3-dicarboxylate
(0.167 g, 0.43 mmol), cyclopropylboronic acid (0.11 g, 1.28 mmol), potassium phosphate (0.45 g, 2.13 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.035 g, 0.042 mmol) in 1,4-dioxane (3.5 ml) was degassed, kept under a nitrogen atmosphere and heated at 90 °C overnight. The solution was filtered through celtie, washing with CH2C¾ and the filtrate was evaporated to dryness. The residue was purified by silica gel chromatography (0-40% EtOAc/hexs) to afford the title compound (0.11 g, 79%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.67 (d, J=1.6 Hz, 1 H), 6.28 (d, J=1.6 Hz, 1 H), 4.02 (s, 3 H), 3.90 (s, 3 H), 2.72 - 2.80 (ra, J=8.5, 8.5, 5.4, 5.2 Hz, 1 H), 1.89 - 1.99 (m, 1 H), 1.18 - 1.26 (m, 2 H), 1.04 - 1.14 (m, 2 H), 0.86 - 0.93 (m, 2 H), 0.77 - 0.86 (m, 2 H).
Step D
5, 7-dicyclopropylpyrazolo[ 1, 5-a]pyridine-2-carboxylic acid
[00214] A solution of dimethyl 5,7-dicyclopropylpyrazolo[l,5-a]pyridme-2,3-dicarboxylate
(0.11 g, 0.34 mmol) in 50% aq H2S04 (1 niL), 1 ,4-dioxane (1 niL), and HOAc (1 niL) was heated at 85 °C for 4.5 hours. The reaction mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (Na2SO;))> filtered, and evaporated to afford the title compound (assumed quant.) which was used without further purification.
Step E
3-chloro~5, 7-dicyclopropylpyrazolo[ 1, 5-a]pyridine-2-carboxyiic acid
[00215] A solution of 5,7-dicyclopropylpyrazolo[l,5-a]pyridine-2-carboxylic acid (0.082 g,
0.34 mmol) and NCS (0.045 g, 0.34 mmol) was heated in 1,2 dichloroethane (3.4 mL) at 60 °C for 4.5 hours. 1M Na2C03 was added (14 mL) and the solution was extracted with CH2C12. The aqueous layer was isolated and acidified by addition of 5M HC1 and extracted with EtOAc. The organic layer was dried (N 2S04), filtered, and evaporated to afford the title compound (assumed quant.) which was used without further purification.
Step F
4-[(3-chloro-5, 7-dicyclopropylpyrazolo[ 1,5-a ]pyridin-2-yl) carbonyl]- 1-( trans-4- hydroxycyclohexyl)-2-piperazinone
[00216] The title compound (0.080 g, 52%) was obtained as a white solid from 3-chloro-
5,7-dicyclopropylpyrazolo[l ,5-a]pyridine-2-carboxylic acid (0.094 g, 0.34 mmol) and \ -(iransA- hydroxycyclohexyl)-2-piperaziiione hydrochloride (0.095 g, 0.41 mmol) using a previously described procedure. 1H NMR (400 MHz, DMSO-c/6) δ ppm 7.20 (br. s„ 1 H), 6.48 (br. s., 1 H), 4.58 (br. s., 1 H), 4.06 - 4.29 (m, 3 H), 3,69 - 3.91 (m, 2 H), 3.25 - 3.41 (m, 3 H), 2.52 - 2.60 (m, 1 H), 2.01 - 2.11 (m, 1 FT), 1.86 (d, J=l 1.4 Hz, 2 H), 1.43 - 1.62 (m, 4 H), 1.16 - 1.30 (m, 2 H), 1.07 - 1.16 (m, 2 H), 0.94 - 1.07 (m, 4 H), 0.82 - 0.91 (m, 2 H). ES-LCMS m/z: 458 (M+l). EXAMPLE 38
4-{[3-chloro-5-(1-methylethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-1-(ira/7s-4-hydroxycyclohexyl)-2-piperazinone
(Compound 38)
Figure imgf000139_0001
H
Step A
Dimethyl 5-(1-methytethyl)pyrazolo[1,5-a]pyridine~2,3-dicarboxylate
[00217] A solution of 4-isopropylpyridine (1.60 gf 13.2 mmol) and O-
(mesitylenesulfonyl)hydroxylamine (2.58 g, 12 mmol) in CH2C12 (55 mL) was stirred at room temperature overnight and evaporated to dryness to afford the cmde N-amino-pyridinium salt as a clear oil. A solution of this residue and dimethylacetylene dicarboxylate (2,05 g, 14.40 mmol) in DMF (28 mL) was stirred at 0 °C, K2C03 (2.49 g, 18.0 mmol) was added and the solution was stirred at room temperature overnight. The reaction mixture was concentrated, diluted with water and extracted with CH2CI2 (3x). The combined organic layers were dried (Na2S04), filtered, evaporated and purified by silica gel chromatography (0-40% EtOAc/hexs) to provide the title compound (1.52 g, 46%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORMS) δ ppm 8.43 (d, J=7.2 Hz, 1 H), 7.97 (s, 1 H), 6.95 (dd, J=7.2, 1.7 Hz, 1 H), 4.03 (s, 3 H), 3.94 (s, 3 H), 2.98 - 3.11 (m, 7=6.8, 6.8, 6.8, 6.8, 6.8, 6.7 Hz, 1 H), 1.33 (d, 7=6.9 Hz, 6 H).
Step B
Dimethyl 5-( 1-methylethyl)-7-(4, 4, 5, 5-tetramethyi- 1, 3, 2-dioxaborolan-2-yi)pyrazolo[ 1, 5- a]pyridine-2, 3-dicarboxylate
[00218] A sealed tube was charged with dimethyl 5-(l-methylethyl)pyrazolo[l,5- a]pyridine-2,3-dicarboxylate (0.55 g, 1.99 mmole), bis-(pinacolato)diboron (0.61 g, 2.39 mmol), 4,4,-bis(l,l-dimethylethyl)-2,2l-bipyridine (0.053 g, 0.20 mmol), and [Ir(OMe)(COD)]2 (0.066 g, 0.10 mmol) and purged with nitrogen gas. n-Heptane (10 ml) was added and the vessel was sealed and heated at 90 °C overnight. The reaction mixture was diluted with CH2C12, washed with water, dried ( S^SO,)), filtered and evaporated to obtain the title compound (assumed quant.) as a brown oil which was used without further purification. Step C
Dimethyl 7-iodo-5-(1-methylethyl)pyrazolo[ 1, 5-a]pyridine-2, 3-dicarboxylate
[00219] Nal (0.60 g, 3.98 mmol) and chloramine-T (0.84 g, 2.99 mmol) were added sequentially to a solution of dimethyl 5-(l-methylethyl)-7-(4s4,5,5-tetramethyl-l,3J2-dioxaborolan- 2-yl)pyrazolo[l,5-a]pyridine-2,3-dicarboxylate (0.40 g, 1.00 mmol) and the sus ension was stirred in the dark for 3 days. Sat'd aqueous Na2S203 was added and the solution was extracted with
EtOAc. The organic layers were combined, dried (Na2S04), filtered, evaporated, and purified by silica gel chromatography (0-35% EtOAc/hexs) to afford the title compound (0.098 g, 25%) as a crystalline solid. IH NMR (400 MHz, CHLOROFORM-<f) 8 ppm 7.99 (d, 7=1.3 Hz, 1 H), 7.48 (d, J=1.7 Hz, 1 H), 4.03 (s, 3 H), 3.92 (s, 3 H), 2.99 (spt, J=6.9 Hz, IH), 1.33 (d, 7=6.8 Hz, 6 H).
Step D
Dimethyl 5-(1-methylethyl)-7-(trifluoromethyI)pyrazolo[1, 5-a]pyridine-2,3-dicarboxylate
[00220] A solution of dimethyl 7-iodo-5-(l-memylethyl)pyrazolo[l,5-a]pyridine-2,3- dicarboxylate (0.098 g, 0.244 mmol), ClCF2C02Me (0.064 ml, 0.61 mmol), potassium fluoride (0.028 g, 0.49 mmol), copper® iodide (0.093 g, 0.49 mmol) in DMF (1 ml) was stirred at 90 °C for 18 hours. The reaction mixture was diluted with water and CH2C12 and filtered through celite. The organic layer was isolated, dried (Na2S04), filtered, evaporated and purified by silica gel chromatography (25% EtOAc/hexs) to afford the title compound (0.05 g, 59%) as a white solid. IH NMR (400 MHz, CHLOROFORM-J) δ ppm 8.18 (s, 1 IT), 7.35 (d, J=l .1 Hz, 1 H), 4.03 (s, 3 H), 3.94 (s, 3 H), 3.09 (spt, 7=6.9 Hz, 1 H), 1.36 (d, J=6.9 Hz, 6 H). Step E
5-(1-Methylethyl)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid
[00221] The title compound (0.04 g, quant.) was obtained from dimethyl 5-(l -methylethyl)-
7-(trifluoromethyl)pyrazolo[li5nfl]pyridine-2,3-dioarboxylate (0.05 g, 0.14 mmol) by a previously described procedure.
Step F
3- Chloro-5-( 1-methylethyl)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine~2-carboxylic acid
[00222] The title compound (quant.) was obtained from 5-(l-methylethyl)-7- (trifluoromethyl)pyrazolo[l,5-a]pyridine-2-carboxylic acid (0.04 g, 0.14 mmol) and NCS (0.023 g, 0.17 mmol) using a previously described procedure.
Step G
4- {[3-C loro-5-( 1-methylethyl)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1- (trans~4~hydroxycyclohexyl)-2-piperazinone
[00223] The title compound (0.020 g, 28%) was obtained as a white solid from 3-chloro-5-
(l-methylemyl)-7-(trifiuoromethyl)pyrazolo[l,5-a]pyridine-2-carboxylic acid (0.044 g, 0.14 mmol) and l-(iraRi'-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (0.041 g, 0.17 mmol) using a previously described procedure. 1H NMR (400 MHz, DMSCW6) 8 ppm 7.76 - 7.81 (m, 1 H), 7.71 (s, 1 H), 4.58 (br. s., 1 H), 4.08 - 4.28 (m, 3 H), 3.68 - 3.88 (m, 2 H), 3.26 - 3.40 (m, 3 H), 3.14 (dt, .7=13.6, 6.8 Hz, 1 H), 1.86 (d, J=11.2 Hz, 2 H), 1.44 - 1.58 (m, 4 H), 1.29 (d, J=6.9 Hz3 6 H), 1.23 (dd, J=ll.l , 7.5 Hz, 2 H). ES-LCMS nVz: 488 (M+l).
EXAMPLE 39
1-(irans-4-hydroxycyclohexy[)-4-{[5-(1-methylethyl)-7-(trifluoromethyl)pyrazolo[1 ,^ a]pyridin-2-yl]carbonyl}-2-piperazinone
Figure imgf000141_0001
H
[00224] The title compound was isolated as a minor component in the reaction described in the previous example. 1H NMR (400 MHz, DMSO-<½) δ ppm 7.90 (s, 1 H), 7.62 (s, 1 H), 7.06 (s, 1 H), 4.44 - 4.70 (m, 2 H), 4.09 - 4.29 (m, 2 H), 3.79 - 4,10 (m, 2 H), 3.32 - 3.44 (m, 3 H), 3.06 (dt, J=13.7, 6.9 Hz, 1 H), 1.86 (d, 7=11.3 Hz, 2 H), 1.38 - 1.64 (m, 4 H), 1.14 - 1.35 (m, 8 H). ES- LCMS m/z: 453 (M+l). EXAMPLE 40
4-{[3-chloro-5-cyclopropyl-7-(methyloxy)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1- ( trans- 4- hy d roxycy clo h exy I ) -2- pi pe razi no ne
Compound 40)
Figure imgf000142_0001
H
Step A
Dimethyl 7-(methyloxy)pyrazolo[1 , 5-a Jpyridine-2, 3-dicarboxylate
[00225] The title compound (0.49 g, 17%) was obtained from l-amino-2-
(methoxy)pyridinium mesitylenesulfonate (3.61 g, 11.1 mmol), dimethylacetylene dicarboxylate (1.9 g, 13.3 mmol) and K2CO3 (3.1 g, 22.2 mmol) by a previously described procedure.1H NMR (400 MHz, CHLOROFORM-^ δ ppm 7.75 (d, J=8.8 Hz, 1 H), 7.44 (dd, J=8.6, 7.9 Hz, 1 H), 6.34 (d, 7=7.6 Hz, 1 H), 4.14 (s, 3 H), 3.97 (s, 3 H), 3.88 (s, 3 H).
Step B
Dimethyl 5~hydroxy-7-(methyloxy)pyrazolo[1,5-a]pyridine-2, 3-dicarboxylate
[00226] The title compound (0.092 g, 58%) was obtained from dimethyl 7-
(methyloxy)pyrazolo[l,5-fl]pyridine-2,3-dicarboxylate (0.15 g, 0.57 mmol), bis- (pinacolato)diboron (0.17 g, 0.68 mmol), 4,4'-bis(l,l-dimethylethyl)-2,2,-bipyi-idine (0,015 g, 0,06 mmol), and [Ir(OMe)(COD)]2 (0.019 g, 0.03 mmol) followed by treatment with acetic acid (0.068 g, 1.14 mmol) and 30% aqueous hydrogen p eroxide (0.12 mL, 1.14 mmol) using a previously described procedure.
Step C
Methyl 5-hydroxy-7-(methyloxy)pyrazolo[ 1, 5-a]pyridine-2-carboxylate [00227] The title compound (0.065 g, 90%) was obtained from dimethyl 5-hydroxy-7-
(methyloxy)pyrazolo[l,5-#]pyridine-2,3-dicarboxylate (0.092 g, 0.33 mmol) by a previously described procedure. Step D
Methyl 7-(methyloxy)-5-{[(trifluoromethyl)sulfonyl]oxy}pyrazolo[ 1, 5-a]pyridine-2- carboxylate
[00228] N^henyltrifluoromethanesulfomirride (0.21 g, 0.59 mmol) was added to a solution of methyl 5-hydroxy-7-(methyloxy)pyrazolo[l,5-a]pyridine-2-carboxylate (0.065 g, 0.30 mmol) and DIPEA (0.21 mL, 1.18 mmol) in CH2C12 (2.7 mL). The reaction mixture was stirred at room temperature overnight, evaporated, and purified by silica gel chromatography (0-50% EtOAc/hexs) to afford the title compound (0.055 g, 52%) as a clear oil.
Step E
Methyl 5~cyclopropyl-7-(methyloxy)pyrazolo[ 1, 5-a]py dine-2-carboxylate
[00229] A solution of methyl 7-(me loxy)-5-
{[(trifluoromethyl)sulfonyl]oxy}pyrazolo[l,5-a]pyridine-2-carboxylate (0,055 g, 0.15 mmol), cyclopropylboronic acid (0.020 g, 0.23 mmol), potassium phosphate (0.078 g, 0.37 mmol), and PdCl2(dppf)-CH2Cl2 adduct (6.3 mg, 7.7 μιηοΐ) in 1,4-dioxane (1.3 ml) was degassed, kept under a nitrogen atmosphere and heated at 90 °C overnight. The reaction mixture was filtered through celite, washed with CH2Cl2j evaporated and purified by silica gel chromatography (0-60%
EtOAc/hexs) to afford the title compound (0.027 g, 71%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-t δ ppm 6.94 (s, 1 H), 6.93 (br. s., 1 H), 5.93 (d, J=1.3 Hz, 1 H), 4.1 (s, 3 H), 3.98 (s, 3 H), 1.90 - 1.99 (mf 1 H), 1.02 - 1.09 (m, 2 H), 0.76 - 0.83 (m, 2 H).
Step F
5-cyclopropyl-7-(methyloxy)pyrazolo[ 1, 5-a]pyridine~2-carboxylic acid
[00230] The title compound (quant.) was obtained from methyl 5-cyclopropyl-7-
(methyloxy)pyrazolo[l,5-i(]pyridine-2-carboxylate (0.027 g, 0.11 mmol) and 1M NaOH (0,55 mL, 0.55 mmole) by a previous described procedure.
Step G
3-chloro-5-cyc!opropyl-7-(methyloxy)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid
[00231] The title compound (quant.) was obtained from 5-cyclopropyl-7- (methyloxy)pyrazolo[l,5-fl]pyridme-2-carboxylic acid (0.04 g, 0.14 mmol) and NCS (0,018 g, 0.13 mmol) using a previously described procedure. Step H
4-{[3-chloro-5-cyclopropyl-7-(methyloxy)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1-(trans-4- hydroxycyclohexyl)-2-piperazin on e
[00232] The title compound (0.024 g, 48%) was obtained as a white solid from 3-chloro-5- cyclopropyl-7-(methyloxy)pyrazolo[l,5-a]pyiidine-2-carboxylic acid (0.029 g, 0.11 mmol) and 1- (iraws-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (0.028 g, 0.12 mmol) using a previously described procedure. 1H MR (400 MHz, DMSO-J6) δ ppm 6.98 (s, 1 H), 6.25 (s, 1 H), 4.04 - 4.28 (m, 6 H), 3.65 - 3.87 (m, 2 H), 3.22 - 3.45 (m, 3 H), 2.03 - 2.19 (m, 1H), 1.85 (d, J=11.7 Hz, 2 H), 1.42 - 1.61 (m, 4 H), 1.15 - 1.33 (m, 2 H), 1.01 - 1.12 (m, 2 H), 0.86 - 0.96 (m, 2 H). ES- LCMS m/z: 448 (M+l).
EXAMPLE 41
4-[(7-bromo-3-chloro-5-cyclopropylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1-(fra/is-4- hydroxycyclo exyl)-2-piperazinone
(Compound 41}
Figure imgf000144_0001
Step A
4-cycIopropylpyridine
[00233] A solution of 4-bromopyridine.HCl (9.7 g, 50 mmol), cyclopropylboronic acid (6.4 g, 75 mol), potassium phosphate (30.5 g, 144 mmol) and Ράα2(άρρι).<¾(¾ adduct (2.04 g, 2.5 mmol) in 1,4-dioxane (100 mL) was degassed and kept under a nitrogen atmosphere. The solution was then heated at 90 °C for 16 hours, diluted with water, filtered tlirough celite and extracted with Et20 (5x). The combined organic layers were dried (MgS04), filtered, and evaporated to give a yellow oil. This residue was taken up in 5N HC1 and extracted with CH2Q2. The acid layer was basified with 5N NaOH and extracted with CH2C12. The organic layer was dried (MgS04), filtered, evaporated to provide the title compound as a brown liquid that was used without further purification. Step B
Dimethyl 5-cyclopropylpyrazolo[ 1, 5-a]pyridine-2, 3-dicarboxylate
[00234] A solution of 4-cyciopropylpyridine (5.96 g, 50 mmol) and O-
(mesitylenesulfonyl)hydroxylamine (10.8 g, 50 mmol) in (¾(¾ (100 mL) was stirred at room temperature overnight and evaporated to dryness to afford the crude N-ainino-pyridinium salt. A solution of this residue and dimethylacetylene dicarboxylate (14.2 g, 100 mmol) in C¾CN (200 mL) was stirred at 0 °C. DBU (15,1 mL, 100 mmol) was added drop-wise and the solution was stirred at room temperature overnight and then heated at 75 °C for 2 hours. The reaction mixture was concentrated and purified by silica gel chromatography (0-50% EtOAc/hexs) to provide the title compound (8.9 g, 65%) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-t/) δ ppm 8.37 (d, J=7.2 Hz, 1 H), 7.86 (s, 1 H), 6.70 (dd, J=7.2, 1.8 Hz, 1 H), 4.03 (s, 3 H), 3.93 (s, 3 H), 1.98 - 2.09 (m, 1 H), 1.12 - 1.20 (m, 2 H), 0.83 - 0.91 (m, 2 H).
Step C.
Dimethyl 5-cyclopropyl-7-(4,4,5,5-tetramethyl-1r3,2-dioxaborolan-2-yl)pyrazolo[1,5- a] ridine-2, 3-dicarboxylate
Figure imgf000145_0001
[00235] A sealed tube vessel was charged with dimethyl 5-cyclopropylpyrazolo[l ,5- a]pyridine-2,3 -dicarboxylate (0.50 g, 1.8 mmol), bis-(pinacolato)diboron (0.56 g, 2.2 mmol), 4,4'- bis(l ,l-dimethylethyl)-2,2'-bipyridine (0.05 g, 0.18 mmol), and [Ir(OMe)(COD)]2 (0.06 g, 0.09 mmol) and purged with nitrogen. n-Hexane (9.1 ml) was added, the vessel was sealed and heated at 75 °C for 2 hours. The solution was then cooled to room temperature, diluted with water and extracted with CH2C12. The organic layer was dried (Na2S04), filtered, and evaporated to provide the title compound as a brown oil (quant.), which was used without further purification.
Step D
Dimethyl 7-bromo-5-cyclopropylpyrazolo[ 1, 5-a]pyridine-2, 3-dicarboxylate
Figure imgf000146_0001
[00236] CuBr2 (1.6 g, 6.8 mmol) was added to a solution of dimethyl 5-cyclopropyl-7-
(4}4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazolo[l ,5-a]pyridine-2,3-dicarboxylate (1.8 mmol) in MeOH (15 niL) and water (15 mL). The reaction mixture was heated at 85 °C overnight and filtered through celite, washing with EtOAc. The aqueous layer was extracted with EtOAc and CH2C12. The combined organic layers were dried (Na2S04), filtered, evaporated and purified by chromatography (0-50% EtOAc/hexanes) to afford the title compound (0.14 g, 22%) as a white solid. IH NMR (400 MHz, CHLOROFORM-tf) 8 ppm 7.87 (d, J=1.4 Hz, 1 H), 7.01 (d, J=1.6 Hz, 1 it), 4.02 (s, 3 H), 3.92 (s, 3 H), 1.95 - 2.07 (m, 1 H), 1.12 - 1.21 (m, 2 H), 0.83 - 0.92 (m, 2 H).
Step E.
7-bromo-3-chloro-5-cyclopropylpyrazolo[ 1, 5-a]pyridine-2~carboxylic acid
Figure imgf000146_0002
[00237] A solution of dimethyl 7-bromo-5-cyclopropylpyrazolo[l ,5-a]pyridine-2,3- dicarboxylate (0.14 g, 0,4 mmol) in 1 ,4-dioxane (1.6 mL) and 50% aq H2S04 (1.5 mL) was heated for 2 hours. 1,4-dioxane ( lmL) was added and the reaction mixture was heated for another 1.5 hours. Water was added and the solution was extracted with EtOAc (3x). The combined organic layers were dried (Na2S04), filtered, and evaporated to provide an off-white solid. A solution of the solid and NCS (0.11 g, 0.8 mmol) in dichloroethane (4 mL) was heated at 60 °C for 5 hours and evaporated to dryness.
Step F.
4-[(7-bromo-3-chloro-5-cyclopropylpyrazolo[1,5-a]pyridin-2^^
hydroxycyclohexyl) -2-piperazin on e
[00238] The title compound (0.047 g, 24%) was obtained as a white solid from 7-bromo-3- cliloro-S-cyclopropylpyrazoloELS-alpyridine^-carboxylic acid (0.13 g, 0.40 mmol) and \-{trcms-A- hydroxycyclohexyl)-2-piperazinone hydrochloride (0.10 g, 0.44 mmol) using a previously described procedure. 1H NMR (400 MHz, DMSO-o?6) δ ppm 7.46 (d, J=3.1 Hz, 1 H), 7.27 (s, 1 H), 4.51 - 4.66 (m, 1 H), 4.10 - 4.27 (m, 3 H), 3.66 - 3.91 (m, 2 H), 3.22 - 3.43 (m, 3 H), 2.06 - 2.17 (m, 1 H), 1.86 (d, .7=11.4 Hz, 2 H), 1.41 - 1.59 (m, 4 H), 1.15 - 1.30 (m} 2 H), 0.99 - 1.09 (m, 2 H), 0.85 - 0.94 (m, 2 H). ES-LCMS m z: 497 (M+l).
EXAMPLE 42
4-{[3-chloro-5-cyciopropyl-7-(1-methylethenyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-
1-(frans-4-hydroxycyclohexyl)-2-piperazinone
Compound 42)
Figure imgf000147_0001
[00239] A mixture of 4-[(7-bromo-3-chloro-5-cyclopropylpyrazolo[l ,5-a]pyridin-2- yl)carbonyl]-l -(iraiJ5-4-hydroxycyclohexyl)-2-piperazinone (0.030 g, 0.06 mniol), potassium isopropenyltrifluoroborate (0.009 g, 0.06 mmol), PdClz (dppf).CH2Clz adduct (0.005 g, 6 umol) in 1,4-dioxane (0.6 mL) was heated at 85 °C for 3 hours. The solvent was removed by evaporation and the residue was dissolved in EtOAc and filtered tlirough celite. The filtrate was concentrated and purified by reverse phase HPLC (10-70% CH3CN/H20 with 0.1% formic acid) to afford the title compound (0.014 g, 51 %) as a white solid. 1H NMR (400 MHz, DMSO-J6) δ ppm 7.33 (s, 1 H), 6.78 (s, 1 H), 5.82 (s, 1 H), 5.55 (br. s., 1 H), 4.58 (br. s., 1 H), 4.10 - 4.30 (m, 3 H), 3.70 - 3.89 (m, 2 H), 3.29 (br. s, 3 H), 2.24 (s, 3 H), 2.08 - 2.19 (m, 1 H), 1.86 (d, J=11.6 Hz, 2 H), 1.44 - 1.61 (m, 4 H), 1.16 - 1.30 (m, 2 H), 1.02 - 1.10 (m, 2 H), 0.85 - 0.96 (m, 2 H). ES-LCMS m/z: 457 (M+l). EXAMPLE 43
4-[(3-chloro-5-cyclopropyl-7-iodopyrazolo[1,5-a]pyridin-2-yl)carbony[]-1-(frans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 43)
Figure imgf000147_0002
[00240] The title compound (0.107 g, 22%) was obtained as a white solid from 3-chloro-5- cyclopropyl-7-iodopyrazolo[l,5-a]pyridine-2-carboxyliG acid (0.33 g, 0.90 mmol) and l-(trans-4- hydroxycyclohexyl)-2-piperazinone hydrochloride (0.21 g, 0.90 mmol) using a previously described procedure. 1H NMR (400 MHz, DMSO-i/6) δ ppm 7.40 (s, 1 H), 7.40 (s, 1 H), 4.58 (br. s., 1 H), 4.10 - 4.26 (m, 3 H), 3.70 - 3.88 (m, 2 H), 3.31 - 3.40 (m, 3H), 2.02 - 2.14 (m, 1 H), 1.86 (d, J=U3 Hz, 2 H), 1.42 - 1.63 (m, 4 H), 1.14 - 1.32 (m, 2 H), 1.00 - 1.09 (ra, 2 H), 0.81 - 0.94 (m, 2 H). ES-LCMS m/z: 544 (M+l).
EXAMPLE 44
4-[(3-chloro-5-cyclopropyl-7-ethylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1-(irans-4- hydroxycyclohexyl)-2-piperazinone
Compound 44)
Figure imgf000148_0001
[00241 ] A mixture of 4-[(3-chloro-5-cyclopropyl-7-iodopyrazolo[l ,5-«]pyridin-2- yl)carbonyl]-l-(iran.y-4-hydroxycyclohexyl)-2-piperazinone (0.082 g, 0.15 mmol), 1 M diethylzinc (0.45 ml, 0.45 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.012 g, 0.015 mmol) in 1,4-dioxane (1.05 ml) was heated at 85 °C for 3 hours. The solvent was evaporated and the residue was taken up in EtOAc and filtered through celite. The filtrate was evaporated and purified by reverse phase cliromatograpliy (10-70% CH3CN/H20 with0.1% FA) to afford the title compound (0.002 g, 3%) as a white solid. 1H NMR (400 MHz, METHANOLS) δ ppm 7.22 (d, J=l .6 Hz, 1 H), 6.67 (br. s., 1 H), 4.27 - 4.45 (m, 3 H), 3.86 - 4.06 (m, 2 H), 3.42 - 3.56 (m, 3 H), 3.06 - 3.16 (m, 2 H), 1.98 - 2.11 (m, 3 H), 1.58 - 1.76 (m, 4 H), 1.36 - 1.44 (m, 4 H), 1.06 - 1.16 (m, 3 H), 0.82 - 0.92 (m, 2 H). ES- LCMS m/z: 446 (M+l). EXAMPLE 45
4-[{3-chloro-5-cyclopropyl-7-phenylpyrazolo[1,5-a]pyridin-2-yl)carbonyl]-1-(frans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 45)
Figure imgf000149_0001
Figure imgf000149_0002
Step A
Methyl 3-chloro-5-cyclopropylpyrazolo[ 1, 5-a ]pyridine-2-carboxy!ate
[00242] A solution of dimethyl 5-cyclopropylpyrazolo[l ,5-a]pyridine-2,3-dicarboxylate
(4.51 g, 16.5 mmol) in 1,4-dioxane (18 mL) and 50% aq. ¾S04 (21 mL) was heated at 85 °C for 5 hours. Water (300 mL) was added and the solution was cooled in an ice bath. The yellow solid was collected by filtration and in EtOAc. The filtrate was extracted with 10% MeOH in EtOAc. The combined organic layers were dried (Na2S0 ), filtered, and evaporated. The residue was dissolved in MeOH (80 mL), cone. H2SO4 (2 drops) was added and the solution was heated at 80 °C for 3 hours. The reaction mixture was evaporated and diluted with EtOAc and water. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were dried (Na2S0 ), filtered and evaporated to obtain methyl 5-cyclopropylpyrazolo[l,5-a]pyridine-2-carboxylate as a brown solid. A solution of this solid andNCS (4.4 g, 33.0 mmol) in 1,2-dichloroethane (70 mL) was heated at 60 °C for 2 hours. Sat'd aqueous Na2S203 was added and the aqueous layer was extracted with CH2C12 (3x). The combined organic layers were dried (Na2S04), filtered, evaporated and purified by silica gel chromatograophy (0-50% EtOAc/hexs) to afford the title compound (3.53 g, 86%) as an off- white solid. 1H NMR (400 MHz, CHLOROFORM-* ) δ ppm 8.32 (d, J=7.3 Hz, 1 H), 6.65 (dd} J=7.3, 2.0 Hz, 1 H), 4.02 (s, 3 H), 1.93 - 2.03 (m, 1 H), 1.07 - 1.14 (m, 2 H), 0.79 - 0.85 (m, 2 H). Ste B
Figure imgf000150_0001
Methyl 3-chloro-5-cyclopropyl-7-(4, 4, 5, 5-tetramethyl-1,3, 2-dioxaborolan-2-yl)pyrazolo[ 1, 5- a ]pyridine-2-carboxyla te
[00243] A sealed tube vessel was charged with methyl 3-chloro-5-cyclopropylpyrazolo[l ,5- a]pyridine-2-carboxylate (0.18 g, 0.71 mmol), bis-(pinacolato)diboron (0.22 g, 0.85 mmol), 4,4'- bis(l,l-dimethylethyl)-2,2'-bipyridine (0.019 g, 0.071 mmol), and [Ir(OMe)(COD)]2 (0.023 g, 0.035 mmol) and purged with nitrogen. n-Hexane (3.6 ml) was added, the vessel was sealed and heated at 85 °C for 3 hours. The solution was then cooled to room temperature, diluted with water and extracted with CH2CI2. The organic layer was dried (Na2SC>4), filtered, and evaporated to provide the title compound (quant.) as a brown oil, which was used without further purification.
Step C
Methyl 3-chloro-5-cyclopropyl-7-phenylpyrazolo[1,5-a]pyridine-2-carboxyIate
[00244] A solution of methyl 3-chloro-5-cydopropyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine-2-carboxylate (0,089 g, 0,24 mmol), potassium carbonate (0.13 g, 0.95 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.019 g, 0.024 mmol) in 2 mL 1,4- dioxane was degassed and stored under a nitrogen atmosphere. Bromobenzene (0.10 ml, 0.95 mmol) was added and the reaction mixture was heated at 85 °C for 2 hours. The reaction mixture was filtered through celite, washed with CH2CI2, evaporated and purified by silica gel
chromatography (0-40% EtOAc/hexs) to afford the title compound (0.028 g, 36%) as a white solid. 1H MR (400 MHz, CHLOROFORM -d) δ ppm 7.86 - 7.92 (m, 2 H), 7.47 - 7.55 (m, 3 H), 7.25 - 7.29 (m, 1 H), 6.73 (d, J=2.0 Hz, 1 H), 3.97 (s, 3H), 1.98 - 2.07 (m, 1 H), 1.08 - 1.15 (m, 2 H), 0.82 - 0.90 (m, 2 H).
Step D
4-[(3-Chloro-5-cyclopropyl- 7-phenylpyrazolo[1 , 5-a]pyridin-2~yl) carbonyl]- 1~(trans-4- hydroxycyclohexyl)-2-piperazinone
[00245] The title compound (0.018 g, 42%) was obtained as a white solid from methyl 3- chloro-5-cyclopropyl-7-phenylpyrazolo[l,5-a]pyridine-2-carboxylate (0.028 g, 0.084 mmol) and 1M NaOH (0,422 mL, 0.42 mmol) followed by treatment with l-(ira¾y-4-hydroxycyclohexyl)-2- piperazinone hydrochloride (0.026 g, 0.11 mmol) using a previously described procedure. IH NMR (400 MHz, DMSO-rf6) δ ppm 7.85 - 7.92 (m, 2 H), 7.50 - 7.59 (m, 3 H), 7.37 - 7.44 (m, 1 H), 6.87 - 6.92 (m, 1 H), 4.07 - 4.23 (m, 3 H), 3.70 - 3.83 (m, 2 H); 3.22 - 3.35 (m, 4 H), 2.12 - 2,21 (m} 1 H), 1.86 (d, J=11.7 Hz, 2 H), 1.41 - 1.58 (m, 4 H), 1.15 - 1.30 (m, 2 H), 1.03 - 1.11 (m, 2 H), 0.92 - 0.98 (m, 2 H). ES-LCMS m/z: 494 (M+l).
EXAMPLE 46
4-{[3-chIoro-5-cyclopropyl-7-(2-furanyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- ( fra/is-4- hyd roxycycloh exyl)-2-pi perazi no ne
Compound 46)
Figure imgf000151_0001
Step A
methyl 3-chloro-5-cyclopropyl~7-(2~furanyl)pyrazolo[1!5-a]pyridine-2-carboxylate
[00246] A solution of ethyl 3-chloro-5-cyclopropyl-7-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)pyrazolo[l ,5-a]pyridine-2-carboxylate (0.089 g, 0.24 mmol), potassium carbonate (0.13 g, 0.95 mmol), and PdCl2(dppf)-CI-I2Cl2 adduct (0.019 g, 0.024 mmol) in 2 mL 1,4- dioxane was degassed and stored under a nitrogen atmosphere. 243romofuran (0.14 g, 0.95 mmol) was added and the reaction mixture was heated at 85 °C for 2 hours and at 45 °C overnight. The reaction mixture was filtered through celite, washed with (¾(¾ evaporated and purified by silica gel clrromatography (0-40% EtOAc/hexs) to afford the title compound (0.028 g, 38%). IH NMR (400 MHz, CHLOROFORM-d) δ ppm 8.06 (d, J=3.5 Hz, 1 H), 7.61 (d, J=l.l Hz, 1 H), 7.26 - 7.29 (m, 1 H), 7.24 (d, J=1.9 Hz, 1 H), 6.63 - 6.68 (m, 1 H), 4.04 (s, 3 H), 1.99 - 2.09 (m, 1 H), 1.09 - 1.17 (m, 2 H), 0.86 - 0.94 (m, 2 H). Step B
4^[3-chlor<>5-cycIopropyl-7-(2-furanyl)pyrazolo[1,5-a]pyrid!n-2^
hydroxycyclohexyl)-2-piperazinone
[00247] The title compound (0.014 g, 33%) was obtained as a white solid from methyl 3- chloro-5-cyclopropyl-7-(2-furanyl)pyrazolo[l,5-ci]pyridine-2-carboxylate (0.028 g, 0.09 mmol) and 1M NaOH (0.9 mL, 0.9 mmol) followed by treatment with. l-(ira?is-4-hydroxycyclohexyl)-2- piperazinone hydrochloride (0.025 g, 0.11 mmol) using a previously described procedure. 1H NMR (400 MHz, DMSCW6) δ ppm 8.04 (s, 1 H), 7.78 - 7.85 (m, 1 H), 7.39 (dd, J=3.4, 1.8 Hz, 1 H), 7.30 (d, J=1.8 Hz, 1 H), 6.81 (td, J=3.6, 1.8 Hz, 1 H), 4.59 (br. s, 1 H), 4.11 - 4.34 (m, 3 H), 3.76 - 3.91 (m, 2 H), 3.33 - 3.44 (m, 3 H), 2.16 - 2.27 (m, 1 H), 1.86 (d, 7=11.2 Hz, 2 H), 1.41 - 1.64 (m, 4 H), 1.16 - 1.32 (m, 2 H), 1.06 - 1.16 (m, 2 H), 0.85 - 1.00 (m, 2 H). ES-LCMS m/z: 484 (M+l).
EXAMPLE 47
4-{[3-chloro-5-cyclopropyl-7-(3-furanyI)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1- (frans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 47)
Figure imgf000152_0001
H
Step A
Methyl 3-chloro-5-cyclopropyl~7~(3-furanyl)pyrazolo[1,5~a]pyridine~2-carboxylate
[00248] A solution of ethyl 3-chloro-5-cyclopropyl-7-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo[l,5-a]pyridrne-2-carboxylate (0.089 g, 0.24 mmol), potassium carbonate (0.13 g, 0.95 mmol), and PdCl2(dppf)-CH2Cl2 adduct (0.019 g, 0.024 mmol) in 2 mL 1,4- dioxane was degassed and stored under a nitrogen atmosphere. 3-bromofuran (0.14 g, 0.95 mmol) was added and the reaction mixture was heated at 85 °C for 2 hours and at 45 °C overnight. The reaction mixture was filtered through celite, washed with CH2C12, evaporated and purified by silica gel chromatography (0-40% EtOAc/hexs) to afford the title compound (0.025 g, 33%). 1H NMR (400 MHz, CHLOROFORM-**) δ ppm 9.02 (s, 1 H), 7.57 (s, 1 H), 7.20 (d, J=\ .6 Hz, 1 H), 6.96 (d, J=1.6 Hz, 1 H), 6.91 - 6.95 (m, 1 H), 4.03 (s, 3 H), 1.96 - 2.08 (m, 1 H), 1.08 - 1.16 (m, 2 H), 0.82 - 0.91 (m, 2 H).
Step B
4-{[3-chloro- 5-cyclopropyI- 7-( 3-furanyl)pyrazolo[ 1, 5-a ]pyridin-2-yl]carbonyl} - 1 - (trans-4- hydroxycycloh exyl) -2-piperazinone [00249] The title compound (0.015 g, 3 %) was obtained as a white solid from methyl 3- chloro-5-cyclopropyl-7-(3-furanyl)pyrazolo[l,5-a]pyridine-2-carboxylate (0.025 g, 0.08 mmol) and 1M NaOH (0.8 mL, 0.8 mmol) followed by treatment with l-(ira;w-4-hydroxycyclohexyl)-2- piperazinone hydrocliloride (0.025 g, 0.11 mmol) using a previously described procedure. 1H NMR (400 MHz, DMSO-fi?6) δ ppm 8.86 - 8,93 (m, 1 H), 7.92 (t, 7=1.7 Hz, 1 H), 7.46 (dd, 7-5,2, 1.6 Hz, 1 H), 7.37 - 7.40 (m, 1 H), 7.33 (dd, 7=4.5, 1.7 Hz, 1 H), 4.59 (br. s., 1 H), 4.09 - 4.36 (m, 3 H), 3.73 - 3.91 (m, 2 H), 3.33 - 3,45 (m, 3 H), 2,1 - 2.22 (m, 1 H), 1 ,86 (d, 7=11.4 Hz, 2 H), 1.43 - 1.63 (m, 4 H), 1.17 - 1.32 (m, 2 H), 1.07 - 1.13 (m, 2 H), 0.95 - 1.03 (m, 2 H). ES-LCMS m/z: 484 (M+l).
EXAMPLE 48
4-{[3,5-dichloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-(irans-4- hydroxycyclohexyl)-2-piperazinone
(Compound 48)
Figure imgf000153_0001
Step A
dimethyl 5-chloro-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2,3-dicarboxylate
Figure imgf000153_0002
100250] A solution of dimethyl 5-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-7-
(triflijorometliyl)pyrazolo[l,5-a]pyridine-2,3-dicarboxylate (0.71 g, 1.65 mmol) and CuCl2 (0.89 g, 6.60 mmol) in MeOH (13.8 mL) and water (13.8 mL) was heated at 90 °C for 7 hours. The solution was diluted with water and extracted with EtOAc. The combined organic layers were dried (Na2S04), filtered, and evaporated to a brown oil (assumed quant.) that was used without further purification. Step B
3, 5~dichloro-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2~carboxylic acid
Figure imgf000154_0001
[00251] A solution of dimethyl 5-chloro-7-(trifluoromethyl)pyrazolo[l ,5-a]pyridine-2,3- dicarboxylate (0.56 g, 1.65 mrnol) in 1,4-dioxane (3 mL) and 50% aqueous H2SO (6 mL) was heated at 100 °C for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc (3x). The combined organic layers were dried (Na2S04), filtered, evaporated and dissolved in 1,2-dichloroethane (15 mL). NCS (0.44 g, 3.3 mmol) was added and the reaction mixture was heated at 60 °C for 2 hours. 1M HC1 was added and the solution was extracted with EtOAc. The organic layer was dried (Na2S04), filtered, evaporated and purified by silica gel cliromatography (8- 80% (5% MeOH/EtOAc)/l exs) to afford the title compound (0.34 g, 70%) as an off-white solid.
Step C
4-{[3, 5-dichloro-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone
[00252] The title compound (0.022 g, 39%) was obtained as a white solid from acid (0.035 g, 0,12 mmol) l-(ira7i1s,-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (0,033 g, 0.14 mmol) using a previously described procedure. 1H NMR (400 MHz, DMSO-£½) δ ppm 8.28 - 8.33 (m, 1 H), 7.88 - 7.92 (m; 1 H), 4.58 (br. s., 1 H), 4.06 - 4.28 (m, 3 H), 3,66 - 3.90 (m, 2 H), 3.22 - 3.35 (m, 3 H), 1.78 - 1.93 (m, 2 H), 1.42 - 1.60 (m, 4 H), 1.14 - 1.32 (m, 2 H). ES-LCMS nVz: 479 (M+l).
EXAMPLE 49
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethy[)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
(3-cyclopenten-1-yl)-2-piperazinone
(Compound 49)
Figure imgf000154_0002
Step A
1, 1 -dimethyle thyl 4-( 3-cyclop enten- 1 -yl) -3-oxo- 1 -piperazinecarboxyla te
[00253] A mixture of 1 -amino-3-cyclopentene hydrochloride (2.98 g, 24.39 mmol), methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate (5 g, 20.32 mmol), DIPEA (4.26 mL, 24.39 mmol) and sodium sulfate (17.32 g, 122 mmol) was stirred in
MeOH (80 mL) for 2 hours, then NaBH4 (0.932 g, 24.39 mmol) was added in portions. The mixture was stirred for 2 hours then 60% NaH dispersion in oil (1.626 g, 40.6 mmol) was added in portions. After 2 hours, aqueous citric acid (10% by wt.) was added slowly to adjust pH to about 5. The mixture was extracted with EtOAc. The combined EtOAc extract was washed with brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-45 % EtOAc/Hexanes) to give 1 ,1-dimethylethyl 4-(3-cyclopenten-1 - yl)-3-oxo-1-piperazinecarboxylate (3.21 g, 59%) as an off-white solid,
Step B
1-(3-cyclopenten-1-yt)-2-piperazinone hydrochloride
[00254] 4M HCI in 1 ,4-dioxane (20 mL, 80 mmol) was added to a solution of 1 ,1- dimethylethyl 4-(3-cyclopenten-1-yl)-3-oxo-1 -piperazinecarboxylate (1.6 g, 6.01 mmol) in 1 ,4-dioxane (25 mL) at room temperature. The mixture was stirred at room temperature overnight and then evaporated under reduced pressure to give 1 -(3-cyclopenten-1 -yl)-2- piperazinone hydrochloride (1.3 g, 100 %) as a brown solid with some brown oil, which contained some 1 ,4-dioxane. The material was used without further purification.
Step C
4-{[3-chloro-5-cyclopropy!-7-(trifluoromethyl)pyrazoio[1,5-a]pyridin^
cyclopenten-1-yl)-2-piperazinone
[00255] A solution of 3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylic acid (1.5 g, 4.92 mmol), 1-(3-cyciopenten-1-yl)-2-piperazinone hydrochloride (1.274 g, 5.91 mmol) and DIPEA (3.44 mL, 19.69 mmol) in N,N- Dimethylformamide (DMF) (20 mL) was stirred at room temperature for 15 minutes, then cooled in an ice bath. 1-Propanephosphonic acid cyclic anhydride (50% wt% in EtOAc, 3.81 mL, 6.40 mmol) was added dropwise. The reaction mixture was stirred for 1.5 hour. The reaction mixture was poured into water and extracted with EtOAc. The combined organic extract was washed with 5% LiCI and brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-55 % EtOAc/Hexanes) to give 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(3- cyclopenten-1-yl)-2-piperazinone (2.10 g, 94%) as a white foam. H NMR (400 MHz, METHANOL-^) δ ppm 7.58 (s, 1 H), 7.31 (s, 1 H), 5.80 - 5.72 (m, 2 H), 5.42 - 5.25 (m, 1 H), 4.42 - 4.30 (m, 2 H), 4.02 - 3.83 (m, 2 H), 3.45 - 3.35 (m, 2 H), 2.75 - 2.60 (m, 2 H), 2.43 - 2.32 (m, 2 H), 2.10 - 2.05 (m, 1 H), 1.20 - 1.10 (m, 2 H), 0.95 - 0.85 (m, 2 H). ES- LCMS m/z: 453 (M+1 ).
EXAMPLE 50
(+/-)-4-{[3-chloro-5-cyclopropyl^
yl]carbonyI}-1-[2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 50)
Figure imgf000156_0001
Step A
(+/-)-4-{[3~chloro-5-cyclopropyl-7-(tnfIuoromethyl)pyrazolo[1,5-a]pyrid
[(trans)~2-hydroxy~3-cyclopenten-1-yl]-2-piperazinone
[00256] To a solution of 4-{[3-chIoro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yi]carbonyl}-1 -(3-cyclopenten-1 -yl)-2-piperazinone (1.5 g, 3.31 mmol) in Tetrahydrofuran (THF) (30 mL) and ,2-dimethoxyethane (DME) (15 mL) was added selenium dioxide (0.368 g, 3.31 mmol). The reaction mixture (in a sealed tube) was heated at 70 °C overnight (14 hours). The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to a brown foam, which was purified by silica gel chromatography (0-3 % MeOH/CH2CI2) to give (+/-) 4-{[3-chloro-5- cyctopropyl-7-(trifluoromethyl)pyrazolo[1 )5-a]pyridin-2-yl]carbonyl}-1-[(trans)-2-hydroxy-3- cyclopenten-1-yl]-2-piperazinone (400 mg, 26%) as a light brown foam. ES-LCMS m/zi 469 (M+1 ).
Step B
(+/-)- 4-{[3-chloro-5-cyciopropyl-7-(trifluoromethyt)pyrazolo[1,5-a]pyri^
[2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
[00257] 1 M Diethylzinc in hexane (12.29 mL, 12.29 mmol) was dissolved in dichloromethane (DCM) (15 mL) and cooled to 0 °C under N2. TFA (0.946 mL, 12.29 mmol) in dichloromethane (DCM) (15 mL) was added very slowly (over 60 minutes) and the mixture was stirred for 20 minutes. Diiodomethane (1.001 mL, 12.29 mmol) in dichloromethane (DCM) (15 mL) was added very slowly (over 60 minutes), and the mixture was stirred for 20 minutes. A solution of (+/-)-4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[(trans)-2-hydroxy-3-cyclopenten-1 - yl]-2-piperazinone (384 mg, 0.819 mmol) in dichloromethane (DCM) (6 mL) was added. The mixture was allowed to warm up to room temperature and stirred overnight. The mixture was diluted with DCM and washed consecutively with saturated aqueous NH4CI, saturated aqueous NaHC03 and brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-3 % MeOH/CH2CI2) to give (+/-)-4-{[3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[2- hydroxybicyclo[3.1.0]hex-3-y!]-2-piperazinone (160 mg, 41 % yield) as a light yellow foam. H NMR (400 MHz, DMSO-c/6) δ ppm 7.72-7.68 (m, 1 H), 7.47-7.41 (m, 1 H), 4.82 - 4.77 (m, 1 H), 4.44 - 3.80 (m, 5 H), 3.70 - 3.54 (m, 1 H), 3.45 - 3.35 (m, 1 H), 3.30 - 3.22 (m, 1 H), 2.28 - 2.17 (m, 1 H), 1.90 - 1.75 (m, 1 H), 1.74 - 1.62 (m, 1 H), 1 .40 - 1.22 (m, 2 H), 1.18 - 1.05 (m, 2 H), 1.00 - 0.90 (m, 2 H), 0.63 - 0.55 (m, 1 H), 0.40 - 0.30 (m, 1 H). ES- LCMS m/z: 483 (M+1 ).
EXAMPLE 51
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - I(1R,2R,3R,5R)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 51)
Figure imgf000157_0001
Step A
(4S)-3-(4-pentenoyl)-4-(phenylmethyl)~1, 3-oxazolidin-2-one
[00258] To a solution of (4S)-(~)-4-(phenylmethyl)-1 r3-oxazolidin-2-one ( 4 g, 22.35 mmol) in Tetrahydrofuran (THF) (64 mL) under N2 at -78 °C was added dropwise 1.QM n- BuLi in hexane (14.67 mL, 23.47 mmol), and the resulting mixture was stirred at -78 °C for 1 hour. Then a solution of 4-pentenoyl chloride (2.54 mL, 22.57 mmol) in Tetrahydrofuran (THF) (16 ml.) was added dropwise. After stirring at -78 °C for 1 hour, the reaction mixture was allowed to warm up to room temperature, stirred overnight and poured into water. The mixture was extracted with EtOAc (2 x 75 ml_). The combined organic extracts were washed with brine, dried over Na2S04l filtered, concentrated and purified by silica gel chromatography (0-20 % EtOAc/Hexanes) to give
(4S)-3-(4-pentenoyl)-4-(phenylmethyl)-1 J3-oxazolidin-2-one (5.14 g, 89%) as a colorless oil. ES-LCMS m/z: 260 (M+1 ).
Step B
(4S)^[(2R,3R,4E)-3~hy roxy-5-p myl-2-(2-propen-1-yt)^
1, 3~oxazolidin-2-one
[00259] A mixture of (4S)-3-(4-pentenoyl)-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (2 g, 7.71 mmol), magnesium chloride (0.073 g, 0.771 mmol), NaSbF6 (0.599 g, 2.314 mmol), Et3N (2.150 mL, 15.43 mmol), (irans)-cinnamaldehyde (1.177 ml_, 9.26 mmol) and T SCI (1.480 mL, 1 1.57 mmol) in ethyl acetate (35 mL) was stirred at room temperature for 23 hours. The reaction mixture was diluted with ether and filtered through a pad of silica gel. The filtrate was concentrated to a brown oil and re-dissolved in 35 mL of MeOH. Two drops of TFA were added, and the solution was stirred at room temperature for 30 minutes, concentrated and purified by silica gel chromatography (0-20 % EtOAc/Hexanes) to give <4S)-3-[(2R,3R,4E)-3-hydroxy-5-phenyl-2~(2-propen-1 -yl)-4-pentenoyl]-4-
(phenylmethyl)-1 ,3-oxazolidin-2-one (2.76 g, 91 %) as a light yellow viscous oil. ES-LCMS m/z: 374 (M+1-H20).
Step C
(2R,3R,4E)~3~hydroxy-5-phenyl-2-(2-propen-1-yl)-4-pentenoic acid
[00260] To a solution of (4S)-3-[(2R,3R,4E)-3-hydroxy-5-phenyi-2-(2-propen-1-yi)-4- pentenoyl]-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (2.76 g, 7.05 mmol) in tetrahydrofuran (THF) (90 mL) and water (30 mL) at 0 °C was added 30% aqueous H202 (3.60 mL, 35.3 mmol) dropwise, followed by LiOH monohydrate (0.604 g, 14. 0 mmol) in water (15 mL). After stirring for 1 hour at 0 °C, the reaction mixture was stirred at room temperature overnight. The excess H202 was quenched by the addition of sodium sulfite (4.48 g) in water (20 mL). The bulk of the solvent was removed by rotary evaporation, and the resulting mixture was extracted with CH2CI2 (3 x 40 mL). The aqueous layer was cooled in an ice bath and acidified to pH ~ 2 with 1 HCI. The resulting cloudy solution was extracted with CHCI3 (3 x 50 mL). The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated to give (2R,3R,4E)-3-hydroxy-5-phenyl-2-(2- propen-1-yl)-4-pentenoic acid (129 g, 79%) as a colorless viscous oil. ES-LCMS m/z: 231 (M-1 ).
Step D
(4R,5R)-5-[(E)-2^henyiet enyl] -(2-propen-1-yl)-1,3-oxaz
[00261] (2 ,3R,4E)-3-hydroxy-5-phenyl-2-(2-propen-1 -yl)-4-pentenoic acid (1.285 g, 5.53 mmol) was dissolved in toluene (60 mL) and diphenylphosphoryl azide (1.849 mL, 8.30 mmol) was added, followed by Et3N (1 .157 mL, 8.30 mmol). The reaction mixture was heated at 80 °C overnight, cooled to room temperature, and washed with saturated aqueous NaHC03 and brine, dried over Na2S04, concentrated and purified by silica gel chromatography (0-40 % EtOAc/Hexanes) to give (4R,5R)-5-[(E)-2-phenylethenyl]-4-(2- propen-1-yl)-1 ,3-oxazolidin-2-one (0.92 g, 73%) as a yellow oil. ES-LCMS m/z: 230 (M+1 ).
Step E
(1E,3R,4R)-4-amino-1-phenyl-1,6-heptadien-3-ol
[00262] To a stirred solution of (4R,5R)-5-[(E)-2-phenylethenyl]-4-(2-propen-1-yl)- 1 ,3-oxazolidin-2-one (0.92 g, 4.01 mmol) in a mixture of ethanol (15 mL) and water (15 mL) was added KOH (0.901 g, 16.05 mmol). The resulting reaction mixture was heated at 80 °C overnight, cooled to room temperature, and the pH was adjusted to about 8 by the addition of 1 N HCI. The reaction mixture was concentrated under reduced pressure to a small volume and extracted with EtOAc (3 x 60 mL). The combined organic extracts were washed with brine, dried over Na2S04i filtered and concentrated to give (1 E,3R,4R)-4- amino-1-phenyl-1 ,6-heptadien-3-ol (0.768 g, 94%) as a light yellow solid. ES-LCMS m/z: 204 (M+1 ).
Step F
(1 E,3R,4R)-3-{[(1 , 1~dimethylethyl)(dimethyl)silyl]oxy}-1^henyl-1,6-heptadien-4-am
[00263] To a stirred solution of (1 E,3R,4R)-4-amino-1 -phenyl-1 ,6-heptadien-3-ol (0.768 g, 3.78 mmol) and 2,6-lutidine (1.754 mL, 15.1 1 mmol) in Dichloromethane (DCM) (14 mL) at 0 °C was added TBSOTf (2.60 mL, 1 1.33 mmol) under N2. The resulting reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 1 hour. The reaction mixture was quenched with MeOH (1 mL), poured into water and extracted with ether (3 x 50 mL). The combined extracts were washed with water, saturated
NaHC03 and brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-4 % MeOH/CH2Cl2) to give (1 E,3R,4R)-3-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}-1 -phenyl-1 ,6-heptadien-4-ami (1 .14 g, 95%) as a yellow oil. ES-LCMS m/z: 318 (M+1 ).
Step G
N1-[(1R,2R,3E)-2~{[(1, 1-dimethylethyl)(dimethyl)s^
buten-1 -yl]-N2-[(4-nitrophenyl) sulfonyljglycinamide
[00264] DIPEA (0.369 mL, 2. 14 mmol) was added to a mixture of N-[(4- nitrophenyl) sulfonyl]glycine (0.275 g, 1 .057 mmol), (1 E,3R,4R)-3-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}-1-phenyl-1 ,6-heptadien-4-amine (0.336 g, 1.057 mmol), EDC (0.243 g, 1.268 mmol) and 1-hydroxybenzotriazole (0.171 g, 1.268 mmol) in N,N- Dimethylformamide (DMF) (5 mL) at room temperature. The mixture was stirred overnight and diluted with EtOAc, washed with 5% LiCI, Saturated aqueous NaHC03 and brine, dried over Na2S04f filtered and concentrated to give N1-[(1 R,2R,3E)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -(2-propen-1 -yl)-3-buten-1 -yl]-N2~[(4- nitrophenyl)suifonyl]glycinamide (0.7 g) as a brown oil, which was pure enough and used for the next step without further purification. ES-LCMS m/z: 558 (M-1 ).
Step H
1-[(1 R, 2R, 3E)~2-{[(1, ^ ίmefh /efr) /j(c//mefhy/js// /;o y;- - ^en /- 2- fo en-^ /j-3- buten- 1-yl]-4-[(4-nitrophenyl)sutfonyl]-2-piperazinone
[00265] To a solution of N1 -[(1 R,2R,3E)-2-{[(1 , 1-dimethylethyl)(dimethy[)silyl]oxy}-4- phenyl-1-(2-propen-1-yl)-3-buten-1 -yl]-N2-[(4-nitrophenyl)sulfonyl]glycinamide (0.7 g, 1.057 mmol) in Ν,Ν-Dimethylformamide (DMF) (7 mL) was added potassium carbonate (1.168 g, 8.45 mmol) and 1 ,2-dibromoethane (0.738 mL, 8.45 mmol). The reaction mixture was heated at 60 °C overnight, cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite. The filtrate was washed with 5% LiCI and brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-25 %
EtOAc/Hexanes) to give 1-[(1 R,2R,3E)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl- 1-(2-propen-1-yl)-3-buten-1 -yl]-4-[(4-nitrophenyi)sulfonyl]-2-piperazinone (0.463 g, 75%) as an off-white foam. ES-LCMS m/z: 586 (M+1 ).
Step I
1-[(1R,2R,3E)-2-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}~4~phenyi-1-(2^rope
buten-1 -yl]-2-piperazinone
[00266] Potassium carbonate (70.8 mg, 0.512 mmol) and thiophenol (0.022 mL, 0.205 mmol) were added to a stirred solution of 1-[(1 R,2R,3E)-2-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -(2-propen-1 -yl)-3-buten-1 -yl]-4-[(4- nitrophenyl)sulfony[]-2-piperazinone (100 mg, 0.171 mmol) in acetonitrile {2.5 mL) at room temperature. After 4 hours, the mixture was heated to 60 °C and stirred for 2 hours. More thiophenol (0.022 mL, 0.205 mmol) was added. Heating was continued at 60 °C for 2 more hours. The reaction mixture was cooled to room temperature, the solid was filtered off and the filtrate was concentrated and purified by silica gel chromatography (0-4 %
MeOH/CH2CI2) to give l -KI R^R.SE^-iKI .I-dimethylethylXdimethylJsilylloxyH-phenyl-l- (2-propen-1-yl)-3-buten-1-yl]-2-piperazinone (57.2 mg, 84%) as a colorless viscous oil. ES-LCMS m/z: 401 (M+1 ).
Step J
4-{[3-chloro-5-cyclopropyI-7-(trifluoromethyl)pyrazolo[1,5-a]pyri^
[(1R,2R^E)-2-{[(1, 1-dimethyiethyI)(dimethyl)s^
1 -yl]-2-piperazinone
[00267] A solution of 3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylic acid (43.5 mg, 0.143 mmol), 1-[(1 R,2R,3E)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -{2-propen-1-yl)-3-buten-1-yl]-2-piperazinone (52 mg, 0.130 mmol) and DIPEA (0.068 mL, 0.389 mmol) in N.N-Dimethylformamide (DMF) (1.5 mL) was cooled in an ice bath. 1-propanephosphonic acid cyclic anhydride (50% wt.% in EtOAc, 0.093 mL, 0.156 mmol) was added dropwise. The reaction mixture was stirred for 3 hours, diluted with EtOAc, washed with 5% LiCI, saturated aqueous NaHCC>3 and brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-30 % EtOAc/Hexanes) to give 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[{1 R,2R,3E)-2-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -{2-propen-1 -yl)-3-buten~1 -yl]-2-piperazinone (84.2 mg, 94%) as a white foam. ES-LCMS m/z: 686 (M+1 ).
Step K
4-{[3-chtoro-5-cyclopropyi-7-(trifiuoromethyl)pyrazolo[1,5-a]pyri^^
((1R,2R)-2-{[(1, 1-dimethyiethyl)(dimethyl)silyl]oxy}-3-cyclopenten^
[00268] A solution of 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-y!]carbonyl}-1 -[(1 R,2R,3E)-2-{[( 1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl- 1-(2-propen-1-yl)-3-buten-1-yl]-2-piperazinone (83.2 mg, 0.121 mmol) in Toluene (6 mL) was degassed three times with N2, then 1 ,3-Bis(2,4,6-trimethylpheny!)-4,5- dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N- dimethylaminosulfonyl)phenyl]methyleneruthenium(ll) dichloride (Zhan Catalyst-1 B) (8.88 mg, 0.012 mmol) was added, the mixture was degassed twice and backfilled with N2 and stirred at room temperature overnight, concentrated and purified by silica gel
chromatography (0-40 % EtOAc/Hexanes) to give 4-{[3-chloro-5-cyclopropyl-7- (trlf luoromethyl) pyrazolo[1 , 5-a]pyridin-2-yl]carbonyl}-1 -((1 R,2R)-2-{[(1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-yl)-2-piperazinone (69 mg, 98%) as an off-white foam. ES-LCMS m/z: 583 (M+1 ).
Step L
4-{[3-chloro-5-cyclopropyl- 7-( trifluoromethyl)pyrazolo[ 1,5-a ]pyridin-2-yl]carbonyl} - 1 - [(1 R,2R)-2-hydroxy-3-cyclopenten-1-yl]-2-piperazinone
[00269] To a solution of 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -((1 R(2R)-2-{[(1 ,1 -dimethylethyl)(dimethyl)silyl]oxy}-3- cyclopenten-1-yl)-2-piperazinone (68 mg, 0.117 mmol) in Tetrahydrofuran (THF) (3 mL) in an ice bath was added 1.0/W TBAF in THF (0.175 mL, 0.175 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours, diluted with ethyl acetate and washed with water/brine. The organic layer was separated and the aqueous layer was extracted with more EtOAc. The combined organic layers were dried over Na2S04l filtered, concentrated and purified by silica gel chromatography (0-30 %
Acetone/CH2CI2) to give 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-[(1 R,2R)-2-hydroxy-3-cyclopenten-1 -yl]-2-piperazinone (51.5 mg, 94%) as a white foam. ES-LCMS m/z: 469 (M+1 ).
Step M
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyi)pyrazolo[1,5-a]pyri^
[(1R,2R,3R,5R)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
[00270] A solution of 4-{[3-chloro-5-cyclopropyl-7~(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -[(1 R,2R)-2-hydroxy-3-cyclopenten-1-yl]-2-piperazinone (50 mg, 0.107 mmol) in Dichloromethane (DCM) (2 mL) was cooled in an ice bath and treated with 1M Diethylzinc in hexane (0.533 mL, 0.533 mmol) dropwise. After stirring at 0 °C for 15 minutes, a solution of diiodomethane (0.087 mL, 1 .066 mmol) in dichloromethane (DCM) (0.5 mL) was added drop-wise. The resulting cloudy solution was stirred at 0 °C for 15 minutes, then allowed to warm up to room temperature. After 3 hours, the reaction mixture was quenched with saturated aqueous NH4CI and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-30 % Acetone/CH2CI2) to give 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyi)pyrazoio[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(1 R,2R,3R,5R)-2-hydroxybicyclo[ 3.1.0]hex-3-yl]-2-piperazinone (34 mg, 66%) as a white foam. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.59 (s, 1 H), 7.31 (s, 1 H), 4.62 - 4.53 (m, 1 H), 4.52 - 4.22 (m, 3 H), 4.21 - 3.96 (m, 1 H), 3.90 - 3.75 (m, 1 H), 3.60 - 3.40 (m, 2 H), 2.20 - 2.10 (m, 1 H), 2.02 - 1.82 (m, 2 H), 1.58 - 1.44 (m, 1 H), 1.40 - 1.28 (m, 1 H), 1 .20 - .10 (m, 2 H), 0,95 - 0.82 (m, 2 H), 0.80 - 0.70 (m, 1 H), 0.53 - 0.42 (m, 1 H). ES- LCMS m/z: 483 (M+1 ).
EXAMPLE 52
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1
[(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 52)
Figure imgf000163_0001
Step A
(4R)~3-(4~pentenoyl)-4-(phenylmethyl)-1,3-oxazolidin-2-one
[00271] To a solution of (4R)-4-(phenylmethyl)-1 ,3-oxazo!idin-2-one (2.5 g, 13.97 mmol) in Tetrahydrofuran (THF) (40 mL) under N2 at -78 °C was added dropwise 1.QM n- BuLi in hexane (9.17 mL, 14.67 mmoi), and the resulting mixture was stirred at -78 °C for 1 hour. A solution of 4-pentenoyl chloride (1.589 mL, 14.1 1 mmol) in Tetrahydrofuran (THF) (10 mL) was added dropwise. After stirring at -78 °C for 1 hour, the reaction mixture was allowed to warm up to room temperature and stirred overnight, poured into water, and the mixture was extracted with EtOAc (2 x 60 mL). The combined organic extracts were washed with brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-20 % EtOAc/Hexanes) to give (4R)~3-(4-pentenoyl)-4-(phenylmethy!)- 1 ,3-oxazolidin-2-one (3.29 g, 91 %) as a light yellow oil.
Step B
(4R)-3-[(2S,3S^E)-3-hydroxy-&phenyl-2-(2^ropen-1-y!)-4^entenoy^^
1, 3-oxazolidin-2-one
[00272] A mixture of (4R)-3-(4-pentenoyl)-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (3.29 g, 12.69 mmol), magnesium chloride (0.121 g, 1 .269 mmol), NaSbF6 (0.985 g, 3.81 mmol), Et3N (3.54 mL, 25,4 mmol), (frans)-cinnamaldehyde (1.936 rriL, 15.23 mmol) and TMSCI (2.434 ml_, 19.03 mmol) in ethyl acetate (58 ml_) was stirred at room temperature for 17 hours. The reaction mixture was diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated and the residue was dissolved in 50 mL of eOH with some EtOAc. TFA (0.1 mL) was added, and the solution was stirred at room temperature for 1 hour, concentrated and purified by silica gel chromatography (0-20 % EtOAc/Hexanes) to give (4R)-3-[(2S,3S,4E)-3-hydroxy-5-phenyl-2-(2-propen-1 -yl)-4- pentenoyl]-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (4.38 g, 88%) as a yellow viscous glass- like oil. ES-LC S m/z: 374 (M+1 -H20).
Step C
(4R) -3-{[ (1S, 2S)-2-hydroxy-3-cyc!openten- 1 -yljcarbonyl} -4-(ph enylmethyi)- 1 , 3-oxazolidin-
2-one
[00273] A solution of (4R)-3-[(2S,3S,4E)-3-hydroxy-5-phenyl~2~(2-propen-1 -yl)-4~ pentenoyl]-4-(phenylmethy!)-1 ,3-oxazolidin-2-one (495 mg, 1.264 mmol) in toluene (60 mL) was degassed three times with N2, then 1 ,3-Bis(2,4,6-trimethylphenyl)-4,5- dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N- dimethylaminosulfonyl)phenyl]methyleneruthenium(ll) dichloride (Zhan Catalyst-1 B) (64.9 mg, 0.089 mmol) was added and the mixture was degassed twice and backfilled with N2 and stirred at room temperature overnight, concentrated and purified by silica gel chromatography (0-40 % EtOAc/Hexanes) to give (4R)-3-{[( S,2S)-2-hydroxy-3- cyclopenten-1 -yl]carbony[}-4-(phenylmethyl)-1 ,3-oxazolidin-2-one (340 mg, 94%) as a dark brown oil, which solidified upon standing. ES-LCMS m/z: 270 (M+1 -H20). Step D
(4R)~3~{[(1S,2S,3S,5S)^hydroxybicycb[3.1 ]hex'3-yl]carbonyl}-4-(phen
oxazolidin-2-one
[00274] A solution of (4R)-3-{[(1 S,2S)-2-hydroxy-3-cyclopenten-1-yl]carbonyl}-4- (phenylmethyl)-1 ,3-oxazolidin-2-one (330 mg, 1.149 mmol) in Dichloromethane (DCM) (15 mL) was cooled in an ice bath and treated with 1 /W Diethylzinc in hexane (5.74 mL, 5.74 mmol) dropwise. After stirring at 0 °C for 20 minutes, diiodomethane (0.936 mL, 1 1.49 mmol) was added dropwise. The resulting cloudy soiution was stirred at 0 °C for 20 minutes and allowed to warm up to room temperature. After 6 hours, the reaction mixture was quenched with saturated aqueous NH4CI and extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-40 % EtOAc/Hexanes) to give (4R)-3- {[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]carbonyl}-4-(phenylmethyi)-1 ,3- oxazolidin-2-one (308 mg, 89%) as a light brown viscous oil. ES-LCMS m/z: 284 (M+1 - H20). Step E
(4R)-3-[((1S,2S,3S, 5S)-2-{[(1, 1-dimethylethyl)(dimethyl)siiyl]oxy}bicyclo[3.1.0]hex-3- yl)carbonyl]-4-(phenyImethyl)- 1, 3-oxazolidin-2-one
[00275] To a stirred solution of (4R)-3-{[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex- S-yllcarbonyiH-iphenylmethylJ-I .S-oxazoiidin^-one (308 mg, 1.022 mmol) and 2,6- iutidine (0.475 mL, 4.09 mmol) in Dichloromethane (DCM) (5 mL) at 0 °C was added
TBSOTf (0.587 mL, 2.56 mmol) under N2. The resulting reaction mixture was stirred at 0 °C for 30 minutes and at room temperature for 1 hour. The reaction mixture was quenched with MeOH (0.3 mL) and poured into water and extracted with ether (75 mL and 25 mL). The combined organic extracts were washed with brine, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-20 % EtOAc/Hexanes) to give (4R)-3-[((1 S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3- yl)carbonyl]-4-(phenylmethyl)~1 ,3-oxazoIidin-2-one (406 mg, 96%) as a colorless oil. ES- LCMS m/z: 416 (M+1 ). Step F
(1S,2S,3S,5S)-2-{[(1, 1-dimethylethyl)(dimethyl)s^
acid
[00276] To a solution of (4R)-3-[((1S!2S,3Sl5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3-yl)carbonyl]-4-(phenylmethyl)-1 ,3- oxazolidin-2-one (405 mg, 0.974 mmol) in tetrahydrofuran (THF) (6 mL) and water (2 mL) at 0 °C was added 30% aqueous H202 (0.796 mL, 7.80. mmol) dropwise, followed by addition of LiOH monohydrate (167 mg, 3.90 mmo!) in water (1 mL). After stirring for 1 hour at 0 °C, the reaction mixture was stirred at room temperature overnight. The excess H202 was quenched by the addition of saturated aqueous Na2S03 (4 mL), The reaction mixture was then adjusted to pH -14 with 0.1 N NaOH (0.2 mL) and washed with Et20 (40 mL). The aqueous layer was acidified to pH ~ 3 with 1 M KHS04, and extracted with EtOAc (3 x 40 mL). The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated to give (1S,2S,3S,5S)-2~{[(1 ,1 -dimethylethyl)
(dimethyl)silyl]oxy}bicycle[3.1.0]hexane-3-carboxylic acid (220 mg, 88%) as a colorless viscous oil. Step G
((1S,2S^S,5$ 2-{l(1, 1-dimeihylethyl)(dlmethyl)silyl]o^
[00277] To a solution of (1 S,2S,3S,5S)-2-{t{1 ,1-Dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1 .0]hexane-3-carboxyiic acid (10 g, 39.0 mmol) in toluene (180 mL) was added Et3N (6.52 mL, 46.8 mmol) and DPPA (8.43 mL, 39.0 mmol). The solution was heated to 80 °C for 5 hours then cooled to 0 °C in an ice bath. To this was added potassium trimethylsilanolate (10.01 g, 78 mmol) in 90 mL of THF, and the mixture was stirred at room temperature for 1 hour. 15% aqueous citric acid was added. The resulting mixture was then made basic with aqueous NaOH and extracted with Et20. The Et20 layer was separated and the aqueous layer was evaporated to a small volume and extracted again with Et20. The combined organic layers were washed with small amount of brine, dried over sodium sulfate, filtered and evaporated to afford ((1 S,2S,3S,5S)-2~{[(1 ,1 - dimethyiethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)amine (8.86 g, 95%) as a pale yellow oil.
Step H
Nl-tflS^S^dS^-ffll^-dimethylethyWdimethytys^
nitroph enyl) sulfonyljglycinamide
[00278] N-[(4-nitrophenyl)sulfonyl]glycine (10.14 g, 39.0 mmol), ((1 S,2S,3S,5S)-2- {[(1 ,1-dimethylethyl)(dimethyl)siIyl]oxy}bicyclo[3.1.0]hex-3-yl)amine (8.86 g, 39.0 mmol),
HOBT (6.56 g, 42.9 mmol) and DIPEA (8.17 mL, 46.8 mmol) were combined in N,N-
Dimethylformamide (DMF) (187 mL). To this solution was added EDC (8.22 g, 42.9 mmol), and the reaction mixture was stirred for 5 hours, diluted with EtOAc and poured into water.
The organic layer was separated and washed with saturated aqueous NaHC03, brine and dried over sodium sulfate, filtered and evaporated to dryness to yield a solid, which was triturated with Et20 to afford N1-((1S,2S,3S,5S)-2-{[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-N2-[(4- nitrophenyl)suifonyl]glycinamide (18.26 g, quant.), which was used without further purification. ES-LCMS m/z: 470 ( +1 ).
Step I
1-((1S,2S,3S,5S)-2-{[(1, 1-dimethylethyl) (dimethyl) silyl]oxy}bicyclo[3.1.0]hex-3-yl)-4-[(4- nitrophenyl)sulfonyl]-2-piperazinone
[00279] N1 -((1 S,2S,3S,5S)-2-{[( 1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclot3.1.0]hex-3-yl)-N2-[(4- nitrophenyl)sulfonyl]glycinamide (18.26 g, 38.9 mmol), 1 ,2-dibromoethane (26.8 mL, 31 1 mmol), and cesium carbonate (50.7 g, 156 mmol) were combined in N,N- Dimethylformamide (DMF) (200 mL) and stirred at room temperature for 6 hours. The reaction mixture was diluted with EtOAc and washed with water, brine and dried over sodium sulfate, filtered and evaporated to dryness to give a solid, which was triturated with Et20 and hexanes to afford a solid. The filtrate was evaporated to an oil, which was purified by silica gel chromatography eluting with EtOAc and hexanes to afford a solid, which was combined with the triturated solid to yield 1 -((1 S,2S,3S,5S)-2-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-4-[(4-nitrophenyI)sulfonyl]-2- piperazinone (15.8 g, 82%) as a yellow solid. ES-LCMS m/z: 496 (M+1 ).
Step J
1-((1S,2S,3S,5S)-2-{[(1 -dimethylethyl)(dimethyl)si^
piperazinone
[00280] A solution of ^((I S^S.aS.SS^-iKI .I-dimethylethy fdimethylisilyljoxy} bicyclo[3.1.0]hex-3-yl)-4-[(4-nitrophenyl)sulfonyl]-2-piperazinone (300 mg, 0.605 mmol) in acetonitrile (6 mL) was treated with thiophenol (0.187 mL, 1.816 mmol), followed by addition of potassium carbonate (335 mg, 2.421 mmol). The reaction mixture was stirred at room temperature for 5 hours. The mixture was diluted with CH2CI2 and filtered through a pad of celite. The filtrate was dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-5 % 2M NH3 in MeOH/CH2CI2) to give 1 -((1 S,2S,3S,5S)~2~ {[(1 ,1-dimethylethyl)(dimethy!)silyl]oxy} bicyclo[3.1.0]hex-3~y!)-2-piperazinone (160 mg, 85%) as a colorless oil.
Step K
4-{[3-chIoro-5~cyclopropyl- 7-(trifluoromethyl)pyrazolo[ 1 , 5-a]pyridin-2-yl]carbonyl}- 1 - ((IS^S S^S^-ttfl, 1-dimethylethyl)(dimetbyl)silyl]oxy}bicyclo[3.1, 0]hex-3-yl)-2- piperazinone
[00281] DIPEA (13.84 mL, 79 mmol) was added to a mixture of 3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (8.45 g, 27.7 mmol) and 1 -((1 S,2S,3S,5S)-2-{[( 1 , 1 -dimethylethyl)(dimethyl)sily!]oxy}bicyclo[3. .0]hex-3-y!)-2- piperazinone (8.2 g, 26.4 mmol) in tetrahydrofuran (THF) (250 mL) at room temperature under N2. The mixture was stirred for 30 minutes and then cooled to 0 °C, 1- propanephosphonic acid cyclic anhydride (50% wt% in EtOAc, 23.58 mL, 39.6 mmol) was added. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Saturated aqueous NaHC03 was then added and the solution was extracted with EtOAc three times. The combined organic extracts were washed with brine, dried over Na2S04, and concentrated to give the crude 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-((1 S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl) (dimethyl)sily!]oxy}bicyclo[3.1 ,0]hex-3-yl)-2-piperazinone as yellow oil which was used in the next step without further purification. ES-LCMS m/z: 597 (M+1 ).
Step L
4-{[3-chloro-5-cyclopropyl- 7-(trifiuoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1- [(1 S, 2S, 3S, 5S)-2-hydroxybicycio[3.1.0]hex-3-yl]-2-piperazinone
[00282] TBAF ( M in TH F, 55.3 mL, 55.3 mmol) was added to a solution of 4-{[3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yi]carbony(}-1-
({1 S,2S,3S,5S)-2-{[(1 -dimethylethyl)(dimethyl)silyl]oxy}bicyc[o[3.1 .0]hex-3-yl)-2- piperazinone (22 g, 36.8 mmol) in tetrahydrofuran (THF) (350 mL) at 0 °C under N2. The reaction mixture was allowed to warm up to room temperature and stirred for 4 hours. Most of solvent (THF) was removed under reduced pressure, and the residue was diluted with EtOAc (250 mL) and washed with saturated aqueous NaHC03. The organic layer was separated and the water layer was further extracted with EtOAc (3x100 mL). The combined organic extracts were dried over a2S04, filtered, concentrated and purified by silica gel chromatography (20-90 % EtOAc (containing 5 % MeOH) in hexanes) to give 4- {[3-chlorO"5"Cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - [(1S,2S,3S,5S)-2-hydroxybicyclo[3.1 ,0]hex-3-yl]-2-piperazinone as a white foam (15.06 g, 85%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42 (d, J=9.56 Hz, 1 H) 7.06 (br. s„ 1 H) 4.30 - 4.63 (m, 4 H) 4.15 - 4.22 (m, 1 H) 3.85 - 3.98 (m, 1 H) 3.40 - 3.54 (m, 2 H) 1.91 - 2.05 (m, 3 H) 1.53 - 1.64 (m, 1 H) 1.42 (br. s„ 1 H) 1.13 - 1.22 (m, 2 H) 0.84 - 0.90 (m, 2 H) 0.75 - 0.84 (m, 1 H) 0.46 - 0.58 (m, 1 H). ES-LCMS m/z: 483 (M+1 ),
EXAMPLE 53
4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1-(trans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 53)
Figure imgf000169_0001
Step A
5-cyclopropyl-3-iodo-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid
[00283] 5-Cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (1g, 3.5 mmol) and DCE (12 mL, 12 vol) were charged into the JLR. The mixture was then heated to reflux and 2-3 vol of solvent was removed. Once the distillation was complete, the solution was cooled to 25 °C. NIS (0.989 g, 4.4 mmol, 1.25 eq) was then charged and the reaction mixture was heated to 50 °C. The reaction was stirred at 50 °C until completion by HPLC. The solution was cooled to 25 °C and 1 NaOH (15 mL, 15 vol) was added. This mixture was stirred for 1-2 hours and the layers were allowed to separate and the aqueous layer was isolated and acidified with QM HCI until pH 1. The mixture was cooled to 10 °C and the solids were filtered and dried at 40 °C under high vacuum for 24 hours to give 5-cyclopropyl-3-iodo-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.97 g, 70%) as an off-white solid. ES-LCMS m/z: 397 (M+1 ).
Step B
methyl 5-cyclopropyl~3-iodo~7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
[00284] To a solution of 5-cyclopropyl"3"iodo-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylic acid (500 mg, 1.262 mmol) in Ν,Ν-Dimethylformamide (DMF) (5 mL) was added potassium carbonate (262 mg, 1 .893 mmol), followed by addition of iodomethane (0.099 mL, 1.578 mmol). The mixture was stirred at room temperature for 4 hours. EtOAc was added, the mixture was then washed with 5% LiCI and brine, dried over Na2S04l filtered, concentrated and purified by silica gel chromatography (0-15%
EtOAc/Hexanes) to give methyl 5-cyclopropyl-3-iodo-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (503 mg, 97%) as a white solid. ES-LCMS m/z: 41 1 (M+1 ).
Step C
methyl 5-cyclopropyl-3-methyI-7~(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
[00285] A mixture of methyl 5-cyclopropyl-3-iodo-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (100 mg, 0.244 mmol), trimethylboroxin (0.103 mL, 0.731 mmol), K2C03 (168 mg, 1.219 mmol) and PdCI2(dppf)-CH2CI2 adduct (19.91 mg, 0.024 mmol) in Ν,Ν-Dimethylformamide (DMF) (1.5 mL) in a sealed tube was heated to 100 °C for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water/brine. The organic layer was separated, dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-15% EtOAc/Hexanes) to give methyl 5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (67 mg, 92%) as a white solid. ES-LCMS m/z: 299 (M+1 ).
Step D
5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[1, 5-a]pyridine-2-carboxylic acid
Ϊ00286] 1 /W NaOH (3.27 mL, 3.27 mmol) was added to a solution of methyl 5- cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (325 mg, 1.090 mmol) in tetrahydrofuran (THF) (15 mL) and Water (10 mL) at room temperature. The reaction mixture was stirred for 3 hours and acidified to pH ~ 2 with 1 /V HCI. The mixture was extracted with EtOAc twice. The combined organic extract was washed with brine, dried over Na2S04, concentrated and dried in vacuo to give 5-cyclopropyl-3-methyl- 7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (310 mg, quant.) as a white solid. ES-LCMS m/z: 285 (M+1 ). Step E
4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[1,5-a]py
4-hydroxycyclohexyl)-2-piperazinone
[00287] To a mixture of 5-cyclopropyl-3-methyl~7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylic acid (75 mg, 0.264 mmol), 1-(irans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride (74.3 mg, 0,31 mmol) in tetrahydrofuran (THF) (3 mL) was added DIPEA (0.184 mL, 1.055 mmol) dropwise. The reaction mixture was stirred at room temperature for 5 minutes, then cooled in an ice bath, and 1-propanephosphonic acid cyclic anhydride (50% wt.% in EtOAc, 0.220 mL, 0.369 mmol) was added drop-wise. The reaction mixture was stirred for 3 hours. Water was added, the mixture was extracted with EtOAc. The combined organic extracts were washed with brine and dried over Na2S0 , filtered, concentrated and purified by silica gel chromatography (0-45% Acetone/CH2CI2) to give 4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyl) pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1-(trans-4-hydroxycyclohexyl)-2-piperazinone (95 mg, 78%) as a white foam. 1H N R (400 MHz, METHANOL-^) δ ppm 7.58 (s, 1 H), 7.19 (s, 1 H), 4.48 - 4.24 (m, 3 H), 4.03 - 3.95 (m, 2 H), 3.55 - 3.42 (m, 3 H), 2.38 (s, 3 H), 2.14 - 1.97 (m, 3 H), 1 .80 - 1 .60 (m, 4 H), 1.47 - 1.30 (m, 2 H), 1.15 - 1.05 (m, 2 H), 0.95 - 0.82 (m, 2 H). ES-LC S m/z: 465 (M+1 ).
EXAMPLE 54
4-{[5-cyclopropy[-3-methyl-7-(trifluorom
1-I{1S,2S,3S,5S)-2-hydroxybicydo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 54)
Figure imgf000171_0001
Step A
4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbony!}- 1- ((1S,2S,3S,5S)-2-{[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex~3-yl)-2- piperazinone
[00288] To a solution of 5-cyclopropyi-3-methyl-7-(trif!uoromethyl)pyrazoio[1 ,5- a]pyridine-2-carboxylic acid (80 mg, 0.281 mmol), 1 -((1S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl) (dimethyl)silyl] oxy}bicyclo[3.1.0]hex-3-yl)-2~piperazinone (87 mg, 0.281 mmol) in N,N- Dimethylformamide (DMF) (3 ml_) was added DIPEA (0.147 mL, 0.844 mmol) drop-wise. The reaction mixture was cooled in an ice bath, 1-propanephosphonic acid cyclic anhydride (50% wt.% in EtOAc, 0.235 mL, 0.394 mmol) was added drop-wise. The reaction mixture was stirred for 2 hours and diluted with EtOAc, washed with 10% citric acid, saturated aqueous NaHC03, 5% LiCI and brine, dried over Na2S04, filtered and concentrated to give crude 4-([5"Cyclopropyl-3-methyI-7-(trifluoromethyl) pyrazolo [1 ,5- a]pyridin-2-yl]carbonyl}-1 -(( 1 S,2S,3S,5S)-2-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3-yl)-2-piperazinone (188 mg) as a light yellow oil, which was used without further purification. ES-LCMS m/z: 577 (M+1 ).
Step B
4-{[5-cyclopropyl-3-methyl-7~(trifluoromethyl)pyrazolo[1,5^
[(IS^S, 3S, 5S)-2-hydroxybicycio[3. 0]hex-3-yi]-2-piperazinone
[00289] To a solution of 4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[ ,5- a]pyridin-2-yl]carbonyl}-1-((1 S,2S,3S,5S)-2-{[(1 , 1-dimethylethy!)(dimethyl)silyl]oxy} bicycio [3.1.0]hex-3-yl)-2-piperazinone (0.162 g, 0.281 mmo!) in tetrahydrofuran (THF) (6 mL) in an ice bath was added 1.0/W TBAF in THF (0.422 mL, 0.422 mmol). The reaction mixture was allowed to warm up to room temperature, stirred for 2 hours and poured into ethyl acetate and washed with water/brine. The organic layer was separated and the aqueous layer was further extracted with EtOAc. The combined organic layers were dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-30 %
Acetone/CH2CI2) to give 4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1-[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone (0.115 g, 88%) as a white foam. 1H N R (400 MHz, METHANOL-^) δ ppm 7.58 (s, 1 H), 7.19 (s, 1 H), 4.61 - 4.46 (m, 2 H), 4.40 - 4.23 (m, 2 H), 4.22 - 4.12 (m, 1 H), 3.92 - 3.75 (m, 2 H), 2.38 (s, 3 H), 2.14 - 2.03 (m, 1 H), 2.01 - 1.85 (m, 2 H), 1.55 - 1 .45 (m, 1 H), 1.40 - 1.25 (m, 2 H), 1.12 - 1.05 (m, 2 H), 0.95 - 0.85 (m, 2 H), 0.80 - 0.70 (m, 1 H), 0.50 - 0.42 (m, 1 H). ES-LCMS m/z: 463 (M+1 ). EXAMPLE 55
4-{[3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolot1 ,5-a]pyridin-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 55)
Figure imgf000172_0001
H
Step A
methyl 3-chloro-5-cyclopropyi- 7~ ( 3-fl uorophenyl)pyrazolo[ 1,5-a Jpyridin e-2-carboxyla te
[00290] A mixture of methyl 7-bromo-3-chloro-5-cyclopropylpyrazolo[1 ,5-a]pyridine-
2- carboxylate (500 mg, 1.517 mmol), PdCI2(dppf)-CH2CI2 adduct (61.9 mg, 0.076 mmol),
3- fluorophenylboronic acid (255 mg, 1.821 mmol) and potassium phosphate (996 mg, 4.55 mmol) in ,4-dioxane (12 mL) was degassed and backfilled with N2, and heated at 90 °C overnight. The reaction mixture was cooled to room temperature, EtOAc was added, and the mixture was filtered through a pad of Celite. The filtrate was washed with brine, dried over Na2S04> filtered, concentrated and purified by silica gel chromatography (0-10 % EtOAc/Hexanes) to give methyl 3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (453 mg, 85%) as a white solid. ES-LCMS m/z: 345 (M+1 ).
Step B
3-chloro-5-cyclopropyl- 7-(3-fluorophenyI)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid
[002911 1 /V NaOH (3.13 mL, 3.13 mmol) was added to a solution of methyl 3-chloro- 5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (360 mg, 1.044 mmol) in tetrahydrofuran (THF) (25 mL) and water (5 mL) at room temperature. The reaction mixture was stirred for 8 hours, acidified to pH ~ 2 with 1 /V HCI, and extracted with EtOAc twice. The combined organic extracts were washed with brine, dried over Na2S04, concentrated and dried in vacuo to give 3-chloro-5-cyclopropyl-7-(3- fluorophenyl)pyrazo!o[1 ,5-a]pyridine-2-carboxylic acid (360 mg, quant.) as a white solid, which was pure enough to use without further purification. ES-LCMS m/z: 331 (M+1 ). Step C
4~{[3-chloro~5-cyc!opropyl-7-(3-fluorophenyl)pyrazoio[1,5~a]pyridin-2-yl]c^
4-hydroxycyclohexyl)-2-piperazinone
[00292] To a mixture of 3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5- a]pyridine-2-carboxylic acid (80 mg, 0.242 mmol), 1-(irans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride (57.5 mg, 0.290 mmol) in Ν,Ν-Dimethylformamide (DMF) (3 mL) was added DIPEA (0.169 mL, 0.968 mmol) drop-wise. The mixture was stirred at room temperature for 5 minutes, cooled to 0 °C, and 1 -propanephosphonic acid cyclic anhydride (50% wt.% in EtOAc, 0.202 mL, 0.339 mmol) was added drop-wise, The reaction mixture was stirred for 3 hours and diluted with EtOAc, washed with 5% LiCI, saturated aqueous NaHC03 and brine. The organic layer was dried over Na2S04, filtered, concentrated and purified by silica gel chromatography (0-40 % Acetone/CH2CI2) to give 4-{[3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazo[o[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans- 4-hydroxycyclohexyl)-2-piperazinone (1 15 mg, 93%) as a white foam. H NMR (400 MHz, METHANOL-^) δ ppm 7.75 - 7.61 (m, 2 H), 7.60 - 7.50 (m, 1 H), 7.36 (d, 1 H, J = 1.7 Hz), 7.33 - 7.20 (m, 1 H), 6.92 - 6.87 (m, 1 H), 4.40 - 4.22 (m, 3 H), 4.00 - 3.80 (m, 2 H), 3.55 - 3.35 (m, 3 H), 2.18 - 2.07 (m, 1 H), 2.06 - 1.96 (m, 2 H), 1.70 - 1.50 (m, 4 H), 1.45 - 1.30 (m, 2 H), .18 - 1.10 (m, 2 H), 0.95 - 0.85 (m, 2 H). ES-LCMS m/z: 51 1 (M+1 ). EXAMPLE 56
4-{[3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [{1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]h8x-3-yl]-2-piperazinone
(Compound 56)
Figure imgf000174_0001
Step A
4^[3-chloro-5~cyclopropyi-7-(3-fluorophenyI)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1- ((1S, 2S, 3S, 5S)-2-{[(1, 1-dimethylethyt)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2- piperazinone
[00293] To a solution of 3-chloro-5-cyciopropyl-7-(3-f[uorophenyl)pyrazolo[ ,5- a]pyridine-2-carboxylic acid (105 mg, 0.305 mmol), 1-((1 S,2S,3S,5S)-2-{[(1 ,1 - dimethylethyl) (dimethyi)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone (1 14 mg, 0.366 mmol) in Ν,Ν-Dimethylformamide (DMF) (3 mL) was added DIPEA (0.160 mL, 0.914 mmol) drop-wise. The reaction mixture was cooled in an ice bath and 1- propanephosphoric acid cyclic anhydride (50% wt.% in EtOAc, 0.254 mL, 0.427 mmol) was added drop-wise. The reaction mixture was stirred for 3 hours and diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHC03l 5% LiCI and brine. The organic layer was dried over Na2S04, filtered, and concentrated to give 4-{[3-chioro-5- cyclopropyl^-iS-fiuoropheny pyrazoloII .S-alpyridin^-y^carbon lJ-l -^ S^S^S^S)^- {[(1 , 1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone (225 mg) as a light yellow viscous oil, which was used without further purification. ES-LCMS m/z: 623 (M+1 ).
Step B
4-{[3-chloro-5-cyciopropyl- 7-(3-fluorophenyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1- 1(1 S, 2S, 3S, 5S) -2-hydroxybicyclo[3.1.0]hex-3-yi]-2-piperazinone
[00294] To a solution of 4-{[3-chioro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5- a]pyridin-2-yI]carbonyl}-1 -((1 S,2S,3S,5S)-2-{[( , 1 -dimethyIethyl)(dimethyl)silyl]oxy} bicyclo[3.1.0]hex-3-yl)-2-piperazinone (190 mg, 0.305 mmol) in tetrahydrofuran (THF) (6 ml.) in an ice bath was added 1.0M TBAF in THF (0.458 mL, 0.458 mmol). The reaction mixture was allowed to warm up to room temperature, stirred for 3 hours and diluted with water/brine and extracted with EtOAc (2 x 30 mL). The combined organic layers were dried over Na2S04l filtered, concentrated and purified by silica gel chromatography (0-30 % Acetone/CH2Cl2) to give 4-{[3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5- alpyridin^-yllcarbonylJ-l-^I S^S.SS.SS^-hydroxybicyclotS.I .Olhex-S-yll^-piperazinone (145 mg, 93%) as a white foam. 1H N R (400 MHz, ETHANOL-c/4) δ ppm 7.75 - 7.61 (m, 2 H), 7.60 - 7.50 (m, 1 H), 7.35 (d, 1 H, J = 2.0 Hz), 7.33 - 7.20 (m, 1 H), 6.92 - 6.87 (m, 1 H), 4.60 - 4.20 (m, 4 H), 4.19 - 3.98 (m, 1 H), 3.85 - 3.70 (m, 1 H), 3.55 - 3.34 (m, 2 H), 2.18 - 2.05 (m, 1 H), 2.00 - 1.80 (m, 2 H), 1.55 - 1 .42 (m, 1 H), 1.40 - 1.30 (m, 1 H), 1 .18 - .08 (m, 2 H), 0.95 - 0.85 (m, 2 H), 0.80 - 0.70 (m, 1 H), 0.50 - 0.40 (m, 1 H). ES- LCMS m/z: 509 (M+1 ).
EXAMPLE 57
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a3pyridin-2-yl]carbonyl}-1-
(cis-4-hydroxycyclohexyl)-2-piperazinone
(Compound 57)
Figure imgf000175_0001
Step A
cis~4-aminocyclohexanoI
[002951 HCI (4N in dioxane) (2 mL, 0.066 mol) was added to a solution of 1 ,1- dimethylethyl (cis-4-hydroxycyclohexyl)carbamate (1.00 g,0.0046 mol) in DCM (10 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with ether. The resulting slurry was filtered and the solid dried under vacuum to give the title compound (0.664 g, 94%) as a white solid.
Step B
1, 1 -dimethylethyl 4-(cis-4-hydroxycyclo exyl)-3-oxo- 1 -piperazinecarboxylate
[00296] The title compound (0.489 g, 91 %) was obtained as a white solid from methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate (0.418 g, 0.00181 mol) and c/s-4-aminocyclohexanol hydrochloride (0.329 g, 0.00217 mol) by a previously described procedure. MS (ESI) m/z= 299 (M+1 ). Step C
1 -(cis-4-hydroxycyclohexyl)~2-piperazinone hydrochloride
[00297] HCI (4N in dioxane) (1 mL, 0.033 mol) was added to a solution of 1 ,1- dimethylethyi 4-(c/s-4-hydroxycyclohexyl)-3-oxo-1-piperazinecarboxylate (0.473 g, 0.0016 mol) in DCM (5 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated to give the title compound as a white solid.
Step D
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin~2-yl]carbonyl}- 1-(cis-4- hydroxycyclohexy!)-2-piperazin on e
[00298] The title compound {0.520 g, 95%) was obtained as an off-white solid from 3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.100 g, 0.00033 mol) and 1-(c/s-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (0.077 g, 0.00033 mol by a previously described procedure. 1H NMR (400 MHz, DMSO- 6) 6 ppm 7.71 (m, 1 H) 7.34 - 7.56 (m, 1 H) 4.34 - 4.64 (m, 1 H) 4.23 (m, 2 H) 4.08 - 4.17 (m, 1 H) 3.63 - 3.95 (m, 4 H) 2.14 - 2.30 (m, 1 H) 1.58 - 1.99 (m, 4 H) 1.37 - 1.61 (m, 2 H) 1.18 - 1 .39 (m, 2 H) 1.05 - 1 .18 (m, 2 H) 0.96 (m, 2 H). MS (ESI) m/z: 485 (M+1 ). EXAMPLE 58
1-(trans-4-aminocyclohexyl)-4-{[3-chloro-5-cyclopropyl-7- (triftuoromethy[)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-2-piperazinone formic acid salt
(Compound 58)
Figure imgf000176_0001
Step A
cis-4-(4-{[3-chloro-5-cyciopropyl-7-(tnfluoromethyl)pyrazoio[1,5~a]pyrid
oxo-1 -piperazinyi)cyclohexyl 4-methylbenzenesulfonate
[00299] p-Toluenesuffonyl chloride (0.219 g, 0.0015 mol) was added to a solution of 4~ {[3-diloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[l,5-a]pyridin-2-yl]carbonyl}-l-(c i'-4- hydroxycyclohexyl)-2-piperazinone (0.186 g, 0,00038 mol) in pyridine (3 mL). The reaction mixture was stirred at room temperature under nitrogen overnight. Most of the pyridine was evaporated in vacuo. Ethyl acetate and IN aqueous HCl were added. The organic layer was washed with saturated aqueous sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography gave the title compound (0.138 g, 56%) as a white foam.
Step B
1-( ans-4-azidocyclohexyl)-4-{[3-chlorO'&cyclopropyl-7~(trifluorom
a]pyridin~2~yl]carbonyl}-2-piperazinone
Sodium azide (0.021 g, 0.00032 mol) was added to a solution of c s-4-(4-{[3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-2-oxo-1- piperazinyl)cyclohexyl 4-methylbenzenesulfonate (0.138 g, 0.00022 mol) in DMF (1.5 ml_). The mixture was heated at 100°C overnight. The cooled reaction mixture was diluted with ethy! acetate and washed with aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate and concentrated to give the crude title compound (0.069 g, 56%) as a white foam. MS (ESI) m/z= 510 ( +1 ).
Step C
1-(trans-4~aminocyclohexyl)~4~{[3~chloro-5-cyclopropyl~ 7-(trifluoromethyt)pyrazolo[ 1, 5- a]pyridin-2-yi]carbony!}-2-piperazinone
Trimethylphosphine (1 M in THF) (0.203 ml_, 0.00020 mol) and water (0.012 mL,
0.00068 mol) were added to a solution of 1 -(frans-4-azidocyclohexyl)-4-{[3-chloro-5- cyclopropyl-T-itrifluoromethylJpyrazoloC ^-alpyridin^-yllcarbonyl^-piperazinone (0.069 g, 0.00013 mol) in THF (1.5 mL). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was purified by reverse phase HPLC
(acetonitrile:water with 0.1 % formic acid) to give the title compound (0.012 g, 16%). 1H
NMR (400 MHz, METHANOL-af4) δ ppm 8.51 (s, 1 H) 7.58 (s, 1 H) 7.32 (s, 1 H) 4.20 - 4.49 (m, 3 H) 3.84 - 4.09 (m, 2 H) 3.48 (m, 2 H) 3.32 (d, 2 H) 3.09 (m, 1 H) 2.03 - 2.28 (m, 3 H) 1.63 - .94 (m, 4 H) 1.54 (m, 2 H) 1.16 (m, 2 H) 0.92 (d, 2 H). MS (ESI) m/z= 484 (M+1 ). MS (ESI) m/z: 510 (M+1 ).
EXAMPLE 59
1 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-
1-{4,4-dimethylcyclohexyl)-2-piperazinone
(Compound 59)
Figure imgf000178_0001
Step A
1-(4, 4-dimethylcyclohexyl)-2~piperazinone hydrochloride The title compound (0.080 g, 39% over 2 steps) was obtained as a white from methyl N-{[(1 ,1-dimethylethyi)oxy]carbonyl}-N-(2-oxoethyl)glycinate (0.239 g, 000103 and (4,4-dimethylcyclohexyl)amine (0.131 g, 0.00103 mol) by a previously described procedure and treatment with 4N HCI in dioxane.
Step B
4-{[3-chloro-5-cyclopropyl~7-(trifluoromethy!)pyrazolo[1,5-a]pyridin-2^
dim ethylcyclohexyl)~2-piperazin on e
The title compound (0.061 g, 80%) was obtained as a white foam from 3-chloro-5- cyclopropyI-7-(trifiuoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxyiic acid (0.045 g, 0.00015 mol) and 1-(4,4-dimethylcyc!ohexyl)-2-piperazinone hydrochloride (0.0365 g, 0.00015 mol) by a previously described procedure. H NMR (400 MHz, D SO~c/6) δ ppm 7.70 (s, 1 H) 7.44 (d, 1 H) 4.06 - 4.35 (m, 3 H) 3.80 - 3.90 (m, 1 H) 3.72 (m, 1 H) 3.39 - 3.52 (m, 1 H) 3.34 - 3.40 (m, 1 H) 2.13 - 2.29 (m, 1 H) 1.51 - 1.77 (m, 2 H) 1.22 - 1.47 (m, 6 H) 1.04 - 1.14 (m, 2 H) 0.94 - 1.01 (m, 2 H) 0.81 - 0.94 (m, 6 H). MS (ESI) m/z: 497 (M+1 ).
EXAMPLE 60
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyra2olo[1,5-a]pyridin-2-yl]carbonyl}-1-
(trans-4-methylcyclohexyl)-2-piperazinone
(Compound 60)
Figure imgf000178_0002
Step A
1-(trans-4-tr>9thylcyclohexyl)-2-piperazinone hydrochloride The title compound (0.1 10 g, 53% over 2 steps) was obtained as a white solid methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate (0.216 g, 0.00093 mol), and (irans-4-methylcyclohexyl)amine (0.106 g, 0.00093 mol) by a previously described procedure followed by treatment with 4N HCI in dioxane. MS (ESI) m/z: 297 (M+1 ).
Step B
4-{[3-chioro-5-cyclopropy!-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbony!}- 1~(trans-
4-methylcyclohexyl)-2-piperazinone
The title compound was obtained as a white foam from 3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.060 g, 0.00020 mol) and 1- (frans-4-methylcyclohexyl)-2-piperazinone hydrochloride (0.046 g, 0.00020 mol) by a previously described procedure. 1H NMR (400 MHz, DMSO-cf6) δ ppm 7.64 - 7.85 (m, 1 H) 7.45 (s, 1 H) 4.07 - 4.40 (m, 3 H) 3.85 (t, 1 H) 3.72 (t, 1 H) 3.38 (t, 1 H) 3.28 - 3.32 (m, 1 H) 2.13 - 2.28 (m, 1 H) 1.61 - 1.81 (m, 2 H) 1.52 (m, 4 H) 1.20 - 1.38 (m, 1 H) 1.10 (d, 2 H) 0.93 - 1.05 (m, 4 H) 0.86 (d, 3 H). MS (ESI) m/z: 483 (M+1 ). EXAMPLE 61
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-
(2-fluoro-4-methylphenyl)-2-piperazinone
(Compound 61)
Figure imgf000179_0001
Step A
1, 1-dimethylethyl 4-(2-fIuoro-4-methylphenyl)-3-oxo-1-piporazinecarboxylate A mixture of 1 ,1-dimethylethyl 3-oxo-1 -piperazinecarboxylate (0.326 g, 0.00163 mol), 1-bromo-2-fluoro-4-methylbenzene (0.308 g, 0.0163 mol), (1 R,2R)-N,N'-dimethyl~ 1 ,2-cyclohexanediamine (0.026 mL, 0.163 mmol), copper(l) iodide (3.10 mg, 0.016 mmol) and potassium carbonate (450 mg, 3.26 mmol) in 1 ,4-dioxane (6 mL) in a septum-sealed vial was heated in an oil bath at 120 °C overnight. The reaction mixture was cooled to room temperature and filtered through Celite washing with ethyl acetate. The filtrate was washed with saturated aqueous ammonium chloride, water and brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel to give the title compound (0. 253 g, 50%). MS (ESI) m/z: 309 (M+1 ).
Step B
1-(2-fluoro~4-methylphenyl)-2-piperazinone hydrochloride
HCI (4M in dioxane) (1 ml_, 0.004 mol) was added to a solution of 1 ,1-dimethylethyl 4-(2-fluoro-4-methylphenyl)-3-oxo-1 -piperazinecarboxylate (0.213 g, 0.00069 mol) in DCM. The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with ether and dried under vacuum to give the title compound (0.151 g, 89%). MS (ESI) m/z: 209 (M+1 ).
Step C
^{[S-chloro-e-cyclopropyl-T-ftrifluoromethytypyrazolol^S-aJp
fluoro-4-methylphenyl)-2-piperazinone
1-Propanephosphonic acid cyclic anhydride (50% by weight in ethyl acetate) (0.203 g, 0.00032 mol) was added drop-wise to a mixture of 3-chloro-5~cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.065 g, 0.00021 mol), 1 -(2- fluoro-4~methylphenyl)-2-piperazinone hydrochloride (0,052 g, 0.00021 mol) and DIPEA (0.082 g, 0.00064 mol) in DMF (2 mL) at 0°C. The mixture was stirred for 30 min. Ethyl acetate and water were added. The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated.
Chromatography on silica gel gave the title compound (0.090 g, 80%). ΊΗ NMR (400 MHz, CHLOROFORM-d) δ ppm 7.44 (d, 1 H) 7, 13 - 7.24 (m, 1 H) 7.07 (m, 1 H) 6.96 - 7.04 (m, 2 H) 4.65 (s, 1 H) 4.54 (s, 1 H) 4.16 - 4.28 (m, 2 H) 3.72 - 3.90 (m, 2 H) 2.37 (d, 3 H) 1.97 - 2.11 (m, 1 H) 1.13 - 1.22 (m, 2 H) 0.71 - 0.97 (m, 2 H). MS (ESI) m/z: 495 (M+1 ).
EXAMPLE 62
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-
(1 -methyl-1 H-imidazol-5-yl)-2-piperazinone
(Compound 62)
Figure imgf000180_0001
Step A
1, 1-dimethylethyl 4-(1-methyl-1H-imidazoI-5-yl)-3-oxo~ 1 -piperazinecarboxylate The title compound (0.138 g, 38%) was obtained from 1 , 1-dimethylethyl 3-oxo-1- piperazinecarboxylate (0.300 g, 0.0015 mol) and 5-bromo-1-methyl-1 H-imidazole (0.241 g, 0.0015 mol) by a previously described procedure. MS (ESI) m/z: 281 (M+1 ).
Step B
1~(1-methyl-1H-imidazol-5-yl)-2-piperazinone hydrochloride HCI (4M in dioxane) (1.5 mL, 0.006 mol) was added to a solution of 1 ,1 - dimethylethyl 4-(1-methyl-1 H-imidazol-5-yl)-3-oxo-1 -piperazinecarboxylate (0.125 g,
0.00045 mol) in DCM (3 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with ether, filtered and dried under vacuum to give the title compound (0.092 g, quant). Step C
4-{[3-chloro-5-cyclopropyl~7~(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1-(1 - methyl-1H-imidazol-5-yl)-2-piperazinone
The title compound (0.051 g, 58%) was obtained as a white solid from 3-chloro-5- cyclopropyl-7-(trif!uoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.057 g, 0.00019 mol) and 1 -(1-methyl-1 H-imidazoi-5-yl)-2-piperazinone dihydrochloride (0.047 g, 0.00019 mol) by a previously described procedure. H NMR (400 MHz, CHLOROFORM-cQ δ ppm 7.44 (d, 2 H) 7.08 (s, 1 H) 6.99 (s, 1 H) 4.48 - 4.76 (m, 2 H) 4.17 - 4.31 (m, 2 H) 3.74 - 3.91 (m, 2 H) 3.50 (d, 3 H) 1.94 - 2.12 (m, 1 H) 1.01 - 1.22 (m, 2 H) 0.70 - 0.99 (m, 2 H). MS (ESI) m/z: 467 (M+1 ).
EXAMPLE 63
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethy[)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-
(2-chlorophenyl)-2-piperazinone
(Compound 63)
Figure imgf000181_0001
Step A
1, 1 -dimethylethyl 4- ( 2-c lorophenyl) -3-oxo- 1 -piperazinecarboxylate The title compound (0.158 g, 33%) was obtained from 1 ,1 -dimethylethyl 3-oxo- 1 - piperazinecarboxylate (0.307 g, 0.0015 mol) and 1-chloro-2-iodobenzene (0.366 g, 0.0015 mol) by a previously described procedure. MS (ESI) m/z: 31 1 (M+1 ).
Step B
1 -(2-chlorophenyl)-2-piperazinone hydrochloride
HCI (4M in dioxane) (1.5 ml_, 6.00 mmol) was added to a solution of 1 , 1- dimethylethyl 4-(2-chlorophenyl)-3-oxo-1 -piperazinecarboxylate (0.146 g, 0.00047 mol) in DCM (3 ml_). The mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was triturated with ether and filtered to give the title compound (0.104 g, 90%) as a solid. MS (ESI) m/z: 21 1 (M+1 ). Ste C
4~{[3-chioro-5-cyciopropyi-7-(trifluoromethyi)pyrazolo[1,5-a]pyridin^
chlorophenyl) -2-piperazinone
The title compound (0.052 g, 47%) was obtained from 3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.067 g, 0.00022 mol) and 1-(2- chlorophenyl)-2-piperazinone hydrochloride (0.054 g, 0.00022 mol) by a previously described procedure. 1H NMR (400 MHz, CHLOROFORM- /) δ ppm 7.48 - 7.57 (m, 1 H) 7.44 (d, 1 H) 7.28 - 7.40 (m, 3 H) 7.03 - 7.10 (m, 1 H) 4.88 and 4.45 (d, 1 H) 4.55 (d, 1 H) 4.37 (d, 1 H) 3.96 - 4.17 (m, 1 H) 3.65 - 3.90 (m, 2 H) 1.80 - 2.18 (m, 1 H) 1 .02 - 1.33 (m, 2 H) 0.65 - .04 (m, 2 H). MS (ESI) m/z: 497 (M+1 ).
EXAMPLE 64
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [2-chloro-4-(methyloxy)phenyl]-2-piperazinone
(Compound 64)
Figure imgf000182_0001
Step A 1, 1-dimethylethyl 4-[2-chloro-4-(methyloxy)phenyl]-3-oxo- 1-piperazinecarboxylate The title compound (0,434 g, 51 %) was obtained from 1 , 1-dimethylethyl 3-oxo-1 - piperazinecarboxylate (0.500 g, 0.0025 mol) and 1 -bromo-2-chloro-4-(methyloxy)benzene (0.553 g, 0.0025 mol) by a previously described procedure. MS (ESI) m/z: 341 (M+1 ).
Step B
1-[2-chloro-4-(methyloxy)phenyl]-2-piperazinone hydrochloride HCI (4M in dioxane) (1.5 mL, 0.006 mol) was added to a solution of 1 ,1- dimethylethyl 4-[2-chloro-4-(methyloxy)phenyl]-3-oxo-1 -piperazinecarboxy!ate (0.392 g, 0.00 15 mol) in DCM (3 mL). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with ether to give the title compound (0.289 g, 91 %). MS (ESI) m/z: 241 (M+1 ).
Step C
4~{[3~chloro-5-cyclopropyl- 7-( trifluoromethyl)pyrazolo[ 1, 5-a ]pyridin-2-yl]carbonyl}- 1-[2- chloro-4-( methyl oxy) phenyl]-2-piperazinone
The title compound (0.076 g, 67%) was obtained as a white powder from 3-chloro- 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.065 g, 0.00021 mol) and 1-[2-chloro-4-(methyloxy)phenyl]-2-piperazinone hydrochloride (0.059 g, 0.00021 mol) by a previously described procedure. 1H NM (400 MHz, CHLOROFORM-cf) δ ppm 7.44 (d, 1 H) 7.18 - 7.26 (m, 1 H) 7.07 - 7.11 (m, 1 H) 7.01 - 7.06 (m, 1 H) 6.89 (m 1 H) 4.86 and 4.46 (d, 1 H) 4.54 (d, 1 H) 4.30 - 4.41 (m, 1 H) 3.94 - 4.16 (m, 1 H) 3.83 (d, 3 H) 3.66 - 3.80 (m, 2 H) 1 .83 - 2.27 (m, 1 H) 1.00 - 1.29 (m, 2 H) 0.74 - .00 (m, 2 H). MS (ESI) m/z: 527 (M+1 ).
EXAMPLE 65
4 4-{[3 hloro-5-cycIopropyi-7-(trifluoromethyi)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}- 1-(2-chioro-4-hydroxyphenyi)-2-piperazinone
(Compound 65)
Figure imgf000183_0001
Boron tribromide (0.179 g, 0.00071 mol) was added to a solution of 4-{[3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[2-chloro-4- (methyloxy)phenyl]-2-piperazinone (0.047 g, 0.000089 mol) in DCM (2 mL) at -78 °C. After 1.5 hours, the cooling bath was changed to an ice-water bath. The reaction mixture was stirred for 3 hours, then diluted with DCM, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated. Purification by reverse phase HPLC (C18, acetonitn'le:water with 0.1 % formic acid) gave the title compound (0.028 g, 61 %) as a white solid. 1H NMR (400 MHz, CHLOROFORM-c) δ ppm 7,50 - 7.85 (m, 1 H) 7.40 - 7.51 (m, 1 H) 7,05 - 7.15 (m, 1 H) 6.92 - 7.04 (m, 1 H) 6.64 - 6.78 (m, 1 H) 6.45 - 6.63 (m, 1 H) 4.79 - 4.99 and 4.51 (m, 1 H) 4.54 - 4.72 (m, 1 H) 4.37 (d, 1 H) 3.96 - 4.16 (m, 1 H) 3.63 - 3.91 (m, 2 H) 1.90 - 2.15 (m, 1 H) 0.96 - 1.27 (m, 2 H) 0.68 - 1.01 (m, 2 H). MS (ESI) m/z: 513 (M+1 ).
EXAMPLE 66
4-{[3-chloro-5-cyclopropyl-7-(trif!uoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-
(2-fluorophenyl)-2-piperazinone
(Compound 66)
Figure imgf000184_0001
The title compound (0.066 g, 60%) was obtained as a white powder from 3-chloro- 5-cyclopropyt-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.066 g, 0.00022 moi) and 1-(2-fluorophenyl)-2-piperazinone hydrochloride (0.050 g, 0.00022 mol) by a previously described procedure. 1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 7.45 (d, 1 H) 7.36 - 7.43 (m, 1 H) 7.07 - 7.20 (m, 3 H) 6.97 - 7.07 (m, 1 H) 4.40 - 5.00 (m, 2 H) 4.05 - 4.36 (m, 2 H) 3.57 - 4.05 (m, 2 H) 1.93 - 2.26 (m, 1 H) .19 (m, 2 H) 0.87 (m, 2 H). MS (ESI) m/z: 481 (M+1 ). EXAMPLE 67
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
(3-fluoro-2-pyridinyl)-2-piperazinone
(Compound 67)
Figure imgf000185_0001
Step A
1, 1 -dimethylethyl 4-( 3-fluoro-2-pyridinyl) -3-oxo- 1 -piperazinecarboxylate The title compound (0.400 g, 54%) was obtained from 1 ,1 -dimethylethyl 3-oxo-1 - piperazinecarboxylate (0.500 g, 0.0025 mol) and 2-bromo-3-fluoropyridine (0.439 g, 0.0025 mol) by a previously described procedure.
Step B
1 - ( 3-fluoro-2-pyridinyl)-2-piperazin one dihydrochloride HCI (4M in dioxane) (3.39 ml_, 13.55 mmol) was added to a solution of 1 ,1- dimethylethyl 4-(3-ffuoro-2-pyridinyl)-3-oxo-1-piperazinecarboxylate (0.400 g, 0.0013 mol) in DCM (5 ml_). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was triturated with ether, filtered and dried under vacuum to give the title compound (0.250 g, 69%) as a white solid.
Step C
4-{[3-chloro-5-cyclopropyl-7-(trif!uoromethyl)pyrazolo[1,5-^^
fluoro-2-pyridinyl)-2-piperazinone
The title compound (0.090 g, 54%) was obtained as a white solid 3-chloro-5~ cyclopropyl~7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (0.104 g, 0.00034 mol) and 1-(3-fluoro-2-pyridinyl)-2-piperazinone hydrochloride (0.079 g, 0.00034 mol) by a previously described procedure. H NMR (400 MHz, CHLOROFORM-c 6 ppm 8.33 (d, 1 H) 7.54 (d, 1 H) 7.39 - 7.49 (m, 1 H) 7.28 - 7.37 (m, 1 H) 7.07 (d, 1 H) 4.53 - 4.79 (m, 2 H) 4.14 - 4.36 (m, 2 H) 4.08 (m, 2 H) 1.91 - 2.20 (m, 1 H) 1 .18 (m, 2 H) 0.60 - 1.03 (m, 2 H). MS (ESI) m/z: 482 (M+1 ).
EXAMPLE 68
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1-[frans-3-(1-hydroxyethyl)cyclobutyl]-2-piperazinone
(Compound 68)
Figure imgf000186_0001
Step A
Trans-3-(4-{[3 :hioro-5 yclopropyt-7~(tnfiuoromethyi)pyrazolo[1,5-a]pynd
2-oxo- 1 -piperazinyl) cyclobutanecarbaldehyde
A solution of 4-{[3-chloro-5-cyclopropy]-7-(trifiuoromethyi)pyrazolo[1 r5-a]pyridin-2- yl]carbonyl}-1 -[ira 7s-3-(hydroxymethyl)cyclobutyl]-2-piperazinone (77 mg, 0.16 mmol) in DCM (8 ml.) was treated with Dess-Martin periodinane (83 mg, 0.20 mmol) and the resulting solution stirred at room temperature. After 2 hours TLC (silica gel, 95:5
DCM/MeOH) indicated approximately 80% conversion to a higher Rf component. The mixture was treated with additional Dess-Martin reagent (20 mg, 0.05 mmol) and stirring at room temperature continued. After another 1.5 hours the solution was concentrated to dryness and the residue dissolved in EtOAc. The solution was washed with 5% aqueous sodium bisulfite (2x), saturated sodium bicarbonate (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue was subjected to flash chromatography (silica gel, gradient from 100% hexane to 00% B where B=95:5
EtOAc/MeOH) to afford the title compound (37 mg, 48%) as white solid. ES-LCMS m/z: 469 (M+1 ).
Step B
4-{[3-Chloro~5-cyclopropyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyi}~1-[trans-
3-(1~hydroxyethyl)cyclobutyl]-2-piperazinone
A solution of fra ?s-3-(4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yi]carbonyl}-2-oxo-1-piperazinyl)cyclobutanecarbaldehyde (37 mg, 0.079 mmol) in anhydrous THF (5 mL) was cooled to -78°C and treated with 3M
methylmagnesium bromide/ether (53 μΐ_, 0.16 mmol). The resulting solution was stirred in the cold bath for several minutes and then allowed to warm to room temperature. After 2 hours LCMS indicated partial conversion of starting material to the desired product. The reaction mixture was again cooled to -78°C, treated with an additional aliquot of 3M methylmagnesium bromide/ether (53 μΙ_, 0.16 mmol) and allowed to warm to room temperature. After 1 hour the solution was diluted with saturated aqueous ammonium chloride followed by EtOAc and the phases were separated. The EtOAc solution was washed with water (1 x), brine ( x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by reverse phase HPLC
(acetonitrile/water with 0.1 % TFA) to afford the title compound (7 mg, 18%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.43 (d, J=10.7 Hz, 1 H) 7.00 - 7.12 (m, 1 H) 4.98 - 5.20 (m, 1 H) 4.35 - 4.51 (m, 2 H) 4.00 - 4.13 (m, 2 H) 3.93 (d, J=QA Hz, 1 H) 3.59 (t, J=5.4 Hz, 2 H) 1.95 - 2.98 (m, 7 H) 1.10 - 1.23 (m, 5 H) 0.78 - 0.94 (m, 2 H). ES-LCMS m/z: 485 (M+1 ).
EXAMPLE 69
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}- 1 -[{1 ?,2S,3 ?,5R)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 69)
Figure imgf000187_0001
A solution of 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- ilcarbonyl -l-KI R^ ^ SR^-hydroxybicycloIS.I .Olhex-S-yO^-piperazinone (30 mg, 0.062 mmol) in 1 :1 TFA/DCM (4 ml_) was stirred at room temperature for 6 hours and concentrated to dryness at reduced pressure. The residue was dissolved in DCM and again concentrated to dryness to remove residual TFA. The residue was dissolved in EtOAc and the resulting solution mixed with an equal volume of water. The mixture was stirred vigorously for several minutes and the phases separated. The EtOAc solution was washed with water (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from 100% hexane to 100% B where B=95:5 EtOAc/MeOH) followed by lyophilization from MeCN/water to afford the title compound (29 mg, 97%) as a white powder. H NMR (400 MHz, METHANOL-^) δ ppm 7.56 (s, 1 H) 7.29 (s, 1 H) 4.12 - 4.57 (m, 4 H) 3.64 - 4.02 (m, 3 H) 3.39 - 3.58 (m, 1 H) 2.17 - 2.34 (m, 1 H) 2.05 - 2.17 (m, 1 H) 1.77 (dd, J=12.0, 7.3 Hz, 1 H) 1.50 (d, J=3.8 Hz, 1 H) 1.36 (dd, J=5.9, 2.6 Hz, 1 H) 1.05 - 1.18 (m, 2 H) 0.90 (dd, J=5.0, 1.6 Hz, 2 H) 0.51 (d, J=5.6 Hz, 1 H) 0.31 (d, J=5.7 Hz, 1 H). ES-LCMS m/z: 483 (M+1 ). EXAMPLE 70
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1-[{1 S,2R,3S,5S)-2-hydroxybicycloE3.1.0]hex-3-yl]-2-piperazinone
(Compound 70)
Figure imgf000188_0001
The title compound was prepared in 90% yield from 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-e]pyridiri-2-yl]carbonyl}-1 -[(1 S,2St3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone according to the procedure described herein for the preparation of 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1 -[(1 ,2S,3R,5R)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone. H NMR (400 MHz, METHANOL-^) δ ppm 7.59 (d, J=1.0 Hz, 1 H) 7.32 (s, 1 H) 4.14 - 4.62 (m, 4 H) 3.99 (dt, J=13.7, 4.4 Hz, 1 H) 3.67 - 3.89 (m, 2 H) 3.42 - 3.61 (m, 1 H) 2.21 - 2.35 (m, 1 H) 2.08 - 2.21 (m, 1 H) 1 .80 (dd, J=12.0, 7.2 Hz, 1 H) 1.47 - 1.61 (m, 1 H) 1.33 - 1 ,43 (m, 1 H) 1 .06 - 1 .25 (m, 2 H) 0.83 - 0.99 (m, 2 H) 0.47 - 0.58 (m, 1 H) 0.25 - 0.40 (m, 1 H). ES- LCMS m/z: 483 (M+1 ).
EXAMPLE 71
4-{[3-Chloro-5-cyc[opropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1-[(1S,2S,3 ?,5S)-2-hydroxybicycloE3.1.0]hex-3-yl]-2-piperazinone
(Compound 71)
Figure imgf000188_0002
Step A
1-[(1R,2R,3E)-2-{[(1, 1-Dimethylethyl)(dimethyi)silyl]oxy}-4^henyl-1-(2^ro
buten-1 -yl]-2-piperazinon e
A solution of 1-[(1 R,2R,3E)-2-{[(1 ,1-dimethylethyl)(dimethyl)siiyl]oxy}-4-phenyl-1- (2-propen-1 -yl)-3-buten-1-yl]-4-[(4-nitrophenyl)sulfonyl]-2-piperazinone (343 mg, 0.586 mmol) in anhydrous MeCN (8 mL) was treated with thiophenol (181 μΙ_, 1.76 mmol) followed by potassium carbonate (324 mg, 2.34 mmol) and the resulting mixture stirred at RT. After 2.5 hours the mixture was filtered to remove solids and the filtrate concentrated to dryness at reduced pressure. The residue was subjected to flash chromatography (silica gel, gradient from DCM to 9:1 DCM/EtOH) to afford the title compound (213 mg, 91 %) as a clear oil. ES-LCMS m/z: 401 (M+1 ).
Step B
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridi
[(1R,2R,3E)-2-{[(1, 1-dimethylethyl)(dimethyi)silyl]oxy}-4^henyl-1-(2^ropen-^
1 -yl]-2-piperazinone
A solution of l - I R^ SE^-i I .I-dimethylethyl dimethy silynox H-phenyl-l -
(2-propen-1-yl)-3-buten-1-yl]-2-piperazinone (213 mg, 0.532 mmol) and 3-ch!oro-5- cyclopropyl-Z-itrifluoromethy pyrazolofl
Figure imgf000189_0001
acid (162 mg, 0.532 mmol) in DMF (8 ml.) was treated with DIPEA (0.28 mL, 1.6 mmol) and cooled in an ice water bath. The solution was treated with 50 wt% 1-propanephosphonic acid cyclic anhydride/EtOAc (0.51 g, 0.80 mmol). The solution was maintained in the ice bath for 30 minutes and then allowed to warm to room temperature. After 3 hours the solution was diluted with EtOAc, washed with water (1x), 5% aqueous LiCI (2x), saturated aqueous sodium bicarbonate (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc) to afford the title compound (308 mg, 84%) as a light yellow foam. ES-LCMS m/z: 687 (M+1 ).
Step C
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]py
((1R,2R)-2-{[(1, 1-dimethylethyl)(dimethyi)silyl]oxy}-3-cyclopenten^
A solution of 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-[(1 R,2R,3E)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1-(2-propen- 1 -yl)-3-buten-1-yl]-2-piperazinone (308 mg, 0.448 mmol) in toluene was sparged with nitrogen for 10 minutes and treated with 1 ,3-Bis(2,4,6-trimethylphenyi)-4,5- dihydroimidazol-2-ylidene[2-(i-propoxy)-5-(N,N- dimethylaminosulfonyl)phenyl]methyleneruthenium(ll) dichloride (Zhan Catalyst-I B) (33 mg, 0.045 mmol). The resulting solution was stirred under nitrogen at room temperature for 18 hours and concentrated to dryness at reduced pressure. The residue was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc) to afford the title compound (233 mg, 89%) as an off-white foam. ES-LCMS m/z: 583 (M+1 ). Step D
4-{[3-Chtoro-5-cyclopropyl- 7-(trifluoromethy!)pyrazoio[ 1, 5-a]pyridin-2-yI]carbonyl}-1- [(1R,2S) -2-hydroxy-3-cyclopenten- 1 -yi]-2-piperazinone A solution of 4-{[3-chloro-5-cyclopropyl~7-(trifIuoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-({1 R,2R)-2-{[(1 ,1 -dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-yl)-2- piperazinone (100 mg, 0.171 mmol) 1 :1 TFA/DCM (8 mL) was stirred at RT for 3 hours and concentrated to dryness at reduced pressure. The residue was dissolved in EtOAc and the solution mixed with 10% aqueous sodium bicarbonate. The resulting mixture was stirred vigorously for 30 minutes and the phases separated. The EtOAc solution was washed with water (2x), brine (1x), dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 9:1 DCM/EtOH) to afford the title compound (71 mg, 88%) as a white foam. ES-LCMS m/z: 451 (M-H20). Step E
4-{[3- Chloro-5-cyclopropyl- 7-( trifl uoromethyI)pyrazo!o[ 1, 5-a]pyridin-2-yl]carbonyl} - 1 - 1(1 S, 2S, 3R, 5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone A solution of 4-{[3-chloro-5-cyciopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-[(1 ,2S)-2-hydroxy-3-cyclopenten-1 -yl]-2-piperazinone
(68 mg, 0.15 mmol) in 5 mL of anhydrous DCM was cooled in an ice water bath and treated with 1.0M diethylzinc/hexane (0.73 mL, 0.73 mmol). After 15 minutes a solution of diiodomethane (0.12 mL, 1.5 mmol) in DCM (1 mL) was added. The resulting solution was stirred at 0°C for 15 minutes and then allowed to warm to RT. After 3 hours the solution was diluted with saturated aqueous ammonium chloride followed by EtOAc and the mixture stirred vigorously for several minutes. The phases were separated and the EtOAc solution was washed with water (1x), brine (1x), dried over sodium sulfate and
concentrated to dryness at reduced pressure. The crude product was subjected to reverse phase HPLC (acetonitrile/water with 0.1 % TFA) followed by lyophilization to afford the title compound (41 mg, 59%) as a white powder. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.56 (s, 1 H) 7.28 (br. s., 1 H) 4.48 - 4.79 (m, 3 H) 4.14 - 4.41 (m, 2 H) 3.37 - 3.98 (m, 4 H) 2.03 - 2.18 (m, 2 H) 1 .54 - 1.70 (m, 2 H) 1.31 - .41 (m, 1 H) 1.07 - 1.17 (m, 2 H) 0.85 - 0.94 (m, 2 H) 0.68 - 0.80 (m, 2 H). ES-LCMS m/z: 483 (M+1 ). EXAMPLE 72
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1-[(1 ?,2R,3S,5/?)-2-hydroxybicycIo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 72)
Figure imgf000191_0001
Step A
1-[(1S, 2S, 3E)-2-{[(1, 1-Dimethylethyl) (dimethyl)silyl]oxy}-4-phenyl- 1-(2-propen-1-yl)-3- buten- 1-yl]-2-piperazinone
The title compound was prepared in 90% yield from 1-[(1 S,2S,3E)-2-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -(2-propen-1-yl)-3-buten-1-yl]-4-[(4- nitrophenyl)sulfonyil-2-piperazinone (synthesized starting with (4 )-4-(phenyImethyl)-1 ,3- oxazolidin-2-one using a route identical to the sequence described herein for the synthesis of 1 -[(1 R,2 3£)-2-{[( 1 , 1 ~dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -(2-propen~1 -y!)-3- buten-1-yl]-4-[(4-nitrophenyl)suifonyl]-2-piperazinone) according to the procedure described herein for the synthesis of 1-[( R,2R,3-E)-2-{[(1 (1- dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -(2-propen-1 -yl)-3-buten-1 -yl]-2-piperazinone. ES-LCMS m/z: 401 (M+1 ).
Step B
4-{[3~Chloro-5~cyclopropyl- 7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin~2~yl]carbonyl}- 1- [(IS^S^Ej^-tfil, 1~dimethylethyl)(dimethyl)silyl]oxy}-4^henyl-1-(2^ro^
1 -yl]-2-piperazinone
The title compound was prepared in 88% yield from 1-[(1 S,2S,3E)-2-{[(1 ,1- dimethylethyl)(dimethy[)silyl]oxy}-4-phenyl-1 -(2-propen-1-yl)-3-buten-1 -yl]-2-piperazinone according to the procedure described herein for the preparation of 4-{[3-chloro-5- cyclopropy!-7-(trif luoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[(1 R,2R,3E)-2-{[( 1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -(2-propen-1-yl)-3-buten-1-yl]-2-piperazinone. ES-LCMS m/z: 687 (M+1 ). Step C
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazoio[1,5-a]pyri^
((1S,2S) -2-{[( 1, 1 -dimethylethyl) (dimethyl) silyl]oxy}-3-cyclopenten- 1 -yl) -2-piperazin on e The title compound was prepared in 84% yield from 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 J5-a]pyridin-2-yl]carbonyl}-1 -[{1 SJ2S,3E)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-4-phenyl-1 -(2-propen-1 -yl)-3-buten-1 -yl]-2-piperazinone according to the procedure described herein for the synthesis of 4-{[3-chloro-5- cyclopropyl-7-(trifluoromethy[)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyi}-1 -((1 R,2f?)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-yl)-2-piperazinone. ES-LCMS m/z: 583 (M+1 ).
Step D
4-{[3-Chloro-5-cyclopropyI-7-(trifluoromethyl)pyrazolo[1,5-a]pyrtf
[( 1 S,2R)-2-hydroxy-3-cyclopenten-1-yl]-2-piperazinone The title compound was prepared in quantitative yield from 4-{[3-ch!oro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -((1 S,2S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-3-cyclopenten-1-y!)-2"piperazinone according to the procedure described herein for the synthesis of 4-{[3-chloro-5-cyclopropy!-7-
{trifluoromethyl)pyrazolo[1 r5-a]pyridin-2-yl]carbonyl}-1-[(1 R,2S)"2-hydroxy-3-cyclopenten- 1 -yl]-2-piperazinone. ES-LCMS m/z: 451 (M-H20).
Step E
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1- [(1R,2R,3S,5R)-2-hydroxybicyclo[3.1.0]hex-3-y!]-2^iperazinone The title compound was prepared in 37% yield from 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethy pyrazoloCI .S-alpyridin^-yllcarbonylJ-l -^I S^R^-hydroxy-S-cyclopenten- 1 -yl]-2-piperazinone according to the method described herein for the synthesis of 4-{[3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -
[(1 S,2S,3R,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone. 1H N R (400 MHz, METHANOL-^) δ ppm 7.56 (s, 1 H) 7.28 (br. s., 1 H) 4.15 - 4.79 (m, 4 H) 3.50 - 3.98 (m, 3 H) 3.37 - 3.49 (m, 1 H) 2.03 - 2.18 (m, 2 H) 1.53 - 1.70 (m, 2 H) 1.32 - 1 .42 (m, 1 H) 1.07 - 1.18 (m, 2 H) 0.84 - 0.95 (m, 2 H) 0.68 - 0.80 (m, 2 H). ES-LCMS m/z: 483 (M+1 ).
EXAMPLE 73
4-{[3~Chloro-5-cyclopropyl-7-(trif[uoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1 -[(1 R,3R,5 ?)-2-oxobicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 73)
Figure imgf000193_0001
A solution of 4-{[3-chloro-5-cyclopropyl-7-(trif!uoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1 -[(1 R,2R,3Rt5R)-2-hydroxybicyclo[3.1 ,0]hex-3-y!]-2~piperazinone (50 mg, 0.10 mmol) in DCM (5 mL) was treated with Dess-Martin periodinane (88 mg, 0.21 mmol) and the resulting mixture stirred at room temperature. After 5 hours the mixture was treated with an additional portion of Dess-Martin periodinane (50 mg, 0.12 mmol) and stirring at room temperature continued. After stirring at room temperature overnight the solution was diluted with EtOAc, washed with 10% aqueous sodium bisulfite (2x), saturated aqueous sodium bicarbonate (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue was subjected to flash chromatography (silica gel, gradient from DCM to 9:1 DCM/EtOH) followed by lyophilization from
MeCN/water to afford the title compound (37 mg, 74%) as a white powder. 1H NMR (400 MHz, METHANOLS) δ ppm 7.55 (s, 1 H) 7.28 (d, J=1.3 Hz, 1 H) 4.29 - 4.58 (m, 3 H) 3.82 - 4.16 (m, 2 H) 3.32 - 3.53 (m, 2 H) 2.25 - 2.40 (m, 2 H) 2.05 - 2.20 (m, 2 H) 1.78 - 1.88 (m, 1 H) 1.07 - 1.32 (m, 4 H) 0.84 - 0.94 (m, 2 H). ES-LCMS m/z: 481 (M+1 ).
EXAMPLE 74
4-{[3-Chloro-5-cyc[opropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}- 1-[(1 S,3S,5S)-2-oxobicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 74)
Figure imgf000193_0002
The title compound was prepared in 88% yield from 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo|;i ,5-a]pyridin-2-yl]carbony!}-1-[(1 S,2S(3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone according to the procedure described herein for the preparation of 4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazoio[1 ,5-a]pyridin- 2-yl]carbonyl}-1-[(1 3R,5 )-2-oxobicyclo[3.1.03hex-3-yl]-2-piperazinone. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.54 (s, 1 H) 7.27 (s, 1 H) 4.26 - 4.60 (m, 3 H) 4.02 - 4.15 (m, 1 H) 3.82 - 4.02 (m, 1 H) 3.30 - 3.54 (m, 2 H) 2.23 - 2.42 (m, 2 H) 2.04 - 2.20 (m, 2 H) 1.77 ~ 1.89 (m, 1 H) 1.03 - 1.33 (m, 4 H) 0.81 - 0.96 (m, 2 H). ES-LCMS m/z: 481 (M+1 ).
EXAMPLE 75
4-{[5-Bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- ( trans-4~ hy droxycy c loh exy l)-2- p i pe razi none
(Compound 75)
Figure imgf000194_0001
H
Step A
dimethyl 5-bromo-7-(trifluoromethyi)pyrazoio[ 1, 5-a]pyridine-2, 3-dicarboxyiate A solution of CuBr2 (1 .57 g, 7.0 mmol) in water (23.4 mL) was added to a solution of dimethyl 5-(4,4,5l5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2,3-dicarboxylate (1 ,0 g, 2.34 mmol) in MeOH (23.4 mL). The reaction mixture was heated at 70 °C for 6 hours. Brine was added and the solution was extracted with EtOAc. The combined organic extracts were dried (Na2S04), filtered, evaporated and purified by silica gel chromatography (0-40% EtOAc/hexs) to afford the title compound (0.31 g, 35%).
Step B
5-Bromo-7-(trifluoromethyI)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid A mixture of dimethyl 5-bromo-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2,3- dicarboxylate (472 mg, 1.24 mmol), dioxane (3 mL), and 50% aqueous sulfuric acid (6 mL) was heated to 100°C with stirring. After 2 hours the mixture was treated with an additional 3 mL of dioxane followed by 5 mL of 50% aqueous sulfuric acid and the temperature increased to 115°C. After another 3 hours the solution was cooled to room temperature and stirred overnight. The cloudy solution was diluted with water and extracted with EtOAc (3x). The combined extracts were washed with brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure to afford the title compound in quantitative yield as a light yellow solid. ES-LCMS m/z: 309 (M+1 ). Step C
5-Bromo-3-chloro-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid A mixture of 5-bromo-7-(trifluoromethyl)pyrazo[o[1 ,5-a]pyridine-2-carboxylic acid (380 mg, 1.23 mmol) and W-chlorosuccinimide (328 mg, 2.46 mmol) in ,2-dichloroethane (12 mL) was heated to 60°C with stirring. After 2 hours LCMS indicated only a few % conversion of starting material to the desired compound. The solution was treated with an additional portion of W-chiorosuccinimide (175 mg, 1.31 mmoi) and the temperature increased to reflux. After 18 hours LCMS indicated 20% conversion to the desired product. The reaction mixture was transferred to a sealed tube, a third portion of N- chlorosuccinimide (175 mg, 1.31 mmol) was added, and the mixture heated to 100°C. After 3 hours LCMS indicated complete reaction. The solution was cooled to room temperature and diluted with DCM. The solution was washed with 1 aqueous HCI (3x), water (1x), 0% aqueous sodium bisulfite (2x) (pH adjusted to 2 by addition of 1 N HCI). TLC of the aqueous washes indicated the presence of some product so the aqueous solutions were combined and back extracted with an additional three portions of DCM.
The combined DCM solutions were dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, gradient from DCM to 85:15 DCM/B where B=95:5 EtOH/AcOH) to give the title compound (400 mg, 95%) as a light yellow solid. ES-LCMS m/z: 343 (M+1 ).
Step D
4-{[5-Bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyrtf 1 -(trans-4- hydroxycyclohexyi)-2-piperazinone
A solution of 5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (30 mg, 0.077 mmol) and 1-(irans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (20 mg, 0.085 mmol) in anhydrous DMF (3 mL) was cooled in an ice water bath and treated with DIPEA (54 μί, 0.31 mmol) followed by 50 wt% 1 - propanephosphonic acid cyclic anhydride/EtOAc (73 mg, 0.12 mmol). The resulting solution was stirred in the ice bath for 30 minutes and then allowed to warm to room temperature. After 3 hours the solution was diluted with EtOAc, washed with 10% aqueous citric acid (2x), saturated sodium bicarbonate (2x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 9:1 DCM/EtOH) followed by lyophilization from MeCN/water to afford the title compound (26 mg, 65%) as a white powder. 1H NMR (400 MHz, METHANOL-^) δ ppm 8.21 - 8.25 (m, 1 H) 7.71 - 7.76 (m, 1 H) 4.24 - 4.42 (m, 3 H) 3.97 - 4.02 (m, 1 H) 3.85 - 3.91 (m, 1. H) 3.39 - 3.57 (m, 3 H) 1.96 - 2.07 (m, 2 H) 1.55 - 1 .76 (m , 4 H) 1.30 - 1 .47 (m, 2 H). ES-LCMS m/z: 525 (M+1 ).
EXAMPLE 76
4-{[5-Bromo-3-chloro-7-(trif[uoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1-
[(IS^S.SSjSSJ^-hydroxybicyclotS.I.Olhex-S-yll^-piperazinone
{Compound 76)
Figure imgf000196_0001
A solution of 5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (68 mg, 0.17 mmol) and 1 -(( 1 S,2S,3S,5S)-2-{[( 1 , 1 - dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1 .0]hex-3-yl)-2-piperazinone (54 mg, 0.1 mmol) in anhydrous DMF (5 mL) was cooled in an ice water bath and treated with DIPEA (91 μΙ_, 0.52 mmol) followed by 50 wt% 1 -propanephosphonic acid cyclic anhydride/EtOAc (170 mg, 0.26 mmol). The resulting solution was stirred in the ice bath for 30 minutes and then allowed to warm to room temperature. After 3 hours the solution was diluted with EtOAc, washed with 10% aqueous citric acid (2x), saturated sodium bicarbonate (2x), brine (1 x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue was dissolved in anhydrous THF (6 mL) and the solution treated with 1 M TBAF/THF (0.35 mL, 0.35 mmol). After stirring at room temperature for 2 hours the solution was diluted with EtOAc, washed with water (2x), brine (1 x), dried over sodium sulfate and
concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, gradient from DCM to 9: 1 DCM/MeOH) followed by
lyophilization from MeCN/water to afford the title compound (41 mg, 45%) as a white solid. 1H NMR (400 MHz, METHANOL-^) δ ppm 8.18 - 8.30 (m, 1 H) 7.70 - 7.79 (m, 1 H) 3.95 - 4.64 (m, 5 H) 3.72 - 3.89 (m, 1 H) 3.39 - 3.61 (m, 2 H) 1 .81 - 2.05 (m, 2 H) 1 .44 - 1 .56 (m, 1 H) 1 .32 - 1 .42 (m, 1 H) 0.70 - 0.81 (m, 1 H) 0.41 - 0.54 (m, 1 H). ES-LCMS m/z: 523 (M+1 ). EXA PLE 77
4-{[3,5-Dichloro-7-{trifluoromethyl)pyrazolo[1,5-alpyridin-2-yl]carbonyl}-1- [(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 77)
Figure imgf000197_0001
The title compound was prepared in 50% yield from 3,5-dichloro-7- (trifluoromethylJpyrazolotl .S-alpyridine^-carboxylic acid and 1-((1 S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone according to the method described herein for the synthesis of 4-{[5-bromo-3-chloro-7- (trifluoromethyl)pyrazolo[1 l5-a]pyridin-2-yl]carbonyl}-1-[(1 SJ2S,3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone. 1H NMR (400 MHz, METHANOL-^) δ ppm 8.02 - 8.07 (m, 1 H) 7.61 - 7.66 (m, 1 H) 4.13 - 4.59 (m, 4 H) 3.94 - 4.04 (m, 1 H) 3.73 - 3.85 (m, 1 H) 3.36 - 3.57 (m, 2 H) 1.79 - 2.01 (no, 2 H) 1.42 - 1.52 (m, 1 H) 1.29 - 1.38 (m, 1 H) 0.68 - 0.77 (m, 1 H) 0.39 - 0.49 (m, 1 H). ES-LCMS m/z: 477 (M+1 ).
EXAMPLE 78
4-{[3-Chloro-5-cyclopropyl-7-(1,3-oxazol-5-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (ira/?s-4-hydroxycyclohexyl)-2-piperazinone
(Compound 78)
Figure imgf000197_0002
Step A
dimethyl !-({[{ 1, 1-dimethylethyl) (dimethyl) sily!]oxy}methyl)pyrazolo[ 1, 5-a]pyridine-2, 3- dicarboxylate The title compound (0.824 g, 31 %) was obtained from 1 -amino-2-({[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}methyl)pyridinium 2,4,6-trimethylbenzenesulfonate (3.05 g, 6.94 mmol), dimethylacetylenedicarboxylate (1 .97 g, 13.87 mmol) and DBU (2.1 1 g, 3.87 mmol) by a previously described procedure. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.1 (d, J=8.8 Hz, 1 H), 7.54 (dd, J=8.6, 7.4 Hz, 1 H), 7.25 - 7.27 (m, 1 H), 5.21 (s, 2 H), 4.04 (s, 3 H), 3.93 (s, 3 H), 1.00 (s, 9 H), 0.18 (s, 6 H).
Step B
dimethyl 7-({[(1, 1-dimethylethyl) (dimethyl) silyl]oxy}methyl)-5-hydroxypyrazolo[ 1, 5- a jpyridin e-2, 3-dicarboxylate
The title compound (0.66 g, 99%) was obtained from dimethyl 7-({[(1 ,1- dimethyiethyl)(dimethyl)silyl]oxy}methyl)pyrazolo[1 ,5~a]pyridine-2,3-dicarboxylate (0.64 g, 1.69 mmo!) by a previously described procedure. 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.31 (br. s., 1 H), 7.66 (d, J=2.6 Hz, 1 H), 6.93 - 6.98 (m, 1 H), 5.15 (s, 2 H), 4.03 (s, 3 H), 3.93 (s, 3 H), 1.00 (s, 9 H), 0.19 (s, 6 H).
Step C
dimethyl 7-({[(1, 1 -dimethylethyl) (dimethyl)silyl]oxy}methyl)-5- {[(trifluoromethyl)sulfony!]oxy}pyrazolo[ 1, 5-a]pyridine-2, 3-dicarboxylate The title compound (0.60 g, 68%) was obtained from dimethyl 7-{{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-hydroxypyrazolo[1 ,5-a]pyridine-2,3- dicarboxylate (0.66 g, 1.68 mmol), N-pheny!trifluoromethanesulfonimide (1 .20 g, 3.35 mmol) and DIPEA (0.87 g, 6.70 mmol) by a previously described procedure. 1 H NMR (400 MHz, CHLOROFORM-c/) 5 ppm 8.03 (d, J=2.7 Hz, 1 H), 7.18 - 7.23 (m, 1 H), 5.20 (s, 2 H), 4.05 (s, 3 H), 3.95 (s, 3 H), 1.00 (s, 9H), 0.19 (s, 6 H).
Step D
dimethyl 5~cyclopropyl~7-({[( 1, 1-dimethy!ethyl)(dimethyl)silyl]oxy}methyl)pyrazolo[ 1, 5- a Jpyridin e-2, 3-dicarboxyla te
The title compound (0.46 g, 97%) was obtained from dimethyl 7-({[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}methyl)-5-{[(trifluoromethy!)sulfonyl]oxy}pyrazolo[1 ,5- a]pyridine-2,3-dicarboxylate (0.60 g, 1.13 mmol), cyclopropyl boronic acid (0.15 g, 1.70 mmol), potassium phosphate (0.720 g, 3.39 mmol) and PdCl2(dppf).CH2Cl2 adduct by a previously described procedure. 1 H NMR (400 MHz, CHLOROFORM-c/) 6 ppm 7.79 (d, J=1.7 Hz, 1 H), 6.89 (d, J=1.8 Hz, 1 H), 5.15 (s, 2 H), 4.03 (s, 3 H), 3.92 (s, 3 H), 2,00 - 2.1 1 (m, 1 H), 1.10 - 1.21 (m, 2 H), 1.00 (s, 9 H), 0.84 - 0.91 (m, 2 H), 0.18 (s, 6 H). Step E
methyl 3-chloro-5-cyclopropyI-7-(hydroxymethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate The title compound (0.26 g, 85%) was obtained from dimethyl 5-cyclopropy!-7- ({[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)pyrazolo[1 ,5-a]pyridine-2,3-dicarboxylate (0.462 g, 1.103 mmol) by a three step sequence that is previously described. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.16 (d, J=1.7 Hz, 1 H), 6.68 - 6.71 (m, 1 H), 5.05 (d, J=6.6 Hz, 2 H), 4.36 (t, J=6.6 Hz, 1 H), 3.96 (s, 3 H), 1.88 - 1.97 (m, 1 H), 1.00 - 1.08 (m, 2 H), 0.73 - 0.81 (m, 2 H).
Step F
Methyl 3-chioro~5-cyclopropyl~7-formylpyrazolo[ 1, 5-a]pyridine-2-carboxylate A solution of methyl 3-ch!oro-5-cyc!opropyl~7~(hydroxymethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (190 mg , 0.68 mmol) in DCM (10 mL) was treated with of Dess- Martin Periodinane (860 mg, 2.0 mmol) and the resulting solution stirred at room temperature. After 2 hours the solution was diluted with DCM, washed with 5% aqueous sodium bisulfite (2x), saturated aqueous sodium bicarbonate (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure to afford the title compound (170 mg, 89%) as a yellow solid. H NMR (400 MHz, CHLOROFORM-t/) δ ppm 10.89 (s, 1 H) 7.52 (d, J=2.0 Hz, 1 H) 7.32 (d, J=2.1 Hz, 1 H) 4.04 (s, 3 H) 1.99 - 2.08 (m, 1 H) 1.1 1 - 1.20 (m, 2 H) 0.82 - 0.90 (m, 2 H).
Step G
Methyl 3-chloro-5-cyclopropyl-7-( 1, 3-oxazol-5-yl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate' A mixture of methyl 3-chloro-5-cyclopropyl-7-formylpyrazolo[1 ,5-a]pyridine-2- carboxylate (170 mg, 0.62 mmol), p-toluenesulfonylmethyl isocyanide (130 mg, 0.69 mmol), and potassium carbonate (130 mg, 0.94 mmol) in MeOH (10 mL) was stirred at room temperature. After 1 hour the mixture was concentrated to one quarter volume by rotary evaporation and diluted with DCM. The solution was washed with water (2x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was purified by flash chromatography twice (silica gel, gradient from hexane to EtOAc; gradient from DCM to 95:5 DCM/EtOH) to afford the title compound (144 mg, 73%) as a light yellow solid. ES-LCMS m/z: 523 (M+1 ).
Step H
3-Chloro-5-cyclopropyl-7-( 1, 3-oxazol-5-yl)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid A suspension of methyl 3-chloro-5-cyclopropyl-7-(1 ,3-oxazo!-5-yl)pyrazoio[1 ,5- a]pyridine-2-carboxylate (140 mg, 0.45 mmol) in 1 :1 :1 THF/water/MeOH (30 mL) was treated with of LiOH monohydrate (38 mg, 0.91 mmol). The solid starting material slowly dissolved affording a light yellow solution. After 2 hours LCMS indicated 70% conversion of starting material to the desired acid. The solution was treated with an additional portion of LiOH monohydrate (25 mg, 0.60 mmol) and stirring at room temperature continued. After another 1 hour the solution was acidified by addition of 3 mL of 1 N aqueous HCI and concentrated to half volume by rotary evaporation at which point a light yellow solid had formed. The suspension was diluted with water, the solid was collected by filtration on a medium frit and dried in vacuo to afford the title compound (122 mg, 88%) as a light yellow solid. ES-LCMS m/z: 304 (M+1 ).
Step I
4-{[3-Chloro-5-cycIopropyl~7-(1,3-oxazol-5-yt)pyrazolo[1,5-a]pyrid
4-hydroxycyclohexyl)-2-piperazinone
The title compound was prepared in 55% yield from 3-chloro-5-cyclopropyl-7-(1 ,3- oxazol-5-yl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1 -(frans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-4- hydroxycycIohexyl)-2-piperazinone. H NMR (400 MHz, METHANOL-^) δ ppm 8.40 - 8.45 (m, 1 H) 8.23 - 8.30 (m, 1 H) 7.29 - 7.35 (m, 1 H) 7,23 - 7.28 (m, 1 H) 4.25 - 4.50 (m, 3 H) 4.02 (t, J=5.5 Hz, 1 H) 3.89 - 3.96 (m, 1 H) 3.40 - 3.58 (m, 3 H) 1.93 - 2.17 (m, 3 H) 1.55 - 1.77 (m, 4 H) 1.30 - 1.48 (m, 2 H) 1.08 - 1.21 (m, 2 H) 0.84 - 0.94 (m, 2 H). ES- LCMS m/z: 484 (M+1 ).
EXAMPLE 79
4-{[3-Chloro-5-cyclopropyl-7-(1 ,3-oxazol-5-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 79)
Figure imgf000201_0001
The title compound was prepared in 58% from 3-chloro-5-cyclopropyl-7-(1 ,3- oxazol-5-yl)pyrazolo[1 ,5-a]pyridine-2-carboxyiic acid and 1-((1 S,2S,3S,5S)-2-{[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yi)-2-piperazinone according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[(1 S,2S,3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone. 1H NMR (400 MHz, METHANOL-c/4) δ ppm 8.43 - 8.48 (m, 1 H) 8.32 - 8.37 (m, 1 H) 7.37 - 7.41 (m, 1 H) 7.32 - 7.36 (m, 1 H) 4.03 - 4.64 (m, 5 H) 3.79 - 3.93 (m, 1 H) 3.39 - 3.63 (mr 2 H) 2.09 - 2.22 (m, 1 H) 1.84 - 2.06 (m, 2 H) 1.45 - 1.56 (m, 1 H) 1.30 - 1.42 (m, 1 H) 1 .10 - 1.22 (m, 2 H) 0.89 - 0.96 (m, 2 H) 0.70 - 0.81 (m, 1 H) 0.42 - 0.53 (m, 1 H). ES-LCMS m/z: 482 (M+ ).
EXAMPLE 80
4-{[5-Chloro-3-methyl-7-(trifluoromethyl)pyrazoloE1,5-a]pyridin-2-yl]carbonyl}-1- [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 80)
Figure imgf000201_0002
Step A
Methyl 5-chloro-3-iodo-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxyiate
A solution of methyl 5-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylate (0.46 g, 1.7 mmol) and W-iodosuccinimide (0.56 g, 2.5 mmol) in 10 mL of 1 ,2- dichloroethane in a sealed tube was heated to 115°C with stirring. After 6 hours the mixture was treated with an additional portion of W-iodosuccinimide (0.56 g, 2.5 mmol). After 18 hours the mixture was cooled to room temperature, diluted with DC , washed with 5% aqueous sodium bisuifate (3x), saturated aqueous sodium bicarbonate (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc) to afford the title compound (0.62 g, 93%) as a white solid. ES-LCMS m/z: 405 (M+1 ).
Step B
Methyl 5-chloro-3-methyl-7-(trifluoromethyI)pyrazolo[ 1, 5-a]pyridine-2-carboxylate A mixture of methyl 5-chloro-3-iodo-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylate (200 mg, 0.49 mmol), trimethylboroxine (190 mg, 1.5 mmol), potassium carbonate (340 mg, 2.5 mmol) and [1 ,1 '-bis(diphenylphosphino)ferrocene]dichloro palladium(ll) DCM complex (40 mg, 0.049 mmol) in 7 ml_ of DMF was sparged with nitrogen for several minutes and heated to 100°C with stirring. After 1 hour the mixture was cooled to room temperature, diluted with EtOAc, washed with water (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, gradient from hexane to 1 :1 hexane/EtOAc) to afford the title compound (95 mg, 66%) as a white solid. ES-LCMS m/z: 293 (M+1 ).
Step C
5-Chloro-3-methyl-7-(t fluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxyiic acid The title compound was prepared in quantitative yield from methyl 5-chloro-3- methyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate according to the proced described herein for the preparation of 3-chloro-5-cyclopropyl-7-(1 ,3-oxazol-5- yl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid. ES-LCMS m/z: 279 (M+1 ).
Step D
4-{[5-Chloro-3-methyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1 - [(1 S, 2S, 3S, 5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone The title compound was prepared in 79% yield from 5-chloro-3-methyl-7-
(trifluoromethyl)pyrazolo[1 ,5-a]pyndine-2-carboxylic acid and 1-((1 S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone using the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[(1 S,2S,3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone. H NMR (400 MHz, METHANOL-^) δ ppm 8.03 - 8.09 (m, 1 H) 7.48 - 7.54 (m, 1 H) 4.46 - 4.62 (m, 2 H) 4.10 - 4.43 (m, 3 H) 3.76 - 3.93 (m, 1 H) 3.40 - 3.61 (m, 2 H) 2.40 (s, 3 H) 1.82 - 2.03 (m, 2 H) 1.46 - 1.55 (m, 1 H) 1.32 - 1.42 (m, 1 H) 0.70 - 0.79 (m, 1 H) 0.42 - 0.52 (m, 1 H). ES-LCMS m/z: 457 (M+1 ).
EXAMPLE 81
4-{[3-Chloro-5-cyclopropy!-7-(3-thienyl)pyrazolo[ ,5-a]pyridin-2-yl3carbonyl}-1 -
(franS"4-hydroxycyclohexyl)-2-piperazinone
(Compound 81)
Figure imgf000203_0001
Step A
methyl 7-bromo-3-chloro-5~cyclopropylpyrazolo[ 1, 5-a]pyridine-2-carboxylate
CuBr2 (24.9 g, 1 1.5 mmol) was added to a solution of methyl 3-chloro-5- cyclopropyl-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-y[)pyrazolo[1 ,5-a]pyridine-2- carboxylate (53.4 mmol) in THF (300 ml_), MeOH (200 mL) and water (100 ml_). The reaction mixture was heated at 40 °C overnight, evaporated to dryness, diluted with water (300 mL), and extracted with EtOAc. The organic phase was dried (Na2S04), filtered, evaporated and purified by silica gel chromatography (PE:DC ) to afford the title compound (12 g, 68%) as a white solid.
Step B
Methyl 3-chloro-5-cyclopropyl-7-(3-thienyl)pyrazolo[1,5-a]pyridine~2-carboxylate
A mixture of methyl 7-bromo-3-chloro-5-cyclopropylpyrazoio[1 ,5-a]pyridine-2- carboxylate (250 mg, 0.759 mmol), 3-thienylboronic acid (194 mg, 1.52 mmol), K3P04 (483 mg, 2.28 mmol), and [1 , 1 '-bis(diphenylphosphino)ferrocene]dichloro pailadium(il) DC complex (31 mg, 0.038 mmol) in 15 mL of 1 ,4-dioxane was sparged with nitrogen for several minutes and subjected to microwave heating at 120°C for 20 minutes. After cooling to room temperature the mixture was diluted with EtOAc, washed with water (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, gradient from hexane to 1 :1 hexane/EtOAc) to afford the title compound (243 mg, 96%) as a viscous oil. ES-LCMS m/z: 333 (M+1 ).
Step C
3-Chloro-5-cyclopropyl- 7-( 3-thienyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid A mixture of methyl 3-chloro-5-cyc!opropyl-7-(3-thienyl)pyrazolo[1 ,5-a]pyridine-2- carboxylate (235 mg, 0.706 mmol) and LiOH monohydrate (87 mg, 2.1 mmol) in 15 mL of 4:1 THF/water was treated with a few drops of MeOH and the resulting solution stirred at room temperature. After 2 hours the solution was acidified by addition of 3 mL of 1 N aqueous HCI and the THF removed by rotary evaporation. The resulting mixture was diluted with water and extracted with 9:1 DCIW/PrOH (3x). The combined extracts were dried over sodium sulfate and concentrated to dryness at reduced pressure. The resulting solid was suspended in ether and the mixture stirred for several minutes. The solid was collected by filtration and dried in vacuo to afford the title compound (168 mg, 75%) as an off white solid. ES-LCMS m/z: 319 (M+1 ).
Step D
4-{[3-Chloro-5-cyclopropyl-7-(3~thienyl)pyrazolo[1,5-a]pyridin^^
hydroxycyclohexyl)-2-piperazin one
The title compound was prepared in 74% yield from 3-chloro-5-cyclopropyl-7-(3- thienyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1 -(/rans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride according to the procedure described herein for the synthesis of 4-{[5"bromo-3-chloro-7~(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1~(trans-4- hydroxycyclohexyl)-2-piperazinone. 1H NMR (400 MHz, METHANOL-^) δ ppm 8.53 - 8.66 (m, 1 H) 7.73 - 7.84 (m, 1 H) 7.51 - 7.61 (m, 1 H) 7.26 - 7.30 (m, 1 H) 7.12 - 7.18 (m, 1 H) 4.24 - 4.44 (m, 3 H) 4.00 (t, J=5A Hz, 1 H) 3.86 - 3.91 (m, 1 H) 3.36 - 3.58 (m, 3 H) 1.96 - 2.17 (m, 3 H) 1.52 - 1.75 (m, 4 H) 1.30 - 1.48 (m, 2 H) 1.08 - 1.17 (m, 2 H) 0.87 - 0.96 (m, 2 H). ES-LCMS m/z: 499 (M+ ).
EXAMPLE 82
4-{[3-Chloro-5-cyclopropyl-7-(3-thienyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 82)
Figure imgf000205_0001
The title compound was prepared in 81 % yield from 3-chloro-5-cyclopropyl~7-(3- thieny!)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1 -((1 S,2S,3S,5S)-2-{[(1 ,1- dimethylethyI)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[(1 S,2S,3S,5S)-2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone. 1H NMR (400 MHz, DMSO-t/6) δ ppm 8.68 - 8.79 (m, 1 H) 7.90 - 7.97 (m, 1 H) 7.72 - 7.77 (m, 1 H) 7.35 - 7.40 (m, 1 H) 7.23 - 7.29 (m, 1 H) 4.73 - 4.85 (m, 1 H) 3.88 - 4.47 (m, 5 H) 3.60 - 3.73 (m, 1 H) 3.26 - 3.48 (m, 2 H) 2.11 - 2.23 (m, 1 H) 1.64 - 1.89 (m, 2 H) 1.30 - 1.42 (m, 1 H) 1.18 - 1.31 (m, 1 H) 1.05 - 1.13 (m, 2 H) 0.93 - 1 .01 (m, 2 H) 0.61 (dq, J=8.5, 4.2 Hz, 1 H) 0.30 - 0.42 (m, 1 H). ES- LCMS m/z: 497 (M+1 ).
EXAMPLE 83
4-{[3-Chloro-5-cyclopropyi-7-(1 W-pyrrol-2-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
( frans-4- hyd r oxy cy c I ohexy l)-2- p i peraz i n o ne
Compound 83)
Figure imgf000205_0002
Step A
Methyl 3^hloro-5-cyclopropyl-7-(1H^yrrol-2-yl}pyrazolo[1,5~a]pyridine-2-carboxylate A mixture of methyl 7-bromo-3-chloro-5-cyclopropyipyrazolo[1 ,5-a]pyridine-2- carboxylate (1.00 g, 3.03 mmol), (1-{[(1 ,1 -dimethyiethyl)oxy]carbonyl}-1 /-/-pyrrol-2- yl)boronic acid (1.92 g, 9.10 mmol), K3P04 (2.58 g, 12.1 mmol) and [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloro palladium(ll) DCM complex (0.12 g, 0.15 mmol) in 30 mL of 1 ,4-dioxane in a sealed tube was sparged with nitrogen for several minutes and heated to 110°C with stirring. After 18 hours the mixture was cooled to room temperature, diluted with EtOAc, washed with water (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The residue was dissolved in 1 : 1 TFA/DCM and the solution stirred at room temperature. After 2 hours the solution was concentrated to dryness at reduced pressure and the residue dissolved in EtOAc. The solution was washed with saturated aqueous sodium bicarbonate (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from hexane to 1 :1
hexane/EtOAc) to afford the title compound (0.46 g, 48%) as a yellow foam. ES-LCMS m/z: 316 (M+1 ).
Step B
3-Chloro-5~cyclopropyi-7-(1H-pyrroi-2-yl)pyrazolo[ 1, 5-a]pyridine-2-carboxytic acid The title compound was prepared in 95 % yieid from methyl 3-chloro-5-cyclopropyl- 7-(1 H-pyrrol-2-yl)pyrazolo[1 ,5-a]pyridine-2-carboxy!ate according to the method described herein for the preparation of 3-chloro-5-cyclopropyl-7-(3-thienyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid. ES-LCMS m/z: 302 (M+1 ).
Step C
4-{[3-Chloro-5-cyclopro yl-7-(1Hφyrrol-2-yl) yrazolo[1l5-a]pyridin-2^
4-hydroxycyclohexyl)-2-piperazinone
The title compound was prepared in 80% yield from 3-chloro-5-cyclopropyl-7-(1 H- pyrrol-2-yl)pyrazo!o[1 ,5-a]pyridine-2-carboxylic acid and 1 -(irans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.19 - 7.23 (m, 1 H) 7.12 - 7.18 (m, 2 H) 7.03 - 7.08 (m, 1 H) 6.29 - 6.34 (m, 1 H) 4.25 - 4.44 (m, 3 H) 4.02 (t, J=5.5 Hz, 1 H) 3.82 - 3.88 (m, 1 H) 3.38 - 3.64 (m, 3 H) 1.96 - 2.14 (m, 3 H) 1.53 - 1.75 (m, 4 H) 1.32 - 1.46 (m, 2 H) 1.07 - 1.20 (m, 2 H) 0.86 - 0.94 (m, 2 H). ES- LCMS m/z: 482 (M+1 ). EXAMPLE 84
4-{[3-Chloro-5-cyclopropyl-7-(1,3-thiazol-4-yI)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1- (frans-4-hyd roxycycioh exy l)-2-pi perazi no ne
(Compound 84)
Figure imgf000207_0001
OH
Step A
Methyl 3-chloro-5-cyclopropyl-7-(1,3-thiazol-4-yl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate A mixture of methyl 3-chloro-5-cyclopropyl-7-(4,4,5,5-tetramethyl- 1 ,3,2- dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyriciine-2-carboxylate (250 mg, 0.664 mmol), 4-bromo- 1 ,3-thiazole (435 mg, 2.66 mmol), KsP04 (564 mg, 2.66 mmol), and [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloro palladium(ll) DC complex (27 mg, 0.033 mmol) in 10 mL of 1 ,4-dioxane was sparged with nitrogen and heated to 85°C with stirring.
After 2 hours the mixture was cooled to room temperature, diluted with EtOAc, washed with water (2x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc) to afford the title compound (76 mg, 34%) as a white foam. ES-LCMS m/z: 334 (M+1 ).
Step B
3-Chloro~5-cyclopropyl-7-(1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridine-2-carboxylic acid The title compound was prepared in 99% yield from methyl 3-chloro-5-cyclopropyl-
7-(1 ,3-thiazol-4-yl)pyrazolo[1 ,5-a]pyridine-2-carboxylate according to the procedure described herein for the preparation of 3-chloro-5-cyclopropy!-7-(3-thienyl)pyrazolo[1 ,5- a]pyridine-2-carboxylic acid. ES-LCMS m/z: 320 (M+1 ). Step C
4-{[3-Chloro-5-cyclopropyl-7-(1,3-thiazol-4~yl)pyrazolo[1,5-a]pyri^
4-hydroxycyclohexyl) -2-piperazin one
The title compound was prepared in 62% yield from 3-chloro-5-cyclopropyl-7-(1 ,3- thiazol-4-yl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1 -(irans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone. 1H NMR (400 MHz, DMSO-cfe) δ ppm 9.34 (m, 1 H) 9.12 - 9.20 (m, 1 H) 7.77 - 7.84 (m, 1 H) 7.45 - 7.51 (m, 1 H) 4.56 - 4.62 (m, 1 H) 4.10 - 4.35 (m, 3 H) 3.73 - 3.91 (m, 2 H) 3.28 - 3.43 (m, 3 H) 2.20 - 2.30 (m, 1 H) 1.81 - 1.91 (m, 2 H) 1.42 - 1.63 (m, 4 H) 1.16 - 1.31 (m, 2 H) 1.08 - 1.17 (m, 2 H) 0.88 - 0.95 (m, 2 H). ES-LCMS m/z: 500 (M+1 ).
Example 85
1-[(trans)-bicyclo[3.1.0]hex-3-yl]-4-{[3-chloro-5-cyclopropyl-7-
(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-2-piperazinone
(Compound 85)
Figure imgf000208_0001
Step A
2-[(trans bicyclo[3.1.0]hex-3-yl]-1H~isoindole-1,3(2H)^^^ DIAD (8.1 1 mL, 41.7 mmol) was added to a solution of (cis)-bicyclo[3.1.0]hexan-3- ol (3.15 g, 32.1 mmol), 1 H-isoindole~1 ,3(2H)-dione (6.14 g, 41.7 mmol), and
triphenylphosphine (10.94 g, 41.7 mmol) in THF (300 mL) at 0 °C. After 1 hour at 0 °C, the starting alcohol appeared to be gone by TLC. The reaction was warmed to room temperature and stirred overnight. Water (25 mL) and EtOAc (50 mL) were added. The organic layer was separated, washed with brine, dried over MgS04, filtered and concentrated to give a yellow solid. The material was purified by silica gel
chromatography (hexanes/EtOAc) to give 2-[(frans)-bicyclo[3.1.0]hex-3-yl]-1 H-isoindole- 1 ,3(2H)-dione (5.5 g, 24.20 mmol, 75%) as a white solid.
Step B
(trans)-bicycio[3.1.0]hexan-3-amine hydrochloride Hydrazine monohydrate (5.50 mL, 1 12 mmol) was added to a suspension of 2- [(irans)-bicyclo[3.1.0]hex-3-yl]-1 H-isoindole-1 ,3(2H)-dione (5.1 g, 22.44 mmol) in EtOH (200 mL) and the mixture was heated at reflux for 16 hours. The reaction mixture was cooled to room temperature and Et20 (50 mL) was added. The solid was filtered off and the filtrate was concentrated (note: amine appears to be volatile). Et20 (30 mL) was added and again the solid was filtered off. The filtrate was concentrated then EtOH (20 mL) and Et20 (20 mL) were added. The solvents were again removed under vacuum in an attempt to remove excess hydrazine and HCI in dioxane (4N, 5mL) was added. The mixture was concentrated to dryness and used as is in the next step.
Step C
1, 1-dimethylethyl 4-[(trans)-bicyclo[3. 1.0]hex-3-yl]-3-oxo-1-piperazinecarboxyiate
A mixture of (£ra/is)-bicyclo[3.1.0]hex-3-ylamine hydrochloride (1.098 g, 8,22 mmol), methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N-(2-oxoethyl)glycinate (1.9 g, 8.22 mmol), Hunig's base (1.579 mL, 9,04 mmol), and sodium sulfate (7.00 g, 49.3 mmol) was stirred in MeOH (30 mL) for 2 hours, then NaBH4 (0.342 g, 9.04 mmol) was added in portions over ca. 10 minutes. The mixture was stirred for 2 hours then 60% NaH dispersion in oil (0.624 g, 15,61 mmol) was added in portions over ca, 10 min. After 2 hours TLC and LCMS shows what appears to product. Aqueous citric acid (30% by wt., 50 mL) was added slowly and the mixture was filtered thru Ce!ite and washed with MeOH, The filtrate was concentrated under reduced pressure to remove the MeOH and the remaining aqueous layer was extracted with ethyl acetate (2 x 150 mL). The organic layers were combined, washed with saturated aqueous NaHC03 solution, brine, dried over Na2S04, filtered and concentrated. The product was purified by silica gel chromatography (hexanes/ethyl acetate) to give 1 , 1 -dimethylethyl 4-[(trans)-bicyclo[3.1.0]hex-3-yl]-3-oxo-1 - piperazinecarboxylate (1.67 g, 5.96 mmol, 73%) as a white solid.
Step D
1~[(trans)-bicycio[3.1.0]hex-3-ylj-2-plperazinone hydrochloride To a solution of 1 , 1 -dimethylethyl 4-[(trans)-bicyclo[3.1.0]hex-3-yl]-3-oxo-1- piperazinecarboxylate ( .67 g, 5.96 mmol) in DCM (30 mL) was added 4M HCI in dioxane (14.89 mL, 59.6 mmol). The solution was stirred for 16 h then the solvent was removed under reduced pressure to give the title compound as a white solid that was used without further purification.
Step E
1-[(trans)-bicyclo[3.1.0]hex'3-yl]-4-{[3-chloro-5-cyclopropyt-7-(tr^
a]pyridin-2-yl]carbonyl}-2-piperazinone DIPEA (0.209 mL, 1.195 mmol) was added dropwise to a stirred solution of 1- [(frans)-bicyclo[3.1.0]hex-3-yl]-2-piperazinone hydrochloride (71.2 mg, 0.329 mmol) and 3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (91 mg, 0.299 mmol) in DMF (2 mL). After 15 minutes, the orange solution was cooled to 0 °C and 50% wt 1-propanephosphoric acid cyclic anhydride in EtOAc (0.255 mL, 0.448 mmol) was added dropwise. The yellow solution was allowed to warm to room temperature overnight with stirring then it was poured into water (75 mL). After stirring for 15 minutes the white precipitate was filtered and dried under vacuum. The crude material was purified by Reverse Phase HPLC (MeCN/water + 0.1 % formic acid) to give the title compound (40 mg, 0.081 mmol, 27%) as a white solid. 1H NMR (400 MHz, DMSO- /6) pppm 7.68 - 7.73 (m, 1 H) 7.41 - 7.47 (m, 1 H) 4.42 - 4.62 (m, 1 H) 4.12 - 4.26 (m, 2 H) 3.68 - 3.88 (m, 2 H) 3.26 - 3.42 (m, 2 H) 2.17 - 2.28 (m, 1 H) 1.76 - 1.91 (m, 2 H) 1.66 - 1 ,76 (m, 2 H) 1 ,20 - 1.34 (m, 2 H) 1 .04 - 1.15 (m, 2 H) 0.92 - 1.02 (m, 2 H) 0.30 - 0.41 (m, 1 H) 0.18 - 0.30 (m, 1 H). LCMS m/z: 467,1 (M+1 ).
Example 86
4-{[3-chIoro-5-cyc[opropyi-7-(3-furanyl)pyrazolo[1 ,5-a]pyriciin-2-yi]carbonyl}-1- [(1Sf2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 86)
Figure imgf000210_0001
Step A
4-{[3-chtoro-5-cyclopropyl-7-(3~furanyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}- ((1S, 2S, 3S, 5S)-2-{[(1, 1-dimethylethyl) (dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2- piperazinone
DIPEA (0.343 mL, 1.962 mmol) was added to a stirred solution of 3-chloro-5- cyclopropyl-7-(3-furanyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (198 mg, 0.654 mmol) and 1 -((I S,2S,3S,5S)-2-{[( 1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2- piperazinone (203 mg, 0.654 mmol) in DMF (5 mL). After 15 minutes, the orange solution was cooled to 0 °C and 50% wt 1 -propanephosphonic acid cyclic anhydride in EtOAc (0.409 mL, 0.687 mmol) was added dropwise. The solution was allowed to warm to room temperature overnight with stirring then water (50 mL) was added. After stirring for 15min EtOAc (100 mL) was added and the organic layer was separated. The aqueous layer was extracted again with EtOAc and the combined organic layers were washed with brine and dried over MgS04. The solution was filtered and concentrated to dryness. The crude product was purified on silica gel (hexanes/EtOAc) to give the title compound (307 mg, 0.516 mmol, 79%) as a white powder. Step B
4-{[3-chloro-5-cyclopropyl-7-(3-furanyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyI}- 1-
[(1S, 2S, 3S, 5S)-2-hydroxybicyclo[3.1.0]hex-3~yl]~2-piperazinone 1 M solution of TBAF in THF (0.619 mL, 0.619 mmol) was added to a solution of 4- {t3-chloro-5-cyclopropyl-7-(3-furanyl)pyrazolo[1 ,5-a]pyhdin-2-yl]carbonyl}-1- ((1 S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2- piperazinone (307 mg, 0.516 mmol) in THF (3 mL) at room temperature. The dark solution was stirred for 6h then water (-75 mL) and EtOAc (-75 mL) were added. The organic layer was washed with separated, brine, dried over MgS04, filtered and concentrated. The crude product was purified on silica gel (hex EtOAc) to give the title compound (230 mg, 0.454 mmol, 88%) as a pale yellow solid. H NMR (400 MHz, DMSO-d6) Oppm 8.90 (d, 1 H) 7.92 (d, 1 H) 7.47 (s, 1 H) 7.38 (dd, 1 H) 7.33 (s, 1 H) 4.75 - 4.87 (m, 1 H) 4.32 - 4.47 (m, 3 H) 4.08 - 4.24 (m, 2 H) 3.89 - 3.98 (m, 1 H) 3.63 - 3.75 (m, 1 H) 3,36 - 3.49 (m, 1 H) 2.11 - 2.23 {m, 1 H) 1 .76 - 1.92 (m, 1 H) 1.66 - 1 .76 (m, 1 H) 1.32 - 1.42 (m, 1 H) 1 ,20 - 1.31 (m, 1 H) 1.05 - 1.14 (m, 2 H) 0.94 - 1.02 (m, 2 H) 0.55 - 0.66 (m, 1 H) 0.28 - 0.41 (m, 1 H). LCMS m/z: 481.4 ( +1 ).
EXAMPLE 87
4-{[5-cyclopropyl-3-(methy[oxy)-7-(trifiuoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-1-(irans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 87)
Figure imgf000212_0001
Step A
methyl 5-cyc!opropyl-3-(4, 4, 5, 5-tetramethyl- 1,3, 2-dioxaborolan-2-yl)-7- (trifluoromethyl)pyrazolo[ 1, 5-a]py dine-2-carboxylate A solution of compound methyl 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (1g, 3.52 mmol), bis(pinacoiato)diboron (1.07 g, 4.23 mmol), [lr(OMe)COD]2 (70mg, 0.106 mmol) and 4,4'-bis(1 , 1 -dimethylethyl)-2,2'-bipyridine (57 mg, 0.21 mmol) in hexane (20mL) was purged with nitrogen and then heated at 80°C overnight. After the addition of H20 (20mL), the solution was extracted with DCM (30mL x 3). The combined organic solution was dried over anhydrous Na2S04. After the removal of the solvent, the crude product was recrystallized from MeOH to give the title compound (1.1g, 76%) as a white solid. 1H NMR (300MHz, CDCI3) δ 7.85 (br, 1 H), 7.03 (br, 1 H), 4.00 (s, 3H), 2.09-2.03 (m, 1 H), 1.43 (s, 12H), 1.19-1.12 (m, 2H), 0.90-0.83 (m, 2H). Step B
methyl 5-cyclopropyl-3-hydroxy-7~(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
To a solution of compound methyl 5-cyclopropyl-3-(4,4,5,5-tetramethyl- ,3,2- dioxaborolan-2-yl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (500 mg, 1.22 mmol) in THF (10mL) was added dropwise cone. H2S04 (0.3 mL, 6.098 mmol) at 0°C. H202 (30% aq., 0.62 mL, 6.098 mmol) was added dropwise at the same temperature. After the addition, the reaction mixture was heated at 50°C for 2 hours. After the addition of water (30mL), the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were dried over anhydrous Na2S04 and concentrated to give methyl 5-cyclopropyl- 3-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (563 mg, quant.) as a red solid. H NMR (300MHz, CDCI3) δ 7.66 (br, 1 H), 7.46 (br, 1 H), 7.07 (br, H), 4.06 (s, 3H), 2.00-1.95 (m, 1 H), 1.14-1.07 (m, 2H), 0.84-0.78 (m, 2H).
Step C
methyl 5-cyclopropyl-3-(methyloxy)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2- carboxylate To a solution of crude compound methyl 5-cyclopropyl-3-hydroxy-7- {trifluoromethyOpyrazoloII .S-alpyridine^-carboxylate (563 mg) and K2C03 (733 mg, 5.601 mmol) in DMF (10ml_) was added Mel (0.5 mL, 7.467 mmol) at room temperature and the reaction mixture was heated at 50 °C for 30 min. After the addition of water (20m L), the mixture was extracted with EtOAc (30mL x 3). The combined organic solution was washed with brine (40mL x 2), dried over anhydrous Na2S04, evaporated and purified by silica gel chromatography (PE:EA - 4:1 ) to give the title compound (200mg, 52% in two steps) as a white solid. 1H N R (300MHz, CDCI3) δ 7.45 (br, 1 H), 7.04 (br, 1 H), 4.05 (s, 3H), 4.02 (s, 3H), 2.03-1.95 (m, 1 H), 1.16-1.10 (m, 2H), 0.86-0.81 (m, 2H).
Step D
5-cyclopropyl-3-(methyloxy)"7'(trifluoromethyl)pyrazolo[1 5~a]pyrid acid To a solution of compound methyl 5~cyclopropyl-3-(methyloxy)-7- (trifluoromethyl)pyrazo!o[1,5-a]pyridine-2-carboxylate (186 mg, 0.56 mmol) in
THF/MeOH/H20 (4mL/4mL/1 mL) was added LiOH (42 mg, 1.76 mmol) and the reaction mixture was stirred for 2 hours. After the removal of the organic solvents, water ( 0 mL) was added and the resulted solution was acidified with cone. HCI (36% aq.) to pH 3. The aqueous solution was extracted with EtOAc (30 mL x 3) and the combined organic phases were washed with brine (50 mL x 2) and evaporated to give the title compound (150 mg, 85%). H NMR (300MHz, CDCI3) δ 7.85 (br, 1 H), 7.03 (br, 1 H), 4.00 (s, 3H), 2.09-2.01 (m, 1 H), 1.17-1.12 (m, 2H), 0.90-0.83 (m, 2H).
Step E
4~{[5-cyclopropyl-3-(methyloxy)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrid
(trans-4-hydroxycyclohexyl) -2-piperazinone
A solution of compound 5-cyclopropyl-3-(methyloxy)-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (50 mg, 0.159 mmol) and TBTU (51 mg, 0.159 mmol) in dry DMF (5 mL) was stirred at room temperature for 10 min. To this solution was added the compound 1 -(frans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (37 mg, 0.159 mmol) and DIPEA (62 mg, 0.477 mmol). The reaction mixture was stirred at room temperature for 30 min. After the addition of water (20 mL), the solution was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (30 mL x 2), dried over anhydrous Na2S04, evaporated and purified by silica gel chromatography (PE:EA=1 :1 ) to give the title compound (40 mg, 53%) as an off- white solid. H NMR (300 MHz, CDCI3) δ 7.43 (s, 1 H), 7.00 (s, 1 H), 4.50 - 4.42 (m, 3 H), 4.05 - 4.02 (m, 5 H), 3.61 - 3.39 (m, 3 H), 2.15 - 1 .96 (m,3 H), 1.81 - 1.77 (m, 2 H), 1.60 - 1.40 (m, 4 H), 1.14 - 1.12 (m, 2 H), 0.84 - 0.82 (m, 2 H). LCMS (m/z, ES+): 481.1 (M+1 ).
EXAMPLE 88
1-cyclobutyl-4-{[5-cyclopropyl-3-(methyloxy)-7-(trifluoromethyl)pyrazolo[1,5- a]pyridin-2-yl]carbonyl}-2-piperazinone
(Compound 88)
Figure imgf000214_0001
The title compound (20 mg, 29%) was obtained as an off-white solid from
5-cyclopropyl-3-(methyloxy)-7-(trifluoromethyl)pyra2olo[1 ,5-a]pyridine-2-carboxylic acid (50 mg, 0.159 mmol), TBTU (51 mg, 0.159 mmol), 1 -cyclobutyl~2-piperazinone
hydrochloride (31 mg, 0.159 mmol) and DIPEA (62 mg, 0.477 mmol) in DMF (5mL) by a previously described procedure. 1H NMR (300 MHz, CDCI3) δ 7.43 - 7.42 (d, 1 H), 6.99 - 6.98 (d, 1 H), 5.02 - 4.96 (m, 1 H), 4.44 - 4.40 (d, 2 H), 4.05 - 4.02 (m, 5 H), 3.54 (m, 2 H), 2.17 - 1 ,98 (m, 5 H), 1.76 - 1.74 (m, 2 H), 1.14 - 1.12 (m, 2 H), 0.84 - 0.82 (m, 2 H). LCMS {m/z, ES+): 437.1 (M+1 ).
EXAMPLE 89
1-cyclobutyl-4-{[5-cyclopropyl-3-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- y]]carbonyl}-2-piperazinone
{Compound 89)
Figure imgf000214_0002
To a solution of compound 1 -cyclobutyl-4-{[5-cyclopropyl-3-(methyloxy)-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yI]carbonyl}-2-piperazinone (74 mg, 0.170 mmol) in DCM (10 mL) was added BBr3 (0.8 mL of a 1 M solution in DCM, 0.848 mmol) at -40°C. The reaction mixture was stirred at -40°C for 2 hours and allowed to warm to room temperature. Water (20 mL) was added and the solution was extracted with DCM (30mL x 3). The combined organic solution was dried over anhydrous Na2S04, evaporated and purified by silica gel chromatography (DCM:MeOH=20:1 ) to give the title compound (50 mg, 69%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6, 20° C) δ= 9.56 - 9.53 (d, 1 H), 7.61 (s, 1 H), 7.24 (s, 1 H), 4.89 - 4.82 (m, 1 H), 4.37 (s, 1 H), 4.20 (s, 1 H), 3.94 - 3.88 (m, 2 H), 3.49 - 3.45 (m, 2 H), 2.19 - 1.99 (m, 5 H), 1.67 - 1.62 (m, 2 H), 1.05 - 0.99 (m, 2 H), 0.85 - 0.83 (m, 2 H). 1H NMR {300 MHz, DMSO-d6, 80°C) 6= 9.27 (s, 1 H), 7.58 (s, 1 H), 7.21 (s, 1 H), 4.89 - 4.82 (m, 1 H), 4.44 - 4.20 (m, 2 H), 4.10 - 3.94 (m, 2 H), 3.49 - 3.45 (m, 2 H), 2.19 - 1.99 (m, 5 H ), 1.72 - 1.61 (m, 2 H), 1.08 - 1.01 (m, 2 H), 0.85 - 0.81 (m, 2 H). LCMS {m/z, ES+) = 423.2 (M+1 ).
EXAMPLE 90
4-{[5-cyclopropyl-3-hydroxy-7-{trifiuoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyi}- 1 -{frans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 90)
Figure imgf000215_0001
To a solution of compound 4-{[5-cyclopropyl-3-(methyloxy)-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(fra/?s-4-hydroxycyclohexyl)--2- piperazinone (70 mg, 0.146 mmol) in DCM (10mL) was added BBr3 (0.7 mL of a 1 M solution in DCM, 0.728 mmol) at -40°C. The reaction mixture was stirred at -40°C for 2 hours and allowed to warm to room temperature. Water (20 mL) was added and the solution was extracted with DCM (30m L x 3). The combined organic extracts were dried over anhydrous Na2S04, evaporated and purified by silica gei chromatography
(DCM:MeOH=20:1 ) to give the title compound (20 mg, 30%) as a off-white solid. 1H NMR (300 MHz, DMSO-c/6, 20'C) δ 9.56 - 9.53 (d, 1 H), 7.61 (s, 1 H), 7.24 (s, 1 H), 4.57 - 4.10 (m, 3 H), 3.91 - 3.82 (m, 2 H), 3.40 - 3.21 (m, 3 H), 2.12 - 2.07 (m, 1 H), 1.87 - 1.84 (d, 2 H), 1.60 - 1.51 (m, 4 H), 1.31 - 1.09 (m, 2 H), 1.05 - 0.99 (m, 2 H), 0.85 - 0.83 (m, 2 H). 1H NMR (300 MHz, DMSOci6, 80°C) δ= 9.27 (d, 1 H), 7.58 (s, 1 H), 7.21 (s, 1 H), 4.33 - 3.96 (m, 5 H), 3.39 - 3.35 (m, 3 H), 2.1 1 - 2.07 (m, 1 H), 1.92 - 1.88 (d, 2 H), 1.60 - 1.55 (m, 4 H), 1.33 - 1.20 (m, 2 H), 1.08 - 1.01 (m, 2 H), 0.85 - 0.81 (m, 2 H). LCMS (m/z, ES+): 467 (M+1 ). EXAMPLE 91
4-{[3 :hloro-5 yclopropyl-7-(trifluorom
[2-fluoro-4-(methyloxy)phenyl]-2-piperazinone
(Compound 91)
Figure imgf000216_0001
CD- Step A
1, 1 -dimethylethyl 4-[2~fluoro~4-(methyloxy)phenyl]-3-oxo-1-piperazinecarboxylate A mixture of 1-Boc-3-oxopiperazine (500 mg, 2.497 mmol), 4-bromo-3- fluoroanisole (512 mg, 2.497 mmol), copper(l) iodide (23.78 mg, 0.125 mmol), frans-Ν,Ν'- dimethylcycIohexane-1 ,2-diamine (0.039 mL, 0.250 mmo!), and potassium carbonate (690 mg, 4.99 mmol) in 1 ,4-dioxane (10 mL) was heated at 120 °C for 3.5 days. The mixture was filtered through a pad of Celite and washed with EtOAc (50 mL). The filtrate was washed with saturated aqueous NH4CI (15 mL), brine (15 mL), dried ( gS04), filtered and concentrated. The crude was absorbed on silica gel and purified by silica gel
chromatography (10-60% EtOAc in hexanes) to give 1 ,1 -dimethylethyl 4-[2-fluoro-4- (methyloxy)phenyl]-3-oxo~1 -piperazinecarboxylate (581.9 mg, 1 .794 mmol, 72 %) as white solid. MS(ESI) m/z: 325.3 (MH+). Step B
1 -[2-fluoro-4-( m ethyloxy)ph enyl]-2-pip erazinone hydrochloride To a solution of 1 ,1 -dimethylethyl 4-[2-fluoro-4-(methyloxy)phenyl]-3-oxo-1- piperazinecarboxylate (575 mg, 1.773 mmol) in DCM (9 mL) was added a solution of 4 M hydrogen chloride in 1 ,4-dioxane (4.43 mL, 17.73 mmol). After 1.5 hours, the solvent was concentrated under reduced pressure to give the product as a foam. This was triturated with ether to give a beige solid which dried under high vacuum to give 1-[2-fluoro-4- (methyloxy)phenyl]-2-piperazinone hydrochloride (475.8mg, quantitative). This was used for the next step without further purification. MS(ESI) m/z: 225.2 (MH+). Step C
4-{[3~chloro-5~cyclopropyl-7-(trifluoromethyl)pyrazolo
fluoro-4-(methyloxy)phenyl]-2-piperazinone
To a solution of 3-chloro-5-cyclopropy!-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (150 mg, 0.492 mmol), 1 -[2-fluoro-4-(methyloxy)phenyl]-2-piperazinone hydrochloride (180 mg, 0.689 mmol), N,N-diisopropylethylamine (0.344 mL, 1.969 mmol) in DMF (1.7 mL) at O °C was added a solution of 1 -propanephosphonic acid cyclic anhydride in EtOAc (50% wt) (0.44 mL, 0.739 mmol). After 75 minutes, the mixture was diluted with EtOAc (25 mL), and washed with saturated aqueous NaHC03 (10 mL), brine (10 mL), dried (Na2S04), filtered and concentrated. The residue was purified by silica gel chromatography [10-70% EtOAc in hexanes] to give 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[2-fluoro-4-(methyloxy)phenyl]-2- piperazinone (253.5 mg, 0.491 mmol, quant.). 1H NMR (400 MHz, DMSO-c 6) δ ppm 0.93 - 1.03 (m, 2 H), 1.06 - 1.14 (m, 2 H), 2.16 - 2.30 (m, 1 H), 3.60 - 3.69 (m, 1.25 H), 3.72 (t, J=5.4 Hz, 0.75 H), 3.78 (d, J=1.3 Hz, 3 H), 3.89 - 3.97 (m, 1.25 H), 4.07 (t, J=5.4 Hz, 0.75 H), 4.36 (s, 0.75 H), 4.44 (s, 1.25 H), 6.83 (dd, J=8.6, 2.1 Hz, 1 H), 6.92 - 7.00 (m, 1 H), 7.35 (td, J=8.9, 6.3 Hz, 1 H), 7.45 (d, J=1.4 Hz, 1 H), 7.71 (s, 1 H); MS(ESI) m/z: 511.2 (MH*). EXAMPLE 92
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-1- [3-fluoro-4-(methyloxy)phenyl]-2-piperazinone
(Compound 92)
Figure imgf000217_0001
Step A
1, 1 -dimethylethyl 4-[3~fluoro-4-(methy!oxy)phenyl]-3-oxo-1-piperazinecarboxylate The title compound (740.4 mg, 91 %) was obtained as semi-solid from 1-Boc-3- oxopiperazine and 4-bromo-2-fluoro-1 -(methyloxy)benzene using a similar procedure to that described in Example 91 , Step A. MS(ESI) m/z: 325.2 (MH+), Step B
1 -[3-fluoro-4-(methyloxy) phenyl]-2-piperazin on e hydrochloride The title compound (576.6 mg, 98%) was obtained as white solid from 1 ,1 - dimethylethyl 4-[3-fluoro-4-(methyloxy)phenyl]-3-oxo-1-piperazinecarboxylate using a similar procedure to that described in Example 91 , Step B. MS(ESI) m/z: 225.2 (MH+).
Step C
4~{[3~chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2^
fluoro-4-(methyloxy)phenyl]-2-piperazinone
The title compound (246.4 mg, 97%) was obtained as white solid from 3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2~carboxylic acid and 1 -[3-fluoro-4- (methyloxy)phenyl]-2-piperazinone hydrochloride using a similar procedure to that described in Example 91 , Step C. 1H N R (400 MHz, DMSO-d6) 5 ppm 0.92 - 1.02 (m, 2 H), 1.05 - 1.15 (m, 2 H), 2.16 - 2.29 (m, 1 H), 3.68 - 3.75 (m, 1 .2 H), 3.78 - 3.87 (m, 3.8 H), 3.92 (t, J=5.2 Hz, 1.2 H), 4.05 (t, J=5.4 Hz, 0.8 H), 4.35 (s, 0.8 H), 4.40 (s, 1 .2 H), 7.07 - 7.24 (m, 2 H), 7.26 - 7.37 (m, 1 H), 7.45 <d, J=1.4 Hz, 1 H), 7.71 (s, 1 H); MS(ESI) m/z: 511.2 (MH+). EXAMPLE 93
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazoIo[1 ,5-a]pyridin-2-yl]carbonyl}^
[4-(methyloxy)phenyl]-2-piperazinone
(Compound 93)
Figure imgf000218_0001
Step A
1, 1 -dimethylethyl 4-[4-(methyloxy)phenyl]-3-oxo- 1-piperazinecarboxylate
The title compound (692.3 mg, 90%) was obtained as white solid from 1 -Boc-3- oxopiperazine and 4-bromoanisole using a similar procedure to that described in Exampl 91 , Step A. MS(ESI) m/z: 307.3 (MH+). Step B
1-[4-(methyloxy)phenyl]-2-piperazinone hydrochloride The title compound (559.1 mg, quant.) was obtained as white solid from 1 ,1 - dimethylethyl 4-[4-(methyloxy)pheny[]-3-oxo-1 -piperazinecarboxylate using a similar procedure to that described in Example 91 , Step B. MS(ESI) m/z: 207.2 (MH+).
Step C
4-{[3-chloro-5-cyclopropyl~7-(trifluoromethyl)pyrazolo[1,5-a]pyridin^^
(methyloxy)phenyl]-2-piperazinone
The title compound (232.9 mg, 95%) was obtained as white solid from 3-chloro-5- cyclopropyl^-itrifluoromethy pyrazoloCI ^-alpyridine^-carboxylic acid and 1-[4- (methyloxy)phenyl]-2-piperazinone hydrochloride using a similar procedure to that described in Example 91 , Step C. 1H NMR (400 MHz, DMSO-af6) 5 ppm 0.92 - 1.03 (m, 2 H), 1.05 - 1.14 (m, 2 H), 2.17 - 2.28 (m, 1 H), 3.66 - 3.72 (m, 1.2 H), 3.76 (s, 3 H), 3.79 (t, J=5.5 Hz, 0.8 H), 3.91 (t, J=5.2 Hz, 1.2 H), 4.05 (t, J=5.4 Hz, 0.8 H), 4.33 (s, 0.8 H), 4.40 (s, 1.2 H), 6.90 - 7.00 (m, 2 H), 7.20 - 7.32 (m, 2 H), 7.45 (d, J=1.2 Hz, 1 H), 7.71 (s, 1 H); MS(ESI) m/z: 493.2 (MH+).
EXAMPLE 94
4-{[3-chIoro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbony!}-1-
[2,3-difluoro-4-(methyloxy)phenyl]-2-piperazinone
(Compound 94)
Figure imgf000219_0001
Step A
1, 1-dimethylethyl 4-[2, 3-difluoro-4-(methyloxy)phenyl]-3-oxo-1-piperazinecarboxyIate The title compound (262.3 mg, 31%) was obtained as an oil from 1 -Boc-3- oxopiperazine and 4-bromo-2,3-difluoroanisole using a similar procedure to that described in Example 91 , Step A. MS(ESl) m/z: 343.3 ( H+). Step B
1-12, 3-difluoro-4-( methyloxy)ph enyl]-2-piperazin one hydrochloride The title compound (205 mg, 97%) was obtained as white solid from 1 ,1- dimethylethyl 4-[2,3-difluoro-4-(methyloxy)phenyl]-3-oxo-1-piperazinecarboxylate using a similar procedure to that described in Example 91 , Step B. MS(ESI) m/z: 243.1 (MH*).
Step C
4-{[3-chloro-5-cyclopropyl-7-(trifiuoromethyl)pyrazolo[1,5-a]pyridin-2^
difluoro-4-(methyloxy)phenyl]-2-piperazinone
The title compound (264.8 mg, 94%) was obtained as white powder from 3-chloro-
5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1-[2,3- difluoro-4-(methyloxy)phenyl]-2-piperazinone hydrochloride using a similar procedure to that described in Example 91 , Step C. H N R (400 MHz, DMSO-<¾) 5 ppm 0.93 - 1.03 (m, 2 H), 1.06 - 1.14 (m, 2 H), 2.16 - 2.28 (m, 1 H), 3.69 (t, J=5.2 Hz, 1 .2 H), 3.78 (t, J=5.4 Hz, 0.8 H), 3.90 (s, 3 H), 3.95 (t, J=5.2 Hz, 1.2 H), 4.08 (t, J=5.3 Hz, 0.8 H), 4.40 (s, 0.8 H), 4.46 (s, 1.2 H), 6.99 - 7.14 (m, 1 H), 7.21 - 7.34 (m, 1 H), 7.45 (d, J=1 .4 Hz, 1 H), 7.72 (s, 1 H); MS(ESI) m/z: 529.2 (MH+).
EXAMPLE 95
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbony[}-1-
[2,5-difluoro-4-(methyloxy)phenyl]-2-piperazinone
(Compound 95)
Figure imgf000220_0001
Step A
1, 1 -dimethylethyl 4-[2, 5-difluoro-4-(methyloxy)phenyl]-3-oxo- 1-piperazinecarboxylate The title compound (262.3 mg, 31 %) was obtained as an oil from 1 -Boc-3- oxopiperazine and 4-bromo-2,5-difluoroanisole using similar procedure as described in Example 91 , Step A. MS(ESI) m/z: 343.2 (MH+). Step B
1 -[2, 5-difluoro~4~(methyloxy)phenyl]-2-piperazinone The title compound (261 mg, quant.) was obtained as white solid from 1 ,1- dimethylethyl 4-[2,5-difluoro-4-(methyloxy)phenyl]-3-oxo-1-piperazinecarboxylate using similar procedure to that described in Example 91 , Step B. MS(ESI) m/z: 243.1 (MH+).
Step C
4-{[3 thloro-5-cyclopropyl-7-(trifluoromethyi)pyrazolo[1,5-a]pyrid
difluoro-4-(m ethyloxy)phenyl]-2-piperazin on e
The title compound (340 mg, 97%) was obtained as white powder from 3-chloro-5- cyclopropy!-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1-[2,5-difluoro- 4-(methyloxy)phenyl]-2-piperazinone hydrochloride using a similar procedure to that described in Example 91 , Step C. 1H NMR (400 MHz, D SO-cfe) δ ppm 0.93 - 1.04 (m, 2 H), 1.05 - 1.15 (m, 2 H), 2.17 - 2.30 (m, 1 H), 3.66 (t, J=5.2 Hz, 1.3 H), 3.74 (t, J=5.4 Hz, 0.7 H), 3.86 (d, J=1.4 Hz, 3 H), 3.93 (t, J=5.2 Hz, 1.3 H), 4.03 - 4.12 (m, 0.7 H), 4.38 (s, 0.7 H), 4.44 (s, 1.3 H), 7.21 - 7.33 (m, 1 H), 7.40 - 7.53 (m, 2 H), 7.72 (s, 1 H); MS(ESI) m/z: 529.2 (MH+).
EXA PLE 96
4-{[3-chloro-5-cyc!opropy!-7-(trifluoro
(2-fluoro-4-hydiOxypheny[)»2-piperazinone
(Compound 96)
Figure imgf000221_0001
H
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 [2-fluoro-4-(methyloxy)phenyl]-2-piperazinone (199 mg, 0.390 mmol) was dissolved in DCM (4 mL) and cooled to -78 °C. After 5 minutes, boron t ibromide (0.295 mL, 3.12 mmol) was added dropwise. After 2 hours, the suspension was placed in an ice-water bath. After another 2 hours, the mixture was diluted with DCM to 25 mL and washed with saturated aqueous NaHC03 (8 mL), brine (8 mL), dried (Na2S04), filtered and concentrated. The residue was absorbed on silica gel and purified by silica gel
chromatography [10-65% EtOAc in hexanes] to give 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 J5-a]pyridin-2-yl]carbonyl}-1 -(2-f!uoro-4-hydroxyphenyl)-2- piperazinone (174.5 mg, 0.348 mmol, 89%) as a white powder (after lyophilization). 1H NMR (400 MHz, D SO-ofe) δ ppm 0.94 - 1.02 (m, 2 H), 1.06 - 1.15 (m, 2 H), 2.13 - 2.28 (m, 1 H), 3.61 (t, J=5.1 Hz, 1.2 H), 3.69 (t, J=5,4 Hz, 0.8 H), 3.91 (t, J=5.2 Hz, 1.2 H), 4.05 (t, J=5.2 Hz, 0.8 H), 4.34 (s, 0.8 H), 4.42 (s, 1.2 H), 6.58 - 6.70 (m, 2 H), 7.14 - 7.27 (m, 1 H), 7.45 (d, J=1.4 Hz, 1 H), 7.71 (s, 1 H), 10.07 (br. s., 1 H); MS(ESI) m/z: 497.2 ( H+). EXAMPLE 97
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- phenyl-2-piperazinone
{Compound 97)
Figure imgf000222_0001
The title compound (80.1 mg, 87%) was obtained as a white powder from 3-chloro-
5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1 - phenylpiperazin-2-one (ChemBridge) using a similar procedure to that described in Example 91 , Step C. 1H NMR (400 MHz, DMSO-cfe) δ ppm 0.91 - 1.04 (m, 2 H), 1.05 - 1.16 (m, 2 H), 2.17 - 2.30 (m, 1 H), 3.76 (t, J=5.5 Hz, 1.2 H), 3.86 (dd, J=5.8, 5.1 Hz, 0.8 H), 3.93 (t, J=4.9 Hz, 1.2 H), 4.05 (dd, J=5.8, 5.0 Hz, 0.8 H), 4.36 (s, 0.8 H), 4.43 (s, 1.2 H), 7.23 - 7.33 (m, 1 H), 7.33 - 7.49 (m, 5 H), 7.72 (s, 1 H); MS(ESI) m/z: 463.2 (MH+).
EXAMPLE 98
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (3-fluoro-4-hydroxypheny[)-2-piperazinone
(Compound 98)
Figure imgf000223_0001
The title compound was obtained (129,1 mg, 62%) as a white powder from 4-{[3- chloro-5-cyciopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[3-fluoro-4- (methyloxy)phenyl]-2-piperazinone using a similar procedure to that described in Example 96. H NMR (400 MHz, DMSO-c¾) 5 ppm 0.92 - 1.03 (m, 2 H), 1.05 - 1.15 (m, 2 H), 2.17 - 2.29 (m, 1 H), 3.68 (t, J=5.2 Hz, 1.2 H), 3.78 (t, J=5.4 Hz, 0.8 H), 3.90 (t, J=5.2 Hz, 1.2H), 4.03 (t, J=5.4 Hz, 0.8 H), 4.33 (s, 0.8 H), 4.39 (s, 1.2 H), 6.87 - 7.05 (m, 2 H), 7.17 -7.26 (m, 1 H), 7.45 (d, J=1.5 Hz, 1 H), 7.71 (s, 1 H), 9.98 (s, 1 H); MS(ESI) m/z: 497.2 (MH+).
EXAMPLE 99
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (2,3-difluoro-4-hydroxyphenyl)-2-piperazinone
(Compound 99)
Figure imgf000223_0002
The title compound was obtained (193.5 mg, 82%) as white powder from 4-{[3- chloro-5-cyclopropy]-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[2,3-difluoro- 4-(methyloxy)phenyi]-2-piperazinone using a similar procedure to that described in Example 96. 1H NMR (400 MHz, DMSO- /6) δ ppm 0.93 - 1.04 (m, 2 H), 1.05 - 1.15 (m, 2 H), 2.16 - 2.29 (m, 1 H), 3.66 (t, J=5.1 Hz, 1.2 H), 3.74 (t, J=5.4 Hz, 0.8 H), 3.95 (t, J=5.0 Hz, 1.2 H), 4.06 (t, J=5.2 Hz, 0.8 H), 4.38 (s, 0.8 H), 4.45 (s, 1.2 H), 6.75 - 6.90 (m, 1 H), 7.03 - .15 (m, 1 H), 7.45 (d, J=1 .3 Hz, 1 H), 7.71 (s, 1 H), 10.60 (br. s., 1 H); MS(ESI) m/z: 515.2 (MH+). EXAMPLE 100
4-{[3-chloro-5-cyc[opropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbo
(4-hydroxyphenyl)-2-piperazinone
(Compound 100)
Figure imgf000224_0001
Step A
1 ,1-dimethylethyl 4-(4-hydroxyphenyl)-3-oxo~1~piperazinecarboxylate The title compound (194.7 mg, 13%) was obtained as an off-white solid from 1-Boc-3- oxopiperazine and 4-bromophenol using a similar procedure to that described in Example 91 , Step A. MS{ESI m/z): 293.3 (MH*).
Step B
1 -(4-hydroxyp enyI)-2-piperazinone hydrochloride The title compound (160.9 mg, quantitative) was obtained as white solid from 1 ,1- dimethylethyl 4-(4-hydroxyphenyl)-3-oxo-1 -piperazinecarboxylate using a similar procedure to that described in Example 91 , Step B. S(ESl) m/z: 193.2 (MH+).
Step C
4-{[3-chloro-5 ;yclopmpyl-7-(trifluoromethyi)pyrazoIo[1,5-a]pyridin^
hydroxyphenyl)~2~piperazinone
The title compound (63 mg, 66%) was obtained as white powder from 3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1-(4- hydroxyphenyl)-2-piperazinone hydrochloride using a similar procedure to that described in Example 91 , Step C. 1H NM (400 MHz, DMSO-c 6) 5 ppm 0.90 - 1.02 (m, 2 H), 1.04 - 1 .15 (m, 2 H), 2.17 - 2.29 (m, 1 H), 3.66 (t, J=5.1 Hz, 1 .2 H), 3.75 (t, J=5.4 Hz, 0.8 H), 3.89 (t, J=5.2 Hz, 1.2 H), 4.04 (t, J=5.4 Hz, 0.8 H), 4.30 (s, 0.8 H), 4.38 (s, 1.2 H), 6.69 - 6.82 (m, 2 H), 7.12 (m, 2 H), 7.45 (d, J=1.1 Hz, 1 H), 7.72 (s, 1 H), 9.43 - 9.59 (m, 1 H);
MS(ESI) m/z: 479.2 ( H+). EXAMPLE 101
4-{[3-chloro-5-cyclopropyl-7-{trifluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (2,5-difluoro-4-hydroxyphenyl)-2-piperazinone
(Compound 101)
Figure imgf000225_0001
The title compound was obtained (233.5 mg, 80%) as a white powder from 4-{[3- chloro-S-cyclopropyl-T-itrifluoromethy pyrazoloEI ^-aJpyridin^-yljcarbonyli-l-p.S-difluoro- 4-(methyloxy)phenyl]-2-piperazinone using a similar procedure to that described in Example 96. 1H NMR (400 MHz, DMSO-c/6) δ ppm 0.91 - 1.02 (m, 2 H), 1.04 - 1.15 (m, 2 H), 2.17 - 2.27 (m, 1 H), 3.64 (t, J=5.2 Hz, 1 .2 H), 3.72 (t, J=5.4 Hz, 0.8 H), 3.92 (t, J=5.2 Hz, 1.2 H), 4.02 - 4.12 (m, 0.8 H), 4.36 (s, 0.8 H), 4.43 (s, 1.2 H), 6.76 - 6.95 (m, 1 H), 7.31 - 7.42 {m, 1 H), 7.44 (d, J=1.3 Hz, 1 H), 7.71 (s, 1 H), 10.55 (br. s., 1 H); MS(ESI m/z): 515.2 (MH+).
EXAMPLE 102
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (4-cyclopropyl-2-fluorophenyl)-2-piperazinone
(Compound 102}
Figure imgf000225_0002
Step A
4~(4~{[3-chloro-5~cyclopropyl~7-(trifluoromethyl)pyrazolo[1,5
1 -piperazinyt)-3-fluoropheny! trifluoromethanesulfonate To a solution of 4~{[3-chloro-5-cyc[opropyl-7-(tnfluoromethy!)pyrazolo[1 ,5-a]py din- 2-yl]carbonyl}-1 -(2-fluoro-4-hydroxyphenyl)-2-piperazinone (89.8 mg, 0.181 mmol) and N,N-diisopropylethylamine (0.079 mL, 0.452 mmol) in DCM (2 mL) at 0 °C was added N- phenyltrifluoromethanesulfonimide (71.0 mg, 0.199 mmol). After 30 minutes, the mixture was allowed to stir at room temperature overnight. The mixture was loaded on silica gel column and eluted with 10-50% EtOAc in hexanes to give 4-(4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-2-oxo-1 -piperazinyl)-3-f!uorophenyl trifluoromethanesulfonate (106.7 mg, 0.168 mmo!, 93%) as a white solid. 1H NMR (400 MHz, DMSO-oiB) δ ppm 0.93 - 1.03 (m, 2 H), 1.07 - 1.14 (m, 2 H), 2.17 - 2.29 (m, 1 H), 3.74 (t, J=5.1 Hz, 1.2 H), 3.83 (t, J=5,4 Hz, 0.8 H), 3.96 (t, J=5.1 Hz, 1.2 H), 4.09 (t, J=5.4 Hz, 0.8 H), 4.42 (s, 0.8 H), 4.48 (s, 1.2 H), 7.45 (d, J=1.5 Hz, 1 H), 7.50 (dd, J=8.8, 1.9 Hz, 1 H), 7.67 - 7.77 (m, 2 H), 7.80 (ddd, J=10.0, 4.8, 2.8 Hz, 1 H); MS(ESI) m/z: 629.2 (MH+).
Step B
4-{[3~chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yi]carbonyl}- 1-(4- cyclopropyl-2-fluorophenyl)~2-piperazinone
A suspension of 4-(4-{[3-chloro-5-cyclopropy]-7-(trifluoromethyl)pyrazo!o[1 ,5- a]pyridin-2-yl]carbonyl}-2-oxo-1 -piperazinyl)-3-fluorophenyl trifluoromethanesulfonate (52 mg, 0.083 mmol), cyclopropyiboronic acid (14.20 mg, 0.165 mmol), palladium(ll) acetate (0.743 mg, 3.31 Mmol), potassium phosphate tribasic (52.7 mg, 0.248 mmol), cataCXium® A (1.186 mg, 3.31 pmol) was heated to 80 °C in toluene (0.7 mL) and water (0.3 mL). After 5 hours 20 minutes, Pd(dppf)CI2.DCM (2 mg) and cyclopropyiboronic acid (10 mg) were added and the mixture was heated at 100 °C overnight. LCMS showed a trace of product. The mixture was transferred to microwave vial and DMF (1 mL), Pd(dppf)CI2.DCM (3 mg) and cyclopropyiboronic acid (10 mg) were added and heated at 100 °C for 10 minutes, then 150 °C for 5 minutes under microwave conditions. The mixture was diluted with EtOAc (25 mL) and washed with saturated aqueous NaHC03 (8 mL), brine (8 mL), dried (Na2S04), filtered and concentrated. The residue was absorbed on silica gel and purified by silica gel chromatography [0-70% EtOAc in hexanes] to give 4-{[3-chloro-5-cyclopropyl- 7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony]}-1 -(4-cyclopropyl-2-fluorophenyl)-2- piperazinone (8.8 mg, 0.016 mmol, 20%) as colorless film and 4-{[3-chloro-5-cyclopropyl- 7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y!]carbonyl}-1-(2-fluoro-4-hydroxyphenyl)-2- piperazinone (15.2 mg, 0.031 mmol, 37%).
Data for 4-{t3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-(4-cyclopropyl-2-fluorophenyl)-2-piperazinone: H NMR (400 MHz,
CHLOROFORM-c δ ppm 0.63 - 0.75 (m, 2 H), 0.82 - 0.91 (m, 2 H), 0.96 - 1.05 (m, 2 H), 1 .10 - 1.22 (m, 2 H), 1.83 - 1 .97 (111 , 1 H), 1.97 - 2.10 (m, 1 H), 3.80 (t, J=5.6 Hz, 2 H), 4.15 - 4.22 (m, 2 H), 4.53 (s, 1 H), 4.63 (br. s., 1 H), 6.85 (ddd, J=1 1.5, 4. , 1.9 Hz, 1 H), 6.91 (ddd, J=7.9, 5.8, 1.8 Hz, 1 H), 7.03 - 7.09 (m, 1 H), 7.11 - 7.23 (m, 1 H), 7.43 (dd, J=7.0, 1.2 Hz, 1 H); MS(ESI m/z): 521.2 (MH+).
Data for 4-{[3-ch[oro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-(2-fluoro-4-hydroxyphenyl)-2-piperazinone: 1H NMR (400 MHz, DMSO-<¾) δ ppm 0.93 - 1.04 (m, 2 H), 1.05 - 1.15 (m, 2 H), 2.16 - 2,28 (m, 1 H), 3.61 (t, J=5.2 Hz, 1.2 H), 3.69 (t, J=5.4 Hz, 0.8 H), 3.91 (t, J=5.2 Hz, .2 H), 4.02 - 4.1 1 (m, 0.8 H), 4.34 (s, 0.8 H), 4.42 (s, 1.2 H), 6.56 - 6.72 (m, 2 H), 7.14 - 7.28 (m, 1 H), 7.45 (d, J=1.5 Hz, 1 H), 7,72 (s, 1 H), 10.05 (s, 1 H); MS(ESI m/z): 497.2 (MH*).
EXAMPLE 103
[4-(4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-2-oxo-1-piperazinyl)-3-fluorophenyl]boronic acid
(Compound 103)
-OH
Figure imgf000227_0001
Step A
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyri^
fluoro-4-(4!4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-piperazinon
A suspension of 4-(4-{[3-chloro-5-cyclopropy[-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyI}-2-oxo-1 -piperazinyl)-3-fluorophenyl trifluoromethanesulfonate (52 mg, 0.083 mmol), bis(pinacolato)diboron (24.48 mg, 0.087 mmol), potassium acetate (24.34 mg, 0.248 mmol), PdCI2(dppf)-CH2C!2 adduct (3.38 mg, 4.13 pmol) was heated to 100 °C in 1 ,4-dioxane (2 mL). After 3.5 hours, bis(pinacolate)diboron (50 mg), and potassium acetate (50 mg) were added to reaction mixture and continued to heat at 100
°C. After 5 hours, the mixture was transferred to a microwave vial and heated at 120 °C for
10 minutes under microwave conditions. The mixture was cooled, diluted with EtOAc (20 mL), washed with brine (8 mL), dried (Na2S04), filtered and concentrated. The crude was purified by silica gel chromatography [0-75% EtOAc in hexanes] to give 4-{[3-chloro-5- cycIopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a^
ietramethyl-1 ,3,2-dioxaborolan-2-y[)phenyl]-2-piperazinone (20.2 mg, 0.033 mmol, 40% yield) as a film. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 0.82 - 0.92 (m, 2 H), 1.13 - 1.22 (m, 2 H), 1.25 (s, 12 H), 1 .99 - 2.1 1 (m, 1 H), 3.85 (t, J=5.0 Hz, 2 H), 4.21 (q, J=5.0 Hz, 2 H), 4.56 (s, 1 H), 4.66 (s, 1 H), 7.07 (br. s., 1 H), 7.33 (dt, J=18.1 , 7.5 Hz, 1 H), 7.44 (d, J=4.9 Hz, 1 H), 7.57 - 7.69 (m, 2 H); MS(ESI m/z): 607.3 (MH+).
Step B
[4-(4~{[3-chioro-5 yclopropyl-7-(trifluoromethyi)pyrazolo[
oxo- 1~piperazinyl)-3-fluorophenyl]boronic acid
To a stirred suspension of 4-{[3-chloro-5-cyciopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2^
1 ,3,2-dioxaborolan-2-yl)phenyl]-2-piperazinone (20 mg, 0.033 mmol) in acetone (1 mL), tetrahydrofuran (THF) (0.5 mL) and water (1 mL) was added ammonium acetate (7.6 mg, 0.099 mmol) and sodium periodate (21.1 mg, 0.099 mmol). After 1 day, the mixture was diluted with EtOAc (25 mL) and the organic phase was separated, dried (Na2S04), filtered and concentrated. The crude was purified by reverse phase HPLC [10-90% ACN,
0.1 %formic acid] to give [4-(4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-2-oxo-1 -piperazinyl)-3-fluorophenyl]boronic acid (8.8 mg, 0.017 mmol, 50% yield) as white powder (after lyophilization). 1H NMR (400 MHz, METHANOL- dA) δ ppm 0.87 - 0.99 (m, 2 H), 1.14 - 1.22 (m, 2 H), 2.09 - 2.23 (m, 1 H), 3.84 (t, J=5,2 Hz, 1.2 H), 3.88 (t, J=5.5 Hz, 0.8 H), 4.12 (t, J=5.2 Hz, 1.2 H), 4.24 (t, J=5.4 Hz, 0.8 H), 4.56 (s, 0.8 H), 4.60 (s, 1 .2 H), 7.30 - 7.35 (m, 1 H), 7.35 - 7.59 (m, 3 H), 7.61 (s, 1 H); MS(ESI m/z): 525.2 (MH+).
EXAMPLE 104
4-{[3-chloro-5-cyclopropyl-7-(trifl^
(3-hydroxyphenyl)-2-piperazinone
(Compound 104)
Figure imgf000229_0001
Step A
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyI)pyrazolo[1,5
(methyloxy)phenyl]-2-piperazinone
The title compound (139.9 mg, 86%) was obtained as white powder from 3-chloro-
5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1 -[3- (methyioxy)phenyl]-2-piperazinone (ChemBridge) using a similar procedure to that described in Example 91 , Step C. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 - 1.02 (m, 2 H), 1.06 - 1.14 (m, 2 H), 2.16 - 2.29 (m, 1 H), 3.70 - 3.79 (m, 4.2 H), 3.81 - 3.88 (m, 0.8 H), 3.92 (t, J=5.2 Hz, 1.2 H), 4.05 (t, J=5.4 Hz, 0.8 H), 4.36 (s, 0.8 H), 4.41 (s, 1.2 H), 6.83 - 6.90 (m, 1 H), 6.93 (d, J=7.9 Hz, 1 H), 6.95 - 7.00 (m, 1 H), 7.26 - 7.36 (m, 1 H), 7.45 (d, J=1.2 Hz, 1 H), 7.72 (s, 1 H); MS(ESI m/z): 493.1 (MH+).
Step B
4-{[3-chloro-5-cyclopropyl-7~(trifluoromethyl)pyrazolo[ 1, 5~a]pyridin~2~yl]carbonyi}- 1-(3- hydroxyphenyl) -2-pip erazinone
The title compound was obtained (92.5 mg, 81 %) as white powder from 4-{[3- ch!oro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a3pyridin-2-yl]carbonyl}-1 -[3- (methyloxy)phenyl]-2-piperazinone using a similar procedure to that described in Example 96. 1H NMR (400 MHz, DMSO-af6) 6 ppm 0.92 - 1 .03 (m, 2 H), 1.05 - 1.15 (m, 2 H), 2.15 - 2.30 (m, 1 H), 3.67 - 3.74 (m, 1.2 H), 3.81 (t, J=5.4 Hz, 0.8 H), 3.90 (t, J=5.2 Hz, 1.2 H), 4.03 (t, J=5.4 Hz, 0.8 H), 4.33 (s, 0.8 H), 4.40 (s, 1.2 H), 6.64 - 6.72 (m, 1 H), 6.73 - 6.80 (m, 2 H), 7.13 - 7.24 (m, 1 H), 7.45 (d, J=1.5 Hz, 1 H), 7.71 (s, 1 H), 9.53 - 9.65 (m, 1 H); MS(ESI m/z): 479.2 (MH+).
EXAMPLE 105
4-{[3-chloro-5-cyclopropyl-7-{trifluoromethyl)pyrazoio[1,5-a]pyridin-2-yl]carbonyl}-1- (4-hydroxyphenyl)-3-methyl-2-piperazinone
(Compound 105)
Figure imgf000230_0001
Step A
4~{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrtf
1-[4-(methyloxy)phenyl]-2-piperazinone
The title compound (141.2 mg, 84%) was obtained as a white powder from 3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine~2~carboxyiic acid and 3- methyl-1 -[4-(methyloxy)phenyl]~2-piperazinone hydrochloride (ChemBridge) using a similar procedure to that described in Example 91 , Step C. 1H NMR (400 MHz, DMSO-c/6) δ ppm 0.92 - 1.04 (m, 2 H), 1.04 - 1.15 (m, 2 H), 1.54 (d, J=7.0 Hz, 1.8 H), 1.59 (d, J=7.Q Hz, 1.2 H), 2.14 - 2.30 (m, 1 H), 3.45 - 3.69 (m, 1.4 H), 3.71 - 3.92 (m, 4.6 H), 3.91 - 4.08 (m, 0.6 H), 4.46 - 4.64 (m, 0.8 H), 4.96 (q, J=6.9 Hz, 0.6 H), 6.87 - 7.03 (m, 2 H), 7.18 - 7.35 (m, 2 H), 7.44 (s, 1 H), 7.72 (d, J=0.9 Hz, 1 H); MS(ESI m/z): 507.2 ( H+).
Step B
4-{[3~chloro~5~cyclopropyI-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1-(4~ hydroxyphenyl)-3-methy!-2-piperazinone
The title compound was obtained (103.2 mg, 87%) as a white powder from 4-{[3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-3-methyl-1-[4- (methyloxy)phenyl]-2-piperazinone using a similar procedure to that described in Example 96. H NMR (400 MHz, DMSO-c 6) δ ppm 0.90 - 1.02 (m, 2 H), 1.05 - 1.14 (m, 2 H), 1 .53 (d, J=7.0 Hz, 1.8 H), 1 .57 (d, J=7.0 Hz, 1.2 H), 2.15 - 2.32 (m, 1 H), 3.42 - 3.67 (m, 1.4 H), 3.68 - 3.88 (m, 1.6 H), 3.91 - 4.06 (m, 0.6 H), 4.44 - 4.62 (m, 0.8 H), 4.94 (q, J=6.9 Hz, 0.6 H), 6.75 (dd, J=8.8, 2.9 Hz, 2 H), 7,07 - 7.16 (m, 2 H), 7.44 (s, 1 H), 7.71 (s, 1 H), 9.52 (br. s., 0.4 H), 9.53 (s, 0.6 H); MS(ESl m/z): 493.2 (MH+).
EXAMPLE 106
4-{[3-chloro-5-cyclopropyl-7-(trif[uoromethyl)pyra2olot1,5-a]pyridin-2-yl]carbonyl}-1- [(5R)-2-hydroxy-1 ,2-oxaborinan-5-yl]-2-piperazinone
(Compound 106)
Figure imgf000231_0001
Step A
[(1R)-1-({[(1, 1-dimethylethyl)(diphenyl)siiyl]oxy}methy!)~2-propen-1^
TBDPSCI (1.143 mL, 4.45 mmol) was added to a solution of (2R)-2-amino-3-buten- 1-ol (500 mg, 4.05 mmol) and imidazole (551 mg, 8.09 mmol) dissolved in N,N- Dimethylformamide (5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction was partitioned between EtOAc and sat'd NaHC03. The organic phase was separated, dried over sodium sulfate and evaporated to an oil. The oil was purified by silica gel chromatography eluting with 0 to 50 % EtOAc and Hexanes to afford [(1 R)-1-({[(1 ,1-dimethylethyl)(diphenyl)si!yl]oxy}methyl)-2-propen-1 -yl]amine (701 mg, 2.153 mmol, 53%) as a clear colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 - 7.73 (m, 4H), 7.34 - 7.49 (m, 6H), 5.76 - 5.88 (m, 1 H), 5.22 (d, J = 17.20 Hz, 1 H), 5.10 (d, J = 10.55 Hz, 1 H), 3.63 - 3.72 (m, 1 H), 3.46 - 3.57 (m, 2H), 1.08 (s, 9H). Ste B
N1-[(1R)-1~({[(1, 1~dimethylethyl)(diphenyl)silyl]oxy}methyl)^rope
nitrophenyl)su!fonyl]glycinamide
N-[(4-nitrophenyl)sulfonyl]glycine (273 mg, 1.048 mmol), [(1 )-1-({[(1 ,1- dimethylethyl)(diphenyl)silyI]oxy}methyl)-2-propen-1 -yl]amine (310 mg, 0.952 mmol), HOBT (146 mg, 0.952 mmol) and DIPEA (0.249 mL, 1.428 mmol) were combined in N,N- Dimethylformamide (8 mL). To this solution was added EDC (183 mg, 0.952 mmol) and the mixture stirred overnight. The reaction mixture was partitioned between water and EtOAc and the organic layer was washed with brine, dried over sodium sulfate and evaporated to afford N1 -[(1 R)-1-({[(1 , 1-dimethylethyl)(diphenyl)si!yl]oxy}methyI)-2-propen- 1 -yl]-N2-[(4-nitrophenyl)sulfonyl]glycinamide (541 mg, 0.953 mmol, quant.) which was used as is without purification. 1H NMR (CHLOROFORM-d) δ ppm 8.32 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 8.8 Hz, 2H), 7.58 - 7.65 (m, 4H), 7.34 - 7.48 (m, 7H), 6.38 (d, J = 8.2 Hz, 1 H), 5.77 (ddd, J = 16.8, 10.9, 5.7 Hz, 1 H), 5.06 - 5.18 (m, 2H), 4.46 (ddd, J = 8.2, 4.1 , 1.4 Hz, 1 H), 3.65 - 3.77 (m, 2H), 3.50 - 3.64 (m, 2H), 0.95 - 1.13 (m, 9H). Step C
1WR)-1~({[(1, 1-dimethylethyl)(diphenyi)siiyl]oxy}m^
nitrophenyl)sulfonyl]-2-piperazinone
N1-[(1 R)-1-({[(1 ,1 -dimethyiethy!)(diphenyl^
nitrophenyl)sulfonyl]glycinamide (541 mg, 0.953 mmol), K2C03 (1054 mg, 7.62 mmol), and 1 ,2-dibromoethane (0.657 mL, 7.62 mmol) were combined in Ν,Ν-Dimethyiformamide (8 mL) and heated to 55 °C. The reaction was poured into water and EtOAc and the organic layer was separated, washed with brine and dried over sodium sulfate. The organic phase was filtered and evaporated to afford 1-[(1 R)-1-({[(1 ,1- dimethyIethyl)(diphenyl)silyl]oxy}methyl)-2-propen-1 -yl]-4-[(4-nitrophenyi)suIfonyl]-2- piperazinone (566 mg, 0.953 mmol, quant.) as a crude product which was used without further purification. ΊΗ NMR (400 MHz, CHLOROFORM-d) δ ppm 8.42 (d, J = 8.79 Hz, 2H), 7.99 (d, J = 8.79 Hz, 2H), 7.57 - 7.63 (m, 4H), 7.33 - 7.47 (m, 6H), 5.69 (ddd, J = 5.77, 10.85, 17.20 Hz, 1 H), 5.23 (d, J - 10.55 Hz, 1 H), 5.15 - 5.21 (m, 1 H), 5.1 1 (d, J - 17.39 Hz, 1 H), 3.66 - 3.92 (m, 4H), 3.31 - 3.43 (m, 3H), 3.1 1 - 3.22 (m, 1 H), 1.02 (s, 9H).
Step D
1-[(1R)-1-({[(1, 1-dimethylethyl)(diphenyl)silyl]oxy}methyI)-2-prope
1 -[(1 R)-1-({[(1 , 1 -dimethylethyi)(diphenyl)silyl]oxy}methyl)-2-propen-1 -y!]-4-[(4- nitrophenyl)sulfonyl]-2~piperazinone (335 mg, 0.564 mmol), Thiophenol (93 mg, 0.846 mmol), and K2C03 (234 mg, 1.693 mmol) were combined in Acetonitrile (5 mL) and heated to 60 °C and monitored by LCMS. Upon reaction completion, solids were filtered off and the filtrate evaporated. The residue was purified by silica gel chromatography, eluting with MeOH and DCM to afford 1 -[(1 R)-1-({[(1 ,1 -dimethylethyl)(diphenyl)silyl]oxy}methyl)-2- propen-1-yl]-2-piperazinone (154 mg, 0.377 mmol, 66%) as an oil. 1H NMR (400 MHz, METHANOLS) δ ppm 7.64 (d, J = 7.23 Hz, 4H), 7.30 - 7.49 (m, 6H), 5.67 - 5.84 (m, 1 H), 5.08 - 5.26 (m, 3H), 3.72 - 3.90 (m, 2H), 3.42 (d, J = 2.93 Hz, 2H), 3.23 - 3.30 (m, 2H), 2.87 - 3.00 (m, 2H), 1.01 (s, 9H). MS (ESI) m/z = 409.4 (MH+). Step E
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1-[(1R)- 1-({[(1, 1-dimethylethyl)(dipheny!)silyl]oxy}methyl)-2^ropen-1-yl]-2-pfc^
1 -[(1 R)-1 -({[( 1 ,1 -dimethylethyl)(diphenyl)silyI]oxy}methyl)-2-propen-1 -yl]-2- piperazinone ( 50 mg, 0.367 mmol) was dissolved in DMF. To this solution was added 3- chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (1 12 mg, 0.367 mmol), and DIPEA (192 μΙ, 1.101 mmol) followed by 1-propanephosphonic acid cyclic anhydride in EtOAc (50% wt) (350 mg, 1.101 mmol). The reaction was stirred at room temperature for 1 hour and poured into water and a precipitate formed. The precipitate was filtered off and washed with water. The yellow solid was dried under vacuum to afford 4-{[3-chloro-5-cyclopropy!-7-(trif!uoromethyl)pyrazolo[1 ,5-a]pyridin-2- yi]carbonyl}-1 -[(1 R)-1 -({[(1 , -dimethylethyl)(diphenyl)silyl]oxy}methyl)-2-propen-1 -yl]-2- piperazinone (213 mg, 0.306 mmol, 83%), 1H NMR (400 MHz, CHLOROFOR -d) δ ppm 7.64 (d, J = 7.42 Hz, 4H), 7.32 - 7.47 (m, 7H), 7.05 (s, 1 H), 5.65 - 5.88 (m, J = 5.76, 10.69, 16.87, 16.87 Hz, 1 H), 5,10 - 5.33 (m, 3H), 4,35 - 4.60 (m, 2H), 3.99 - 4.10 (m, 1 H), 3.69 - 3.94 (m, 3H), 3.30 - 3.59 (m, 2H), 1.09 - 1.21 (m, 2H), 1.03 (s, 9H), 0.78 - 0.92 (m, 3H).
Step F
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyi)pyrazolo[1,5-a]p^
2-hydroxy- 1, 2-oxaborinan-5-yl]-2-piperazinone
Chloro(1 ,5cyclooctadiene)lridium(1 ) dimer (1.449 mg, 2.158 μmol) and 1 ,2- bis(diphenylphosphino)ethane (1.719 mg, 4.32 μιηοΙ) were placed in a 1 dram vial with .5 ml of DCM and stirred for 10 min. To this was added 4-{[3-chloro-5-cyclopropy!-7- (trifluoromethyl)pyrazolo[1 l5-a]pyndin-2-yl]carbonyl}-1 -[(1 R)-1 -({[(1 ,1 - dimethyIethy!)(diphenyl)silyl]oxy}methyl)-2-propen-1 -yl]-2-piperazinone (30 mg, 0.043 mmol) followed by pinacol borane (0.043 mL, 0.043 mmol) at 0 °C. The reaction was stirred in the ice bath followed by stirring at room temperature once the ice melted.
Another portion of Chloro(1 ,5cyclooctadiene)lridium(1 ) dimer (1 .449 mg, 2.158 μητιοΙ), and 1 ,2-bis(diphenylphosphino)ethane (1.719 mg, 4.32 pmoi) were put into a 1 dram vial with .5 mL of DCM and stirred. The catalyst was added to the reaction mixture along with a second addition of pinacol borane (0.043 mL, 0.043 mmol). The reaction mixture was quenched with methanol and evaporated to a residue. The residue was purified by prep HPLC (10 to 100% ACN H20 0.1 % TFA) to afford the protected intermediate. This was evaporated to a residue and treated with 4 N HCL in dioxane to deprotect the compound and close the CBO ring. The mixture was evaporated to a residue and repurified on Prep HPLC (10 to 100% ACN H20 0.1 % TFA) to afford 4-{[3-chloro-5-cyclopropyl-7- (trifluoromethy])pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}-1 -[(5R)-2-hydroxy-1 ,2-oxaborinan-5- yl]-2-piperazinone (4.2 mg, 8.67 μιηοΙ, 20%) as a film. 1H NMR (400 MHz, METHANOL- d4) δ ppm 7.59 (s, 1 H), 7.32 (s, 1 H), 4.27 - 4.60 (m, 3H), 3.74 - 4.18 (m, 3H), 3.37 - 3.60 (m, 2H), 2.06 - 2.22 (m, 1 H), 1.67 - 1.93 (m, 1 H), 1.13 - 1.21 (m, 2H), 0.73 - 0.97 (m, 3H). MS (ESI) m/z: 485.3 (MH+). Example 107
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyi}-1- [(5S)-2-hydroxy-1 ,2-oxaborinan-5-yl]-2-piperazinone
(Compound 107)
Figure imgf000234_0001
OH
Step A
[(1S)-1-({[(1, 1-dimethylethyl)(dimethyl)siIyl]oxy}methyl)-2^ro
To a stirred solution of (2S)-2-amino-3-buten-1-ol (1.5 g, 17.22 mmol) and 2,6- lutidine (8.00 mL, 68.9 mmol) in Dichloromethane (DCM) (14 mL) at 0 °C was added TBSOTf (1 1.86 mL, 51 .7 mmol) under a nitrogen atmosphere. The resulting reaction mixture was stirred at 0 °C for 30 minutes, then room temperature for 1 h. The reaction was quenched with MeOH (1 mL), poured into water and extracted with ether (3 x 50 mL). The combined extracts were washed with water, saturated NaHC03, brine, and dried over Na2S04. The organic phase was filtered and evaporated to a residue which was purified by silica gel chromatography eluting with 0 to 5 % MeOH in DCM to afford [(1 S)-1-({[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-propen-1-yI]amine (1.26 g, 6.26 mmol, 36%) as a light brown oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.77 - 5.85 (m, 1 H), 5.19 (dt, J = 1.71 , 17.30 Hz, 1 H), 5.01 - 5.09 (m, 1 H), 3.35 - 3.50 (m, 2H), 3.29 (q, J = 5.67 Hz, 1 H), 2.09 (br. s., 2H), 0.86 (s, 9H), 0.03 (s, 6H).
Step B
N1-[(1S)-1-({[(1, 1-dimethy!ethyl)(dimethyl)s^
nitrophenyl)sulfonyl]giycinamide
N-[(4-nitrophenyl)sulfonyl]glycine (1.75 g, 6.72 mmol), [(1S)-1-({[(1 ,1 - dimethylethyi)(dimethyl)silyl]oxy}methyl)-2-propen-1 -yl]amine (1.231 g, 6. 1 mmol), HOBT (0.936 g, 6.1 1 mmol) and DIPEA (1.602 mL, 9.17 mmol) were combined in N,N- Dimethylformamide (8 mL). To this solution was added EDC (1.172 g, 6.1 1 mmol) and the mixture stirred overnight. The reaction mixture was partitioned between water and EtOAc and the organic layer was washed with brine, dried over sodium sulfate and evaporated to afford N1 -[(1 S)~1-({[( 1 , 1 -dimethylethyl)(dimethy!)silyl]oxy}methyl)-2-propen-1 -yl]-N2-[(4- nitrophenyl)su!fonyl]glycinamide (2.48 g, 5.59 mmol, 91 %) as a tacky gum. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.37 (d, J = 8.78 Hz, 2H), 8.07 (d, J = 8.78 Hz, 2H), 6.16 (d, J = 7.41 Hz, 1 H), 5.75 (ddd, J = 5.95, 10.68, 16.93 Hz, 1 H), 5.47 (br. S„ 1 H), 5.05 - 5.23 (m, 2H), 4.35 - 4.48 (m, 1 H), 3.72 (d, J = 5.46 Hz, 2H), 3.58 - 3.69 (m, 2H), 0.89 (s, 9H), 0.05 (s, 6H). MS (ESI) m/z = 444.3 (MH+), Step C
1-[(1S)-1-({[(1, 1-dimethylethyl)(dimethyi)sily^
nitrophenyl)sulfonyl]-2-piperazinone
N1 -[(1 S)-1 -({[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-prop8n- 1 -yl]-N2-[(4- nitrophenyl)sulfonyl]glycinamide (2.48 g, 5.59 mmol), 1 ,2-dibromoethane (3.85 mL, 44.7 mmol), and K2C03 (6.18 g, 44.7 mmol) were combined in N,N-Dimethylformamide (15 mL) and stirred overnight. The reaction mixture was filtered and partitioned between EtOAc and water and the organic phase was washed with brine, dried over sodium sulfate and evaporated to a residue. The residue was purified by silica gel chromatography, eluting with 0 to 80 % EtOAc and hexanes to afford 1-[(1 S)-1 -({[(1 ,1- dimethylethyl)(dimethyl)siiyi]oxy}methyl)-2-propen-1 -yl]-4-[(4-nitrophenyl)sulfonyl]-2- piperazinone (1.95 g, 4.15 mmol, 74%) as a yellow solid. H NMR (400 MHz,
CHLOROFORM-d) 6 ppm 8.41 (d, J = 8.79 Hz, 2H), 7.99 (d, J = 8.79 Hz, 2H), 5.75 (ddd, J = 5.96, 10.84, 17.19 Hz, 1 H), 5.1 1 - 5.31 (m, 2H), 4.94 - 5.08 (m, 1 H), 3.81 - 3.92 (m, 1 H), 3.69 - 3.81 (m, 3H), 3.36 - 3.58 (m, 3H), 3.17 - 3.32 (m, 1 H), 0.83 (s, 9H), 0.01 (d, J = 4.30 Hz, 6H). MS (ESI) m/z = 470.4 (MH+).
Step D
1-[(1S)-1-({[(1, 1<limethylethyl)(dimethyl)silyl]oxy}methyl)-2^
1 -[(1 S)-1 -({[(1 ,1 -dimethylethyl)(dimethyl)silyl3oxy}methyl)-2-propen-1-yl]-4-[(4- nitrophenyl)sulfonyl]-2-piperazinone (1.95 g, 4.15 mmol), Thiophenol (0.686 g, 6.23 mmol), and K2C03 (1.722 g, 12.46 mmol) were combined in Acetonitriie (5 mL) and heated to 60 °C. The reaction was monitored by LCMS. The reaction mixture was filtered and the organic phase washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and evaporated to a residue. The residue was purified by silica gel chromatography, eluting with 0 to 0 % MeOH in DCM to afford 1 -[(1S)-1-({[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-propen-1-yl]-2-piperazinone (595 mg, 2.092 mmol, 50%) as a yellow liquid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.85 (ddd, J = 5.86, 10.80, 17.15 Hz, 1 H), 5.15 - 5.35 (m, 2H), 5.09 (q, J = 5.80 Hz, 1 H), 3.81 (d, J = 5.86 Hz, 2H), 3.57 (s, 2H), 3.23 - 3.43 (m, 2H), 2.94 - 3.17 (m, 2H), 1.90 (br. s., 1 H), 0.88 (s, 9H), 0.06 (s, 6H). Step E
4-{[3-chloro-5-cyclopropyl- 7-(trifluoromethyl) pyrazolo[ 1 , 5-a]pyridin-2-yl]carbonyi} -1~[(1S)-1- ({[(1, 1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-2^ropen-1-yl^^
1 -[(1 S)-1 -({[(1 , 1 -dimethyiethyl)(dimethyl)silyl]oxy}methyl)-2-propen-1 -yl]-2- piperazinone {150 mg, 0.527 mrnol), 3-chloro-5-cyclopropyl-7-
(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxy[ic acid (161 mg, 0.527 mrnol), and DIPEA (0.276 mL, 1.582 mrnol) were combined in N,N-Dimethylformamide (5 mL). To this solution was added 1-propanephosphonic acid cyclic anhydride in EtOAc (50% wt) (503 mg, 1.582 mmoi) and the reaction was stirred for 2 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and evaporated to a residue. The residue was purified by silica gel chromatography, eluting with 0 to 100 % EtOAc and hexanes to afford 4-{[3-chloro-5- cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-[(1 S)-1-({[(1 ,1 - dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-propen-1-yl]-2-piperazinone (121.8 mg, 0.213 mrnol, 40 % yield) as an oil. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.42 (d, J = 5.67 Hz, 1 H), 7.06 (d, J = 1.37 Hz, 1 H), 5.77 - 5.96 (m, 1 H), 5.22 - 5.38 (m, 2H), 5.02 - 5.21 (m, 1 H), 4.37 - 4.64 (m, 2H), 4.03 - 4.21 (m, H), 3.75 - 3.94 (m, 3H), 3.38 - 3.66 (m, 2H), 1.98 - 2.10 (m, 1 H), 1.69 (br. s., 2H), 1.12 - .22 (m, 2H), 0.88 (d, J = 3.91 Hz, 9H), 0.07 (s, 6H).
Step F
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyi}-1-[(5S)-2- hydroxy- 1, 2-oxaborinan-5-yl]-2-piperazinone
Chloro(1 ,5cyclooctadiene)!ridium(1 ) dimer (5.70 mg, 8.49 pmol) and 1 ,2- bis(diphenylphosphino)ethane (6.77 mg, 0.017 mrnol) were placed in a 1 dram viai with 0.5 ml of DCM and stirred for 10 min. To this was added 4-{[3-chloro-5-cyc!opropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -[(1 S)-1-({[(1 , 1- dimethylethyl)(dimethyl)silyl]oxy}methyl)-2-propen-1-yl]-2-piperazinone (97 mg, 0.170 mrnol) followed by pinancol borane (0.170 mL, 0.170 mrnol) at 0 °C. The reaction was stirred in an ice bath followed by stirring at room temperature once the ice melted. Another solution of Chloro(1 ,5cyclooctadiene)lridium(1 ) dimer (5.70 mg, 8.49 pmol), and 1 ,2- bis(diphenyiphosphino)ethane (6.77 mg, 0.017 mrnol) in 0.5 mL of DCM was made and added to the reaction mixture along with a second addition of pinacol borane (0.170 mL, 0.170 mrnol). The reaction mixture was quenched with methanol and evaporated to a residue. The residue was stirred in 4 N HCI in dioxane for 30 min. The reaction was evaporated to a residue and purified by Prep HPLC (10 to 100% ACN water 0.1% TFA) to afford 4-{[3-chloro-5-cyclopropyl-7-(triflu^
[(5S)-2-hydroxy-1 ,2-oxaborinan-5-yl]-2-piperazinone (28 mg, 0.058 mmol, 34%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.43 (d, J - 5.08 Hz, 1 H), 7.08 (d, J = 1.17 Hz, 1 H), 4.37 - 4.71 (m, 3H), 3.99 - 4.20 (m, 2H), 3.85 - 3.97 (m, 2H), 3.46 - 3.63 (m, 1 H), 3.30 - 3.44 (m, 1 H), 1.97 - 2.1 1 (m, 1 H), 1.74 - 1.93 (m, 2H), 1.12 - 1.23 (m, 3H), 0.97 - 1.12 (m, 1 H), 0.79 - 0.93 (m, 2H). MS (ESI) m/z = 485.4 (MH+).
Example 108
3-chloro-N,5-dicyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1- piperazinyl]carbonyl}pyrazolo[1 ,5-a]pyridine-7-carboxamide
Compound 108)
Figure imgf000237_0001
Step A
Methyl 3-chloro-5-cyciopropyt-7-[(cyclopropylamino)carbonyl]pyrazolo[ 1, 5-a]pyridine-2- carboxylate
Methyl 7-bromo-3-chloro-5-cycIopropylpyrazolo[1 ,5-a]pyridine-2-carboxylate (250 mg, 0.759 mmol), Xantphos (43.9 mg, 0.076 mmol), palladium(ll) acetate (8.52 mg, 0,038 mmol), and K3P0 (644 mg, 3.03 mmol) were combined in a microwave vial and sealed. The solids were degassed with vacuum and nitrogen backfilled. To this was added Toluene (2 mL) and cyclopropyl amine (130 mg, 2.276 mmol) the mixture was degassed again followed by heating to 80 °C over night under an a balloon filled with carbon monoxide. LCMS indicated product and the reaction was filtered and evaporated to a residue. The residue was purified by prep HPLC (10 to 100% ACN water 0.1 % formic acid) to afford methyl 3-chloro-5-cyclopropyl-7-[(cyclopropylamino)carbonyl]pyrazolo[1 ,5- a]pyridine-2-carboxylate (55 mg, 0.165 mmol, 21 %). H NMR (CHLOROFORM-d) δ ppm 10.35 (br. s., 1 H), 7.81 (d, J = 2.0 Hz, 1 H), 7.42 (d, J = 2.0 Hz, 1 H), 4.02 (s, 3H), 3.06 (td, J = 7.3, 3.7 Hz, 1 H), 1.95 - 2.12 (m, 1 H), 1.07 - 1.19 (m, 2H), 0.85 - 0.99 (m, 4H), 0,69 - 0.78 (m, 2H). MS (ESI) m/z = 500.4 (MH+). Step B
3- chloro-5-cycIopropyl- 7-[ ( cyclopropylamino) carbonyl]pyrazolo[ 1, 5-a jpyridin e-2-carboxylic acid
Methyl 3-chloro-5-cyclopropyI-7-[(cyclopropylamino)carbonyl]pyrazolo[1 ,5- a]pyridine-2-carboxylate (55 mg, 0.165 mmol) was dissolved in Tetrahydrofuran (1 ml_) and Methanol (0.5 ml_). To this solution was added 1 N LiOH (500 μΙ, 0.500 mmol) and stirred at room temperature for 2 hours and evaporated to a residue to afford 3-chloro-5- cyclopropyl-7-[(cyclopropylamino)carbonyl]pyrazolo[1 ,5-a]pyridine-2-carboxylic acid as a crude product with 1 N LiOH in it. Yeild assumed to be 100%. H NMR (M ETHAN OL-d4) δ ppm 7.62 (d, J = 2.0 Hz, 1 H), 7.47 (d, J = 1.8 Hz, 1 H), 2.92 - 3.08 (m, 1 H), 2.01 - 2.15 (m, 1 H), 1.06 - 1.17 (m, 2H), 0.78 - 0.96 (m, 6H). MS (ESI) m/z = 320.3 (MH+).
Step C
3-chloro~N,5~dicyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1- piperazinyl]carbonyl}pyrazolo[ 1, 5-a]pyridine-7~carboxamide
3-chloro-5-cyclopropyl-7-[(cyclopropylamino)carbonyl]pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (52.7 mg, 0.165 mmol), 1 -(trans-4-hydroxycyclohexy!)~2-piperazinone (32.7 mg, 0.165 mmol), and DIPEA (0.086 mL, 0.494 mmol) were disolved in N,N- Dimethylformamide (2 mL). To this solution was added 1-propanephosphonic acid cyclic anhydride in EtOAc (50% wt) (79 mg, 0.247 mmol) and the reaction stirred over night. The reaction mixture was partitioned between EtOAc and water; the organic layer was washed with brine and evaporated to a residue. The residue was purified by prep HPLC (10 to 100% ACN water 0.1 % formic acid) to afford 3-chloro~N,5~dicycIopropyl-2-{[4-( frans-
4- hydroxycyclohexyl)-3-oxo-1-piperazinyl]carbonyl}pyrazolo[1 ,5-a]pyridine-7-carboxamide (24.1 mg, 0.048 mmol, 29%) as a foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm
9.99 (br. s., 1 H), 7.75 - 7.84 (m, 1 H), 7.40 (s, 1 H), 4.38 - 4.58 (m, 2H), 4.27 (s, 1 H), 4.03 (t, J = 5.28 Hz, 1 H), 3.75 (t, J = 4.89 Hz, 1 H), 3.52 - 3.64 (m, 1 H), 3.42 (t, J = 5.28 Hz, 1 H), 3.33 (t, J = 4.89 Hz, 1 H), 3.00 (td, J = 3.52, 7.13 Hz, 1 H), 1.98 - 2.13 (m, 4H), 1.74 (d, J = 10.36 Hz, 2H), 1.37 - 1.66 (m, 4H), 1.06 - 1.21 (m, 2H), 0.84 - 0,98 (m, 4H), 0.65 - 0.79 (m, 2H). MS (ESI) m/z = 500.4 (MH+).
Example 109
3-chloro-5-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1- piperaziny[]carbonyl}-N-methylpyrazolo[1 ,5-a]pyridine-7-carboxamide
(Compound 109)
Figure imgf000239_0001
Step A
Methyl 3-chloro-5-cyclopropyl-7-[(methylamino)carbonyi]pyrazolo[ 1, 5-a]pyridine-2- carboxylate
Methyl 7-bromo-3-chloro-5-cyclopropylpyra2olo[1 ,5-a3pyridine-2-carboxylate (250 mg, 0,759 mmol), methyiamine hydrochloride (154 mg, 2.276 mmol), Xantphos (43.9 mg, 0.076 mmol), palladium(ll) acetate (8.52 mg, 0.038 mmol), and K3P04 (644 mg, 3.03 mmol) were combined in a microwave vial and sealed. The solids were degassed with vacuum and nitrogen backfilled. To this was added Toluene (2 mL) and the mixture was degassed again followed by heating to 80 °C overnight under an a balloon filled with carbon monoxide. The reaction was filtered and evaporated to a residue. The residue was purified by prep HPLC (10 to 100% ACN water 0.1 % formic acid) to afford methyl 3-chloro- 5-cyclopropyl-7-[(methylamino)carbonyl]pyrazolo[1 ,5~a]pyridine-2-carboxylate (54 mg, 0.175 mmol, 23%). H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.13 (br. s., 1 H), 7.81 (d, J = 1.95 Hz, 1 H), 7,42 (d, J = 1.95 Hz, 1 H), 4.02 (s, 3H), 3.14 (d, J = 4.89 Hz, 3H), 1.97 - 2.10 (m, 1 H), .09 - 1 .21 (m, 2H), 0.82 - 0.97 (m, 2H).
Step B
3-chloro-5-cyclopropyl-7-[(methyiamino)carbonyi]pyrazolo[1,5-a]pyri^
Methyl 3-chloro-5-cyclopropyl-7-[(methyiamino)carbonyl]pyrazolo[1 ,5-a]pyridine-2- carboxylate (54 mg, 0.175 mmol) was dissolved in Tetrahydrofuran (1 mL) and Methanol (0.5 mL). To this solution was added 1 N LiOH (0.263 mL, 0.263 mmol) and the mixture was stirred at room temperature for 2 hours and evaporated to a residue to afford 3- chloro-5-cyclopropyl-7-[(methylamino)carbonyl]pyrazolo[1 ,5-a]pyridine-2-carboxylic acid as a crude product with 1 N LiOH in it. Yield assumed to be 100%. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.51 (d, J = 1.95 Hz, 1 H), 7.35 (d, J = 1.76 Hz, 1 H), 3.06 (s, 3H), 1.95 - 2.05 (m, 1 H), 1.02 - 1.13 (m, 2H), 0.72 - 0.84 (m, 2H). Step C
3-chloro-5-cyclopropyl-2-{[ 4- ( trans-4-hydroxycyclohexyl) -3-oxo- 1 -piperazinyl]carbonyl}-N- methylpyrazolo[1,5-a]pyridine-7-carboxamide
3-ch!oro-5-cyclopropyl-7-[(methylamino)carbonyl]pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (51 mg, 0.174 mmol), 1 ~(£ra/7s-4-hydroxycyclohexyl)-2-piperazinone (34.4 mg, 0.174 mmol), and DIPEA (0.091 mL, 0.521 mmol) were dissolved in N,N- Dimethylformamide (2 mL). To this solution was added 1-propanephosphonic acid cyclic anhydride in EtOAc (50% wt) (83 mg, 0.260 mmol) and the reaction stirred overnight. The reaction mixture was partitioned between EtOAc and water; the organic layer was washed with brine and evaporated to a residue. The residue was purified on prep HPLC (10 to 100% ACN water 0.1 % formic acid) to afford 3-chloro-5-cyclopropyl-2-{[4-(trans-4- hydroxycyclohexyl)-3-oxo-1 -piperazinyl]carbonyl}-N-methyipyrazolo[1 ,5-a]pyridine-7- carboxamide (43.8 mg, 0.091 mmol, 52%) as a foam. H NMR (CHLOROFORM-d) δ ppm 9.92 (br. s., 1 H), 7.71 - 7.87 (m, 1 H), 7.41 (s, 1 H), 4.38 - 4.57 (m, 2H), 4.25 (s, 1 H), 4.04 (t, J = 5.5 Hz, 1 H), 3.72 (t, J = 5.1 Hz, 1 H), 3.52 - 3.66 (m, 1 H), 3.43 (t, J = 5.4 Hz, 1 H), 3.32 (t, J = 5.0 Hz, 1 H), 3.07 - 3.15 (m, 3H), 1.99 - 2.13 (m, 3H), 1.75 (d, J = 8.6 Hz, 2H), 1.39 - 1.68 (m, 5H), 1.11 - 1.20 (m, 2H), 0.91 (q, J = 5.5 Hz, 2H). MS (ESI) m/z = 474.3 (MH+).
Example 110
3-chloro-5-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1- piperazinyl]carbonyl}-N,N-dimethylpyrazolo[1,5-a]pyridine-7-carboxamide
Compound 110)
Figure imgf000240_0001
Step A
Methyl 3-chloro-5-cyclopropyl- 7-[(dimethylamino)carbonyl]pyrazolo[ 1, 5-a]pyridine-2- carboxylate
Methyl 7-bromo-3-chloro-5-cyclopropylpyrazolo[1 ,5-a]pyridine-2- carboxylate (250 mg, 0.759 mmol), dimethyiamine hydrochloride (186 mg, 2.276 mmol), Xantphos (43.9 mg, 0.076 mmol), palladium(ll) acetate (8.52 mg, 0.038 mmol), and K3P04 (644 mg, 3.03 mmol) were combined in a microwave vial and sealed. The solids were degassed with vacuum and nitrogen backfilled. To this was added Toluene (2 mL) and the mixture was degassed again followed by heating to 80 °C over night under an a balloon filled with carbon monoxide. The reaction was filtered and evaporated to a residue. The residue was purified by prep HPLC (10 to 100% ACN water 0.1 % formic acid) to afford methyl 3-chloro-5-cyclopropyl-7-[(dimethylamino)carbonyl]pyrazolo[1 ,5- a]pyridine-2-carboxylate (175.3 mg, 0.545 mmol, 71 %). MS (ESI) m/z = 322.3 (MH+).
Step B
3-chIoro-5~cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo- 1-piperazinyl]carbonyl}-
N, N-dimethylpyrazolo[ 1, 5-a]pyridine-7-carboxamide Methyl 3-chloro-5-cyc[opropyl-7-[(dimethylamino)carbonyl]pyrazolo[1 l5-a]pyridine-2- carboxylate (175.3 mg, 0.545 mmol) was dissolved in Methanol (2 mL), and
Tetrahydrofuran (3 mL). To this solution was added 1 N LiOH (1.090 mL, 1.090 mmol) and the reaction was stirred at room temperature. The reaction was monitored by LCMS and upon completion the reaction was evaporated to a residue. The residue was combined with 1-(fra/is-4-hydroxycyclohexyl)-2-piperazinone (128 mg, 0.545 mmol), DIPEA (0.381 mL, 2.179 mmol) and dissolved in N,N-Dimethylformamide (3 mL). To this solution was added 1 -propanephosphonic acid cyclic anhydride in EtOAc (50% wt) (260 mg, 0.817 mmol) and the reaction stirred overnight. The reaction mixture was partitioned between EtOAc and water; the organic washed with brine, dried over sodium sulfate and evaporated to a residue. The residue was purified on prep HPLC (10 to 100% ACN water 0.1 % formic acid) to afford 3-chloro-5-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo- 1 -piperazinyl]carbonyI}-N,N-dimethylpyrazolo[1 ,5-a]pyridine-7-carboxamide (69.5 mg, 0.142 mmol, 26%) as a foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (d, J - 1.56 Hz, 1 H), 6.64 (dd, J = 1.66, 7.52 Hz, 1 H), 4.24 - 4.48 (m, 3H), 3.92 (br. s., 1 H), 3.75 (br. s., 1 H), 3.49 (dd, J = 4.49, 10.15 Hz, 1 H), 3.33 (t, J = 5.37 Hz, 1 H), 3.24 (br. s., 1 H), 3.14 (d, J = 3.71 Hz, 3H), 2.80 (d, J = 8.40 Hz, 3H), 1.85 - 2.06 (m, 3H), 1.65 (br. s., 2H), 1.29 - .58 (m, 4H), 1.07 (d, J = 8.20 Hz, 2H), 0.79 (d, J = 4.49 Hz, 2H). MS (ESI) m/z = 488.4 (MH+).
EXAMPLE 111
(fTrartsJ-4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- ylJcarbonyl}-1 -(3-oxabicyclo[3.1.0]hex-6-yl)-2-piperazinone
(Compound 111)
Figure imgf000242_0001
Step A
(Trans)-Ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate Ethyl diazoacetate (8.79 mL, 84 mmol) in THF{40 mL) was added by a syringe pump (50 hours) to a solution of 2,5-dihydrofuran (5.16 mL, 70 mmol) and rhodium(ll) acetate dimer (1 .547 g, 3.50 mmol) in dichloromethane (250 mL) at room temperature under N2. The mixture was then filtered through a pad of celite. After removal off the solvent, the residue was purified by silica gel chromatography (0-25% EtOAc in hexane) to give the desired product as a colorless oil (5.5 g, 50%). 1H NMR (400 MHz,
CHLOROFORM-d) δ ppm 4.14 (q, J=7.09 Hz, 2 H) 3.93 (d, J=8.59 Hz, 2 H) 3.75 (d, J=8.39 Hz, 2 H) 2.16 (br. s., 2 H) 1.61 (t, J=3.02 Hz, 1 H) 1.27 (t, J=7.12 Hz, 3 H).
Step B
(Trans)-3-oxabicyclo[3.1.0]hexane-6-carboxylic acid A solution of LiOH (1.528 g, 36.4 mmol) in water (30 mL) was added to a solution of (trans)-ethyl 3-oxabicyclo[3.1.0]hexane-6-carboxylate (5.17 g, 33.1 mmol) in methanol (80 mL) at room temperature under N2. The mixture was stirred overnight and partially concentrated to remove the MeOH. It was cooled in an ice-bath and HCI in dioxane (4 N) was added to adjust the pH to 5. The mixture was then concentrated almost to dryness and extracted with EtOAc (3X). The combined organic extracts were dried over Na2S0 , filtered, and concentrated to give 2.89 g (68%) of desired product as a white solid which required no further purification.
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.96 (d, J=8.78 Hz, 2 H) 3.77 (d, J=8.78 Hz, 2 H) 2.24 (br. s., 2 H) 1.62 (t, 1 H).
Step C
(Trans)-1, 1-dimethylethyl 3-oxabicyclo[3.1.0]hex-6-yicarbamate
A mixture of (trans)-3-oxabicyclo[3.1 .0]-hexane-6-carboxylic acid (2.85 g, 22.24 mmol), diphenyl azidophosphate (5.27 mL, 24.47 mmol) and TEA (6.51 mL, 46.7 mmol) in tert-butanol (150 mL) was stirred at reflux for 2 days. The solution was concentrated to dryness and the residue was dissolved in EtOAc, washed with 1 N HCI solution, saturated NaHC03 and brine, and dried over Na2S04. The residue was purified by silica gel chromatography (0-40% EtOAc in hexane) to give the desired product as a white solid (0.71 g, 16%). H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.66 (br. s., 1 H) 3.97 (d, J=8.39 Hz, 2 H) 3.71 (d, J=8.39 Hz, 2 H) 2.40 (br. s., 1 H) 1.77 (br. s., 2 H) 1.45 (s, 9 H).
Step D
(Trans)-3-oxabicyclo[3.1.0]hex-6-ylamine hydrochloride 4N HCI/dioxane (17.8 ml, 586 mmol) was added to a solution of 1 ,1-dimethylethyl 3-oxabicyc!o[3.1.0]hex-6-ylcarbamate (710 mg, 3.56 mmol) in 1 ,4-dioxane (18 mL) under N2 at room temperature, it was stirred overnight and then concentrated to dryness to give the desired product as a white solid which was used without purification and assumed to be quantitative.1 H NMR (400 MHz, METHANOL-^) δ ppm 3.94 (d, J=8.78 Hz, 2 H) 3.69 (d, J=8.78 Hz, 2 H) 2.37 (s, 1 H) 2.05 (d, J=0.98 Hz, 2 H). Step E
(Trans)-1, 1-dimethylethyl 4-(3-oxabicyclo[3.1.0]hex-6-yl)-3-oxo-1-piperazinecarboxylate To a solution of methyl N-{[(1 ,1 -dimethylethyl)oxy]carbonyl}-N-(2- oxoethyl)glycinate (0.745 g, 3.22 mmol) in methanol (16 mL) was added sodium sulfate (2.74 g, 19.32 mmol) followed by (trans )-3-oxabicyclo[3.1.0]hex-6-ylamine hydrochloride (0.480 g, 3.54 mmol) and DIPEA (0.675 mL, 3.86 mmol). The mixture was stirred for 1 hour before NaBH4 (0.146 g, 3.86 mmol) was added in portions in order to control effervescence. A mild exotherm was observed. After 2 hours, NaH (0.258 g, 6.44 mmol) was added portionwise in order to control effervescence. The mixture was stirred for 2 hour. Foliowing removal of most of the solvent, the residue was diluted with EtOAc. It was then filtered through a pad of celite, and the filtrate was mixed with 10 % aqueous citric acid. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2S04, filtered and evaporated. The residue was purified by silica gel chromatography (0-4 % 2 M NH3 solution of MeOH in DCM) to give the desired product (0.55 g, 60 %) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 4.00 - 4.08 (m, 4 H) 3.76 (d, J=8.39 Hz, 2 H) 3.62 (t, J=5.37 Hz, 2 H) 3.32 (t, J=5.37 Hz, 2 H) 2.52 (br. s., 0 H) 1.94 (s, 2 H) 1.47 (s, 9 H). LCMS: m/z 283 (M+1 ).
Step F
(Trans) -1-(3-oxabicyclo[3.1.0]hex-6-yl)-2-piperazinone hydrochloride 4N HCI/dioxane (9.65 mL, 38.6 mmol) was added to a solution of (trans)-1 ,1- dimethylethyl 4-(3-oxabicyclo[3.1 .0]hex-6-y[)-3-oxo-1 -piperazinecarboxylate (545 mg, 1.93 mmol) in 1 ,4-dioxane (10 mL) under N2 at room temperature. It was stirred for 6 hours and then concentrated to dryness to give the desired product as a white solid which was used without purification and assumed to be quantitative.1H NMR (400 MHz, METHANOL-d4) δ ppm 3.96 (s, 1 H) 3.94 (s, 1 H) 3.74 - 3.80 (m, 2 H) 3.62 - 3.72 (m, 3 H) 3.50 - 3.57 (m, 2 H) 3.41 - 3.49 (m, 2 H) 2.46 (s, 1 H) 2.02 (s, 2 H).
Step G
(Trans)-4^[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrM
1 -(3-oxabicycto[3.1.0]hex-6-yi)-2-piperazinone
DIPEA (0.1 12 mL, 0.643 mmol) was added to a mixture of 3-chloro-5-cyclopropyl- 7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (49 mg, 0.161 mmol) and (trans)-1-(3-oxabicyclo[3.1.0]hex-6-yl)-2-piperazinone hydrochloride (35.2 mg, 0.161 mmol) in Ν,Ν-dimethylformamide (2.0 mL) at room temperature under N2. The mixture was stirred for 30 minutes at room temperature, cooled to 0 0 C, and treated with 1- propanephosphonic acid cyclic anhydride (0.144 mL, 0.24 mmol) was added. The mixture was allowed to warm up to room temperature and stirred for 1 hour. Saturated NaHC03 was then added. The mixture was extracted with EtOAc. The EtOAc solution was washed with 5 % aqueous LiCI, dried over Na2S04, filtered and evaporated. The residue was purified by reverse phase HPLC to afford the title compound as a white solid (62 mg, 82 %). 1H NMR (400 MHz, CHLOROFORM-of) δ ppm 7.42 (d, J=9.37 Hz, 1 H) 7.07 (s, 1 H) 4.43 (s, 1 H) 4.35 (s, 1 H) 3.96 - 4.09 (m, 4 H) 3.71 - 3.81 (m, 2 H) 3.44 - 3.52 (m, 2 H) 2.54 (br. s., 1 H) 2.00 - 2.10 (m, 1 H) 1.97 (d, J=13.27 Hz, 2 H) 1.14 - 1.22 (m, 2 H) 0.82 - 0.90 (m, 2 H). LCMS: m/z 469 (M+1 ).
EXAMPLE 112
4-{t3-Chloro-5-cyclo ro yl·7-(trifluoromethyl) yrazolo[1 ,5-a]pyridin-2-yl]carbonyl}- 1 -[{1 R,3R)-3-(hydroxymethyl)cyclopentyl]-2-piperazinone
{Compound 112)
Figure imgf000244_0001
Step A
1, 1-Dimethylethyl [(1R,3R)-3-(hydroxymethyl)cyclopentyl]methylcarbamate Ethyl chloroformate (0.197 mL, 2.055 mmol) was added to a stirred solution of (1 R,3R)-3-[{[(1 ,1-dimethylethyl)oxy]carbonyl}(methyl)amino]cyclopentanecarboxylic acid (500 mg, 2.06 mmol) and TEA (0.301 mL, 2.16 mmol) in dry THF(5.0 mL) at 0 0 C under N2. it was stirred for 30 minutes at 0 °C and then filtered to remove the precipitate, the filtrate was slowly added to a stirred suspension of NaBH4 (233 mg, 6.17 mmol) in 20 % aqueous THF (5.0 mL) at 10 0 C. The mixture was stirred for another 30 minutes at the same temperature and then acidified with 1 N HCI to pH = 4. The mixture was extracted with EtOAc (3X) and the organic layer was washed with 2N NaOH (2X), water (2X), brine and dried over Na2S04. The solution was concentrated and then dried in vacuo to give the desired product as a white solid (465 mg, 99 %) which was used without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.50 (br. s., 1 H) 3.97 (br. s., 1 H) 3.52 (d, J=6.83 Hz, 2 H) 2.26 (ddd, J=14.88, 7.80, 7.56 Hz, 1 H) 1.98 - 2.09 (m, 1 H) 1.82 - 1.92 (m, 1 H) .66 - 1 .76 (m, 1 H) 1.55 - 1.65 (m, 2 H) 1.44 (s, 9 H) 1.23 - 1.42 (m, 2 H).
LCMS: m/z 228.5 (M-1 ).
Step B
[(1R,3R)-3-(methylamino)cyclopentyl]methanol hydrochloride 4N HCI/dioxane (9.65 mL, 38.6 mmol) was added to a solution of 1 ,1-dimethylethyl
4-(3-oxabicyclo[3.1.0]hex-6-yl)-3-oxo-1 -piperazinecarboxylate (545 mg, 1.930 mmol) in 1 ,4-dioxane ( 0 mL) under N2 at room temperature. The mixture was stirred for 6 hours. It was then concentrated and dried in vacuo to give the desired product as a tacky oil which was used without purification and assumed to be quantitative. 1H NMR (400 MHz,
METHANOL-d4) δ ppm 3.63 (s, 2 H) 3.54 - 3.62 (m, 1 H) 3.43 (qd, J=10.68, 6.44 Hz, 2 H) 3.28 (dt, J=3.22, 1.71 Hz, 2 H) 2.31 (ddd, J=14.84, 7.32, 7.13 Hz, 1 H) 2.07 - 2.17 (m, 1 H) 1.92 (dddd, J=12.55, 8.25, 8.01 , 4.20 Hz, 1 H) 1.70 - 1.87 (m, 2 H) 1.54 - 1.66 (m, 1 H) 1.33 - 1.47 (m, 1 H). Step C
1, 1-Dimethylethyl 4-[( 1R,3R)-3-(hydroxymethyl)cyclopentyl]-3~oxo-1-piperazinecarboxylate To a solution of methyl N-{[(1 ,1-dimethylethyl)oxy]carbonyl}-N~(2- oxoethyl)glycinate (358 mg, 1.55 mmol) in methanol (10 mL) was added sodium sulfate
(1.32 g, 9.30 mmol) followed by [(1 R,3R)-3-(methylamino)cyclopentyl]methanol hydrochloride (282 mg, 1.705 mmol) and DIPEA (0.325 mL, 1 .860 mmol). The mixture was stirred for 1 hour before NaBH4 (70.4 mg, 1.860 mmoi) was added in portions in order to control effervescence. A mild exotherm was observed. After 2 hours, NaH (124 mg, 3.10 mmol) was added in portions in order to control effervescence. The mixture was stirred for 2 hours. Following removal of most of the solvent, the residue was diluted with EtOAc. It was then filtered through a pad of celite and the filtrate mixed with 10 % aqueous citric acid. The organic layer was separated and the aqueous phase was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2S04j filtered and evaporated. The residue was purified by silica gel chromatography (0-4 % MeOH in DCM) to give the desired product (66 mg, 14 %) as a colorless oil. H NMR (400 MHz,
CHLOROFORM-d) δ ppm 5.02 (quin, J=8.63 Hz, 1 H) 4.01 - 4.15 (m, 2 H) 3.57 - 3.69 (m, 2 H) 3.55 (d, J=6.63 Hz, 2 H) 3.28 (t, J=5.17 Hz, 2 H) 2.27 (ddd, J=15.02, 7.80, 7.61 Hz, 1 H) 1.86 - 1 .98 (m, 2 H) 1 .69 (t, J= ,0 Hz, 2 H) 1.51 - 1.59 (m, 1 H) 1.47 (s, 9 H) 1 .24 - 1.37 (m, 1 H). LCMS: m/z 299 (M+1 ).
Step D
1-[(1R, 3R)-3-(hydroxymethyl)cyclopentyl]-2-piperazinone hydrochloride
4N HCI/dioxane (1.11 mL, 4.42 mmol) was added to a solution of 1 , 1-dimethylethyl 4-[(1 R,3R)-3-(hydroxymethyl)cyclopentyl]-3-oxo-1 -piperazinecarboxylate (66 mg, 0.221 mmol) in 1 ,4-dioxane (1 .0 mL) under N2 at room temperature. The mixture was stirred for 4 hours. It was then concentrated and dried in vacuo to give the desired product as a white solid which was used without purification and assumed to be quantitative. LCMS: m/z 198 (M+1 ).
Step E
4-{[3-Chloro-5-cyclopropyl- 7-(triftuorom ethyl)pyrazo!o[ 1, 5-a ]pyridin-2-yl]carbonyl}- 1 - [( 1R, 3R)-3-(hydroxymethyl)cyclopentyl]-2-pip9razinone
DIPEA (0.077 mL, 0.440 mmol) was added to a mixture of 3-chloro-5-cyclopropyl- 7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (33.5 mg, 0.1 10 mmol) and 1- t(1 R,3R)-3-(hydroxymethyl)cyclopenty]]"2-piperazinone hydrochloride (25.8 mg, 0.110 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature under N2. The mixture was stirred for 30 minutes at room temperature and was then cooled to 0 0 C and 1- propanephosphonic acid cyclic anhydride (0.098 mL, 0.17 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. Saturated NaHC03 was added and the mixture extracted with EtOAc. The EtOAc solution was washed with 5 % aqueous LiCI, dried over Na2S04j filtered and concentrated. The residue was purified by reverse phase HPLC to afford the title compound as a white solid (35 mg, 66 %). 1H NM (400 MHz, CHLOROFORM-d) δ ppm 7.42 (d, J=9.95 Hz, 1 H) 7.06 (s, 1 H) 4.89 - 5.10 (m, 1 H) 4.38 - 4.54 (m, 1 H) 4.36 (s, 1 H) 4.01 - 4.1 1 (m, 1 H) 3.89 - 4.01 (m, 1 H) 3.56 {dd, J=6.63, 3.90 Hz, 2 H) 3.40 - 3.48 (m, 2 H) 2.23 - 2.36 (m, 1 H) 1 ,99 - 2.10 (m, 1 H) 1.88 - 1 .99 (m, 2 H) 1.70 - 1 .77 (m, 2 H) 1.53 - 1.65 (m, 1 H) 1.26 - 1.39 (m, 1 H) 1 .13 - 1.22 (m,
2 H) 0.82 - 0.90 (m, 2 H). LCMS: m/z 485.2.
EXAMPLE 113
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyl}-
1-(5-oxo-3-pyrrolidinyl)-2-piperazinone
(Compound 113)
Figure imgf000247_0001
Step A
1, 1-Dimethylethyl 3-oxo-4-(5-oxo-3-pyrroiidinyl)-1-piperazinecarboxylate
To a solution of methyl N-{[(1 ,1-dimethylethy[)oxy]carbonyl}-N-(2- oxoethyl)glycinate (768 mg, 3.32 mmol) in methanol (16 m!_) was added sodium sulfate (2.829 g, 19.92 mmol) followed by 4-amino-2-pyrrolidinone hydrochloride (499 mg, 3.65 mmol) and DIPEA (0.696 ml_, 3.98 mmol). The mixture was stirred for 1 hour before NaBH4 (151 mg, 3.98 mmol) was added in portions in order to control effervescence. A mild exotherm was observed. After 2 hours, NaH (398 mg, 9.96 mmol) was added in portions in order to control effervescence. The mixture was stirred for 2 hour and quenched with 10 % citric acid. The organic layer was separated and the aqueous phase was extracted with 10 % MeOH in DCM. The combined extracts were washed with brine, dried over Na2S04, filtered and evaporated. The residue was purified by silica gel chromatography (0-8 % MeOH in DCM) to give the desired product (296 mg, 32%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 5.87 (br. s., 1 H) 5.42 - 5.55 (m, 1 H) 4.12 (s, 2 H) 3.60 - 3.79 (m, 3 H) 3.27 - 3.40 (m, 3 H) 2.67 (dd, .7=17.76, 9.37 Hz, 1 H) 2.38 (dd, J=17.76, 5.07 Hz, 1 H) 1.48 (s, 9 H). LCMS: m/z 284 (M+1 ). Step B
1-(5-Oxo-3-pyrrolidinyl)-2-piperazinone hydrochloride 4N HCI/dioxane (5.22 mL, 20.89 mmol) was added to a solution of 1 ,1- dimethylethyl 3-oxo-4-(5-oxo-3-pyrrolidinyl)-1-piperazinecarboxylate (296 mg, 1.045 mmol) in 1 ,4-dioxane (5.0 mL) under N2 at room temperature. The mixture was stirred for 4 hours. It was then concentrated and dried in vacuo to give the desired product as a white solid which was used without purification and assumed to be quantitative. 1H NMR (400 MHz, METHANOL-^) δ ppm 5.15 (td, J=8.54, 4.59 Hz, 1 H) 3.85 (s, 2 H) 3.72 (dd, J=11.12, 8.19 Hz, 1 H) 3.65 (s, 2 H) 3.59 - 3.64 (m, 1 H) 3.52 - 3.58 (m, 2 H) 3.41 - 3.48 (m, 1 H) 2.69 (dd, J=17.66, 9.46 Hz, 1 H) 2.44 ~ 2.53 (m, 1 H) 1.59 (s, 1 H).
Step C
4~{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazoIo[1,5-a]py din-2-yl^^^
3-pyrrolidinyl)-2-piperazinone
DIPEA (0.080 mL, 0.46 mmoi) was added to a mixture of 3-chloro-5-cyclopropyl-7-
(triflupromethyl)pyrazoio[1 ,5-a]pyridine-2-carboxylic acid (35 mg, 0.115 mmol) and 1-(5- oxo-3-pyrrolidinyl)-2-piperazinone hydrochloride (25.2 mg, 0.1 15 mmol) in N,N- dimethylformamide (1.0 mL) at room temperature under N2. The mixture was stirred for 30 minutes at room temperature, cooled to 0 0 C and treated with 1 -propanephosphonic acid cyclic anhydride (0.103 mL, 0.172 mmol). The mixture was allowed to warm up to room temperature and stirred for 1 hour. Saturated NaHC03 was added and the mixture extracted with EtOAc. The EtOAc solution was washed with 5 % aqueous LiCi, dried over Na2S04, filtered and evaporated. The residue was purified by reverse phase HPLC to afford the title compound as a white solid (40 mg, 74 %).
1H NMR (400 MHz, DMSO-d6) δ ppm 7.66 - 7.78 (m, 2 H) 7.44 (s, 1 H) 5.05 - 5.24 (m, 1 H) 4.26 (d, J=2.15 Hz, 1 H) 4.20 (s, 1 H) 3.85 - 3.99 (m, 1 H) 3.79 (t, J=4.98 Hz, 2 H) 3.40 - 3.53 (m, 2 H) 3.14 - 3.26 (m, 1 H) 2.36 - 2.48 (m, 1 H) 2.16 - 2.35 (m, 2 H) 1.05 - 1.15 (m, 2 H) 0.93 - .02 (m, 2 H). LCMS: m/z 470 (M+1 ). EXAMPLE 114
(Trans/Cis)-4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-(6-oxabicyclo[3.1.0]hex-3-yl)-2-piperazinone
(Compound 114)
Figure imgf000249_0001
m-CPBA (290 mg, 1.177 mmol) was added in portions to a mixture of 4-{[3-chioro- 5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(3-cyc!openten-1 - yl)-2-piperazinone (410 mg, 0.905 mmol) and sodium bicarbonate (122 mg, 1.449 mmol) in dichloromethane (10 ml.) at room temperature under N2. The mixture was stirred overnight and then filtered to remove the white precipitate. The filtrate was washed with saturated Na2S03, 10 % NaHC03, water, and dried over Na2S04. The drying agent was removed by filtration and the filtrate concentrated to dryness at reduced pressure. The residue was purified by silica gel chromatography (0-60 % EtOAc in hexane) to give the title compound (208 mg, 73 %) as a white solid. 1H N R (400 MHz, CHLOROFORM-d) δ ppm 7.42 (d, J=10.15 Hz, 1 H) 7.07 (br. s., 1 H) 5.32 - 5.51 (m, 0.5 H) 4.48 - 4.64 (m, 0.5 H) 4.44 (s, 1 H) 4.35 (d, J=11.71 Hz, 1 H) 4.01 (t, J=5.07 Hz, 1 H) 3.94 (ddd, J=9.95, 5.27, 5.07 Hz, 1 H) 3.49 - 3.63 (m, 3 H) 3.42 (q, J=4.94 Hz, 1 H) 2.20 - 2.41 (m, 2 H) 1.83 - 2.05 (m, 3 H) 1.11 - 1.22 (m, 2 H) 0.82 - 0.91 (m, 2 H). LCMS: m/z 469 (M+1 ).
EXAMPLE 115
Isomer 1 : 4-{t3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-(6,6-difluorobicyclo[3.1.0]hex-3-y[)-2-piperazinone
(Compound 115)
and
EXAMPLE 116
Isomer 2: 4-{[3-Chloro-5-cyclopropyl-7-(trif luoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-(6,6-difluorobicyclo[3.1.0]hex-3-yl)-2-piperazinone
(Compound 116)
Figure imgf000250_0001
A solution of 4-{[3-chloro-5-cyclopropyl-7-(t fluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-(3-cyclopenten-1-yl)-2-piperazinone (160 mg, 0.353 mmol) in diglyme (4.0 mL) was heated at 160 °C and stirred vigorously. Sodium chloro(difluoro)acetate (440 mg, 2.83 mmol) was added. The reaction mixture was heated at 160 °C for 1 h. LCMS showed 33 % possible products along with 67 % starting material. More sodium
chloro(difluoro)acetate (1.76 g, 1 1.32 mmol) was added in portions over 4 hours at 160 °C. LCMS showed 69% possible products along with 31 % starting material. The mixture was cooled to room temperature, mixed with water and extracted with EtOAc. The extracts were dried over Na2S04, filtered and concentrated to dryness. The residue was purified by silica gel chromatography (0-20 % EtOAc in DCM) to give a brown oil (120 mg). The cis/trans isomers were separated by SFC (Supercritical Fluid Chromatography).
Isomer 1 (ChiralPak ASH column, 250x10 mm i.d., 5um; Daicel Chemical Ind.; Osaka, Japan; 10 % MeOH, flow rate = 10 'mL/min. tr = 7.65 minute): white solid, 21 mg (12 %). 1H NMR (400 MHz, CHLOROFORM-c ) δ ppm 7.43 (d, J=10.15 Hz, 1 H) 7.07 (s, 1 H) 4.83 - 4.98 (m, 1 H) 4.44 (s, 1 H) 4.37 (s, 1 H) 4.02 (br. s., 2 H) 3.45 (br. s., 2 H) 2.00 - 2.27 (m, 7 H) 1.18 (d, J=8.00 Hz, 2 H) 0.83 - 0.91 (m, 2 H). LCMS: m/z 503 (M+1 ).
Isomer 2 (ChiralPak ASH column, 250x10 mm i.d., 5um; Daicel Chemical ind.; Osaka, Japan; 10 % MeOH, flow rate = 10 mL/min. tr = 8.71 minute): white solid, 4.8 mg (3 %). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 7.42 (d, J=8.19 Hz, 1 H) 7.07 (br. s., 1 H) 5.47 (s, 1 H) 4.46 (s, 1 H) 4.38 (s, 1 H) 3.95 - 4.04 (m, 2 H) 3.34 - 3.41 (m, 2 H) 2.23 (br. s., 2 H) 2.00 - 2.09 (m, 3 H) 1.65 - 1.75 (m, 2 H) 1.15 - 1.22 (m, 2 H) 0.84 - 0.91 (m, 2 H). LCMS: m/z 503 (M+1 ). EXAMPLE 117
4-{[3-Chloro-5-[(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-(frans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 117)
Figure imgf000251_0001
Step A
Dimethyl 5-[(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2,3- dicarboxylate
A mixture of dimethyl 5-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2,3- dicarboxyiate (1.0 g, 3.14 mmol), chiorodifluoroacetic acid sodium salt (1 ,437 g, 9.43 mmol) and Cs2C03 (1.536 g, 4,71 mmol) in N,N-dimethylformamide (25 mL) was stirred at 90 °C for 5 hours under N2. The mixture was cooled to RT and concentrated at reduced pressure. The residue was diluted with EtOAc. The solution was washed with water, 5% aqueous LiOH, dried over Na2S04 and concentrated to dryness to give a brown oil. The crude material was purified by silica gel chromatography eluting with 0-20 % EtOAc (containing 5 % MeOH) in hexane to give the desired product as a white solid (0.9 g, 78 %). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8,04 (d, J=2.15 Hz, 1 H) 7.30 (d, J=2.54 Hz, 1 H) 6.54 - 6.93 (m, 1 H) 4.04 (s, 3 H) 3.94 (s, 3 H). LCMS: m/z 369 (M+1 ).
Step B
5-[(Difluoromethyl)oxy]-7~(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid To a solution of dimethyl 5-[(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridine-2,3-dicarboxylate (890 mg, 2.417 mmol) in 1 ,4-dioxane (10 mL) was added H2S04 (8.0 mL, 75 mmol, 50 %). The resulting mixture was heated to 100 0 C with the vessel open to allow MeOH to escape. After stirring for 8 hours at 100 0 C, it was cooled down to room temperature and diluted with water. The mixture was extracted with EtOAc (3X). The combined extracts were washed with brine, dried over Na2S0 , and
concentrated to dryness at reduced pressure to afford the desired product as a light-green solid which was used for the next step without further purification. Quantitative recovery was assumed. LCMS: m/z 297 (M+1 ).
Step C
3-Chloro-5-[( difluorom ethyl ) oxy]- 7-(trifluorom ethyl) pyrazoio[ 1,5-a Jpyridin e-2-carboxylic acid
A solution of 5-[(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylic acid (0.711 g, 2.4 mmol) and NCS (0.385 g, 2.88 mmol) in 1 ,2-dichloroethane (24 ml) in a seal tube was heated at 100 °C for 4 hours and then 65 0 C overnight. It was cooled to room temperature and then diluted with DC . The mixture was washed with 10 % aqueous sodium bisulfite. The aqueous phase was back extracted with 10 % MeOH in DCM. The combined organics were dried over Na2S04 and concentrated to dryness at reduced pressure to give a white solid. The crude product was carried to the next step without further purification. LCMS: m/z 331 (M+1 ).
Step D
4~{[3-Chloro-5-[(difluoromethyl)oxy]-7~(trifluorome
1-(trans-4-hydroxycyclohexyI)-2-piperazinone
DIPEA (0.279 ml_, 1.6 mmol) was added to a mixture of 3-chloro-5- [(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (156 mg, 0.4 mmol) and 1 -(trans-4-hydroxycyclohexy!)-2-piperazinone hydrochloride (94 mg, 0.400 mmol) in THF at room temperature under N2. After stirring for 30 minutes at room temperature the solution was cooled to 0°C and treated with 1-propanephosphonic acid cyclic anhydride (0.36 ml_; 0.6 mmol). The mixture was allowed to warm up to room temperature and stirred for 1 hour. Saturated NaHC03 was added and the mixture extracted with EtOAc. The combined extracts were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by silica gel
chromatography eiuting with 0-90 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (102 mg, 50 %). 1H NMR (400 MHz, CHLOROFORM-c/) 5 ppm 7.43 (dd, J=1 1.80, 2.05 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 6.48 - 6.88 (m, 1 H) 4.38 - 4.57 (m, 2 H) 4.34 (s, 1 H) 3.99 (ddd, J=1 1 .61 , 5.66, 5.37 Hz, 2 H) 3.54 - 3.64 (m, 1 H) 3.35 - 3.45 (m, 2 H) 2.08 (d, J=13.46 Hz, 2 H) 1.71 - 1.82 (m, 2 H) 1.42 - 1.55 (m, 4 H). LCMS: m/z 51 1 (M+1 ).
EXAMPLE 118
4~{[3-Chioro-5-[{difiuoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-1-[(1S,2S,3S,5S)-2-hydroxybicyclo[3,1.0] ex-3-yl]-2-piperazinone
(Compound 118)
Figure imgf000253_0001
Step A
4-{[3-Chloro-5-[(difluoromethyl)oxy]-7-(trifluoromethy^
1-((1S,2S,3S,5S)-2-{[(1, 1-dimethylethy!)(dimethyl)s^
piperazinone
DIPEA (0.169 mL, 0.966 mmol) was added to a mixture of 3-chloro-5- [(difluoromethyl)oxy]-7-(trifluoromethyl)pyra2olo[1 ,5-a]pyridine-2-carboxylic acid (0.125 g, 0.322 mmol) and 1-((1 S,2S,3S,5S)-2-{[(1 ,1- dimethyIethyl)(dimethyl)silyl]oxy}bicycioE3.1.0]hex-3-yl)-2-pipera2inone (0.100 gr 0.322 mmol) in tetrahydrofuran (4.0 mL) at room temperature under N2. After stirring at RT for 30 minutes, the solution was cooled to 0° C and treated with 1-propanephosphonic acid cyclic anhydride (0.288 mL, 0.483 mmol). The mixture was allowed to warm up to room temperature and stirred for 1 hour. Saturated NaHC03 was added and the mixture extracted with EtOAc. The combined extracts were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude material was purified by silica gel
chromatography eluting with 0-30 % EtOAc (containing 5 % MeOH) in hexane to afford the desired product as a light-yellow foam (152 mg, 76 %). 1H NMR (400 MHz,
CHLOROFORM-cO δ ppm 7.42 (dd, J=12.59, 2.05 Hz, 1 H) 7.18 - 7.24 (m, 1 H) 6.48 - 6.88 (m, 1 H) 4.65 - 4.80 (m, 1 H) 4.24 - 4.57 (m, 2 H) 3.80 - 4.10 (m, 3 H) 3.37 - 3.57 (m. 2 H) 1.97 - 2.05 (m, 1 H) 1.83 - 1.96 (m, 1 H) 1.36 - 1.47 (m, 1 H) 1.29 - 1.36 (m, 1 H) 0.83 - 0.90 (m, 9 H) 0:71 - 0.80 (m, 1 H) 0.40 - 0.50 (m, 1 H) 0.08 (s, 3 H) 0.05 (s, 3 H). ES- LCMS: m/z 623 (M+1 ).
Step B
4-{[3-Chloro-5-[(difluoromethyI)oxy]-7-(trifluoromethyl)^
1-1(1 S, 2S, 3S, 5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone To a solution of 4-{[3-chloro-5-[(difluoromethyl)oxy]-7-(trifiuoromethyl)pyrazolot1 ,5- a]pyridin-2-yl]carbonyl}-1 -((1 S,2S,3S,5S)-2-{[(1 , 1 - dimethylethyI)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone (150 mg, 0.241 mmol) in tetrahydrofuran (2.5 mL) was added 1 M TBAF/THF (0.481 mL, 0.481 mmol) and the resulting solution was stirred at RT. After 1 hour the solution was concentrated by rotary evaporation and the residue mixed with EtOAc (20 mL) and 10% aqueous NaHC03 (20ml_). The phases were separated and the aqueous solution extracted with EtOAc (3x20 mL). The combined EtOAc solutions were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by silica gel
chromatography eluting with 0-70 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (87 mg, 71 %). 1H NMR (400 MHz, CHLOROFORM-d) 5 ppm 7.43 (dd, J=12.10, 1.76 Hz, 1 H) 7.19 - 7.24 (m, 1 H) 6.49 - 6.89 (m, 1 H) 4.30 - 4.63 (m, 4 H) 4.13 - 4.21 (m, 1 H) 3.93 (ddd, J=13.51 , 6.68, 4.78 Hz, 1 H) 3.40 - 3.54 (m, 2 H) 1.93 - 2.04 (m, 2 H) 1.55 - 1 .64 (m, 1 H) 1 .38 - 1.47 (m, 1 H) 0.76 - 0.87 (m, 1 H) 0.48 - 0.58 (m, 1 H). ES-LCMS: m/z 509 (M+1 ).
EXAMPLE 119
4-{[3-Chloro-5-(difluoromethyl)-7-{trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-1 -(trans-4-hydroxycyclohexyl)-2-piperazinone
{Compound 119)
Figure imgf000254_0001
Step A
Dimethyl 5-(4, 4, 5, 5-teframethyI- 1, 3, 2-dioxaborolan-2-yl)-7-(trifluoromethyt)pyrazoto[ 1, 5- a ]pyridine-2, 3-dicarboxylate
A sealed tube was charged with dimethyl 7-(trifluoromethyl)pyrazoio[1 ,5-a]pyridine- 2, 3-dicarboxylate (6,0 g, 19.9 mmol), bis-(pinacoiato)diboron (5.55 g, 21.8 mmol), dtbpy (0.426 g, 1.59 mmol), and [lr(O e)(COD)]2 (0.658 g, 0.993 mmol) and purged with nitrogen. n-Hexane (100 ml) was added and the vessel was sealed and heated at 80°C overnight. It was cooled down and the solution concentrated to dryness, The residue was partitioned between water and CH2CI2 and the phases separated. The aqueous solution was back extracted with CH2CI2. The combined extracts were dried over Na2S04 and concentrated to dryness at reduced pressure to give the title compound (8.5 g, quantitative) as a brown oil which was carried to the next step without purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (s, 1 H) 7.77 (s, 1 H) 4.04 (s, 3 H) 3.97 (s, 3 H) 1.39 (s, 12 H). ES-LCMS: m/z 347 (M+1 ). Step B
Dimethyl 5-bromo-7-(trifluoromethyl)pyrazolo[ 1, 5-a]py dine-2, 3-dicarboxylate Dimethyl 5-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-7- (trifluoromethyl)pyrazo!o[1 ,5-a]pyndine-2, 3-dicarboxylate (8.50 g, 19.9 mmol) was dissolved in 120 mL MeOH. To this was added a solution of copper(ll) bromide (17.74 g, 79 mmol) in 120 mL H20. The mixture was stirred at 70 °C overnight. The mixture was cooled to room temperature and concentrated to remove MeOH. The remaining aqueous mixture was mixed with EtOAc (150 mL) and stirred vigorously for a few minutes. The mixture was filtered through a pad of celite to remove solids. The filtrate was transferred to a separatory funnel and the phases separated. The aqueous layer was extracted with EtOAc (2X). The combined EtOAc solutions were dried over Na2S04 and concentrated to dryness at reduced pressure to give a brown oii. This material was dissolved in 100 mL of MeOH and the solution treated with 10 drops of cone. H2S04. The resulting solution was heated to reflux with stirring for 2 h, cooled to RT and concentrated to dryness at reduced pressure. The residue was dissolved in DCM. The solution was washed with saturated NaHC03, brine, dried over Na2S04 and concentrated to dryness. The crude product was purified by silica gel chromatography e!uting with 0-20 % EtOAc in hexane to give the desired product as a white solid (4.26 g, 56 %). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.59 (d, J=1.76 Hz, 1 H) 7.55 (d, J=1.76 Hz, 1 H) 4.04 (s, 3 H) 3.95 (s, 3 H). ES- LCMSi m/z 383 (M+1 ).
Step C
5-Bromo-7-(irifiuoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylic acid To a solution of dimethyl 5-bromo-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2,3- dicarboxylate (4.2 g, 11.02 mmol) in 1 ,4-dioxane (45 mL) was added cone. H2S04 (40 mL, 375 mmoi). The resulting mixture was heated to 100 0 C with the vessel open to allow MeOH to escape. After stirring for 24 h at 100 °C the mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (3X). The combined extracts were washed once with brine, dried over Na2S04! and concentrated to dryness at reduced pressure to afford a light-green solid which was used in the next step without further purification and the yield assumed to be quantitative. LCMS: m/z 313 (M+ ).
Step D
5~Bromo-3-chloro-7~(trifluoromethyl)pyrazolo[1,5-a)pyridine~2-carboxylic acid A solution of 5-bromo-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid
(3.40 g, 1 1.0 mmol) and NCS (1.76 g, 13.2 mmoi) in 1 ,2-dichloroethane ( 10 ml) in a seal tube was heated at 100°C. After 6 hours LCMS indicated only a few % conversion of starting material to the desired compound. The solution was treated with an additional 1.2 equiv. of NCS (1.76 g, 13.2 mmol) and stirred at 100 °C overnight. LCMS indicated 37% of starting material still remained. Another 1.2 equiv. of NCS (1.76 g, 13.2 mmol) was added and the mixture was stirred at 100 0 C for another 8 hours and then cooled to RT. The mixture was diluted with DCM. The resulting solution was washed with 10 % aqueous sodium bisulfite. The aqueous phase was back extracted with DCM. The combined DCM solutions were dried over Na2S04 and concentrated to dryness at reduced pressure to give crude product as a light-yellow solid (3.78 g, 100 %). The crude material was carried to the next step without further purification and the yield assumed to be quantitative. ES- LCMS: m/z 345 (M+1 ).
Step E
Methyl 5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate
Figure imgf000256_0001
Cone. H2S04 (0. 0 mL, 1.9 mmol) was added to a solution of 5-bromo-3-chloro-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (3.68 g, 10.71 mmol) in methanol (100 mL). The solution was refluxed overnight under N2. After cooling to RT the solution was concentrated to dryness and the residue dissolved in DCM. The resulting solution was washed with saturated NaHC03, dried over Na2S04 and concentrated to dryness at reduced pressure. The residue was purified by silica gel chromatography eiuting with 0-50 % DCM in hexane to give the desired product as a white solid (3.48 g, 91 %). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.02 (d, J=1.76 Hz, 1 H) 7.48 (d, J=1.56 Hz, 1 H) 4.03 (s, 3 H). ES-LCMS: m/z 359 (M+1 ).
Step F
Methyl 3-chloro-5-ethenyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate Triethylamine (0.195 mL, 1.40 mmol) was added to a mixture of methyl 5-bromo-3- chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (100 mg, 0.280 mmol), potassium isopropenyltrifluoroborate (49.7 mg, 0.336 mmol) and PdCl2(dppf)-CH2CI2 adduct (11 .4 mg, 0.0140 mmol) in n-propanol (3.0 mL) under N2. The mixture was heated to 100°C and stirred for 3 hours. After cooling to RT the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness. The residue was dissolved in EtOAc. The solution was washed with saturated aqueous NaHC03, dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-10 % EtOAc in hexane to give the desired product as a white solid (69 mg, 77 %). H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.71 (d, J-1.56 Hz, 1 H) 7.60 (d, J=1.56 Hz, 1 H) 5.64 (s, 1 H) 5.41 (d, J=1 .17 Hz, 1 H) 4.03 (s, 3 H) 2.24 (s, 3 H). ES-LCMS: m/z 305 ( +1 ).
Step G
Methyl 3-chloro-5-formyl-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylate Osmium tetroxide (0.15 mL, 0.012 mmol) was added to a solution of methyl 3- chloro-S-ethenyl^-itrifluoromethy pyrazolofl .S-alpyridine^-carboxylate (180 mg, 0.591 mmol) in tetrahydrofuran (4 mL) and water (4 mL) at room temperature to afford a brown solution within 2 minutes. Sodium periodate (316 mg, 1.48 mmol) was added to above mixture which afforded an off-white suspension that was stirred for 3 h. The mixture was diluted with EtOAc, washed with H20, brine, dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-20 % EtOAc in hexane to give the desired product as a white solid (160 mg, 88 %). H NMR (400 MHz, CHLOROFORM-d) 5 ppm 10.09 (s, 1 H) 8.36 (d, J=1.37 Hz, 1 H) 7.91 (d, J=1.37 Hz, 1 H) 4.06 (s, 3 H). ES-LCMS: m/z 307 (M+1 ).
Step H
Methyl 3-chlorc 5-(difluoromethyl)-7-(trifluoromethyl)pyrazo
Diethylaminosulfur trifluoride (DAST) (0.134 mL, 1.02 mmol) was added to a solution of methyl 3-chloro-5-formyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylate (156 mg, 0.509 mmol) in dichloromethane (2.0 mL) at 0°C under N2. The reaction mixture was allowed to warm to room temperature and stirred for 2 hours and then slowly quenched by addition of water. After the phases were separated, the aqueous phase was extracted with DCM. The combined DCM extracts were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-20 % EtOAc in hexane to give the desired product as a white solid (155 mg, 93 %). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (s, 1 H) 7.53 (s, 1 H) 6.60 - 6.91 (m, 1 H) 4.05 (s, 3 H). ES-LCMS: m/z 329 (M+1 ).
Step I
3-Chloro-5-( difluoromethyl) - 7~(trifIuoromethyi)pyrazolo[ 1, 5-a ]pyridine-2-carboxylic acid 1 M aqueous sodium hydroxide (0.694 mL, 0.694 mmol) was added to a solution of methyl 3-chloro-5-(difluoromethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (152 mg, 0.463 mmol) in tetrahydrofuran (3.0 ml_) at room temperature and the solution stirred for 4 hours. After diluting with water, the solution was acidified to pH=2-3 by addition of 1 N aqueous HCl. The resulting mixture was extracted with EtOAc (3x). The combined extracts were washed with brine, dried over sodium sulfate and concentrated to dryness at reduce pressure to give the title compound as a white solid. The crude product was carried to the next step without further purification and the yield assumed to be quantitative. ES-LCMS: m/z 315 (M+1 ). Step J
4-{[3-Chloro-5-(difluoromethyl)-7-(trifluoromethyi)pyra^
(trans-4-hydroxycycto exyi)-2-piperazinone
DIPEA (0.089 ml, 0.51 mmol) was added to a mixture of 3-chloro-5- (difluoromethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxy!ic acid (40 mg, 0.13 mmol) and 1-(trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (29.8 mg, 0.127 mmol) in tetrahydrofuran (2.0 ml) at room temperature under N2. After stirring at RT for 30 minutes the solution was cooled to 0 0 C and treated with 1 -propanephosphonic acid cyclic anhydride (0.1 14 ml, 0.191 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours. Saturated NaHC03 was added to the mixture. The resulting mixture was extracted with EtOAc (3X). The combined EtOAc extracts were washed with brine, dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue purified by silica gel chromatography eluting with 20-90 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (48 mg, 76 %). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.97 (d, J=8.19 Hz, 1 H) 7.49 (s, 1 H) 6.61 - 6.92 (m, 1 H) 4.39 - 4.57 (m, 2 H) 4.35 (s, 1 H) 3.95 - 4.05 (m, 2 H) 3.55 - 3.67 (m, 1 H) 3.39 - 3.46 (m, 2 H) 2.08 (d, J=1 1.71 Hz, 2 H) 1.71 - 1.84 (m, 2 H) 1.39 - 1.54 (m, 4 H). ES-LCMS: m/z 495 (M+1 ).
EXAMPLE 120
4-{[3-Chloro-5-(difIuoromethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2- ylIcarbonyl}-1 -[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 120)
Figure imgf000259_0001
Step A
4-{[3-Chloro-5-(difluoromethyl)-7-(trifIuoromethyl)pyrazo
((1S,2S,3S,5S 2-{[(1, 1~dimethylethyl)(dimethyi)silyl]ox^ 1.0]hex-3-yl)-2~ piperazinone
DIPEA (0.083 ml, 0.477 mmol) was added to a mixture of 3-chloro-5- (difluoromethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (50 mg, 0.159 mmol) and 1-((1 S,2S,3S,5S)-2-{[(1 ,1-dimethylethyl){dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3- yl)-2-piperazinone (49.4 mg, 0.159 mmol) in tetrahydrofuran (2.0 ml) at room temperature under N2. After stirring at RT for 30 minutes the solution was cooled to 0°C and treated with 1 -propanephosphonic acid cyclic anhydride (0.142 ml, 0.238 mmol). The mixture was allowed to warm to room temperature and stirred for 1 hour. Saturated NaHC03 was added to the mixture. The resulting mixture was extracted with EtOAc (3X). The combined EtOAc extracts were washed with brine, dried over Na2S0 and concentrated to dryness at reduced pressure to give the title compound as a yellow oil. The crude product was used for the next step without further purification and the yield assumed to be quantitative. ES-LCMS: m/z 607 (M+1 ).
Step B
4~{[3-Chloro-5-(difluoromethyl)-7-(trifluoromethyl)pyrazolo[1, 5-a]pyridin-2~yl]carbonyl}-1- [(1S,2S, 3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
1 M TBAF/THF (0.316 mL, 0.316 mmol) was added to a solution of 4-{[3-chloro-5- (difluoromethy])-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y!]carbony!}-1 -((1 S,2S,3S,5S)- 2-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone (96 mg, 0.16 mmol) in tetrahydrofuran (2.0 mL) at room temperature under N2. After stirring for 1 hour the solution was concentrated nearly to dryness at reduced pressure. The residue was mixed with EtOAc (10 mL) followed by 10% aqueous sodium bicarbonate (10 mL) and the phases separated. The water layer was extracted with EtOAc (3x10 mL). The combined EtOAc extracts were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by silica gel chromatography eiuting with 10-80 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (52 mg, 67 %). 1H NMR (400 MHz, CHLOROFORM-d) 6 ppm 7.98 (d, J=7.80 Hz, 1 H) 7.49 (d, J=3.32 Hz, 1 H) 6.59 - 6.93 (m, 1 H) 4.29 - 4.65 (m, 4 H) 4.08 - 4.22 (m, 1 H) 3.89 - 4.00 (m, 1 H) 3.37 - 3.56 (m, 2 H) 1.95 - 2.04 (m, 2 H) 1.59 (d, J=3.71 Hz, 1 H) 1.37 - 1.48 (m, 1 H) 0.75 - 0.86 (m, 1 H) 0.48 - 0.58 (m, 1 H), ES-LCMS: m/z 493 (M+1 ).
EXAMPLE 121
(f+/.J-4-{I3-Chloro-5-(2-hydroxy-1-methylethyl)-7-{trifluoromethyl)pyrazolo[1I5- a]pyridin-2-yl]carbonyl}-1-(frans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 121)
Figure imgf000260_0001
Step A
Methyl 3-chIoro-5-( 1 -methylethenyl)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2- carboxylate
Triethylamine (0.975 mL, 6.99 mmol) was added to a mixture of methyl 5-bromo-3- chloro-7-(trifiuoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxyIate (500 mg, 1.399 mmol), potassium isopropenyltrifluoroborate (248 mg, 1.678 mmol) and PdCI2(dppf)-CH2Cl2 adduct (57.1 mg, 0.070 mmol) in n-propanol (15 mL) under N2. The mixture was heated to 00 °C and stirred for 3 h. After cooling to room temperature, the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to dryness. The residue was dissolved in EtOAc. The resulting solution was washed with satd. NaHC03, dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-10 % EtOAc in hexane to give the desired product as a white solid (344 mg, 77%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.71 (d, J=1.56 Hz, 1 H) 7.60 (d, J=1 .56 Hz, 1 H) 5.65 (s, 1 H) 5.41 (d, J=0.98 Hz, 1 H) 4.03 (s, 3 H) 2.25 (s, 3 H). ES-LCMS: m/z 319 (M+1 ).
Step B
( ÷/-)-Methyl 3-chloro-5-(2-hydroxy- 1 -methylethyl)-7-( trifluoromethyl)pyrazolo[1 , 5- a ]pyridin e-2-carboxylate 1 M BH3-THF in THF (1 ,88 mL, 1 ,88 mmol) was added dropwise to a solution of methyl 3-chloro-5-(1-methylethenyl)-7-(thfluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxyiate (200 mg, 0.628 mmol) in tetrahydrofuran (5 mL) at 0 0 C under N2. The mixture was stirred at 0 0 C for 40 minutes and then allowed to warm to room temperature and stirred for 4 hours. A solution of NaB03.4H20 (309 mg, 2.01 mmol) in water (8.0 mL) was added. The mixture was stirred for 30 minutes and then diluted with brine. The resulting mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-40 % EtOAc in hexane to give the desired product as a white solid (168 mg, 80 %).
1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.66 (s, 1 H) 7.36 (s, 1 H) 4.03 (s, 3 H) 3.78 - 3.91 (m, 2 H) 3.03 - 3.18 (m, 1 H) 1.38 (d, J = 7.02 Hz, 3 H). ES-LCMS: m/z 337 (M+1 ).
Step C
( +/-)-3-Chloro-5~(2-hydroxy-1-methylethyl)- 7-(trifluoromethyi)pyrazolo[ 1, 5-a ]pyridine-2- carboxylic acid
1 M aqueous NaOH (0.74 mL, 0.74 mmol) was added to a solution of methyl 3- chlorO"5-(2-hydroxy-1-methylethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (166 mg, 0.493 mmol) in tetrahydrofuran (3.0 mL) at room temperature and the mixture was stirred for 4 hours. The mixture was diluted with water and then acidified to pH = 2-3 with 1 N HCI. The resulting mixture was extracted with EtOAc (3X). The combined extracts were washed with brine, dried over Na2S04 and concentrated to dryness at reduced pressure to give the desired product as a white solid. The crude material will be carried to the next step without further purification and the yield assumed to be
quantitative. H NMR (400 MHz, METHANOL-d4) δ ppm 7.75 (s, 1 H) 7.57 (s, 1 H) 3.66 - 3.79 (m, 2 H) 3.10 (m, 1 H) 1.34 (d, 3 H). ES-LCMS: m/z 323 (M+1 ).
Step D
(+/-)-4-{[3-Chlorc 5-(2-hydroxy-1-methylethyl)-7-( ifluoro
yljcarbonyl}- 1-(trans-4-hydroxycyclohexyl)-2-piperazinone
T ethylamine (0.043 mL, 0.310 mmol) was added to a mixture of 3-chloro-5-(2- hydroxy-1-methylethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (40 mg, 0.12 mmol), 1-(trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (29.1 mg, 0.124 mmol), EDC (28.5 mg, 0.149 mmol) and HOBT (22.8 mg, 0.149 mmol) in N,N- dimethylformamide (2.0 mL) at room temperature. The mixture was stirred for 2 days. The solvent was removed at reduced pressure and the residue mixed with EtOAc and aqueous NaHC03. The resulting mixture was extracted with 10% eOH/EtOAc. The combined organic extracts were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by silica gel chromatography eluting with 50-100 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (51 mg, 82 %). 1H NMR (400 MHz, CHLOROFOR -d) δ ppm 7.63 (d, J=8.39 Hz, 1 H) 7.31 (s, 1 H) 4.37 - 4.55 (m, 2 H) 4.35 (s, 1 H) 3.99 (q, J=5.20 Hz, 2 H) 3.75 - 3.92 (m, 2 H) 3.52 - 3.67 (m, 1 H) 3.35 - 3.45 (m, 2 H) 3.04 - 3.17 (m, 1 H) 2.08 (br. s., 1 H) 1.69 - 1.83 (m, 2 H) 1.42 - 1 .58 (m, 5 H) 1.38 (dd, J=7.02, 1.76 Hz, 3 H). ES-LCMS: m/z 503 (M+1 ).
EXAMPLE 122
4-{[3-Chloro-5-(2-hydroxy-1-methylethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-1-[(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 112)
H
Step A
4^[3-Chloro-5-(2-hydroxy-1-methyiethyl)-7-(trifluoro
yl]carbonyt}-1-((1S,2S,3S S)-2-{[(1, 1-dimethylethyl)^ 1.0]hex-3- yt) -2-piperazin one
A mixture of 3-chioro-5-(2-hydroxy-1 »methylethyl)-7-(trifluoromethyl)pyrazolot1 ,5- a]pyridine-2-carboxylic acid (50 mg, 0.16 mmol), ^(( S^S.SS.SS^-iff l .l - dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone (48.1 mg, 0.155 mmol), EDC (35.6 mg, 0.186 mmol) and HOBT (28.5 mg, 0.186 mmoi) in N,N- dimethylformamide (2.0 mL) was stirred for 5 hours at room temperature. The solvent was removed in vacuo and the residue dissolved in DCM. The solution was washed with aqueous NaHC03, 5% aqueous LiCI, brine, dried over Na2S04 and concentrated to dryness at reduced pressure to give the title compound as a yellow foam. The crude product was used in the next step without further purification and the yield assumed to be quantitative. ES-LCMS: m/z 615 (M+1 ). Step B
4-{[3-Chloro-5-(2-hydroxy-1-methyiethyl)-7-(trifluoromethyl)pyrazolo[1,^
yi]carbonyl}-1-[(1S, 2S! 3S, 5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone To a stirred solution of 4-{[3-chloro-5-(2-hydroxy-1 -methylethyl)-7- (trifiuoromethyl)pyrazo!o[1 ,5-a]pyridin-2-yl]carbonyl}-1-((1 S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1 .0]hex-3-yl)-2-piperazinone (95 mg, 0.154 mmol) in tetrahydrofuran (2.0 ml) was added 1 M TBAF/THF (0.31 ml, 0.31 mmol) and the resulting solution stirred at RT under N2. After 1 hour the solution was concentrated at reduced pressure and the residue mixed with EtOAc (10 mL) and 10% aqueous NaHC03 (10 mL). The phases were separated and the aqueous solution extracted with EtOAc (3x 0 mL). The combined EtOAc solutions were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was subjected to silica gel
chromatography e!uting with 20-90 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (73 mg, 94 %).
H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.63 (d, J=8.58 Hz, 1 H) 7.32 (br. s., 1 H) 4.30 - 4.62 (m, 4 H) 4.13 - 4.21 (m, 1 H) 3.77 - 3.98 (m, 3 H) 3.41 - 3.54 (m, 2 H) 3.05 - 3.17 (m, 1 H) 1.95 - 2.04 (m, 2 H) 1.54 - 1.63 (m, 1 H) 1.31 - 1.46 (m, 4 H) 0.75 - 0.86 (m, 1 H) 0.47 - 0.57 (m, 1 H). ES-LCMS: m/z 501 (M+1 ). EXAMPLE 123
4-{[5-Acetyl-3-chloro-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2-yl]carbonyI}-1- ( trans-A- hy d roxycyclo h exyl)-2- i pe razi none
(Compound 123)
Figure imgf000263_0001
OH
Step A
Methyl 5-acetyl-3-ch!oro-7-(trifluoromethyi)pyrazolo[ 1, 5-a]pyridine-2-carboxylate Osmium tetroxide (0.26 mL, 0.021 mmol) was added to a solution of methyl 3- chloro-5-(1-methylethenyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (330 mg, 1.04 mmol) in tetrahydrofuran (8.0 imL) and water (8.0 mL) at room temperature. The resulting solution was treated with sodium periodate (554 mg, 2.59 mmol) to give a white suspension that was stirred for 3 h. The mixture was diluted with EtOAc, washed with H20, brine, dried over Na2S04and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-25 % EtOAc in hexane to give the desired product as a white solid (300 mg, 90 %). H NMR (400 MHz,
CHLOROFORM-d) δ ppm 8.37 (d, J=1.56 Hz, 1 H) 7.99 (d, J=1.37 Hz, 1 H) 4.05 (s, 3 H) 2.73 (s, 3 H). ES-LCMS: m/z 321 (M+1 ). Step B
5~Acetyl-3-chloro-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2-carboxylic acid LiOH (26.9 mg, 1.12 mmol) in water (0.6 mL) was added to a mixture of methyl 5- acetyl-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2~carboxylate (120 mg, 0.374 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.6 mL) at room temperature under N2. The mixture was stirred overnight. The mixture was diluted with water, acidified to pH = 2- 3 with 1 N HCI and extracted with EtOAc (3X). The combined extracts were washed with brine, dried over Na2S04 and concentrated to dryness at reduced pressure to give the title compound as a yellow solid. The crude material will be carried to the next step without further purification and the yield assumed to be quantitative. ES-LCMS: m/z 305 (M-1 ).
Step C
4-{[5-Acetyi-3-chloro- 7-(trifluoromethy!)pyrazoIo[ 1, 5-a]pyridin-2-yl]carbonyl}~ 1 -(trans-4- hydroxycycloh exyl) -2-pip erazinon e
DIPEA (0.328 ml, 1.88 mmol) was added to a mixture of 5-acetyl-3~chloro-7- (trifluoromethyl)pyrazolo[ ,5-a]pyridine-2-carboxylic acid (115 mg, 0.375 mmol) and 1 - (trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (123 mg, 0.525 mmol) in THF (4.0 ml) at room temperature under N2. The mixture was stirred for 30 minutes at room temperature, cooled to 0°C and treated with 1-propanephosphonic acid cyclic anhydride (0.447 ml, 0.750 mmol). The mixture was allowed to warm up to room temperature and stirred for 2 hours. The solution was mixed with saturated aqueous NaHC03 and extracted with 5 % MeOH in EtOAc (3X), The combined extracts were washed with brine, dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by silica gel chromatography eluting with 50-90 % EtOAc (containing 10 % MeOH) in hexane to afford the title compound as a light-yellow solid (25 mg, 14 %). Ή NMR (400 MHz, CHLOROFORM-d) δ ppm 8.35 (dd, J=7.71 , 1.27 Hz, 1 H) 7.93 - 7.99 (m, 1 H) 4.38 - 4.57 (m, 2 H) 4.37 (s, 1 H) 3.98 - 4.05 (m, 2 H) 3.54 - 3.66 (m, 1 H) 3.43 (t, J=4.78 Hz, 2 H) 2.74 (s, 3 H) 2.08 (d, J=10.54 Hz, 2 H) 1.72 - 1.84 (m, 2 H) 1.43 - 1.55 (m, 4 H). ES- LCMS: m/z 487 (M+1 ).
EXAMPLE 124
4-{[3-Chloro-5-(1,1-difluoroethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-1-(frans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 124)
Figure imgf000265_0001
0
Step A
Methyl 3-chloro-5-( 1, 1 -difluoroethyl)~7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-2- carboxylate
Diethylaminosulfur trifluoride (DAST) (0.082 mL, 0.62 mmol) was added to a solution of methyl 5-acetyl-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylate (100 mg, 0.312 mmol) in dichioromethane (2.0 mL) at 0°C under N2. The reaction mixture was allowed to warm up to room temperature and stirred for 2 hours. Analysis of the reaction mixture by LCMS indicated only a trace amount of the desired product. The mixture was heated to 40°C and additional DAST (0.49 mL, 3.74 mmol) was added in small portions over a period of 5 days. The mixture was cooled to RT and slowly mixed with water and DCM. The phases were separated and the aqueous solution extracted with DCM. The combined DCM solutions were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-20 % EtOAc in hexane to give the desired product as a white solid (102 mg, 95 %).1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.98 (s, 1 H) 7.49 (s, 1 H) 4.05 (s, 3 H) 2.03 (t, 3 H). ES-LCMS: m/z 343 (M+1 ).
Step B
3-Chloro-5-( 1, 1-difluoroethyl)-7-(trifluoromethyl)pyrazoIo[ 1, 5-a]pyridine-2-carboxylic acid 1 N aqueous NaOH (0.455 mL, 0.455 mmol) was added to a solution of methyl 3- chlon 5~(1 ,1-difluoroethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxyiate (104 mg, 0.304 mmol) in tetrahydrofuran (2.5 mL) at room temperature and the resulting solution stirred for 7 hours. The mixture was diluted with water, acidified to pH = 2-3 with 1 N HCl and extracted with EtOAc (3X). The combined extracts were dried over Na2S04 and concentrated to dryness at reduced pressure to afford the title compound as a white solid. The crude material will be carried to the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.01 (s, 1 H) 7.53 (s, 1 H) 2.04 (t, 3 H). ES-LCMS: m/z 327 (M-1 ).
Step C
4-{[3-C loro-5-(1, 1-difluoroethyl)-7-(trifluoromethyI)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}-1-
(trans-4-hydroxycyclohexyl)-2-piperazinone
DIPEA (0.128 ml, 0.730 mmol) was added to a mixture of 3-chloro-5-(1 ,1- difluoroethyl)-7-(trifluoromethy[)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid (48 mg, 0.15 mmol) and 1-(trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (48.0 mg, 0.204 mmol) in THF (2.0 ml) at room temperature under N2. After stirring at RT for 30 minutes the solution was cooled to 0°C and treated with 1-propanephosphonic acid cyclic anhydride (0. 74 ml, 0.292 mmol). The resulting solution was allowed to warm to RT and stirred for 2 hours. The solution was mixed with EtOAc and saturated aqueous NaHC03 and the phases separated. The water solution was extracted with EtOAc (3x10 mL). The combined EtOAc solutions were dried over Na2S04 and concentrated to dryness at reduced pressure. The residue was purified by silica gel chromatography eluting with 20- 90 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (45 mg, 61%). H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.95 (d, J=8.59 Hz, 1 H) 7.45 (s, 1 H) 4.38 - 4.57 (m, 2 H) 4.35 (s, 1 H) 4.00 (dt, J=1 1.07, 5.49 Hz, 2 H) 3.53 - 3.66 (m, 1 H) 3.37 - 3.46 (m, 2 H) 1.97 - 2.14 (m, 5 H) 1.70 - 1.85 (m, 2 H) 1.39 - 1.54 (m, 4 H). ES-LCMS: m/z 509 (M+1 ).
EXAMPLE 125
(+/-)-4-{[3-Chloro-5-(2,2-difluorocyclopropyl)-7-(trifluoromethyl)pyrazolo[1,5- a]pyridin-2-yl]carbonyl}-1-(ira ?s-4-hydroxycyclohexyl)-2-piperazinone
(Compound 125)
Figure imgf000267_0001
Step A
( +/-)~Methyl 3-chloro-5-(2, 2-difluorocyclopropyl)-7-(trifluoromethyl)pyrazolo[ 1, 5-a]pyridine-
2-carboxylate
A solution of methyl 3-chloro-5-ethenyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2- carboxylate (200 mg, 0.656 mmol) in diglyme (6.0 ml_) was heated at 160°C and stirred vigorously. To the solution was added sodium chloro(difluoro)acetate (817 mg, 5.25 mmol) and the mixture was stirred for 1.5 hours at 160°C. After cooling to RT the mixture was mixed with aqueous brine and extracted with EtOAc. The EtOAc solution was dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by chromatography on silica gel eluting with 0-20 % EtOAc in hexane to give the desired product as a white solid (230 mg, 99%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.64 (s, 1 H) 7.26 - 7.28 (m, 1 H) 4.01 - 4.06 (m, 3 H) 2.84 (td, J=1 1 .67, 8.30 Hz, 1 H) 2.04 (m, J=11.69, 1 1.69, 8.25, 5.47 Hz, 1 H) 1.79 (m, J=12.60, 8.35, 8.35, 3.91 Hz, 1 H). ES-LCMS: m/z 355 (M+1 ).
Step B
(+/-)-3-Chtoro-5-(2,2-difluorocyclopropyl)-7-(trifluoromethyi)pyrazolo[1,^
carboxylic acid
1 N aqueous NaOH (0.89 ml_, 0.89 mmol) was added to a solution of methyl 3- chloro-5-(2,2-difluorocyclopropyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (210 mg, 0.592 mmol) in tetrahydrofuran (5.0 ml_) at room temperature and the resulting solution stirred for 4 hours. The mixture was diluted with water, acidified to pH = 2-3 with 1 N HCI and extracted with EtOAc (3X). The combined extracts were dried over Na2S04 and concentrated to dryness at reduced pressure to give the title compound as a white solid. The crude material will be carried to the next step without further purification. 1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 7.68 (s, 1 H) 7.32 (d, J=1 .37 Hz, 1 H) 2.87 (td, J=11.61 , 8.19 Hz, 1 H) 2.01 - 2.13 (m, 1 H) 1.76 - 1.88 (m, 1 H). ES-LCMS: m/z 339 (M-1 ).
Step C
(+/-)-4~{[3-Chloro-5-(2,2-difluorocyclopropyl)~7~(trifl^^ yljcarbonyl} -1-( trans-4-hydroxycyclohexy!) -2-piperazinone DIPEA (0.154 ml, 0.881 mmol) was added to a mixture of (+/-)-3-chloro-5-(2,2- difiuorocyclopropyl)-7-(trifluoromethyl)pyrazo[o[1 ,5-a]pyridine-2-carboxylic acid (60 mg, 0.18 mmol) and 1-(trans-4-hydroxycyclohexyl)-2-piperazinone hydrochloride (49.6 mg, 0.21 1 mmol) in tetrahydrofuran (2.0 ml) at room temperature under N2. After stirring at RT for 30 minutes the solution was cooled to 0°C and treated with 1-propanephosphonic acid cyclic anhydride (0.157 ml, 0.264 mmol). The resulting solution was allowed to warm to RT and stirred for 2 hours. The solution was mixed with EtOAc and saturated aqueous NaHC03 and the phases separated. The water solution was extracted with EtOAc (3x10 ml_). The combined EtOAc solutions were dried over Na2S04 and concentrated to dryness at reduced pressure. The crude residue was purified by silica gel
chromatography eluting with 20-90 % EtOAc (containing 5 % MeOH) in hexane to afford the title compound as a white foam (86 mg, 94 %). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.61 (d, J=8.39 Hz, 1 H) 7.23 (s, 1 H) 4.38 - 4.57 (m, 2 H) 4.35 (s, 1 H) 3.94 - 4.04 (m, 2 H) 3.54 - 3.65 (m, 1 H) 3.36 - 3.44 (m, 2 H) 2.79 - 2.92 (m, 1 H) 2.05 - 2.12 (m, 3 H) 1 .70 - 1.85 (m, 3 H) 1.38 - 1.54 (m, 4 H). ES-LCMS: m/z 521 (M+1 ).
EXAMPLE 126
4-{[3-Chloro-5-cyclopropyl-7-(1W-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}- 1-(irans-4-hydroxycyclohexyl)-2-piperazinone
(Compound 126)
Figure imgf000268_0001
Step A
Methyl 3-chloro-5-cyclopropyl- 7-(1 H-pyrazol-4-y!)pyrazolo[ 1, 5-a ]pyridine-2-carboxylate The title compound was prepared in 50% yield from methyl 7-bromo-3-chloro-5- cyclopropylpyrazolo[1 ,5-a]pyridine-2-carboxylate and 1 ,1-dimethylethyl 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 /-/-pyrazole-1 -carboxylate according to the procedure described herein for the synthesis of methyl 3-chloro-5-cyclopropyl-7-(1 H- pyrrol-2-yl)pyrazolo[1 ,5-a]pyridine-2-carboxyla†e. ES-LCMS m/z: 317 (M+1 ).
Step B
3- Chloro-5^yclopropyl-7'(1H^yrazo!-4-yl)pyrazolo[1,&a]pyridine-2-carboxylic acid The title compound was prepared in 85% yield from methyl 3-chloro-5-cyclopropyl-
7-{1 H-pyrazol-4-yl)pyrazolo[1 !5-a]pyridine-2-carboxylate according to the procedure described herein for the synthesis of 3-chloro-5-cyclopropyl-7-(3-thienyl)pyrazolo[1 ,5- a]pyridine-2-carboxylic acid. ES-LCMS m/z: 303 (M+1 ). Step C
4- {[3-Chloro-5-cyclopropyl-7-(1H^yrazol-4-yi)pyrazoio[1,5-a]pyndin-2-yl]carbon
(trans-4-hydroxycyclohexy!)-2-piperazinone
The title compound was prepared in 36% yield from 3-chloro-5-cyclopropyl-7-(1 H- pyrazol-4-yl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1-(£rans-4-hydroxycyclohexyl)-2- piperazinone hydrochloride according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-4- hydroxycyc!ohexyl)-2-piperazinone. H NMR (400 MHz, METHANOL-^) δ ppm 8.74 - 8.85 (m, 1 H) 8.42 (br. s., 1 H) 7.18 - 7.26 (m, 2 H) 4.25 - 4.48 (m, 3 H) 4.03 (t, J=5.4 Hz, 1 H) 3.91 (t, J=5.2 Hz, 1 H) 3.39 - 3.58 (m, 3 H) 2.06 - 2.16 (m, 1 H) 1.97 - 2.06 (m, 2 H) 1.55 - .76 (m, 4 H) 1.32 - 1.48 (m, 2 H) 1.08 - 1.17 (m, 2 H) 0.88 - 0.96 (m, 2 H). ES-LCMS m/z: 483 (M+1 ).
EXAMPLE 127
4-{[3-C loro-5-cyelopropyl-7-(4-isothiazolyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (ira/7s-4-hydroxycyclohexyl)-2-piperazinone
(Compound 127)
Figure imgf000269_0001
H
Step A
Methyl 3-chloro-5-cyclopropyl-7-(4-isothiazolyl)pyrazolo[ 1, 5-a]pyridine-2-carboxytate A mixture of methyl S-chloro-S-cyclopropyl-Z^^.S.S-tetramethyl-I .S^- dioxaborolan-2-yl)pyrazolo[1 ,5-a]pyridine-2-carboxylate (250 mg, 0.664 mmol), 4- bromoisothiazole (435 mg, 2.66 mmol), K3P04 (564 mg, 2.66 mmol) and [1 ,1 '- bis(diphenylphosphino)ferrocene]dichloro palladium(ll) DC complex (27 mg, 0.033 mmol) in 10 mL of 1 ,4-dioxane in a sealed tube was sparged with nitrogen and heated to 100°C with stirring. After 2 hours the mixture was treated with an additional portion of methyl 3-chloro-5-cyclopropyl-7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (250 mg, 0.664 mmol) and heating at 100°C continued. After another 1 hour the mixture was cooled to room temperature and allowed to sit for 5 days. The mixture was diluted with EtOAc, washed with water (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica ge!, gradient from hexane to 1 :1 hexane/EtOAc) to afford the title compound (46 mg, 10%) as a light yellow solid. ES-LC S m/z: 334 (M+1 ).
Step B
4~{[3-Chloro-5-cyclopropyl-7-(4-isothiazoIyl)pyrazolo[1,5-a]pyrid
4-hydroxycycioh exyl)-2-piperazin on e
A solution of methyl 3-chloro-5-cyclopropyl-7-(4-isothiazolyl)pyrazolo[1 ,5- a]pyridine-2-carboxylate (46 mg, 0.14 mmol) in 10 mL of 1 :1 :1 THF/water/MeOH was treated with LiOH monohydrate (17 mg, 0.41 mmol) and the resulting solution stirred at room temperature. After 2 hours the solution was treated with 0.5 mL of 1 N aqueous HCi and concentrated to dryness at reduced pressure to give a yellow solid. This material was dissolved in 4 mL of DMF and the solution treated with 1-(£rans-4-hydroxycyclohexyl)~2- piperazinone hydrochloride (36 mg, 0.15 mmol) followed by DIPEA (99 ί, 0.57 mmol). The solution was cooled in an ice water bath and treated with 50 wt% 1 - propanephosphonic acid cyclic anhydride/EtOAc (175 mg, 0.28 mmol). The resulting solution was stirred in the ice bath for 30 minutes and then allowed to warm to room temperature. After 2 hours the solution was diluted with EtOAc, washed with 10% aqueous citric acid (2x), saturated aqueous sodium bicarbonate (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude material was subjected to flash chromatography (silica gel, gradient from DCM to 9:1 DCM/EtOH) to give the title compound (53 mg, 77%) as a yellow solid. H N R (400 MHz,
CHLOROFORM-c δ ppm 8.09 - 8.13 (m, 1 H) 7.98 - 8.00 (m, 1 H) 7.68 (d, J=3.1 Hz, 1 H) 7.40 - 7.43 (m, 1 H) 4.66 (s, 1 H) 4.40 - 4.58 (m, 2 H) 4.04 - 4. 1 (m, 2 H) 3.54 - 3.66 (m, 1 H) 3.38 - 3.47 (m, 2 H) 2.02 - 2.17 (m, 3 H) 1.71 - 1 .83 (m, 2 H) 1.40 - 1.65 (m, 5 H) 1.13 - 1.21 (m, 2 H) 0.93 - 0.99 (m, 2 H). ES-LCMS m/z: 500 ( +1 ).
EXAMPLE 128
4-[(3-Ch[oro-5-cyclopropyl-7-phenylpyrazolo[1,5-a]pyridin-2-y[)carbonyl]-1- [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.03hex-3-yl]-2-piperazinone
Compound 128)
Figure imgf000271_0001
The title compound was prepared in 70% yield from 3-chioro-5-cyclopropyl-7- pheny!pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1 -((1 S,2S,3S,5S)-2-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}bicyclo[3.1.0]hex-3-yl)-2-piperazinone according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chioro-7- (trifluoromethy pyrazolofl .S-ajpyridin^-y carbonylJ-l-Cil S.aS^S.SS)^- hydroxybicyclo[3.1 .0]hex-3-yl]-2-piperazinone. 1H NMR (400 MHz, METHANOL-^) δ ppm 7.82 - 7.88 (m, 2 H) 7.49 - 7.57 (m, 3 H) 7.31 - 7.35 (m, 1 H) 6.82 - 6.86 (m, 1 H) 3.95 - 4.61 (m, 5 H) 3.69 - 3.84 (m, 1 H) 3.32 - 3.56 (m, 2 H) 2.06 - 2.16 (m, 1 H) 1.81 - 2.02 (m, 2 H) 1.45 - 1.54 (m, 1 H) 1.36 (m, 1 H) 1 .09 - 1.17 (m, 2 H) 0.88 - 0.94 (m, 2 H) 0.71 - 0.78 (m, 1 H) 0.43 - 0.51 (m, 1 H). ES-LCMS m/z: 491 (M+1 ).
EXAMPLE 129
4-{[3-Chloro-5-cyclopropyl-7-(trif!uoromethyl)pyrazoIo[1 ,5-a]pyridin-2-yl]carbonyl}- 1-[(1/?S,3 ?S,5 ?S)-2,2-difluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 129)
Figure imgf000272_0001
Step A
1, 1-Dimethylethyl ((1RS)-1-{[ ethyl(methyloxy)amino]carbonyl}-3-buten~1-yl)carbamate A solution of (2RS)-2-({[(1 ,1-dimethylethyl)oxy]carbonyl}amino)-4-pentenoic acid (30.0 g, 139 mmol) in THF (137 mL) and DCM (540 mL) was cooled to -20°C and treated with /V-methylpiperidine (16.9 mL, 139 mmol). To this solution was slowly added methyl chloroformate (10.7 mL, 139 mmol). This was followed by slow addition of a chilled solution of dimethylhydroxylamine hydrochloride (13.6 g, 139 mmol) and N- methylpiperidine (16.9 mL, 139 mmol) in DCM (71 mL). The mixture was allowed to warm to room temperature with stirring. After 2 hours the mixture was cooled to 5°C, washed with 0.2 N aqueous HCI (2x150 mL), 0.5 N aqueous NaOH (2x150 mL), brine (1x), dried over magnesium sulfate and concentrated to dryness at reduced pressure to afford the title compound as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.66 - 5.78 (m, 1 H) 5.03 - 5.22 (m, 3 H) 4.68 - 4.78 (m, 1 H) 3.75 (s, 3 H) 3.18 (s, 3 H) 2.40 - 2.52 (m, 1 H) 2.26 - 2.40 (m, 1 H) 1.40 (s, 9 H).
Step B
1, 1-Dimethylethyl [( 1RS)-2-oxo-1-(2-propen-1-yl)-3-buten-1-yl]carbamate
A stirred solution of 1 ,1-dimethylethyl (( iRS)-1- {[methyl(methyloxy)amino]carbonyi}-3-buten-1-yl)carbamate (10.0 g, 38.8 mmol) in THF (50 mL) was cooled to -78°C and treated with 1 vinylmagnesium bromide/THF (136 mL, 136 mmol). The resulting solution was slowly warmed to 15°C. The reaction mixture was then cooled in an ice water bath and added to 100 mL of chilled 3N aqueous HCI over a 5 minute period. This was followed by addition of EtOAc (40 mL). After stirring for several minutes the phases were separated. The EtOAc solution was washed with 1 :1 3N aqueous HCI/13% aqueous NaCI (1x), 13% aqueous NaCI (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure to give the title compound (8.50 g, 97%) as a yellow oil. H NMR (400 MHz, CHLOROFORM- ) δ ppm 6.31 - 6.55 (m, 2 H) 5.87 (d, J=10.3 Hz, 1 H) 5.56 - 5.70 (m, 1 H) 5.28 (s, 1 H) 5.02 - 5.15 (m, 2 H) 4.61 - 4.72 (m, 1 H) 2.54 - 2.67 (m, 1 H) 2.29 - 2.42 (m, 1 H) 1.42 (s, 9 H). Step C
Bis( 1, 1-dimethylethyl) [(1RS)-2-oxo~3-cyclopenten-1-yl]imidodicarbonate
To a stirred solution of 1 ,1 -dimethyl ethyl [(-/RS)-2-oxo-1-(2-propen-1-yl)-3-buten-1- yl]carbamate (8.73 g, 38.8 mmol) in DCM (87 mL) under nitrogen was added Hoveyda- Grubbs 2nd generation catalyst (0.44 g, 0.70 mmol) and the solution stirred at room temperature. After 45 minutes the solution was treated with an additional portion of catalyst (87 mg, 0.10 mmol). After 18 hours a third portion of catalyst was added (87 mg, 0.10 mmol). After an additional 2 hours the solution was concentrated to dryness at reduced pressure. The residue was dissolved in MeCN (76 mL) and the solution treated with dimethylaminopyridine (0.48 g, 3.9 mmol) followed by Boc-anhydride ( 2.7 g, 58.2 mmol). The resulting solution was stirred at room temperature. After 1 hour the solution was treated with an additional portion of Boc-anhydride (4.78 g, 21.9 mmol). After stirring at room temperature for 2 days the solvent was removed by rotary evaporation and the residue dissolved in EtOAc (100 mL). The solution was washed with saturated aqueous ammonium chloride (2x25 mL), brine (1x25 mL), and concentrated to dryness at reduced pressure. The crude residue was subjected to flash chromatography (silica gel, gradient from heptane to 8:2 heptane/EtOAc) to afford the title compound (7.66 g, 67%) as a solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.54 - 7.59 (m, 1 H) 6.21 - 6.27 (m, 1 H) 4.74 (dd, J=7.0, 3.7 Hz, 1 H) 2.93 - 3.05 (m, 1 H) 2.68 - 2.79 (m, 1 H) 1.38 - 1.51 (m, 18 H).
Step D
Bis(1, 1-dimethylethyl) [(1RS,3RS,5RS)-2-oxobicyclo[3.1.0]hex-3-yl]imidodicarbonate To 95% sodium hydride (0.391 g, 16.3 mmol) was added anhydrous DMSO (33 mL). To this was added trimethylsulfoxonium iodide (3.91 g, 17.8 mmol) and the resulting mixture was stirred at room temperature for 20 minutes to give the ylide solution. To a separate vessel was added bis(1 , 1-dimethylethyl) [(1 ?S)-2-oxo-3-cyclopenten-1- yl]imidodicarbonate (2.20 g, 7.4 mmol) followed by anhydrous DMSO (15.4 mL). The mixture was heated to 50°C and treated with 20 mL of the ylide solution. Additional smaller aliquots of the ylide solution were added periodically until the reaction was determined to be complete by HPLC. The mixture was cooled to room temperature and poured into a mixture of water (60 mL) and MTBE (100 mL). After separating the phases, the MTBE solution was washed with water (1x30 mL) and concentrated to dryness at reduced pressure. The crude material was purified by flash chromatography (silica gel, 9:1 hexane/EtOAc) to afford the title compound (1.4 g, 61 %) as a tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.55 (t, J=8.7 Hz, 1 H) 2.33 (dd, J=8.7, 2.9 Hz, 2 H) 1.98 - 2.09 (m, 1 H) 1.79 - .91 (m, 1 H) 1.32 - 1.55 (m, 18 H) 1.12 - 1.25 (m, 1 H) 0.85 - 0.96 (m, 1 H). Step E
1, 1-Dimethylathyl [(1RS, 3RS, 5RS)-2-oxobicyc!o[3.1.0]hex-3-yl]carbamate
A solution of bis(1 ,1-dimethylethyl) [(1 RS,3RS,5RS)-2-oxobicyclo[3.1.0]hex-3- yl]imidodicarbonate (0.366 g, 1.18 mmol) in MeCN (5 mL) was treated with CeCI3-7H20 (0.438 g, 1 .18 mmol) followed by sodium iodide (0.176 g, 1.18 mmol) and the resulting mixture was stirred at room temperature. After 16 hours the mixture was diluted with water and extracted with EtOAc (3x). The combined EtOAc extracts were dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc, cerric ammonium molybdate stain) to afford the title compound (0.216 g, 87%) as a light tan solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.82 (br. s., 1 H) 3.90 - 4.03 (m, 1 H) 2.69 (dd, J=12.5, 8.1 Hz, 1 H) 2.04 - 2.16 (m, 1 H) 1.80 - 1.94 (m, 2 H) 1.38 - 1.49 (m, 9 H) 1.19 - 1.34 (m, 2 H).
Step F
1, 1-Dimethylethyl [(1RS,3RS, 5RS)-2,2-difluorobicyclo[3.1.0]hex-3~yl]carbamate
A solution of 1 ,1 -dimethylethyl [(1 RS,3RS,5RS)-2-oxobicyclo[3.1.0]hex-3- yrjcarbamate (210 mg, 0.994 mmol) in 1 ,2-dichloroethane (6 mL) in a screw cap polyethylene vessel was treated with diethyiaminosulfur trifluoride (0.53 mL, 4.0 mmol). The resulting solution was heated to 60°C with stirring. After 18 hours the solution was cooled to room temperature and slowly added to a rapidly stirred mixture EtOAc and 5% aqueous sodium bicarbonate. After separating the phases the EtOAc solution was washed with water (2x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was purified by flash chromatography (silica ge!, gradient from hexane to 1 :1 hexane/EtOAc) to give the title compound (147 mg, 63%) as a tan solid. H NMR (400 MHz, CHLOROFORM-c/) δ ppm 4.59 - 4.73 (m, 1 H) 3.87 - 4.08 (m, 1 H) 2.25 (dd, J=12.6, 7.7 Hz, 1 H) 1 .62 - 1.79 (m, 2 H) 1.37 - 1.60 (m, 10 H) 0.71 - 0.86 (m, 2 H).
Step G
[(1RS,3RS,5RS)-2,2-Difluorobicyclo[3.1.0]hex-3-yl]amine hydrochloride
A solution of 1 ,1 -dimethylethyl [(1 RS,3f?S,5RS)-2,2-difluorobicyclo[3.1.0]hex-3- yl]carbamate (140 mg, 0.60 mmol) in EtOAc (4 mL) was treated with 4N HCI/dioxane (1.5 mL) and the resulting solution stirred at room temperature. After 6 hours the solution was concentrated to dryness at reduced pressure to afford the title compound in quantitative yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.76 (br. s„ 3 H) 3.58 - 3.77 (m, 1 H) 2.20 (dd, J=12.8, 7.7 Hz, 1 H) 1.81 - 2.04 (m, 2 H) 1.60 - 1 .74 (m, 1 H) 0.89 - 0.98 (m, 1 H) 0.74 - 0.86 (m, 1 H).
Step H
N1-[(1RS, 3RS, 5RS)-2, 2-Difluorobicyclo[3.1.0]hex-3-yl]-N2-[(4- nitroph enyt) sulfonyljglycin amide
A solution of [(1 S,3RS,5RS)-2,2-difluorobicyclo[3.1.0]hex-3-y[]amine
hydrochloride (100 mg, 0.590 mmol), A/-[(4-nitrophenyl)sulfonyl]glycine (153 mg, 0.590 mmol), HOBt (96 mg, 0.71 mmol), and DIPEA (0.31 mL, 1.8 mmol) in DMF (5 mL) was treated with EDC (136 mg, 0.708 mmol) and the resulting solution stirred at room temperature. After 18 hours the solution was diluted with EtOAc, washed with 5% aqueous citric acid (2x), saturated aqueous sodium bicarbonate (3x), brine (1x), dried over sodium sulfate and concentrated to dryness at reduced pressure to give the title compound (209 mg, 94%) as a tan solid. 1H NMR (400 MHz, D SO-cfe) δ ppm 8.34 - 8.45 (m, 3 H) 7.96 - 8.07 (m, 3 H) 3.98 - 4.16 (m, 1 H) 3.56 - 3.68 (m, 2 H) 1 .92 (dd, J=12.5, 7.9 Hz, 1 H) 1.62 - 1.78 (m, 2 H) 1.49 - 1.60 (m, 1 H) 0.68 - 0.83 (m, 2 H).
Step I
1-[(1RS,3RS,5RS)-2,2-Difluorobicyclo[3.1.0]hex-3-yl]-4-[(4-nitrophenyl)sulfonyl]-2- piperazinone
A mixture of N1-[(1f?S,3RS,5RS)~2,2-difluorobicyclo[3.1.0]hex-3-yl]-N2-[(4- nitrophenyl)sulfonyl]glycinamide (204 mg, 0.543 mmol), 1 ,2-dibromoethane (0.38 mL, 4.4 mmol), and Cs2C03 (708 mg, 2.17 mmol) in DMF (4 mL) was stirred at room temperature. After 1.5 hours the mixture was heated to 45°C. After stirring at 45°C for 18 hours the mixture was cooled to room temperature, diluted with EtOAc, washed with water (3x), brine (1x), dried over sodium sulfate, and concentrated to dryness at reduced pressure. The crude residue was subjected to flash chromatography (silica gel, gradient from hexane to EtOAc) to afford the title compound (125 mg, 57%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-of) δ ppm 8.43 (d, J=8.9 Hz, 2 H) 8.00 (d, J=8.9 Hz, 2 H) 4.94 (m, J=19.2, 1 .4, 8.1 , 8.1 Hz, 1 H) 4.04 (d, J=16.8 Hz, 1 H) 3.74 (d, J=16.8 Hz, 1 H) 3.57 - 3.70 (m, 2 H) 3.41 - 3.51 (m, 1 H) 3.20 (ddd, J=1 1.6, 8.9, 2.9 Hz, 1 H) 2.12 - 2.23 (m, 1 H) 1.94 (dd, J=12.6, 8.1 Hz, 1 H) 1.53 - 1.75 (m, 2 H) 0.79 - 0.89 (m, 2 H). ES-LCMS m/z: 402 (M+1 ).
Step J
1-[(1RS,3RS, 5RS)-2, 2-Difluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone The title compound was prepared in 40% yield from 1 -[(1 RS,3RS,5RS)-2,2- difluorobicyclo[3.1.0]hex-3-yl]-4-[(4-nitrophenyl)sulfonyl]-2-piperazinone according to the procedure described herein for the preparation of 1 -[(1 f?,2R,3E)-2-{[(1 ,1- dimethylethyl){dimethyl)silyl]oxy}-4-phenyl-1-(2-propen-1 -y[)-3-buten-1 -yl]-2-piperazinone. 1H NMR (400 MHz, CHLOROFORM-c/) δ ppm 5.1 1 (m, J=19.7, 1 1.7, 8.1 , 8.1 Hz, 1 H) 3.47 - 3.70 {m, 3 H) 3.31 (ddd, J=1 1.8, 7.5, 4.4 Hz, 1 H) 3.02 - 3.16 (m, 2 H) 2.27 (td, J=12.1 , 4.8 Hz, 1 1-1) 1.92 (dd, J=12.5, 8.0 Hz, 1 H) 1.59 - 1.78 {m, 3 H) 0.92 (td, J=3.8, 2.2 Hz, 1 H) 0.79 - 0.87 (m, 1 H).
Step K
4-{{3-Chioro-5-cyclopropyl- 7-(t fluoromethyl)pyrazolo[ 1, 5-a]pyridin-2-yl]carbonyl}- 1 - [(1RS,3RS, 5RS)-2,2-dieuorobicydo[3.1.0]hex-3-yl]-2^iperazinone
The title compound was prepared in 95% yield from 3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridine-2-carboxylic acid and 1-[(1 RS,3RS,5f?S)-2,2- difluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone according to the procedure described herein for the synthesis of 4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[ ,5-a]pyridin-2- yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2-piperazinone. H NMR (400 MHz,
METHANOL-^) δ ppm 7.56 (br. s., 1 H) 7.29 (br. s., 1 H) 4.89 - 5.07 (m, 1 H) 4.29 - 4.55 (m, 2 H) 3.48 - 4.19 (m, 4 H) 2.23 - 2.41 (m, 1 H) 2.05 - 2.17 (m, 1 H) 1.89 - 2.02 (m, 1 H) 1.61 - 1.78 (m, 2 H) 1.07 - 1.18 (m, 2 H) 0.76 - 0.93 (m, 4 H). ES-LCMS m/z: 503 (M+1 ). EXAMPLE 130
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazoIo[1,5-a]pyridin-2-yl]carbonyl}- 1-[{1 S,3S,5S)-2-fluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone
(Compound 130}
Figure imgf000276_0001
4-{[3-chloro-5-cyc]opropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [( S,2R,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yi]-2-piperazinone (200 mg, 0.414 mmol) was dissolved in DCM and the solution cooled in an ice bath. To this was added DAST (0.109 mL, 0.828 mmol) and the reaction stirred in the ice bath. The reaction mixture was quenched with saturated NaHCC^ and the organic layer separated. The organic solution was dried over sodium sulfate and evaporated to a residue. The residue was purified by reverse phase HPLC (acetonitrile/water with 0,1 % formic acid) to afford the title compound (11 .2 mg, 5%) as a 2:3 diastereomer mixture as determined by H and 9F NMR. 1H NMR (METHANOLS) 5: 7.55 (s, 1 H), 7.28 (s, 1 H), 4.87 - 5.08 (m, 1 H), 4.52 (d, J = 18.4 Hz, 2H), 4.38 (d, 1 H), 4.25 - 4.33 (m, 1 H), 3.91 - 4.22 (m, 1 H), 3.48 - 3.85 (m, 3H), 2.20 - 2.39 (m, 1 H), 2.05 - 2.19 (m, 1 H), 1.78 - 1.95 (m, 1 H), 1.52 - 1.71 (m, 2H), 1.06 - 1.23 (m, 2H), 0.85 - 0.98 (m, 2H), 0.59 - 0.71 (m, 1 H), 0.31 - 0.47 (m, 1 H). ES-LCMS m/z: 485 (M+1 ).
Example 131
4-{[3-chloro-5-[(difluoromethyl)oxy]-7-(triffuoromethyl)pyrazolo[1,5-a]pyridin-2- yl]carbonyl}-1-[(1S,3S,5S)-2-oxobicyclo[3.1.0]hex-3-yl]-2-piperazinone
{Compound 131)
Figure imgf000277_0001
A solution of 4-{t3-chloro-5-[(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-1 -[( 1 S,2S, 3S,5S)-2-hydroxybicyclo[3.1 .0]hex-3-yl]-2-piperazinone (200 mg, 0.393 mmol) in DCM (20 mL) was treated with Dess-Martin periodinane (333 mg, 0.786 mmol) and the resulting mixture stirred at room temperature. After stirring at room temperature overnight, LCMS showed complete reaction. The solution was diluted with EtOAc, washed with 10% aqueous sodium bisulfite (2x), saturated aqueous sodium bicarbonate (2x), dried over sodium sulfate and concentrated to dryness at reduced pressure. The crude product was purified by Reverse Phase HPLC (water/MeCN + 0.1 % formic acid) to give the title compound (128 mg, 0.250 mmol, 64 % yield) as a white solid. 1H NMR (400 MHz, DMSO-of6) δ ppm 7.73 - 7.80 (m, 2 H) 7.39 - 7.75 (m, 1 H) 4.47 - 4.58 (m, 1 H) 4.18 - 4.30 (m, 2 H) 3.78 - 3.99 (m, 1 H) 3.71 - 3.78 (m, 1 H) 3.18 - 3.44 (m, 2 H) 2.14 - 2.31 (m, 2 H) 2.04 - 2.14 (m, 1 H) 1.74 - 1.83 (m, 1 H) 1.14 - 1.27 (m, 2 H). LCMS m/z: 507.2 (M+t).
Administration and Formulation
[00300] The chemical entities provided herein may inhibit viral replication by inhibiting the enzymes involved in replication, such as the non-structural proteins including RNA dependent RNA polymerase. They may also inhibit other enzymes utilized in the activity or proliferation of viruses in the Flavivi dae family, such as HCV. The chemical entities are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease.
[00301] In another embodiment, there is provided a pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
[00302] The compounds of the present invention can also be supplied in the form of a pharmaceutically acceptable salt. The terms "pharmaceutically acceptable salt" refer to salts prepared from pharmaceutically acceptable inorganic and organic acids and bases.
[00303] Pharmaceutically acceptable inorganic bases include metallic ions. More preferred metallic ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts and other physiological acceptable metal ions. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like and in their usual valences. Exemplary salts include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
[00304] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, including in part, trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine; substituted amines including naturally occurring substituted amines; cyclic amines; quaternary ammonium cations; and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N- dibenzylethylenediamine, diethylamine, 2-diethyiaminoethanol, 2-dimethy!aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. [00305] Illustrative pharmaceutically acceptable acid addition salts of the
compounds of the present invention can be prepared from the following acids, including, without limitation formic, acetic, propionic, benzoic, succinic, glycolic, gluconic, lactic, maleic, malic, tartaric, citric, nitic, ascorbic, glucuronic, ma!eic, fumaric, pyruvic, aspartic, glutamic, benzoic, hydrochloric, hydrobromic, hydroiodic, isocitric, trifluoroacetic, pamoic, propionic, anthranilic, mesylic, oxalacetic, oleic, stearic, salicylic, p-hydroxybenzoic, nicotinic, phenylacetic, mandelic, etnbonic (pamoic), methanesulfonic, phosphoric, phosphonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hydroxyethanesulfonic, sulfanilic, sulfuric, salicylic, cyclohexylaminosulfonic, algenic, p- hydroxybutyric, galactaric and galacturonic acids. Preferred pharmaceutically acceptable salts include the salts of hydrochloric acid and trifluoroacetic acid.
All of the above salts can be prepared by those skilled in the art by conventional means from the corresponding compound of the present invention. For example, the
pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418, the disclosure of which is hereby incorporated by reference only with regards to the lists of suitable salts.
[00306] The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. Pharmaceutically acceptable solvates include hydrates and other solvates wherein the solvent of crystallization may be isotopically substituted, e.g. D20, d6-acetone, d6- DMSO.
[00307] Compounds of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of formula (I) contains an alkenyl or alkenylene group or a cycloalkyl group, geometric cis/trans (or Z/E) isomers are possible. Where the compound contains, for example, a keto or oxime group or an aromatic moiety, tautomeric isomerism ('tautomerism') can occur. It follows that a single compound may exhibit more than one type of isomerism.
[00308] Included within the scope of the claimed compounds present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of formula (I), including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, D-lactate or L-lysine, or racemic, for example, DL-tartrate or DL-arginine.
[00309] Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional
crystallisation.
[00310] Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
[00311] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
[00312] Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine.
Concentration of the eluate affords the enriched mixture.
[00313] Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. [see, for example, "Stereochemistry of Organic
Compounds" by E L Eliel (Wiley, New York, 1994).]
[00314] The present invention includes all pharmaceutically acceptable isotopically- labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature. [00315] Examples of isotopes suitabie for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2H and 3H, carbon, such as 1C, 3C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123l and 125l, nitrogen, such as 13N and 5N, oxygen, such as 150, 170 and 180, phosphorus, such as 3 P, and sulphur, such as 35S,
[00316] Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
[00317] Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
[003 8] Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labelled reagents in place of the non-labelled reagent previously employed.
[00319] The compounds of the present invention may be administered as prodrugs. Thus, certain derivatives of compounds of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of formula (I) having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'.
[00320] Administration of the chemical entities described herein can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, sublingually, subcutaneously, intravenously, intranasally, topically, transdermal^, intraperitoneally, intramuscularly, intrapulmonaril!y, vaginally, rectally, or intraocularly. In some embodiments, oral or parenteral administration is used.
[00321] Pharmaceutical compositions or formulations include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g., tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The chemical entities can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and/or timed, pulsed administration at a predetermined rate. In certain embodiments, the compositions are provided in unit dosage forms suitable for single administration of a precise dose. [00322] The chemical entities described herein can be administered either alone or more typically in combination with a conventional pharmaceutical carrier, excipient or the like (e.g., mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like). If desired, the pharmaceutical composition can also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g., sodium acetate, sodium citrate,
cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, and the like). Generally, depending on the intended mode of administration, the pharmaceutical composition will contain about 0.005% to 95%; in certain embodiments, about 0.5% to 50% by weight of a chemical entity. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
[00323] In certain embodiments, the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrroiidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils or triglycerides) is encapsulated in a gelatin capsule.
[00324] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and optional pharmaceutical adjuvants in a carrier (e.g., water, saline, aqueous dextrose, glycerol, glycols, ethanol or the like) to form a solution or suspension. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection. The percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject. However, percentages of active ingredient of 0.01 % to 10% in solution are employable, and will be higher if the composition is a solid which wiil be subsequently diluted to the above percentages. In certain embodiments, the composition will comprise from about 0.2 to 2% of the active agent in solution.
[00325] Pharmaceutical compositions of the chemical entities described herein may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the pharmaceutical composition have diameters of less than 50 microns, in certain embodiments, less than 10 microns.
[00326] In general, the chemical entities provided will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the chemical entity, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the chemical entity used, the route and form of administration, and other factors. The drug can be administered more than once a day, such as once or twice a day.
[00327] Therapeutically effective amounts of the chemical entities described herein may range from approximately 0.01 to 200 mg per kilogram body weight of the recipient per day; such as about 0.01-100 mg/kg/day, for example, from about 0.1 to 50 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range may be about 7-3500 mg per day.
[00328] In general, the chemical entities will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or
subcutaneous) administration. In certain embodiments, oral administration with a convenient daily dosage regimen that can be adjusted according to the degree of affliction may be used. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. Another manner for administering the provided chemical entities is inhalation.
[00329] The choice of formulation depends on various factors such as the mode of drug administration and bioavailability of the drug substance. For delivery via inhalation the chemical entity can be formulated as liquid solution, suspensions, aerosol propellents or dry powder and loaded into a suitable dispenser for administration. There are several types of pharmaceutical inhalation devices-nebulizer inhalers, metered dose inhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices produce a stream of high velocity air that causes the therapeutic agents (which are formulated in a liquid form) to spray as a mist that is carried into the patient's respiratory tract. MDIs typically are formulation packaged with a compressed gas. Upon actuation, the device discharges a measured amount of therapeutic agent by compressed gas, thus affording a reliable method of administering a set amount of agent. DPI dispenses therapeutic agents in the form of a free flowing powder that can be dispersed in the patient's inspiratory air-stream during breathing by the device. In order to achieve a free flowing powder, the therapeutic agent is formulated with an excipient such as lactose. A measured amount of the therapeutic agent is stored in a capsule form and is dispensed with each actuation.
[00330] Recently, pharmaceutical compositions have been developed for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Patent No. 4, 107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1 ,000 nm in which the active material is supported on a cross-linked matrix of macromolecules. U.S. Patent No. 5, 145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid ■ medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
[00331] The compositions are comprised of, in general, at least one chemical entity described herein in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the at least one chemical entity described herein. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
[00332] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, for injectable solutions, include water, saline, aqueous dextrose, and glycols.
[00333] Compressed gases may be used to disperse a chemical entity described herein in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing
Company, 18th ed., 1990).
[00334] The amount of the chemical entity in a composition can vary within the full range employed by those skilled in the art. Typically, the composition will contain, on a weight percent (wt%) basis, from about 0.01 -99.99 wt% of at least one chemical entity described herein based on the total composition, with the balance being one or more suitable pharmaceutical excipients. In certain embodiments, the at least one chemical entity described herein is present at a level of about 1-80 wt%. Representative pharmaceutical compositions containing at least one chemical entity described herein are described below.
[00335] In another embodiment, there is provided a method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses, which method comprises administering to a mammal that has been diagnosed with said viral infection or is at risk of developing said viral infection a compound described herein. In another embodiment, the virus is hepatitis C virus.
[00336] In another embodiment, the method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses further comprises administration of a therapeutically effective amount of one or more agents active against hepatitis C virus. In another embodiment, the agent is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase. In another embodiment, the agent is interferon. In another embodiment, the agent is ribavirin. In yet another embodiment, the agent(s) is a combination of interferon and ribavirin that is administered either simultaneously or sequentially.
[00337] In addition, the chemical entities described herein can be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like. Suitable medicinal and pharmaceutical agents include therapeutically effective amounts of one or more agents active against HCV. In some embodiments, the agent active against HCV is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.
[00338] Active agents against HCV include ribavirin, levovirin, viramidine, thymosin alpha-1 , an inhibitor of NS3 serine protease, and inhibitor of inosine monophosphate dehydrogenase, interferon-alpha, either alone or in combination with ribavirin or levovirin. In some embodiments, the additional agent active against HCV is interferon-alpha or pegylated interferon-alpha alone or in combination with ribavirin or levovirin. In some embodiments, the agent active against hepatitis C virus is interferon.
[00339] The above other therapeutic agents, when employed in combination with the chemical entities described herein, may be used, for example, in those amounts indicated in the Physicians' Desk Reference (PDR) or as otherwise determined by one of ordinary skill in the art.
[00340] Additionally, the present specification is directed to a pharmaceutical composition comprising a therapeutically effective amount of at least one chemical entity described herein in combination with a therapeutically effective amount of another active agent against RNA-dependent RNA virus and, in particular, against HCV. Agents active against HCV include, but are not limited to, ribavirin, levovirin, viramidine, thymosin alpha- 1 , an inhibitor of HCV NS3 serine protease, or an inhibitor of inosine monophosphate dehydrogenase, interferon-alpha pegylated interferon-alpha (peginterferon-alpha), a combination of interferon-alpha and ribavirin, a combination of peginterferon-alpha and ribavirin, a combination of interferon-alpha and levovirin, and a combination of peginterferon-alpha and levovirin. Interferon-alpha includes, but is not limited to, recombinant interferon-alpha2a (such as ROFERON interferon available from Hoffman- LaRoche, Nutley, NJ), interferon-alpha2b (such as Intron-A interferon available from Schering Corp., Kenilworth, New Jersey, USA), a consensus interferon, and a purified interferon-alpha product. For a discussion of ribavirin and its activity against HCV, see J.O. Saunders and S.A. Raybuck, "Inosine Monophosphate Dehydrogenase:
Consideration of Structure, Kinetics and Therapeutic Potential, " Ann. Rep. Med. Chem., 2:201-210 (2000).
[00341] The following examples serve to more fully describe the manner of making and using the above-described invention. It is understood that these examples in no way serve to limit the true scope of the invention, but rather are presented for illustrative purposes.
BIOLOGICAL EXAMPLES
EXAMPLE 216
ANTI-HEPATITIS C ACTIVITY
[00342] Compounds can exhibit anti-hepatitis C activity by inhibiting viral and host cell targets required in the replication cycle. A number of assays have been published to assess these activities. A general method that assesses the gross increase of HCV virus in culture is disclosed in U.S. Patent No. 5,738,985 to Miles, ef al. In vitro assays have been reported in Ferrari, et al., J. of Vir., 73:1649-1654, 1999; Ishii, et a!., Hepatology, 29:1227-1235, 1999; Lohmann et al., J. of Bio. Chem., 274:10807-10815, 1999; and Yamashita, et al., J. of Bio. Chem., 273:15479-15486, 1998.
Replicon Assay
[00343] Two cell lines were used for screening of compounds for inhibiting HCV RNA replication (genoytype 1 a and 1 b). Genotype 1 a replicon cells, are a Huh-7 derived cell line bearing the genotype 1a H77 NS3-5B bicistronic subgenomic replicon. See, Blight, er a/., J Virol. (2003) 77(5): 3181-3190.
[00344] The genotype 1a replicon contains several adaptive mutations (NS4B Q31 H, NS5A K68R, NS5A S232I), the luciferase gene and encodes for neomycin resistance. The genotype 1 b replicon, also refered to as the ET replicon, is stably transfected with RNA transcripts harboring a l389luc-ubi-neo/NS3-37ET replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein and EMCV-IRES driven NS3-5B polyprotein containing the cell culture adaptive mutations (E1202G; T1280I;
K1846T) See, Kreiger, er a/., Journal of Virology 75:4614-4624 (2001 ). Both cell lines were grown in DMEM, supplemented with 10% fetal calf serum, 2 mM Giutamine,
Penicillin (100 IU/mL)/Streptomycin (100 pg/mL), 1x nonessential amino acids, and 250 pg/mL G418 ("Geneticin"). They were ail available through Life Technologies (Bethesda, Md.). The cells were plated at 0.5 x 104 cells/well in 384 well plates containing
compounds. The final concentration of compounds ranged between 0.1 nM to 50 μΜ and the final DMSO concentration of 0.5%.
[00345] Luciferase activity was measured 48 hours later by adding a Steady glo (Promega, Madison, Wis.). Percent inhibition of replication data was plotted relative to no compound control. Under the same condition, cytotoxicity of the compounds was determined using cell titer glo (Promega, Madison, Wis). EC50 values were determined from a 10 point dose response curve using 2-4 fold serial dilutions for each compound, which spans a concentration range of at least a 1000 fold. Replicon EC50 values, the concentration of compound required to inhibit 50% of the assay response, were calculated by curve fitting data to the Hill equation, using a non-linear least-squares curve-fitting program. The software tested the data for quality and rejected compounds with high and low activity before fitting the equation below.
y = a +[(b-a) / (1 + (10x/10c)d)] where y = response, a= minimum response (i.e. no inhibition), b=
maximum response, x=compound concentration, c=EC50, and
d=Hill coefficient. If the data fit did not meet quality control
criteria, six secondary models with different levels of data
constraint were used. Analysis was performed using an XC50
module and BioAssay Enterprise (Cambridge Soft). [00346] Further, compounds of the present disclosure, which were tested against more than one genotype of HCV replicon, were found to have similar inhibitory properties. [00347] As detailed in Table 3 below, the compounds tested were found to exhibit EC50 percent inhibition values at a specific concentration, such as, 10 μ , for example, which can also be derived from the equation above. Therefore, in certian aspects, the compounds of Formula (I) will exhibit a % inhibition of at least 80 % at the aforesaid 10 μΜ. In other aspects, the % inhibition is at least 50 % at 10 μΜ. In still other aspects, the % inhibition is at least 10 % at 10 μΜ.
[00348] As also detailed in Table 3 below, the compounds tested were found to exhibit EC50 values of about 60,000 nM or less, or about 25,000 nM or less. In other embodiments, the compounds will exhibit EC50 values of about 10,000 nM or less. In still other embodiments, the compounds will exhibit EC50 values of about 5,000 nM or less. In some embodiments, the compounds will exhibit EC50 values of about 1 ,000 nM or less, and in other embodiments, the compounds will exhibit EC50 values of about 500 nM or less, and in still further embodiments, about 100 nM or less, in some embodiments, about 50 nM or less, and in some embodiments, about 10 nM or less. Finally, in still further embodiments, the compounds will exhibit EC50 values of about 1 nM or less.
[00349] In some embodiment, after testing, certain compounds of Table 1 were found to demonstrate EC50 values as indicated in Table 3 for genotype 1 a and 1 b next to each compound reference number.
Table 3
Compound Number HCV Genotvoe 1A HCV Genotvoe 1 B
(From Table 1) Replicon Replicon
ECso (μ ) EC50 (μΜ)
1 0.0070 0.2550
2 0.1800 0.1090
3 5.0120 5.0120
4 0.0564 0.0335
5 0.4850 1.1720
6 0.0130 0.0230
7 0.0050 0.0060
8 0.0010 0.0030
9 0.0830 0.0600
10 0.0040 0.0030
1 1 0.0100 0.0040
12 0.00200 0.0004 13 0.0020 0.0005
14 0.0010 0.0003
15 0.0360 0.0150
16 0.0060 0.0020
17 0.0020 0.0010
18 0.0400 0.0180
19 0.0060 0.0020
20(b) 0.0020 0.0010
21 0.0020 0.0008
22(b) 0.0020 0.0200
23(b) 0.0002 0.0020
24(b) 0.0005 0.0020
25(b) 0.0008 0.0050
26 0.0119 0.0099
27 0.0053 0.0034
28 0.0039 0.0007
29 0.1584 0.1995
30 0.1995 0.1584
31 0.0631 0.3981
32 0.0100 0.0020
33 0.0408 0.1753
34 0.0018 0.0242
35 0.0125 0.0125
36 0.0012 0.0031
37 0.0004 0.0050
38 0.0005 0.0025
39 0.0125 0.0501
40 0.0794 0.3981
41 0.0012 0.0079
42 0.0001 0.0012
43 0.0006 0.0039 44 0,0007 0.0063
45 0.0002 0.0025
46 0.0003 0.0025
47 0.0001 0.0015
48 0.0079 0.0251
49 0.0031 0.0010
50 0.0010 0.0006
51 0.0020 0.0015
52 0.0005 0.0002
53 0.0002 0.0020
54 0.0005 0.0002
55 0.0003 0.0039
56 0.0000 0.0005
57 0.0792 0.0400
58 0.3981 0.1258
59 0.0251 0.3162
60 0.0025 0.0199
61 0.1995 0.1995
62 0.1258 0.0794
63 0.0794 0.0100
64 0.0050 0.0063
65 0.0031 0.0050
66 0.1000 0.0251
67 0.1000 0.0158
68 0.0794 0.0501
69 0.0100 0.0039
70 0.0251 0.0158
71 0.1995 0.0316
72 0.0631 0.0316
73 0.0007 0.0004
74 0.0010 0.0005 75 0.0012 0.0100
76 0.0031 0.0025
77 0.0079 0.0031
78 0.0020 0.0251
79 0.0031 0.0012
80 0.0251 0.0100
81 0.0001 0.0007
82 0.0002 0.0001
83 0.0004 0.0050
84 0.0008 0.0100
85 0.0001 0.00002
86 0.0003 0.00020
87 0.0199 0.0398
88 0.1584 0.0158
89 0.1000 0.0501
90 0.0100 0.1000
91 0.0007 0.0020
92 0.0039 0,0100
93 0.0020 0,0079
94 0.0079 0,0158
95 0.0100 0.0501
96 0.0003 0.0012
97 0.0631 0.0063
98 0.0025 0.0100
99 0.0031 0.0158
100 0.0010 0.0025
101 0.0050 0.0125
102 0.1584 0.1995
103 0.0158 0.0501
104 0.3162 0.0316
105 0.0316 0.251 1 106 0.0015 0.0125
107 0.0020 0.0125
108 0.1000 3.1623
109 0.0158 0.3981
110 0.1259 0.5012
1 1 1 0.0794 0.1000
1 12 0.0020 0.0125
1 13 0,0251 0.0794
1 14 0.0158 0.0039
1 15 0.0004 0.0010
1 16 0.0050 0.0063
1 17 0.0012 0.0100
1 18 0.0015 0.0012
1 19 0.0016 0.0501
120 0.0032 0.0050
121 0.0100 0.1995
122 0.0126 0.0398
123 0.0100 0.1000
124 0.01000 0.03980
125 0.00080 0.00790
126 0.05010 0.15850
127 0.00060 0.00790
128 0.00040 0.00030
129 - -
130 - -
131 0.00400 0.00160
Formulation Examples
The following are representative pharmaceutical formulations containingormula (I) or a pharmaceutically acceptable salt thereof. EXAMPLE 217
Tablet formulation
[00351] The following ingredients are mixed intimately and pressed into single scored tablets.
Ingredient Quantity per tablet (mg)
compound 400
cornstarch 50
croscarmellose sodium 25
lactose 120
magnesium stearate 5
EXAMPLE 218
Capsule formulation
[00352] The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule.
Ingredient Quantity per capsule (mg) compound 200
Lactose, spray-dried 148
magnesium stearate 2
EXAMPLE 219
Suspension formulation
[00353] The foliowing ingredients are mixed to form a suspension for oral administration.
ingredient Amount
compound 1.0 g
fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
propyl paraben 0.05 g
granulated sugar 25.0 g
sorbitol (70% solution) 3.00 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 mL
colorings 0.5 mg distilled water q.s. (quantity sufficient) to 100 ml_
EXAMPLE 220
Injectable formulation
100354] The following ingredients are mixed to form an injectable formulation.
Ingredient Amount compound 0.2 mg-20 mg
sodium acetate buffer solution, 0.4 M 2.0 mL
HCI (1 N) or NaOH (1 N) q.s, to suitable pH
water (distilled, sterile) q.s. to 20 mL
EXAMPLE 221
Suppository Formulation
[00355] A suppository of total weight 2.5 g is prepared by mixing the compound with Witepsol® H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition:
Ingredient Amount
compound 500 mg
Witepsol® H-15 balance
[00356] Although the invention has been shown and described above with reference to some embodiments, those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention. It should be understood that various modifications can be made without departing from the spirit of the invention.
[00357] For example, for claim construction purposes, it is not intended that the claims set forth hereinafter be construed in any way narrower than the literal language thereof, and it is thus not intended that exemplary embodiments from the specification be read into the claims. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitations on the scope of the claims. Accordingly, the invention is limited only by the following claims. All publications, issued patents, patent applications, books and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I):
(I)
Figure imgf000295_0001
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (Ci-C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo, (Ci-C6)alkyl, (C
C6)alkoxy, (C-|-C6)alkenyl, (Ci-C6)alkynyl, (C3-C14)cycloalky[, aryl, hydroxyl,
-NR R , -NR6C(0)NR6R6, -OR6(R6)m, -R6(R5)m, ~SOzNR6R6, -
C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O, (C2~C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R 0;
R is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (C-r C6)alkyl, (d-C6)aIkoxy, (d-CeJalkenyl, (C Ce)alkynyl, -C(0)N(R6)2l -R9R6, -S02NR6R6, -S02R6, (C3-C 4)cycloalkyl, aryl, (C2-C6)heterocyc!ic having 1- 3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R11 ;
R2 is independently selected from the group consisting of hydrogen, hydroxyl, oxo, (Ci-C6)alkyl, (C3-C14)cycloalkyl, -alkylR8, and aryl, or optionally two R2 alkyl groups, together with any intervening atoms, form a spiro or fused (C3- Ci4)cycloalkyl ring;
R3 is selected from the group consisting of hydrogen, (C -C^alkyl, (C3- C 4)cycloalkyl, halo, -alkylR , and cyano;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (C C6)alkyl, (CrC6)alkoxy, (CrC6)alkenyl, (d-Cs^lkynyl, (C3-C14)cycloalkyl, aryl, -OR6(R5)m, -R6(R5)m, -alkyl(R5)mR6, -alky!R9R6, -NR6R6, -
NR6C(0)NRsR6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02R6, - NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O, (C2- C6)heterocyc!ic having 1 -3 heteroatoms selected from S, N and O; wherein said alky], alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R10;
R5 is independently selected from the group consisting of hydrogen and halo; R6 is independently selected from the group consisting of hydrogen and (Ci- C6)alkyl;
R7 is (C3-C14)cycloalkyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of {CrC6)alkyl, {Cr
C6)alkoxy, (CrC6)alkenyl, (C C6)alkynyl, hydroxyl, oxo, carboxyl, cyano, halo, -C{0)NH2, -S02NH2, -SR6, -S(0)R6, -S(0)2R6, -
S(0)2NR6R6, -NR6R6, -NR6C(0)NR6R6, -NR6C(S)NR6R6, -
NR6S(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NR6R6, -C(0)NR6R6, - C(0)OR6, -C(0)R6, (C3-C14)cycloalkyl, aryl, (C2-C6)heterocyciic having 1 -3 heteroatoms selected from S, N and O, and {C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O;
R 1 is independently selected from the group consisting of (Ci-C6)alkyl, (d- C6)alkoxy, (CrC6)alkenyl, (C C6)alkynyl, oxo, hydroxyl, -NR6Re - NR6C(0)R6, -OC(0)R6, -OR6(R5)m, -R6{R5)m, halo, -C(0)NR6 R6,
-S02NR6R6, -S02R6, -alkylR8, -alkylR9, -alkylR9R6, (C3- C14)cycloalkyl, aryl, (C2-C6) heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O; or optionally two R1 1 groups, together with any intervening atoms, form a fused (C3-Ci4)cycloalkyl ring or a fused (C2- C6)heterocyclic ring having 1 -3 heteroatoms selected from S, N and O; wherein said fused cycloalkyl or heterocyclic ring is optionally substituted with one to three R12;
R12 is independently selected from the group consisting of (d-CeJalkyl, (C C6)alkoxy( oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -R6(R6)m, and - NR8R6;
m is an integer from 1 to 3; and
n is zero or an integer from 1 to 4.
2. The compound according to any of the preceding claims, wherein Z is a bond.
3. The compound according to any of the preceding claims, wherein W is N.
4. The compound according to any of the preceding claims, wherein W is CH.
5. The compound according to any of the preceding claims, wherein A is selected from the group consisting of hydrogen, (CrC6)alkyl, halo, hydroxyl, (C CeJalkoxy, -OR7, -alkoxy(R5)m, (C3-C14)cycloalkyl, -R6(C3-C14)cycloalkyl, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryi having 1 -3 heteroatoms selected from S, N, and 0.
6. The compound according to any of the preceding claims, wherein A is selected from the group consisting of hydrogen, hydroxyl, bromo, fluoro, chloro, iodo, methyl, ethyl, propyl, butyl, pentyl, cyclopropyl, cyclopropylmethyl, cyclopropyloxy, methoxy, ethoxy, propoxy, dif!uoromethoxy, pyrazolyl, furanyl, pyrrolyl, triazoly!, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyi, and imidazolyl.
7. The compound according to any of the preceding claims, wherein A is selected from the group consisting of methoxy, ethoxy, hydroxyl, cyclopropyl, methyl, ethyl, isobutyl, bromo, chloro, furanyl, and difluoromethoxy.
8. The compound according to any of the preceding claims, wherein A is selected from the group consisting of methoxy, hydroxyl, and cyclopropyl.
9. The compound according to any of the preceding claims, wherein A is cyclopropyl.
10. The compound according to any of the preceding claims, wherein R1 is selected from the group consisting of hydrogen, (CrC6)alkyl, (C3-C 4)cycloalkyl, aryl, (C2- C6)heterocyclic having 1-3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1-3 heteroatoms selected from S, N, and O.
1 1. The compound according to any of the preceding claims, wherein R1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, hydroxyl, acetate, thiazolyl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyciopentyl, bicyciooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyl,
12. The compound according to any of the preceding claims, wherein R is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyl, and cyclohexyl. 3. The compound according to any of the preceding claims, wherein R1 is cyclohexyl.
1 . The compound according to any of the preceding claims, wherein R1 is substituted with one or two R11.
15. The compound according to any of the preceding claims, wherein R1 is substituted with one R11.
16. The compound according to any of the preceding claims, wherein R2 is selected from the group consisting of hydrogen, oxo, and methyl.
17. The compound according to any of the preceding claims, wherein R2 is hydrogen.
18. The compound according to any of the preceding claims, wherein R2 is oxo.
19. The compound according to any of the preceding claims, wherein R3 is selected from the group consisting of hydrogen, (C C6)alkyl, halo, cyano, -alkylR8, and (C3-Ci4)cycloalkyl.
20. The compound according to any of the preceding claims, wherein R3 is selected from the group consisting of hydrogen, methyl, ethyl, chloro, bromo, cyano, hydroxymethyl, and cyclopropyl.
21. The compound according to any of the preceding claims, wherein R3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano.
22. The compound according to any of the preceding claims, wherein R3 is chloro.
23. The compound according to any of the preceding claims, wherein R4 is selected from the group consisting of hydrogen, (C Ce)alkyl, (C C6)alkenyl, -OR6(R5)m, - R6(R5)m, -alkyl(R5)mR6.
24. The compound according to any of the preceding claims, wherein R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, dimethylamino, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, chloro, fluoro, bromo, difluoroethyl, and trifluoromethyl.
25. The compound according to any of the preceding claims, wherein R4 is selected from the group consisting of trifluoromethyl, ethyl, and isopropylene.
26. The compound according to any of the preceding claims, wherein R4 is trifluoromethyl.
27. The compound according to any of the preceding claims, wherein R11 is selected from the group consisting of hydroxyl, oxo, -OC(0)R6, -alkylR8, -R6(R5)m, halo, (Ci-C6)alkyl, and (C C6)alkoxy.
28. The compound according to any of the preceding claims, wherein R1 is selected from the group consisting of hydroxyl, oxo, hydroxymethyl, acyloxy, fluoro, trifluoromethyl, methoxy, and methyl.
29. The compound according to any of the preceding claims, wherein R is selected from the group consisting of methyl, hydroxyl, and oxo.
30. The compound according to any of the preceding claims, wherein R1 is oxo.
31. The compound according to any of the preceding claims, wherein R11 is hydroxyl.
32. The compound according to any of the preceding claims, wherein R11 is absent.
33. The compound according to any of the preceding claims, wherein m is three.
34. The compound according to any of the preceding claims, wherein m is two.
35. The compound according to any of the preceding claims, wherein n is one.
A compound of Formula (I):
(I)
Figure imgf000300_0001
a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, bromo, fluoro, chloro, iodo, methyl, ethyl, propyl, buty!, pentyl, cyclopropyl, cyclopropyloxy, methoxy, ethoxy, propoxy, difluoromethoxy, pyrazolyl, furanyl, pyrro!yl, triazolyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, pyridyl, and imidazolyl;
R is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, pentyl, cyano, carboxyl, acetate, thiazolyl, cyclopropyl, cyclobutyl, bicyclohexyl, bicyclopentyl, bicyclooctyl, cyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, phenyl, benzyl, pyridyl, pyridinyl, pyrrolidinyl, piperidinyl, thiophenyl, oxazolidinone, pyrazolyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, and thienyi, wherein R is optionally substituted with one to two R11;
R2 is independently selected from the group consisting of hydrogen, oxo, methyl, ethyl, cyclopropyl, hydroxymethyl, and phenyl, or optionally two R2 groups, together with any intervening atoms, form a spiro or fused cycloalkyl ring;
R3 is selected from the group consisting of hydrogen, chloro, bromo, fluoro, and cyano;
R4 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, dimethylamino, methylamino, isopropylene, methoxy, ethoxy, cyclopropyl, chloro, fluoro, bromo, difiuoroethyl, and trifluoro methyl;
R5 is independently selected from the group consisting of hydrogen and halo;
R is independently selected from the group consisting of hydroxyl, oxo,
hydroxymethyl, acyloxy, fluoro, trifluoromethyl, methoxy, and methyl; and n is zero or an integer from 1 to 4.
A compound of Formula (I):
(I)
Figure imgf000301_0001
R
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, (Ci-C6)alkoxy, hydroxyl, and
(C3-C14)cycloalkyl;
R1 is selected from the group consisting of (C3-Ci4)cycloalkyl and (C2-
Ce)heterocyclic having 1-3 heteroatoms selected from S, N and O, wherein
R1 is optionally substituted with one to two R11;
R2 is oxo;
R3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano; R4 is trifluoromethyl;
R5 is independently selected from the group consisting of hydrogen and halo; R11 is independently selected from the group consisting of methyl, hydroxy!, and oxo; and
n is zero or an integer from 1 to 4. 38. A compound of Formula (I):
(I)
Figure imgf000302_0001
R
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of methoxy, hydroxyl, and cyclopropyl; R is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyl, and cyclohexyl, wherein R1 is optionally substituted with one to two R11;
R2 is oxo;
R3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano; R4 is trifluoromethyi;
R5 is independently selected from the group consisting of hydrogen and chloro; R11 is independently selected from the group consisting of methyl, hydroxyl, and oxo; and
n is zero or an integer from 1 to 4.
39. A compound selected from the group consisting of:
3-(1-{[5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidin-2-one,
3-(1-{[3-bromo-5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3-(1-{[5-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyhdin"2-yl]carbonyl}-4-piperidinyl)-1 ,3-- oxazolidin-2-one,
3-(1-{[3-chloro-5-(methy!oxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3-(1-{[3,4-dichloro-5-(methyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin-2-one,
3-(1-{[5-cydopropyl-7-(tnfluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yI]carbonyl}-4-piperidinyl)- 1 ,3-oxazolidin-2-one,
3-(1 -{[3-bromo-5-cyclopropyi-7-(trifiuoromethyI)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazo[idin-2-one,
3_( 1 -{[3-ch loro-5-cyclop ropyl -7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4- piperidinyl)-1 ,3-oxazolidin~2-one,
3-(1-{[5-cyclopropyi-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-4-pip 1 ,3-oxazolidine-2,4-dione,
3- (1-{[3-chloro-5-cyclopropyl-7-(^
piperidinyl)-1 ,3-oxazolidine-2,4-dione,
1- cyclopentyl-4-{[5-cyc[opropy[-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony^ piperazinone,
4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- cyclopentyl-2-piperazinone,
2- [(4-cyc!opentyi-3-oxo-1-piperazinyl)carbonyl]-5-cyclopropyl-7- (tnfluoromethyl)pyrazolo[1 ,5-a]pyridine-3-carbonitrile,
4- {[3-ch!oro-5-cyclopropyl-7-(trifluoromethy[)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - cyclopentyl-2-piperazinone,
1 -cyclobutyl-4-{[5-cyclopropyl-7-(tffl^
piperazinone,
4-{[3-bromo-5-cyctopropyi-7-(trifluoromeihyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}^ cyclobutyl-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trif Iuoromethyl)pyrazolo[1 , 5-a] pyrid i n-2 -yl]ca rbo nyl}- 1 - cyclobutyl-2-piperazi no ne ,
4-{[5-cyclopropyl-7-(tnfluoromethyi)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyI}-1-(3- methylcyclobutyl)-2-piperazinone,
4- {[3-bromo-5-cyclopropyl-7-(trifluoromethy[)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-{3- methylcyclobutyl)-2-piperazinone,
5- cyclopropyl-2-{[4-(3-inethylcyclobutyi)-3-oxo-1 -piperazinyl]carbonyl}-7- (trifluoromethyl)pyrazolo[1 I5-a]pyridine-3-carbonitrile,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(3- methy!cyclobutyl)-2-piperazinone,
4-{[5-cyclopropyl-7-(trifluoroinethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(4~ hydroxycyciohexyl)-2-piperazinone,
4-{[5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony^ hydroxycyclohexyl)-2-piperazinone,
4»{[3"Chioro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony!}-1 ^ 4-hyd roxycyclohexyl )-2-pi perazi no ne ,
4-{[3-bromo-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(4- h yd roxycyclohexyl )-2- pi pe razi n o n e ,
4-{[3-bromo-5-cyclopropyl-7-(trifluorom
4- hyd roxycyclohexyl )-2-pi pe razi no ne ,
5- cyclopropyl-2-{[4-{4-hydroxycyclohexyl)-3-oxo-1 -piperazinyl]carbonyl}-7- (trifluoromethylJpyrazolotl ^-alpyridine-S-carbonitrile,
5-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyi)-3-oxo-1-piperazinyl]carbonyl}-7- (trifluoromethyl)pyrazolo[ ,5-a]pyridine-3-carbonitrile,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - E(1 S,3S)-3-hydroxycyclopentyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluorornethyl)pyrazolo[1 ,5-a]pyndin-2-yl]carbonyl}-1 - [(1 R,3R)-3-hydroxycyclopentyl]-2"piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trif luoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}~1 - [(1 R,3S,4S)-3-ethyl-4-hydroxycyc!opentyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 ^
[(1 R,3S,4S)-3-ethyl-4-hydroxycyclopentyl]-2-piperazinone (Isomer 1 ),
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}-1- [(1 R,3S,4S)-3-ethyI-4-hydroxycyclopentyl]-2-piperazinone (Isomer 2),
4-{[3-chloro-5-cyclopropyl-7-(trffl^
[(1 R,3S,4S)-3-ethy -hydroxycyclopentyl]-2-piperazinone (Isomer 3),
4-{[3-ch[oro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(3- methylcyclopentyl)-2-piperazinone,
4-{[5-{ethyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl3carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-(ethyloxy)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
1 -[(1 R,5S,6r)-bicyclo[3.1.0]hex-6-yl]-4-{[3-chloro-5-cyclopropyl-7- (trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-2-piperazinone,
4-{[3-chloro-5-cyciopropyl-7-(trifluoro^
3- { hydroxymethyl )cycl ob utyl] -2-pi pe razi none ,
4- [(3-chloro-5,7-dicyclopropylpyrazolo[1 ,5-a3pyridin-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-(1-methylethyi)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}-1- (trans-4-hyd roxycyclohexyl )-2-pi pe razi none , 1 -(trans-4-hydroxycyclohexyl)-4-{[5-(1 -methylethyl)-7-(trif luoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbony[}-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(methy[oxy)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}-1 -(trans-4- hydroxycyclohexyl )-2-pi perazi none,
4-[(7-bromo-3-c loro-5-cyclopropylpyrazolo]i ,5-a]pyridin-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexy])-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(1-methylethenyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-[(3-chloro-5-cyclopropyl-7-iodopyrazolo[1 ,5-a]pyridin-2-yl)carbony[]-1-(trans-4- hyd roxycyclohexyl)-2-p i perazino ne ,
4-[(3-chloro-5-cyclopropy]-7-ethylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1-(trans-4- hydroxycyclohexyl)-2-piperazinone,
4-[(3-chloro-5-cyc!opropyl-7-phenylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1 -(trans-4- hydroxycyclohexyl)-2~piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(2-furany!)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-4" hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(3-furanyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-4- hyd roxycyclo h exy I )-2- pi pe razi n one ,
4-{[3,5-dichloro-7-(trifluoromethyI)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hyd roxycyclo hexy I )-2-pi pe razi n o n e ,
4-{[3-ch!oro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyi}-1 -(3- cyclopenten-1-yl)-2-piperazinone,
4-{[3-ch!oro-5-cyclopropyl-7-(trifluorom
hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}"1-
[(1 R,2R,3R,5R)-2-hydroxybicyclo[3.1 ,0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
[(IS^S.SS.SS^-hydroxybicycloIS.I .Olhex-S-yll^-piperazinone,
4-{[5-cyclopropyl-3-methyl-7-(trifluorom
4-hyd roxycyclohexyl )-2- pi perazinone ,
4-{[5-cyclopropyl-3-methyl-7-(trifluoromethyl)pyrazolo[1 !5-a]pyridin-2-yl]carbony[}-1 - [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(3-fluorophenyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans- 4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyi-7-(3-fluorophenyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(I S^S.SS.SS^-hydroxybicyclo^. .Olhex-S-yl^-piperazinone, 4-{[3-chloro-5-cyclopropyl-7-(trifluo^
hydroxycyclohexy[)-2-piperazinone,
125 1-(trans-4-aminocyclohexyl)-4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5- a]pyridin-2-yl]carbonyl}-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluorom8thyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -( dimethylcyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluorom
130 4-methylcyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoro^
fluoro-4-methylp eny[)-2-piperazinone,
4-{[3-chioro-5-cyclopropyl-7-(trifluoromethyl)pyrazo[o[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(1 - methyl-1 H-imidazol-5-yl)-2-piperazinone,
135 4"{[3-chloro-5-cyclopropyl-7-(trif iuoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(2- chlorophenyl)-2-piperazinone,
4 [3~chloro-5-cyciopropyl-7-(irifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl3carbonyl}-1-[2- chloro-4-(methyloxy)phenyll-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y[]carbonyl}-1-(2- 140 ch!oro~4-hydroxyphenyI)-2-piperazinoneJ
4-{[3-ch!oro-5-cyclopropy[~7-(trifl^
fluorophenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony[}-1 -( fluoro-2-pyridinyl)-2-piperazinone,
145 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y!]carbonyl}-1 - hydroxyethyl)cyclobutyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropy!-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
[{I R^S.SR.SR^-hydroxybicyclo^.l .Olhex-S-yll^-piperazinone,
4-{[3-chIoro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
150 [{1S,2R,3S,5S)-2-hydroxybicyclo[3.1 ,0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromeihyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
Figure imgf000306_0001
4-{[3-chloro-5-cyc!opropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-- [(1 R,2R,3S,5R)-2-hydroxybicyclo[3.1.0]hex-3-yi]-2-piperazinone,
155 4-{[3-chloro-5-cydopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - [(1 R,3R,5R)-2-oxobicyclo[3.1.0]hex-3-yl]-2-piperazirtone,
4-{[3-chloro-5-cyclopropyl-7-(trifiuoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1- [(1S,3S,5S)-2-oxobicyclo[3.1.0]hex-3-yl]-2-piperazinone, 4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yi]carbonyl}-1 -(tra 160 hydroxycyclohexyI)-2-piperazinone,
4-{[5-bromo-3-chloro-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-
[(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3,5-dichloro-7~{trifluoromethyl)pyrazolo[1 ,5-a]pyndin-2-y[]carbonyl}-1 -[(1 S,2S,3S,5 hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
165 4-{[3-chloro-5-cyclopropyl-7-(1 ,3-oxazol-5-y[)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-
4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(1 ,3-oxazol-5-yl)pyrazolo[1 ,5-a]pyridin-2-y[3carbonyl}-1- [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinonel
4-{[5-chloro-3-methyl-7-(trifluoromethyl)pyrazolo[1 J5-a]pyridin-2-yl]carbonyl}-1 - 170 [{1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinon8,
4-{[3-chloro-5-cyclopropyl-7-(3-thienyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans-4- hydroxycyclohexyl)-2-piperazinone,
-{[3-Chloro-5-cyclopropyI-7-(3-thienyl)pyrazolo[1 l5-a]pyridin-2-yl]carbonyl}-1 - [(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
175 4-{[3-chloro-5-cyclopropyl-7-( H-pyrrol-2-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(trans- 4-hydroxycyclohexyl)-2-piperazinone,
4~{[3-Ch lo ro-5-cyclo pro pyl-7-( , 3-th iaz
4-hydroxycyclohexyl)-2-piperazinone ,
1 -[(trans)-bicyclo[3.1.0]hex-3-yl]-4-{[3-chloro-5-cyclopropyl-7-(trif luoromethyl)pyrazolo[1 ,5- 80 a]pyridin-2-yl]carbonyl}-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(3-furanyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -
[(1 S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[5-cyclopropyl-3-(methyloxy)~7-(trifl^
(trans-4-hyd roxycyclo hexyl )-2-p i perazi none ,
185 1 -cyciobuty!-4-{[5-cycIopropyl-3-(methyloxy)-7-(t fluoromethyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-2-piperazinone,
1-cyc!obutyi-4-{[5-cyclopropy[-3-hydroxy-7-(trifluorom6thyl)pyrazolo[1 ,5-a]pyridin-2- yl]carbonyl}-2-piperazinone,
4-{[5-cyclopropyl-3-hydroxy-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl3carbonyl}-1- 190 (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyi}-1-[2- fiuoro-4-(methyloxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-^ fiuoro-4-(methyloxy)phenyl]-2-piperazinone, 195 4-{[3-chloro-5-cyclopropyl-7-(trifluoro
(methyloxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7~(trifluoro^
difluoro-4-(methyloxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluorom^
200 difluoro-4-(methyloxy)phenyl]-2-piperazinone,
4-{[3-chloro-5-cyciopropy!-7-(trifiuoromethyl)pyrazo]o[1 ,5-a]pyridin-2-yl]carbony]}-1-(2- fluoro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-y!]carbonyl}-1-phen 2-piperazinone,
205 4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(3- fluoro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chloro~5~cyclopropyl-7-(trifl^^
difluoro-4-hydroxyphenyl)~2-piperazinone,
4-{[3-chloro~5-cyclopropyl-7-(tr^
210 hydroxyphenyl)-2-piperazinone,
4-{[3-chtoro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbony[}-^ difluoro-4-hydroxyphenyl)-2-piperazinone,
4-{[3-chIoro-5-cyclopropyl-7-{trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}"1- cyclopropyl-2-fluorophenyl)-2-piperazinone,
215 E4-(4-{E3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazoio[1 l5-a]pyridin-2-yl]carbonyl}-^ oxo-1 -piperazinyl)-3-fluorophenyl]boronic acid,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 -(3- hyd roxyphenyl )-2-pi perazinone,
4-{[3~chloro-5-cyclopropyl-7-(tffl
220 hydroxyphenyl)-3-methyi-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7~(tffl
2- hydroxy-1 ,2-oxaborinan-5-yS]-2-piperazinone,
4-{[3-chloro-5-cyciopropyl-7-{trifluorom^^
hydroxy-1 ,2-oxaborinan-5-yl]-2-piperazinone,
225 3-chloro-N,5-dicyclopropyl-2-{[4-{trans-4-hydroxycyclohexyl)-3-oxo-1 - piperazinyl]carbony[}pyrazolo[1 ,5-a]pyridine-7-carboxamide,
3- ch loro-5-cyclopropy[-2-{[4-(tra ns-4-hyd roxycyclohexyl )-3-oxo- 1 -pi pe razi nyl] ca rbo nyi}- N- methylpyrazo lo[1 , 5-a] pyrid i ne-7-ca rboxam ide ,
3-chloro-5-cyclopropyl-2-{[4-(trans-4-hydroxycyclohexyl)-3-oxo-1-piperazinyl]carbonyl}- 230 N,N-dimethylpyrazolo[1 ,5-a]pyridine-7-carboxamide, (Trans)-4-{[3-chloro-5-cyclopropyl-7-(trifl^^
1 -(3-oxabicyclo[3.1.0]hex-6-yl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(tnTluorom
[(1 R,3R)-3-(hydroxymethyl)cyclopenty[]-2-piperazinone,
4-{[3-chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(5-oxo-
3- pyrrolidinyl)-2-piperazinone,
4- {[3-chloro-5-cyctopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(6- oxabicyclo[3.1.0]hex-3-yl)-2-piperazinone,
4-{[3-chloro-5-cyclopropyi-7-(tnfluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(6,6- difluorobicyclo[3.1.0]hex-3-yl)-2-piperazinone (Isomer 1 ),
4-{[3-chloro-5-cyclo pro pyl-7-(trifl ^
difluorobicyclo[3!l .0jhex-3-yl)-2-piperazinone (Isomer 2),
4-{[3-chloro-5-[(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yI]carbonyl}- 1-(trans~4-hydroxycyclohexyl)-2-piperazinone!
4-{[3-chloro-5-[(difluoromethyl)oxy]-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2^
1- [(1S,2S,3S,5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
4-{[3-chloro-5-(difluoromethy[)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl^
(trans-4-hyd roxycyclohexyl )-2-pi pe razi no n e ,
4-{[3n.:hloro-5-(difluoromethyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbon
[(1S,2S,3Sl5S)-2-hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone,
(+/-)-4-{[3-Chloro-5-(2-hydroxy-1 -methylethyl)-7-(trifluoromethyl)pyrazolo[1 ^
yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-chloro-5-(2-hydroxy-1 -m
yncarbonyll-l-KIS^S.SS.SS^-hydroxybicyclop.l .Olhex-S-ylJ^-piperazinone,
4-{[5-Acetyl-3-chloro-7-(trifluoromethyl)pyrazo!o[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans-4- hyd roxycyclohexyl )-2-piperazi none,
4-{[3-Chloro~5-( 1 , 1 -d if I uoroethyl )-7-^
(trans-4-hyd roxycyclohexyl )-2-p i perazi none ,
(+/-)-4-{[3-Chloro-5-(2!2-difluorocycIopropyl)-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin^^ yl]carbonyl}-1-(trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(1 H-pyrazol-4-yl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - (trans-4-hydroxycyclohexyl)-2-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(4-isothiazolyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1-(trans- 4-hydroxycyclohexyl)-2-piperazinone,
4-[(3-Chloro-5-cyclopropyl-7-phenylpyrazolo[1 ,5-a]pyridin-2-yl)carbonyl]-1 -[(1 S,2S,3S,5S)-
2- hydroxybicyclo[3.1.0]hex-3-yl]-2-piperazinone, 4-{[3-Chloro-5-cyc[opropyl-7^
[{1 RS,3RS,5RS)-2,2-difluorobieyclo[3.1 .0]hex-3-yl]-2-piperazinone,
4-{[3-Chloro-5-cyclopropyl-7-(trifluoromethyl)pyrazolo[1 ,5-a]pyridin-2-yl]carbonyl}-1 - 270 [{1 S,3S,5S)-2-fluorobicyclo[3.1.0]hex-3-yl]-2-piperazinone, and
4-{[3-chloro-5-[(difluoromethyl)oxy]-7-^
l-KI S.SS.SS^-oxobicyclo^. l .Olhex-S-yQ^-piperazinone,
or a pharmaceutically acceptable salt thereof.
40. A compound selected from the group consisting of those compounds in Table 2.
A compound having the structure:
Figure imgf000310_0001
Figure imgf000310_0002
or a pharmaceutically acceptable salt thereof.
43. The use of a compound or salt as defined in any of the claims in the manufacture of a medicament for use in the treatment of a viral infection in a human.
44. A pharmaceutical composition comprising a pharmaceutically acceptable diluent and a therapeutically effective amount of a compound as defined in any of the claims.
45. A method for treating a viral infection in a mammal mediated at least in part by a virus in the Flaviviridae family of viruses which method comprises administering to a mammal, that has been diagnosed with said viral infection or is at risk of developing said viral infection, a compound of any one of the claims.
46. The method of claim 45, wherein said virus is hepatitis C virus.
47. The method of claim 45, further comprising administration of a
therapeutically effective amount of one or more agents active against hepatitis C virus.
48. The method of claim 47, wherein said agent active against hepatitis C virus is an inhibitor of HCV protease, HCV polymerase, HCV helicase, HCV entry, HCV assembly, HCV egress, HCV replicase, HCV NS5A protein, or inosine 5'-monophosphate dehydrogenase.
49. The method of claim 47, wherein said agent active against hepatitis C virus is interferon.
50. The method of claim 47, wherein said agent active against hepatitis C virus is ribavirin.
51 . The method of claim 47, wherein said agent active against hepatitis C virus is interferon in combination with ribavirin.
52. A compound of Formula (I):
(I)
Figure imgf000312_0001
R1
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or methylene;
W is selected from CH or N;
A is selected from the group consisting of methoxy, hydroxyl, and cyclopropyl; R1 is selected from the group consisting of oxazolidinone, cyclopentyl, cyclobutyl, and cyclohexyl, wherein R1 is optionally substituted with one to two R11;
R2 is hydrogen;
R3 is selected from the group consisting of hydrogen, chloro, bromo, and cyano; R4 is trifluoromethyl;
R5 is independently selected from the group consisting of hydrogen and chloro; R 1 is independently selected from the group consisting of methyl, hydroxyl, and oxo; and
n is zero or an integer from 1 to 4.
A compound of Formula (II):
(II)
Figure imgf000312_0002
or a pharmaceutically acceptable salt thereof, wherein:
Z is optionally a bond or (C C3)alkylene;
W is selected from CH or N;
A is selected from the group consisting of hydrogen, halo, (Ci-Ce)alky!, (C C6)alkoxy, (CrC6)alkenyl, (CrC6)alkyny[, (C3-C14)cycloalkyl, aryl, hydroxyl, - R6Re, -NR6C(0)NR6Re, -OR6(R5)m, -R6(R5)m, -S02NR6R6, -
C(0)NR6R6, -OR7, -R6R7, -S02R6, -NR6C(S)NR6R6, -NRsS(0)2R6, -alky!R9R6, -NR6C(0)OR6, -NR6C(0)R6, (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O, (C2-C6)heterocyclic having 1 -3 eteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R10;
R1 is selected from the group consisting of hydrogen, halo, cyano, hydroxyl, (C C6)alkyl, (CrC^alkoxy, (d-CeJalkenyl, (CrC6)a[kynyl, -C(0)N(Re)2, -R9R6, -S02NR6R6, -S02R6, (C3-C14)cycloalkyl, aryl, (C2-C6)heterocyclic having 1 - 3 heteroatoms selected from S, N and O, and (C2-C6)heteroary! having 1 -3 heteroatoms selected from S, N, and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R11 ;
R3 is selected from the group consisting of hydrogen, (C C6)alkyl, (C3- C 4)cycloalkyl, halo, -alkylR8, and cyano;
R4 is selected from the group consisting of hydrogen, hydroxyl, halo, nitrile, (Cr C6)aikyl, {C C6)alkoxy, (CrC6)alkenyl, (C C6)alkynyl, {C3-C14)cycloalkyl, aryl, -OR6(R5)m, -R6(R5)m, -alkyl(R5)mR6, -alkylR9R6, -NR6R6, - NR6C(0)NR6R6, -S02NR6R6, -C(0)NR6R6, -OR7, -R6R7, -S02R6, - NR6C(S)NR6R6, -NR6S(0)2R6, -alkylR9R6, -NR6C(0)OR6, -NR6C(0)R6,
(C2-Ce)heteroaryl having 1 -3 heteroatoms selected from S, N, and O, (C2- C6)heterocyclic having 1-3 heteroatoms selected from S, N and O; wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or heterocyclic is optionally substituted with one to three R 0;
R5 is independently selected from the group consisting of hydrogen and halo;
R6 is independently selected from the group consisting of hydrogen and (C
C6)a!ky[;
R7 is (C3-C1 )cycloalkyl;
R8 is hydroxyl;
R9 is carboxyl;
R10 is independently selected from the group consisting of (Ci-C6)alkyl, (C
C6)a!koxy, (Ci-C6)atkenyl, (CrC6)alkynyl, hydroxyl, oxo, carboxyl, cyano, halo, -C(0)NH2, -S02NH2, -SR6, -S(0)R6, -S(0)2R6, -
S(0)2NR6RB, -NR6R6, -NR6C(0)NR6R6, -NR6C(S)NR6R6, - NR6S(0)2R6 -NR6C(0)OR6, -NR6C(0)R6, -C(NR6)NR6R6, -C{0)NReR6, - C(0)OR6, -C(0)R6, (C3-Ci4)cycloaikyl, aryl, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-CB)heteroaryl having 1 -3 heteroatoms selected from S, N, and O;
R 1 is independently selected from the group consisting of (C1-C6)alkyl, (C
C6)alkoxy, (C C6)alkenyl, (CrCe)aIkynyl, oxo, hydroxyl, -NR6R6,- NR6C(0)R6, -OC(0)R6, -OR6(R5)m, -R6(R5)m, halo, -C(0)NR6 R6,
-S02NR6R6, -S02R6, -alkyiR8, -alkylR9, -alkyiR9R6, (C3-
Ci4)cyc!oalkyl, aryl, (C2-C6)heterocyclic having 1 -3 heteroatoms selected from S, N and O, and (C2-C6)heteroaryl having 1 -3 heteroatoms selected from S, N, and O; or optionally two R groups, together with any intervening atoms, form a fused (C3-C 4)cycloalkyl ring or a fused (C2- C6)heterocyclic ring having 1 -3 heteroatoms selected from S, N and O; wherein said fused cycloalkyi or heterocyclic ring is optionally substituted with one to three R12;
R12 is independently selected from the group consisting of (C C6)alkyl, (Cr
C6)alkoxy, oxo, halo, hydroxyl, carboxyl, cyano, -OR6(R5)m, -R6(R5)m, and - NR6R6; and
m is an integer from 1 to 3.
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