Preparation of pyrazolopyridine and triazolopyridine derivatives as novel diacylglycerol o-acyltransferase 2 inhibitors

Abstract

Compounds of Formula I, Formula Ib, or Formula Ic, and pharmaceutically acceptable salts, esters, and prodrugs thereof are provided, which are DGAT2 inhibitors. Also provided are methods of preparing compounds of Formula I, Formula Ib, or Formula Ic, pHARMACEUTICAL COMPOSITIONS COMPRISING COMPOUNDS OF Formula I, Formula Ib OR Formula Ic AND USE OF THEIR FOR THE TREATMENT OF LIVER STEATIVE DEGENERATION, NON-ALCOHOLIC STEATIVE HEPATITIS (NASH), FIBROSIS, TYPE 2 DIABETES, OBESITY, HYPERLiPIA, HYPERCHROCHROLEASE, Atherosclerosis, DECIDERATION OF COGNITION, DEmentia, HEART-KITE DISEASES (e.g. And methods of treating diseases and conditions related thereto, comprising administering to a patient in need thereof a compound of Formula I, Formula Ib, or Formula Ic. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This international application claims the benefit of the priority of U.S. Provisional Application No. 63 / 421,381, filed on November 1, 2022, the entire content of which is incorporated herein by reference. Technical field

[0003] The present invention relates to inhibiting diacylglycerol O - acyltransferase 2 (“DGAT2”), and can be used for preventing and treating hepatic steatosis, non - alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio - renal diseases (such as chronic kidney disease and heart failure), and related diseases and disorders or as a reversing agent for these diseases or disorders. The present invention also relates to methods for preparing such compounds and pharmaceutical compositions comprising such compounds and a pharmaceutical carrier. Background art

[0004] Triacylglycerol (“TG”) plays multiple functions in organisms. One such function of TG is energy storage. TG also plays a role in the synthesis of membrane lipids. TG synthesis in cells can protect cells from the potential toxic effects of excess fatty acids (“FA”). In enterocytes and hepatocytes, TG is synthesized for the assembly and secretion of lipoproteins that transport FA between tissues. TG plays a role in the water barrier on the skin surface, and TG in adipose tissue provides insulation for the organism.

[0005] The glycerol - phosphate pathway and the monoacylglycerol pathway are the major pathways for TG biosynthesis. However, the last step in TG synthesis involves the reaction of fatty acyl - CoA with diacylglycerol (“DAG”) to form TG. This reaction is catalyzed by acyl - CoA:diacylglycerol acyltransferase (“DGAT”). Two DGAT enzymes have been identified, DGAT1 and DGAT2. Although DGAT1 and DGAT2 catalyze the same reaction, they differ significantly at the DNA level and protein sequence. DGAT2 can utilize endogenous fatty acids to synthesize TG in in vitro assays, while DGAT1 seems to be more dependent on exogenous fatty acids (Yen et al., J. Lipid Research, 2008, 49, 2283). Inactivation of DGAT2 impairs the growth of cytosolic lipid droplets, while inactivation of DGAT1 has the opposite effect. (Li et al., Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080).

[0006] DGAT2 is an integral membrane protein of the endoplasmic reticulum and is strongly expressed in adipose tissue and the liver. DGAT2 appears to be the major DGAT enzyme controlling TG homeostasis in the body. DGAT2-deficient mice survive only a few hours after birth. In contrast, DGAT1-deficient mice are viable (Yen et al., J. Lipid Research, 2008, 49, 2283).

[0007] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been understood mainly through the results of studies with antisense oligonucleotides (ASO) in rodents. In this context, knockdown of DGAT2 in ob / ob mice with DGAT2 gene-specific ASO resulted in a dose-dependent decrease in very low density lipoprotein (“VLDL”) and reduced plasma TG, total cholesterol, and ApoB (Liu, et al., Biochim. Biophys Acta 2008, 1781, 97). In the same study, treatment of ob / ob mice with DGAT2 antisense oligonucleotides showed decreased body weight gain, fat mass, and liver TG content. Id. In another study, antisense treatment of ob / ob mice improved hepatic steatosis and hyperlipidemia (Yu, et al., Hepatology, 2005, 42, 362). Another study showed that diet-induced hepatic steatosis and insulin resistance were improved by knockdown of DGAT2 in rats. These effects appear to be unique to the inhibition of DGAT2, as ASO directed against DGAT1 did not produce similar beneficial effects. Although the molecular mechanisms underlying these observations remain uncertain, the combined data suggest that inhibition of DGAT2 is associated with reduced expression of lipogenic genes (SREBPlc, ACC1, SCD1, and mtGPAT) and increased expression of oxidative / thermogenic genes (CPT1, UCP2) (Choi et al., J. Bio.Chem., 2007, 282, 22678).

[0008] DGAT2 inhibitors can be used to treat diseases associated with metabolic syndrome, such as hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (such as chronic kidney disease and heart failure), and related diseases and conditions.

[0009] DGAT2 inhibitor compounds are described in WO2022050749, WO2021133035, WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, W02013150416, US20150259323, WO2015077299, W02017011276, WO2018033832, US201801628, and W02003053363. Summary of the Invention

[0010] The present disclosure relates to compounds having Structural Formula I:

[0011]

[0012] and pharmaceutically acceptable salts, esters, and prodrugs thereof, which are DGAT2 inhibitors. Also provided are methods for preparing the compounds of Formula I, pharmaceutical compositions comprising the compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (such as chronic kidney disease and heart failure), and related diseases and conditions, which comprise administering a compound of Formula I to a patient in need thereof. Detailed Description of the Invention

[0014] The present disclosure relates to compounds having Structural Formula I:

[0015]

[0016] or a pharmaceutically acceptable salt thereof, wherein:

[0017] X 3 is selected from C(R 3 ) and N;

[0018] X, Y, and Z are independently selected from N and C(R 4 );

[0019] R 1 is

[0020] (1) a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 5 substituents, or

[0021] (2)-(C 1-6An alkyl - heteroaryl, wherein the heteroaryl is a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituted;

[0022] R 2 is

[0023] (1) A 4 - to 7 - membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0024] (2)-(C 1-6 )alkyl - heterocyclic group, wherein the heterocyclic group is a 3 - to 6 - membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,

[0025] (3)-(C 1-6 )alkyl,

[0026] (4)-(C 3-6 )cycloalkyl,

[0027] (5)-(C 1-6 )hydroxyalkyl,

[0028] (6)-SO2(C 1-6 )alkyl, or

[0029] (7)-(C 1-6 )alkyl - NH - SO2-(C 1-6 )alkyl,

[0030] wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from R 5 ;

[0031] When present, R 3 is

[0032] (1) Hydrogen,

[0033] (2) Halogen,

[0034] (3)-NH2,

[0035] (4)(C 1-6 )alkyl,

[0036] (5)(C 1-6 )haloalkyl,

[0037] (6)(C 1-4 )alkyl hydroxy, or

[0038] (7)-(C 3-6 )cycloalkyl;

[0039] When present, each R 4 is independently

[0040] (1) hydrogen,

[0041] (2) a halogen, or

[0042] (3) (C 1-3 )alkyl;

[0043] When present, each R 5 is independently

[0044] (1) -OC 1-6 alkyl,

[0045] (2) -O(C 1-6 )haloalkyl,

[0046] (3) a halogen,

[0047] (4) cyano,

[0048] (5) O-(C 3-6 )cycloalkyl, optionally substituted with a halogen,

[0049] (6) (C 1-3 )hydroxyalkyl,

[0050] (7) (C 1-6 )haloalkyl-,

[0051] (8) (C 1-3 )hydroxyhaloalkyl, or

[0052] (9) (C 1-6 )alkyl-(C 3-7 )cycloalkyl-OH;

[0053] When present, each R 6 is independently

[0054] (1) oxo,

[0055] (2) (C 1-6 )alkyl, or

[0056] (3) (C 1-6 )haloalkyl-.

[0057] In the present disclosure, Embodiment 2 is a compound of Formula I or a pharmaceutically acceptable salt thereof, and is a compound of Formula Ib;

[0058]

[0059] or a pharmaceutically acceptable salt thereof, wherein:

[0060] R 1 is

[0061] (1) A 6 - membered heteroaryl containing 1 or 2 nitrogen atoms, wherein said heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents, or

[0062] (2) -(C 1-6 )alkyl - heteroaryl, wherein said heteroaryl is a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein said heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents;

[0063] R 2 is

[0064] (1) A 4 - to 7 - membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0065] (2) -(C 1-6 )alkyl - heterocyclic group, wherein said heterocyclic group is a 3 - to 6 - membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,

[0066] (3) -(C 1-6 )alkyl,

[0067] (4) -(C 3-6 )cycloalkyl,

[0068] (5) -(C 1-6 )hydroxyalkyl,

[0069] (6) -SO2(C 1-6 )alkyl, or

[0070] (7) -(C 1-6 )alkyl - NH - SO2-(C 1-6 )alkyl,

[0071] wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from R 6 ;

[0072] When present, R 3 is

[0073] (8) Hydrogen,

[0074] (9) Halogen,

[0075] (10) -NH2

[0076] (11) (C 1-6 )alkyl,

[0077] (12) (C 1-6 )haloalkyl,

[0078] (13) Hydroxy (C 1-4 ) alkyl, or

[0079] (14)-(C 3-6 ) cycloalkyl;

[0080] Each R 4 is independently selected from

[0081] (1) hydrogen,

[0082] (2) halogen, or

[0083] (3)(C 1-3 ) alkyl;

[0084] When present, each R 5 is independently selected from

[0085] (1)-OC 1-6 alkyl,

[0086] (2)-O(C 1-6 ) haloalkyl,

[0087] (3) halogen,

[0088] (4) cyano,

[0089] (5) O-(C 3-6 ) cycloalkyl, optionally substituted by halogen,

[0090] (6)(C 1-3 ) hydroxyalkyl,

[0091] (7)(C 1-6 ) haloalkyl-,

[0092] (8)(C 1-3 ) hydroxyhaloalkyl, or

[0093] (9)(C 1-6 ) hydroxyalkyl-(C 3-7 ) cycloalkyl;

[0094] When present, each R 6 is independently

[0095] (4) oxo,

[0096] (5)(C 1-6 ) alkyl, or

[0097] (6)(C 1-6 ) haloalkyl-.

[0098] In the present disclosure, Embodiment 3 is a compound of Formula I or a pharmaceutically acceptable salt thereof, which is a compound of Formula Ic;

[0099]

[0100] or a pharmaceutically acceptable salt thereof, wherein:

[0101] X 2 is CH or N;

[0102] R 2 is

[0103] (1) a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0104] (2)-(C 1-6 )alkyl-heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,

[0105] (3)-(C 1-6 )alkyl,

[0106] (4)-(C 3-6 )cycloalkyl,

[0107] (5)-(C 1-6 )hydroxyalkyl,

[0108] (6)-SO2(C 1-6 )alkyl, or

[0109] (7)-(C 1-6 )alkyl-NH-SO2-(C 1-6 )alkyl,

[0110] wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents selected from R 6 ;

[0111] When present, R 3 is

[0112] (8) hydrogen,

[0113] (9) halogen,

[0114] (10)-NH2

[0115] (11)(C 1-6 )alkyl,

[0116] (12)(C 1-6 )haloalkyl,

[0117] (13) hydroxy(C 1-4 )alkyl, or

[0118] (14)-(C 3-6 ) cycloalkyl;

[0119] Each R 4 is independently

[0120] (1) hydrogen,

[0121] (2) halogen, or

[0122] (3) (C 1-3 ) alkyl;

[0123] When present, each R 5a is independently

[0124] (1) -OC 1-6 alkyl,

[0125] (2) -O(C 1-6 ) haloalkyl, or

[0126] (3) O-(C 3-6 ) cycloalkyl;

[0127] When present, each R 5b is independently

[0128] (7) halogen,

[0129] (8) cyano,

[0130] (9) -OC 1-6 alkyl,

[0131] (10) (C 1-3 ) hydroxyalkyl,

[0132] (11) (C 1-3 ) hydroxyhaloalkyl, or

[0133] (12) (C 1-6 ) hydroxyalkyl-(C 3-7 ) cycloalkyl;

[0134] When present, each R 6 is independently

[0135] (4) oxo,

[0136] (5) (C 1-6 ) alkyl, or

[0137] (6) (C 1-6 ) haloalkyl-.

[0138] In the present disclosure, Embodiment 4 is a compound of Formula I or Formula Ib, or a compound of Embodiment 1-3 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0139] (1) a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from halogen, OC 1-6 alkyl, O(C 1-6 ) haloalkyl, O-(C 3-6 ) cycloalkyl, cyano, (C 1-6 ) hydroxyalkyl-(C 3-6 ) cycloalkyl and (C 1-3 ) hydroxyhaloalkyl, or

[0140] (2)-(C 1-6 ) alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and the heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from halogen, OC 1-6 alkyl and O(C 1-6 ) haloalkyl.

[0141] In the present disclosure, Embodiment 5 is a compound of Formula I or Formula Ib, or a compound of Embodiment 1-4 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0142] (1) a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from halogen, OC 1-6 alkyl, O(C 1-6 ) haloalkyl, O-

[0143] (C 3-6 ) cycloalkyl, cyano, (C 1-6 ) hydroxyalkyl-(C 3-6 ) cycloalkyl, (C 1-3 ) hydroxyalkyl and (C 1-3 ) hydroxyhaloalkyl, or

[0144] (2)-(C 1-6 ) alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing 1 nitrogen heteroatom, and the heteroaryl is unsubstituted or substituted with one or two substituents independently selected from halogen, OC 1-6 alkyl and O(C 1-6 ) haloalkyl.

[0145] In the present disclosure, Embodiment 6 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, OC 1-6 alkyl, O(C 1-6 ) haloalkyl, O-(C 3-6 ) cycloalkyl, cyano, (C 1-6 ) hydroxyalkyl-(C 3-6 ) cycloalkyl, (C 1-3 ) hydroxyalkyl and (C 1-3 ) hydroxyhaloalkyl.

[0146] In the present disclosure, Embodiment 7 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-6 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, OCH2CF3, OCH2CF2H, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH3)OH and CH(CF3)OH.

[0147] In the present disclosure, Embodiment 8 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-7 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 nitrogen atom, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from F, Cl, OCH2CF3, OCH2CF2H, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH3)OH and CH(CF3)OH.

[0148] In the present disclosure, Embodiment 9 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-3 ) alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from Cl, OCH3, OCH2CH3 and OCH2CHF2.

[0149] In the present disclosure, Embodiment 10 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-5, 9 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-3An alkyl - heteroaryl, wherein the heteroaryl is a 6 - membered heteroaryl containing 1 nitrogen atom, and the heteroaryl is unsubstituted or substituted by one or two substituents independently selected from Cl, OCH3, and OCH2CHF2.

[0150] In the present disclosure, Embodiment 11 is a compound of Formula I or Formula Ib, or a compound of Embodiment 1 - 5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0151]

[0152] In the present disclosure, Embodiment 12 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiment 1 - 11 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

[0153] (1) A 4 - to 7 - membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted by one, two, three, four or five substituents independently selected from oxo, C 1-3 alkyl or C 1-3 haloalkyl,

[0154] (2) -(C 3-6 ) cycloalkyl,

[0155] (3) -(C 1-6 ) hydroxyalkyl, or

[0156] (4) -(C 1-6 ) alkyl - NH - SO2-(C 1-6 ) alkyl.

[0157] In the present disclosure, Embodiment 13 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiment 1 - 12 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

[0158] (1) A 4 - to 7 - membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted by one, two, three, four or five substituents independently selected from oxo, CH3, CHF2 or CH2CF3,

[0159] (2) -(C 3-6 ) cycloalkyl,

[0160] (3) -(C 1-6 ) hydroxyalkyl,

[0161] (4) -(C 1-6 ) alkyl - NH - SO2-(C 1-6 ) alkyl.

[0162] In the present disclosure, Embodiment 14 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-12 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted with one, two, three, four or five substituents independently selected from oxo, C 1-3 alkyl or C 1-3 haloalkyl.

[0163] In the present disclosure, Embodiment 15 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-14 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1 or 2 heteroatoms independently selected from N, O and S, optionally substituted with one, two, three, four or five substituents independently selected from oxo, CH3, CHF2 or CH2CF3.

[0164] In the present disclosure, Embodiment 16 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-15 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-membered heterocyclic group containing 1 sulfur heteroatom, optionally substituted with one, two or three substituents independently selected from oxo or CH3.

[0165] In the present disclosure, Embodiment 17 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-15 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 5-membered heterocyclic group containing 1 sulfur heteroatom, optionally substituted with one, two or three substituents independently selected from oxo or CH3.

[0166] In the present disclosure, Embodiment 18 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-15 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 6-membered heterocyclic group containing 1 sulfur heteroatom, optionally substituted with one, two or three substituents independently selected from oxo, CH3, CHF2 or CH2CF3.

[0167] In the present disclosure, Embodiment 19 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-13 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 5-membered cycloalkyl.

[0168] In the present disclosure, Embodiment 20 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-13 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C(CH3)2CH2C(CH3)2OH.

[0169] In the present disclosure, Embodiment 21 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-14 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 6-membered heterocycle containing 1 nitrogen atom, optionally substituted by one or two substituents independently selected from oxo, -(C 1-3 )alkyl, and -(C 1-3 )haloalkyl.

[0170] In the present disclosure, Embodiment 22 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-14 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 5-membered heterocycle containing 1 nitrogen atom, optionally substituted by one or two substituents independently selected from oxo, -(C 1-3 )alkyl, and -(C 1-3 )haloalkyl.

[0171] In the present disclosure, Embodiment 23 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-13 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -(C 1-6 )alkyl-NH-SO2-(C 1-6 )alkyl.

[0172] In the present disclosure, Embodiment 24 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-13 or 23, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is CH(CH3)2CH2NHSO2CH3.

[0173] In the present disclosure, Embodiment 25 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-13 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

[0174] In the present disclosure, Embodiment 26 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-25 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, halogen, (C 1-6 )alkyl, -(C 1-6 )haloalkyl, -(C1-6 ) hydroxyalkyl, -(C 3-6 ) cycloalkyl or -NH2,

[0175] In the present disclosure, Embodiment 27 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-26 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, halogen, CH3, CH2CH3, CH(CH3)2, CH(F2), CH2OH, CF3, CH(OH)CH3, CH2C(OH)(CH3)2, cyclopropyl or -NH2.

[0176] In the present disclosure, Embodiment 28 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-27 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, F, Cl, CH3, CH2CH3, CH(CH3)2, CH(F2), CH2OH, CF3, CH(OH)CH3, CH2C(OH)(CH3)2, cyclopropyl or -NH2.

[0177] In the present disclosure, Embodiment 29 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-28 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is hydrogen, halogen or (C 1-6 ) alkyl.

[0178] In the present disclosure, Embodiment 30 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-29 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is H, Cl, F or CH3.

[0179] In the present disclosure, Embodiment 31 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-3 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 is -OC 1-6 alkyl, -O(C 1-6 ) haloalkyl, halogen, cyano, O-(C 3-6 ) cycloalkyl, (C 1-6 ) haloalkyl-, (C 1-3 ) hydroxyhaloalkyl, (C 1-3 ) hydroxyalkyl or -(C 3-7 ) cycloalkylhydroxy.

[0180] In the present disclosure, Embodiment 32 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-3, 31 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5-OC 1-6 alkyl, -O(C 1-6 ) haloalkyl, halogen, cyano, O-(C 3-6 ) cycloalkyl, (C 1-3 ) hydroxyhaloalkyl, (C 1-3 ) hydroxyalkyl or -(C 3-7 ) cycloalkylhydroxy.

[0181] In the present disclosure, Embodiment 33 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-3, 31-32 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 is halogen, OCH3, OCH2CH3, -OCH2CF3, OCH2CHF2, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH3)OH or CH(CF3)OH.

[0182] In the present disclosure, Embodiment 34 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-3, 31-33 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 is F, Cl, OCH3, OCH2CH3, -OCH2CF3, OCH2CHF2, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH3)OH or CH(CF3)OH.

[0183] In the present disclosure, Embodiment 35 is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-3, 31-34 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 is OCH2CF3 or OCH2CHF2.

[0184] In the present disclosure, Embodiment 36 is a compound of Formula Ic, or a compound of Embodiments 3, 12-30 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5a is OCH2CHF2, OCH2CF3, O-cyclopropyl.

[0185] In the present disclosure, Embodiment 37 is a compound of Formula Ic, or a compound of Embodiments 3, 12-30, or 36, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5b is halogen, CH(cyclopropyl)OH, CN, CH(CH3)OH, CH(CF3)OH.

[0186] In the present disclosure, Embodiment 38 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-11, 26-37 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6 is oxo, (C 1-6)alkyl or (C 1-6 )haloalkyl-.

[0187] In the present disclosure, Embodiment 39 is a compound of Formula I, Formula Ib or Formula Ic, or a compound of Embodiments 1-11, 26-38 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6 is oxo, CH3, CHF2 or CH2CF3.

[0188] In the present disclosure, Embodiment 40 is a compound of Formula I, or a compound of Embodiments 1, 4-39 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 3 is C(R 3 ).

[0189] In the present disclosure, Embodiment 41 is a compound of Formula I, or a compound of Embodiments 1, 4-39 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X 3 is N.

[0190] In the present disclosure, Embodiment 42 is a compound of Formula I, or a compound of Embodiments 1, 4-39 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ), Y is C(R 4 ), and Z is C(R 4 ).

[0191] In the present disclosure, Embodiment 43 is a compound of Formula I, or a compound of Embodiments 1, 4-39 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is C(R 4 ), and Z is C(R 4 ).

[0192] In the present disclosure, Embodiment 44 is a compound of Formula I, or a compound of Embodiments 1, 4-39 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ), Y is N, and Z is C(R 4 ).

[0193] In the present disclosure, Embodiment 45 is a compound of Formula I, or a compound of Embodiments 1, 4-39 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ), Y is C(R 4 ), and Z is N.

[0194] In the present invention, Embodiment 46 is a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt thereof, and is:

[0195] N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0196] 5-((3-(2,2,2-Trifluoroethoxy)pyridin-2-yl)oxy)-N-(2,3,3-trimethyl-1,1-dioxoisothiazolidin-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0197] N-(2-Methyl-1-(methylsulfonamido)propan-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0198] N-(4-Hydroxy-2,4-dimethylpentan-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0199] N-(2-Oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0200] N-(3-Methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0201] (S)-N-(Tetrahydrofuran-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0202] N-Cyclopentyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0203] (R)-5-((3-(2,2-Difluoroethoxy)pyrazin-2-yl)oxy)-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0204] 5-((3-(2,2-Difluoroethoxy)pyrazin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0205] 5-((3-Cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0206] 5-((3-(2,2-Difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0207] 5-((3-Cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0208] N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0209] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0210] 5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0211] 5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0212] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0213] (R)-5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0214] 3-Methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0215] 3-Methyl-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0216] 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0217] 3-Fluoro-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0218] (R)-3-Fluoro-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0219] 3-Chloro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0220] 3-Chloro-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0221] (R)-3-Chloro-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0222] (S)-3-Chloro-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0223] 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0224] (R)-3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0225] 3-Chloro-5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0226] 5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-3-fluoro-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0227] 5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0228] 3,4-Dichloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0229] 3-Chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0230] 3-Chloro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0231] 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0232] 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0233] 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0234] 3-chloro-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0235] 3-chloro-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0236] 3-chloro-5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0237] 5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0238] (R)-5-((5-(cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0239] (S)-5-((5-(cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0240] (R)-5-((5-(1-hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0241] (S)-5-((5-(1-Hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0242] (R)-N-(3-Methyl-1,1-dioxothietan-3-yl)-5-((5-(2,2,2-trifluoro-1-hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0243] (S)-N-(3-Methyl-1,1-dioxothietan-3-yl)-5-((5-(2,2,2-trifluoro-1-hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0244] 3-Ethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0245] 3-Ethyl-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0246] 3-Isopropyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0247] 3-(Difluoromethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0248] 3-(Hydroxymethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0249] N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0250] (R)-3-(1-Hydroxyethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0251] (S)-3-(1-Hydroxyethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0252] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(2-hydroxy-2-methylpropyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0253] 3-Cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0254] 3-Amino-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0255] 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0256] 6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0257] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0258] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0259] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide,

[0260] 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide,

[0261] 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide,

[0262] 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0263] 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-(difluoromethyl)-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0264] 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(1,1-dioxo-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0265] 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0266] 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide,

[0267] 5-((6-methoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide,

[0268] 5-((6-ethoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide, or

[0269] 5-((3-chloro-6-methoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide.

[0270] Embodiment 47, the compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof, is:

[0271]

[0272]

[0273]

[0274] Embodiment 48, the compound of formula Ib or a pharmaceutically acceptable salt thereof, is:

[0275]

[0276]

[0277]

[0278] Embodiment 49 is a compound or a pharmaceutically acceptable salt thereof, which is

[0279]

[0280] Embodiment 50 is a compound or a pharmaceutically acceptable salt thereof, which is

[0281]

[0282] Embodiment 51 is a compound or a pharmaceutically acceptable salt thereof, which is

[0283]

[0284] Embodiment 52 is a compound or a pharmaceutically acceptable salt thereof, which is

[0285]

[0286] Embodiment 53 is a compound or a pharmaceutically acceptable salt thereof, which is

[0287]

[0288] Embodiment 54 is a compound or a pharmaceutically acceptable salt thereof, which is

[0289]

[0290] Embodiment 55 is a compound or a pharmaceutically acceptable salt thereof, which is

[0291]

[0292] Embodiment 56 is a compound or a pharmaceutically acceptable salt thereof, which is

[0293]

[0294] Embodiment 57 is a compound or a pharmaceutically acceptable salt thereof, which is

[0295]

[0296] Embodiment 58 is a compound or a pharmaceutically acceptable salt thereof, which is

[0297]

[0298] The present disclosure includes pharmaceutically acceptable salts of the compounds defined herein.

[0299] In one embodiment, the present disclosure is a composition comprising an effective amount of at least one compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof.

[0300] The present disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0301] The present disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (e.g., a chemotherapeutic agent).

[0302] The present disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (e.g., a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

[0303] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (e.g., chronic kidney disease or heart failure), comprising an acceptable carrier and a compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof.

[0304] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (e.g., chronic kidney disease or heart failure), comprising a compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof.

[0305] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (e.g., chronic kidney disease or heart failure), comprising a compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0306] In one embodiment, the present disclosure provides a method of treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (e.g., chronic kidney disease or heart failure) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof.

[0307] In one embodiment, the present disclosure provides a method of treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (e.g., chronic kidney disease or heart failure) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0308] The method of the present disclosure includes administering a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0309] In another embodiment, the present disclosure includes a method of treating NASH and / or fibrosis, which includes administering to a patient in need a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt thereof.

[0310] In another embodiment, the present disclosure includes a method of treating NASH and / or fibrosis, which includes administering to a patient in need a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0311] In another embodiment, the present disclosure includes a method of treating NASH and / or fibrosis, which includes administering to a patient in need a composition comprising a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt thereof.

[0312] In another embodiment, the present disclosure includes a method of treating NASH and / or fibrosis, which includes administering to a patient in need a composition comprising a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0313] In another embodiment, the present disclosure provides the use of a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH and / or fibrosis.

[0314] In another embodiment, the present disclosure includes the use of a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH and / or fibrosis.

[0315] "Alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. If no number is specified, a straight-chain alkyl has 1-6 carbon atoms and a branched-chain alkyl has 3-7 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, octyl, nonyl, etc. For example, the term "C 1-6 alkyl" includes all "C 1-4 alkyl" as defined below, plus straight-chain or branched-chain alkyls having 5 or 6 carbon atoms, including all possible isomers. "C 1-6 alkyl" refers to straight-chain or branched-chain alkyls having 1, 2, 3, 4, 5 or 6 carbon atoms, including all possible isomers, and includes C 1-6Each alkyl group within the alkyl group, including each hexyl and pentyl isomer and n-butyl, iso-butyl, sec-butyl, and tert-butyl (n-butyl, isobutyl, sec-butyl, tert-butyl, collectively referred to as "C4 alkyl"; Bu = butyl), n-propyl and iso-propyl (n-propyl, isopropyl, collectively referred to as "C3 alkyl"; Pr = propyl), ethyl (Et), and methyl (Me). The common abbreviations for alkyl groups are used throughout the specification. For example, methyl can be represented by the conventional abbreviations, including "Me" or CH3 or as an extended bond symbol at the end group, such as Ethyl can be represented as "Et" or CH2CH3, propyl can be represented as "Pr" or CH2CH2CH3, butyl can be represented as "Bu" or CH2CH2CH2CH3, etc. For example, the structure Has an equivalent meaning. If no number is specified, it is a straight-chain or branched-chain alkyl group.

[0316] "Alkoxy" refers to an alkyl group linked to oxygen. Examples of alkoxy groups include methoxy, ethoxy, propoxy, etc.

[0317] "Aryl" refers to an aromatic monocyclic or polycyclic moiety containing 6 to 14 ring carbon atoms. In one embodiment, the aryl group contains about 6 to 10 ring carbon atoms. Monocyclic aromatic rings include, but are not limited to, phenyl. Polycycles include, but are not limited to, naphthyl and bicyclic, such as 8- to 10-membered fused bicyclic heterocycles. The aryl group may optionally be substituted with one or more substituents as defined herein. The bonding can occur through any carbon atom on any ring.

[0318] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine.

[0319] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic system containing about 3 to 10 ring carbon atoms. If no number of atoms is specified, it means having 3 - 10 carbon atoms. The cycloalkyl group can also be fused to form 1 - 3 carbon rings. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C 1-6 Cycloalkyl" refers to a cycloalkyl group having 1 to 6 ring carbon atoms. The term "C 3-6 Cycloalkyl" refers to a cycloalkyl group having 3 to 6 ring carbon atoms. Thus, for example, "C 3-6 Cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group is unsubstituted or substituted with one or more ring system substituents, which may be the same or different and as defined therein. When the cycloalkyl group is a substituent on an alkyl group, the cycloalkyl substituent can be bonded to any available carbon atom on the alkyl group. The following is an illustration of a -C 3-6 Cycloalkyl substituent on an alkyl group, where the substituent is cyclopropyl and is shown in bold:

[0320] "Halogenated alkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are replaced by a halogen. In one embodiment, the halogenated alkyl has 1 to 6 carbon atoms. Non-limiting examples of halogenated alkyls include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CH2CH3, CF2CHF2, -C(CH3)2F, CH2Cl, and CCl3. The term "C 1-6 halogenated alkyl" or "halogenated C 1-6 alkyl" refers to a halogenated alkyl having 1 to 6 carbons.

[0321] "Halogenated alkoxy", "halogenated alkyl - O", and its derivatives such as "halogenated (C 1-6 ) alkoxy" are used interchangeably and refer to a halogen - substituted alkyl group linked through an oxygen atom. Halogenated alkoxys include mono - halogen - substituted alkoxys as well as poly - halogen - substituted alkoxys. For example, it includes trifluoromethoxy, chloromethoxy, and bromomethoxy, as well as OCH2CF3, OCH2CHF2, OCF2CF3, OCH2CF2CH3, OCH2CF2CHF2, OCHF2, and OCF2CHF2.

[0322] "Heterocyclic group", "heterocycle", or "heterocyclic" refers to a monocyclic structure in which one or more atoms in the ring, i.e., heteroatoms, are elements other than carbon. Heteroatoms are typically O, S, or N atoms. Heterocycles containing more than one heteroatom may contain different heteroatoms. Bicyclic moieties include fused bicyclics, spirocycles, and bridged bicyclics, and may contain one or more heteroatoms in either ring. The ring attached to the rest of the molecule may or may not contain heteroatoms. Either ring of a bicyclic heterocycle may be saturated, partially unsaturated, or unsaturated. The heterocycle may be attached to the rest of the molecule via a ring carbon atom, a ring oxygen atom, or a ring nitrogen atom. Examples of heterocyclic groups include: piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, oxiranyl, or aziridinyl, etc.

[0323] "Bicyclic heterocyclic group", "bicyclic heterocycle", or "bicyclic heterocyclic" refers to a heterocycle fused to another ring system. The fusion may be bridged or unbridged.

[0324] Unless otherwise specified, the term "heteroaryl" as used herein refers to a stable monocyclic, bicyclic, or tricyclic ring having up to 10 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N, and S. Heteroaryls within the scope of this definition include, but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetrahydroquinoline.

[0325] "Oxo" refers to an oxygen atom attached by a double bond. An example of an oxo group is the double bond oxygen in a ketone, sulfoxide, sulfone, sulfate, or the double bond oxygen fused to a non-aromatic cycloalkyl or heteroalkyl group.

[0326] "Hydroxyalkyl" or "hydroxy(C 1-3 )alkyl-" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy (-OH) group. Examples of hydroxyalkyls are CH2OH, C(CH3)2OH, CH2CH2OH, or CH(OH)CH3.

[0327] "Hydroxyhaloalkyl" refers to an alkyl group having one or more hydrogen atoms replaced by a hydroxy (-OH) group and one or more hydrogen atoms replaced by a halogen substituent. Examples include CH(CF3)OH.

[0328] The term "composition" is intended to cover a product consisting of specified amounts of particular ingredients, as well as any product directly or indirectly resulting from the combination of specified amounts of particular ingredients.

[0329] The term "at least one" means one or more than one. In terms of the number of compounds of the present disclosure, the meaning of "at least one" is independent of the meaning in terms of the number of chemotherapeutic agents.

[0330] The term "chemotherapeutic agent" refers to a drug (agent or pharmaceutically active ingredient) used for treating cancer (i.e., an anti-tumor agent).

[0331] The term "effective amount" means "therapeutically effective amount". The term "therapeutically effective amount" means the amount of an active compound or agent that elicits a biological or pharmaceutical response in a tissue, system, animal, or human that is sought by a researcher, veterinarian, physician, or other clinician.

[0332] The term "treating cancer" or "treatment of cancer" refers to administering treatment to a mammal having a cancerous condition and means reducing the effects of the cancerous condition by killing cancer cells, and also means causing an effect that inhibits cancer growth and / or metastasis.

[0333] Unless otherwise indicated herein, the term "carbocyclic ring" (and variants thereof such as "carbocyclic" or "carbocyclic group") refers to a C3 to C6 monocyclic ring, such as a 3-6 monocyclic carbocyclic ring. The carbocyclic ring can be attached to any carbon atom of the remainder of the molecule to form a stable compound. Saturated carbocyclic rings include, for example, "cycloalkyl" rings such as cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings include, for example

[0334] A "stable" compound is a compound that can be prepared and isolated and whose structure and properties remain unchanged or substantially unchanged over a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., for therapeutic or prophylactic administration to a subject).

[0335] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I, Formula Ib, or Formula Ic and their embodiments. For example, certain moieties defined in Formula I, Formula Ib, or Formula Ic may be unsubstituted or substituted, and the latter is intended to cover the substitution patterns (i.e., the number and type of substituents) that are chemically feasible for that moiety and that result in a stable compound.

[0336] The term "substituted" means that one or more hydrogens on a specified atom are replaced by a group selected from the specified group, provided that no more than the normal valence of the specified atom in the existing situation is exceeded and that the substitution results in a stable compound. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently substituted by one or more of the disclosed or claimed substituent moieties (single or multiple). Independently substituted means that the (two or more) substituents may be the same or different. Such combinations are permitted only if the combination of substituents and / or variables results in a stable compound. If a substituent itself is substituted by more than one group, it should be understood that these multiple groups may be on the same carbon or different carbons, as long as a stable structure can be obtained. Optionally substituted means a compound containing the specified optional substituent as well as a compound not containing the optional substituent.

[0337] The wavy line used herein represents the point of attachment to the remainder of the compound.

[0338] When the ring atom is represented by a variable (e.g., "X"), for example The definition of the variable indicates the atom located at the variable ring position and does not describe the ring bonds associated with that atom. For example, when X in the above ring is nitrogen, the definition will show "N" and will not describe the bonds associated with it. For example, "=N-" will not be shown. Similarly, when X is a carbon atom substituted by bromine, the definition will show "C-Br" and will not depict the bonds associated with it. For example,

[0339] The present disclosure also includes derivatives of the compounds of formula I, formula Ib or formula Ic that are used as prodrugs and solvates. Any pharmaceutically acceptable prodrug modification of the compounds of the present invention that results in the conversion in vivo to a compound within the scope of the present invention is also within the scope of the present disclosure. After administration to a patient, the prodrug is converted in vivo to a compound of formula I, formula Ib or formula Ic through normal metabolic or chemical processes, such as hydrolysis in the blood. Such prodrugs include those that exhibit enhanced bioavailability, tissue specificity, and / or cellular delivery to improve the drug absorption of the compounds of formula I. The effects of such prodrugs may result from changes in physicochemical properties, such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine the permeation properties of the drug.

[0340] For example, esters can optionally be prepared by esterification of available carboxylic acid groups or by forming esters on available hydroxyl groups in the compound. Similarly, labile amides can be prepared. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared as prodrugs, which can be hydrolyzed back to the acid (or -COO - , depending on the pH value of the liquid or tissue where the conversion occurs) or the hydroxyl form, especially in vivo, and are therefore also included in the scope of the present invention. Those esters and acyl groups known in the art for altering solubility or hydrolysis characteristics for use in sustained release or prodrug formulations are included. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 alkyl esters and –C 1-6 alkyl-substituted phenyl esters.

[0341] (Fluka) Diatomite is diatomaceous earth and can be referred to as "celite".

[0342] When any variable (e.g., R 1When (such as etc.) appears more than once in any component or Formula I, Formula Ib, Formula Ic or other general formulas herein, its definition at each occurrence is independent of its definition at all other occurrences. Such combinations are permitted only if the combination of substituents and / or variables can result in a stable compound. When selecting the compounds of the present invention, those of ordinary skill in the art will recognize that various substituents (i.e., R 1 etc.) should be selected in accordance with well-known principles of chemical structure connectivity and stability. Unless otherwise expressly stated to the contrary, substitution of the designated substituents is permitted on any atom in a ring (such as an aryl, heteroaryl or saturated heterocyclic ring), provided that such ring substitution is chemically permitted and results in a stable compound.

[0343] It should be noted that if there is a difference between the chemical name and the structure, the structure shall prevail.

[0344] The compounds of Formula I or Formula Ib may contain one or more asymmetric centers and thus may occur in the form of racemates and racemic mixtures, single enantiomers, mixtures of diastereomers and individual diastereomers. The asymmetric centers present in the compounds of Formula I, Formula Ib or Formula Ic may each independently have the S configuration or the R configuration. When the bonds at a chiral carbon in the structural formulas herein are depicted as straight lines, it should be understood that the (R) configuration or the (S) configuration of the chiral carbon, as well as its enantiomers and mixtures, are included in the chemical formula. Similarly, when there is no chiral name for a chiral carbon when stating the compound name, it should be understood that the name encompasses the (R) and (S) configurations of the chiral carbon, as well as the individual enantiomers and their mixtures. The generation of specific stereoisomers or mixtures thereof can be determined in the examples in which such stereoisomers or mixtures are obtained, but this in no way limits the inclusion of all stereoisomers and their mixtures within the scope of the present disclosure.

[0345] The compounds of the present disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers in all proportions, such as mixtures of enantiomers and / or diastereomers. Thus, enantiomers are the subject matter of the present invention in the form of enantiomerically pure forms, left- and right-handed enantiomer forms, racemic forms and mixtures of the two enantiomers in various proportions. In the case of cis / trans isomers, the present invention includes cis and trans, as well as mixtures of these forms in various proportions. The present disclosure is intended to cover all such stereoisomeric forms of the compounds of Formula I, Formula Ib or Formula Ic.

[0346] The compounds of formula I, formula Ib or formula Ic can be separated into their individual diastereoisomers, for example, by fractional crystallization from a suitable solvent (e.g., MeOH or EtOAc or mixtures thereof), or via chiral chromatography using an optically active stationary phase. Optionally, derivatization can be carried out prior to the separation of stereoisomers. The separation of the stereoisomer mixture can be carried out in an intermediate step during the synthesis of the compounds of formula I, formula Ib or formula Ic, or can be carried out on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which can be derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer or isomer of the compounds of formula I, formula Ib or formula Ic can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. The formula I and formula Ib of the present disclosure include all such isomers, as well as salts, solvates (including hydrates) and solvated salts and mixtures thereof of such racemates, enantiomers, diastereoisomers and tautomers.

[0347] If desired, the racemic mixture of the compound can be separated to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, for example, by coupling the racemic mixture of the compound with an enantiomerically pure compound to form a mixture of diastereoisomers, and then separating the individual diastereoisomers by standard methods (e.g., fractional crystallization or chromatography). The coupling reaction typically uses an enantiomerically pure acid or base to form a salt. The diastereoisomer derivative can then be converted to the pure enantiomer by cleavage of the added chiral residue. The racemic mixture of the compound can also be directly separated by chromatography using a chiral stationary phase, which methods are well known in the art.

[0348] For the compounds of formula I, formula Ib or formula Ic containing an olefinic double bond described herein, unless otherwise specified, they are meant to include both the E and Z geometric isomers.

[0349] Certain compounds described herein may exist in tautomeric forms, which have different hydrogen attachment points and are accompanied by one or more double bond displacements. For example, a ketone and its enol form are keto-enol tautomers. The compounds of formula I, formula Ib or formula Ic encompass the individual tautomers and mixtures thereof.

[0350] In the compounds of Formula I, Formula Ib or Formula Ic, the atoms may exhibit their natural isotope abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention, as described and claimed herein, is intended to embrace all suitable isotopic variants of the compounds of Formula I, Formula Ib or Formula Ic and their embodiments. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H, also referred to herein as D). Protium is the major hydrogen isotope found in nature. Enrichment of deuterium may have certain therapeutic advantages, such as increasing the in vivo half-life or reducing the dosage requirements, or may provide compounds that can be used as standards for characterizing biological samples. Isotopically enriched compounds within Formula I, Formula Ib or Formula Ic can be prepared by conventional techniques well known to those skilled in the art or by methods similar to those described in the protocols and examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0351] It should be understood that when the compounds of Formula I, Formula Ib or Formula Ic are used as precursors of free compounds or their pharmaceutically acceptable salts or for other synthetic operations, they can be prepared as pharmaceutically acceptable salts or non-pharmaceutically acceptable salts. The compounds of the present invention, including the compounds of the examples, may also include all salts of the compounds of Formula I, Formula Ib or Formula Ic, which are not directly suitable for use in medicine due to low physiological compatibility but which can be used, for example, as intermediates in chemical reactions or for the preparation of physiologically acceptable salts.

[0352] The compounds of the present invention may be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids (including inorganic or organic bases and inorganic or organic acids).

[0353] Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention, which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, the following: acetates, ascorbates, benzenesulfonates, benzoates, bicarbonates, bisulfates, bitartrates, borates, bromides, butyrates, camphorates, camphorsulfonates, dextrocamphorsulfonates, carbonates, chlorides, clavulanates, citrates, dihydrochlorides, edetates, ethanedisulfonates, propionates, esulfonates, fumarates, glucoheptonates, glucuronates, glutamates, glycollylarsanilates, hexylresorcinates, hydrabamines, hydrobromides, hydrochlorides, hydroxynaphthoates, iodides, isothionates, lactates, lactobionates, laurates, malates, maleates, mandelates, mesylates, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonates, acetals, naphthalenesulfonates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, phosphates / diphosphates, polygalacturonates, propionates, salicylates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, teoclates, thiocyanates, toluenesulfonates, triethyl iodide, valerates, etc. In addition, when the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, etc. In one embodiment, salts of acidic compounds are as follows: ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts.

[0354] Together with basic reagents (such as hydroxides, carbonates, bicarbonates, alkoxides, and ammonia), organic bases, or basic amino acids, the compounds of formula I, formula Ib, or formula Ic form stable alkali metal salts, alkaline earth metal salts, or optionally substituted ammonium salts.

[0355] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexylamine, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. Also included are those that can be quaternized with reagents such as lower alkyl halides, such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl; dialkyl sulfates, such as dimethyl, diethyl, dibutyl; and dipentyl sulfates; long-chain halides, such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; aralkyl halides, such as bromides of benzyl and phenethyl, etc.

[0356] The preparation of pharmaceutically acceptable salts from the compounds of formula I, formula Ib or formula Ic capable of forming salts (including their stereoisomeric forms) is carried out by known methods, for example, by mixing an equal amount of the compound of the present invention with a solution containing the required acid, base, etc., and then collecting the required salt by filtering the salt or distilling off the solvent. The compounds of formula I and formula Ib and their salts can form solvates with solvents such as water, ethanol or glycerol. Depending on the type of side chain substituents, the compounds of formula I and formula Ib can form acid addition salts and salts with bases simultaneously.

[0357] If the compounds of formula I, formula Ib or formula Ic contain both acidic and basic groups in the molecule, in addition to the above salt forms, the present disclosure also includes inner salts or betaines (zwitterions). The salts can be obtained from the compounds of formula I, formula Ib or formula Ic by conventional methods known to those skilled in the art, such as by combining with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

[0358] The present invention includes the compounds of formula I, formula Ib or formula Ic and their salts, especially pharmaceutically acceptable salts, solvates of such compounds and their solvated salt forms, and such forms are possible unless otherwise stated.

[0359] In addition, the compounds of Formula I, Formula Ib or Formula Ic can exist in amorphous form and / or one or more crystalline forms. Accordingly, all amorphous and crystalline forms of the compounds of Formula I or Formula Ib, and mixtures thereof (including the Examples), are intended to be encompassed within the scope of the present disclosure. Further, some of the compounds in the present disclosure can form solvates with water (i.e., hydrates) or common organic solvents (such as, but not limited to, EtOAc). Such solvates and hydrates of the compounds of the present disclosure, particularly pharmaceutically acceptable solvates and hydrates, as well as the non-solvated and anhydrous forms, are likewise encompassed within the scope of the present disclosure.

[0360] Accordingly, the compounds within the structural formulas, embodiments and specific compounds described in the Examples and claims herein encompass salts, all possible stereoisomers and tautomers, physical forms (such as amorphous and crystalline forms), solvate and hydrate forms, and any combination of these forms, as well as salts, prodrug forms and salts of prodrug forms, which are possible unless otherwise stated.

[0361] The present invention also relates to a medicament comprising at least one compound of Formula I, Formula Ib or Formula Ic and / or a pharmaceutically acceptable salt of a compound of Formula I, Formula Ib or Formula Ic and / or, optionally, a stereoisomeric form of a compound of Formula I, Formula Ib or Formula Ic or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of Formula I, Formula Ib or Formula Ic, as well as a pharmaceutically acceptable carrier, vehicle, additive and / or other active substances and adjuvants.

[0362] The medicament of the present invention can be administered orally, by inhalation, rectally or transdermally, or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral administration is preferred.

[0363] The present invention also relates to a method for preparing a medicament, which comprises bringing at least one compound of Formula I, Formula Ib or Formula Ic into a suitable form for administration using a pharmaceutically acceptable carrier and, optionally, other suitable active substances, additives or adjuvants.

[0364] The present invention also relates to a process for preparing a compound of Formula I, Formula Ib or Formula Ic as described below, by which the compounds of the present invention can be obtained.

[0365] The terms "therapeutically effective (or efficacious) amount" and like descriptions such as "effective therapeutic amount" are intended to denote the amount of a drug capable of alleviating the symptoms of a disorder, condition or disease being treated in an animal or human (i.e., a disorder, condition or disease associated with DGAT2 activity). The terms "preventively effective (or efficacious) amount" and like descriptions, such as "effective preventive amount", are intended to denote the amount of a drug that can prevent or alleviate the symptoms or occurrence of a disorder, condition or disease being treated in an animal or human (i.e., a disorder, condition or disease associated with DGAT2 activity). A dosage regimen using the compounds of the invention is selected in accordance with a variety of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound selected for administration; the route of administration; and the renal and hepatic function of the patient. These factors can be taken into account by the ordinary clinician in determining the therapeutically effective or preventively effective dose required to prevent, counter or arrest the progress of a condition. It should be understood that a particular daily dose can be both a therapeutically effective amount (e.g., for treating hepatic steatosis, diabetes, obesity, hyperlipidemia, hypercholesterolemia) and a preventively effective amount (e.g., for treating NASH).

[0366] Disorders, conditions and diseases that can be treated or prevented by inhibiting DGAT2 with a compound of formula I, formula Ib or formula Ic are, for example, diseases such as: non-alcoholic steatohepatitis (NASH), hepatic fibrosis, hyperlipidemia, type I diabetes, type II diabetes, cognitive decline, dementia, coronary heart disease, ischemic stroke, vascular restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial hyperlipidemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue diseases, hyperapo B lipoproteinemia, non-alcoholic fatty liver disease, cardio-renal diseases (such as chronic kidney disease and heart failure) and related diseases and conditions.

[0367] Compounds of formula I, formula Ib or formula Ic and their pharmaceutically acceptable salts, solvates, prodrugs and polymorphic forms can be administered to animals, preferably mammals, especially humans, either as the drug itself, as a mixture with each other or in the form of a pharmaceutical preparation. Compounds of formula I, formula Ib or formula Ic and their pharmaceutically acceptable salts, solvates, prodrugs and polymorphic forms can be administered to animals, including dogs and cats, either as the drug itself, as a mixture with each other or in the form of a pharmaceutical preparation. The term "patient" includes animals, preferably mammals, especially humans, who use the active agent of the present invention to prevent or treat a medical condition. Administering a drug to a patient includes self-administration by the patient and administration to the patient by another person. A patient may need or wish to treat an existing disease or medical condition, or may need or wish to receive prophylactic treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, a patient "needs" treatment of an existing condition or prophylactic treatment includes both the need determined by a medical professional and the patient's desire for such treatment.

[0368] In addition, the present invention provides a pharmaceutical preparation (or pharmaceutical composition) comprising a therapeutically effective dose of at least one compound of formula I, formula Ib or formula Ic and / or its pharmaceutically acceptable salt, solvate, prodrug or polymorphic form as an active ingredient and a conventional pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0369] Accordingly, one subject matter of the present invention is, for example, the use of the compounds and their pharmaceutically acceptable salts as drugs, pharmaceutical preparations comprising a therapeutically effective dose of the compounds and / or their pharmaceutically acceptable salts as active ingredients and a conventional pharmaceutically acceptable carrier, and the use of the compounds and / or their pharmaceutically acceptable salts in the treatment or prevention of the above syndromes and their use in the preparation of drugs for these purposes.

[0370] The drugs described herein can be administered orally, for example, in the form of pills, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft capsules, aqueous solutions, alcoholic solutions or oil solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be parenteral, for example, subcutaneously, intramuscularly or intravenously in the form of injection or infusion solutions. Other suitable forms of administration are, for example, percutaneous or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or inhalation administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred form of administration depends, for example, on the disease to be treated and its severity.

[0371] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, starch (e.g. corn starch or starch derivatives), talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions (e.g. injection solutions or emulsions or syrups) are, for example, water, physiological sodium chloride solution, alcohols (e.g. ethanol, glycerol, polyols), sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of formula I, formula Ib or formula Ic and their pharmaceutically acceptable salts, solvates, solvates and prodrugs and to use the resulting lyophilizates, for example, for the preparation of injection or infusion preparations. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0372] Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injection solutions and preparations with a prolonged release of the active substance, in which conventional excipients are used, such as carriers, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavoring agents, sweetening agents and solubilizers. Frequently used auxiliaries that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils (e.g. cod liver oil, sunflower oil, peanut oil or sesame oil), polyethylene glycols and solvents (e.g. e.g. sterile water) and monoalcohols or polyols such as glycerol.

[0373] In addition to the active compound and the carrier, the pharmaceutical preparation may also contain conventional additives, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweetening agents, colorants, flavoring agents, fragrances, thickening agents, diluents, buffer substances, solvents, solubilizers, agents for achieving a sustained release effect, salts for altering the osmotic pressure, coating agents or antioxidants.

[0374] The dose of the active compound of formula I, formula Ib or formula Ic and / or its pharmaceutically acceptable salt, solvate, prodrug or polymorphic form administered depends on the individual case and, as a rule, is adapted to the individual case to achieve the best effect. Thus, it depends on the nature and severity of the disorder, condition or disease to be treated, also on the sex, age, weight and individual response of the human or animal to be treated, on the efficacy and duration of action of the compound used, on whether the treatment is acute, chronic or prophylactic, or on whether other active compounds are administered in addition to the compounds of formula I, formula Ib or formula Ic.

[0375] Combined medicament

[0376] The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents or other suitable agents disclosed herein, depending on the condition being treated. Thus, in some embodiments, one or more compounds of the present invention will be co-administered with other agents described herein. When used in combination therapy, the compounds described herein are administered simultaneously or separately from the second agent. Such co-administration can include co-administering the two agents in the same dosage form simultaneously, co-administering in separate dosage forms simultaneously, and administering separately. That is, the compound of formula (I) and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of formula (I) and any of the above agents can be administered simultaneously, where the two agents are present in separate formulations. In another alternative, the compound of formula (I) can be administered first, followed immediately by any of the above agents, or vice versa. In some embodiments of the separate administration scenario, the compound of formula (I) and any of the above agents are administered at intervals of a few minutes, a few hours, or a few days.

[0377] The present disclosure contemplates the use of combinations of pharmaceutically active compounds that can be administered alone to treat a disease / condition. The present disclosure also relates to combining separate pharmaceutical compositions into a kit form. The kit contains two separate pharmaceutical compositions: a compound of formula (I), and a second pharmaceutical compound. The kit includes containers for holding the separate compositions, such as separate bottles or separate foil packages. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, parenteral; IV, transdermal, and subcutaneous), at different dosing intervals, or when a prescribing healthcare professional needs to titrate each component in the combination.

[0378] One or more additional pharmaceutically active agents can be co-administered with a compound of formula I, formula Ib, or formula Ic. One additional active agent (or more additional active agents) is intended to mean one pharmaceutically active agent (or more pharmaceutically active agents) that is active in the body, including prodrugs that are converted to a pharmaceutically active form after administration, which is different from the compound of formula I, formula Ib, or formula Ic, and also includes the free acids, free bases, and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable one or more additional active agents, including but not limited to anti-hypertensive agents, anti-obesity agents, anti-inflammatory agents, anti-fibrotic agents, and anti-atherosclerotic agents (e.g., lipid-regulating compounds), anti-diabetic agents, and / or anti-obesity agents, can be used in combination with a compound of formula I, formula Ib, or formula Ic in any combination in a single dosage formulation (fixed-dose drug combination), or can be administered to a patient in one or more separate dosage formulations, which allows for simultaneous or sequential administration of the active agents (co-administering the separate active agents).

[0379] Examples of additional active agents that may be employed include, but are not limited to, angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., losartan valsartan, candesartan, olmesartan, telmesartan, and those in combination with hydrochlorothiazide (e.g., )Any of these drugs used in combination); neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., urea derivatives of dipeptides and tripeptides, amino acids and derivatives, amino acid chains linked by non-peptide bonds, dipeptide and tripeptide derivatives, peptidyl aminodiols and peptidyl β-aminoacyl aminodiol carbamates; also, and small molecule renin inhibitors, including diol sulfonamides and N-morpholino derivatives, N-heterocyclic alcohols and pyrolimidazolones; also, pepstatin derivatives and fluoro and chloro derivatives of statone-containing peptides, enalkrein, remikiren, A65317, terlakiren, ES1005, ES8891, SQ34017, aliskiren, SPP600, SPP630 and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholitics, β-adrenergic blockers (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol or metoprolol tartrate), α-adrenergic blockers (e.g., doxazosin, prazosin or alpha methyldopa) central α-adrenergic agonists, peripheral vasodilators (e.g., hydralazine);Hypolipidemic agents, such as HMG-CoA reductase inhibitors, such as simvastatin and lovastatin, which are in the form of lactone prodrugs as; and sold and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open-ring acid HMG-CoA reductase inhibitors, such as atorvastatin (especially the calcium salt sold), rosuvastatin (especially the calcium salt sold), pravastatin (especially the sodium salt sold), fluvastatin (especially the sodium salt sold), cerivastatin and pitavastatin; cholesterol absorption inhibitors such as ezetimibe and ezetimibe in combination with any other hypolipidemic agent such as the above HMG-CoA reductase inhibitors and especially with simvastatin or in combination with atorvastatin calcium; immediate-release or controlled-release forms of niacin, and / or in combination with HMG-CoA reductase inhibitors; niacin receptor agonists such as acipimox and acifran, and niacin receptor partial agonists; anti-cholesterol agents such as PCSK9 inhibitors (alirocumab, evolocumab, Nexletol TM (bempedoic acid, ACL inhibitor) and (Eicosapentaenoic acid ethyl ester); metabolic modifiers, including insulin and insulin analogs (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, including (i) β-klotho / FGFR1 activating monoclonal antibodies (e.g., MK-3655), pan-FGFR1-4 / KLB modulators, FGF19 analogs (e.g., Aldafermin) (ii) PPARγ agonists, such as glitazones (e.g., pioglitazone, AMG131, mitoglitazone, lobeglitazone, rosiglitazone, and balaglitazone) and other PPAR ligands, including (1) PPARα / γ dual agonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARα agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (2) selective PPARγ modulators (SPPARγM’s), (e.g., those disclosed in, for example, WO02 / 060388, WO02 / 08188, WO2004 / 019869, WO2004 / 020409, WO2004 / 020408, and WO2004 / 066963); (4) PPARγ partial agonists; (5) PPARα / δ dual agonists (e.g., Elafibranor); (iii) biguanides, such as metformin and its pharmaceutically acceptable salts, particularly metformin hydrochloride, and its sustained release formulations, such as Glumetza TM , Fortamet TM and GlucophageXR TM; and (iv) protein tyrosine phosphatase-IB (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, degludec insulin, insulin glargine, insulin lispro, and their inhalation formulations); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylureas and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide, and repaglinide); α-glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol); glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-2409021, and KT6-971); incretin analogs, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including their intranasal, transdermal, and once-weekly formulations), bile acid sequestrants (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of cross-linked dextran), acyl-CoA:cholesterol acyltransferase inhibitors (e.g., avasimibe); anti-obesity compounds; agents intended for inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKA) (e.g., AZD6370); 11β-hydroxysteroid dehydrogenase type 1 inhibitors (e.g., those disclosed in U.S. Patent No. 6,730,690 and LY-2523199);CETP inhibitors (such as anacetrapib, torcetrapib, and evacetrapib); inhibitors of fructose 1,6-bisphosphatase (such as those disclosed in, for example, U.S. Patent Nos. 6,054,587, 6,110,903, 6,284,748, 6,399,782, and 6,489,476); inhibitors of acetyl-CoA carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated protein kinase (AMPK) activators; other agonists of G protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (such as MBX2982 and PSN821), and (iii) GPR-40 (such as TAK875); SSTR3 antagonists (such as those disclosed in, for example, WO2009 / 001836); neuromedin U receptor agonists (such as those disclosed in, for example, WO2009 / 042053, including but not limited to neuromedin S (NMS)); SCD modulators (such as Aramchol); GPR-105 antagonists (such as those disclosed in, for example, WO2009 / 000087); glucose pathway modulators, such as SGLT inhibitors (such as ASP1941, SGLT-3, SGLT-2, such as empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, BI-10773, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); dual SGLT-1 / 2 inhibitors (such as licogliflozin); glucose-6-P dehydrogenase inhibitors (such as fluasterone); LAPS glucagon combination (such as HM14320); SGLT-1 inhibitors (such as SGL5213); acyl-CoA carboxylase inhibitors (ACC, MK-4074); inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); fatty acid synthase inhibitors; inhibitors of acyl-CoA:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR) agonists; ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; IL-1b antibodies (such as XOMA052 and canakinumab);Anti-fibrotic and / or anti-inflammatory agents (CCR2 / CCR5 dual receptor antagonists (e.g., cenicriviroc); galectin-3 inhibitors (e.g., belapectin, GB-1107, GB-1211), siRNA against HSP 47 (e.g., BMS-986263); NSAIDs derived from pirfenidone (e.g., hydronidone), A3AR agonists (e.g., namodenoson, FM101); TGFTX4 (e.g., nitazoxanide);5-lipoxygenase inhibitors (such as tipelukast), bifunctional urate inhibitors (such as ACQT1127), adiponectin receptor agonists (such as ALY688), TNF receptor antagonists (such as atrosimab), autotaxin inhibitors (such as BLD-0409, TJC0265, TJC0316), CCL24-blocking monoclonal antibodies (such as CM101), IL-11 inhibitors (such as ENx108A), LPA1 receptor antagonists (such as EPGN696), dual JAK1 / 2 inhibitors (such as EX76545), GPR antagonists (such as GPR91 antagonists), integrin avb1, avb3, and avb6 inhibitors (such as IDL2965), NLRP3 antagonists (such as IFM-514), inflammasome inhibitors (such as JT194, JT349), cell membrane permeability inhibitors (such as Larazotide), CCR5 antagonists (such as Ieronlimab), TNF inhibitors (such as LIVNate), integrin avβ6 inhibitors (such as MORFbeta6), NLRP inflammasome antagonists, siRNA (such as OLX701), dual TFGβ / Hedgehog inhibitors (such as Oxy200), GPR40 agonist / GPR84 antagonist (such as PBI-4547), neutrophil elastase inhibitors (such as PHP-303), integrin inhibitors (such as PLN-1474), TGFβ1 regulators (such as PRM-151), CCK receptor antagonists (such as proglumide), LOXL2 inhibitors (such as PXS-5338K, PXS-5382A), IL-11 inhibitors, MPY protein inhibitors (such as cGAS / STING antagonists), kinase-inhibiting RNase, membrane protein mAb, tumor necrosis factor inhibitors, NRF2 activators (such as SCO116), SSAO inhibitors (such as TERN201), TRAIL2 agonists (such as TLY012), IL-6 receptor antagonists (such as TZLS501), AOC3 inhibitors (such as UD-014), SSAO / VAP-1 inhibitors, TREM2); antioxidants (such as vitamin E); anti-inflammatory agents (such as norfloxacin, ciprofloxacin, ceftriaxone); blood coagulation regulators (such as anticoagulants, antiplatelets, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonists (such as tirzepetide);Dual GLP-1 / GRA agonists (e.g., cotadutide, ALT-801, DD 01, G49, PB-718); dual GLP-1 (e.g., CT 868); GLP-1 / GRA / GIP triple agonists (e.g., HM15211); GRP120 stimulator / inflammasome regulator / PPAR dual agonists (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW 003); selective thyroid hormone receptor-β agonists (e.g., resmetirom); apoptosis regulators (JNK-1 inhibitors (e.g., CC-90001), peroxidase inhibitors (e.g., AZM198), ASK-1 inhibitors (e.g., CS-17919, SRT 015)); erythropoietin stimulants (erythropoietin receptor agonists (e.g., cibinetide)); immunomodulators (TLR4 inhibitors (e.g., GBK-233), immunomodulatory polyclonal antibodies (e.g., IMM-124E), TLR4 antagonists (e.g., JKB-122), anti-CD3 monoclonal antibodies (e.g., foralumab), TLR4 antagonists (e.g., JKB 133), TLR4 inhibitors (e.g., mosedipimod), macrophage inhibitors targeting CD206 (e.g., MT2002), TLR2 / 4 antagonists (e.g., VB-201, VB-703), immunomodulatory polyclonal antibodies (e.g., IMM-124E)); incretin-based therapies (GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW 003), GLP-1 / glucagon dual receptor agonists (e.g., HM12525A), prandial insulin (e.g., ORMD 0801));Lipid regulators (AMPK activators / glutathione transferases (e.g., oltipraz), THR-β agonists (e.g., remeptin, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN 501), IBAT inhibitors (e.g., elobixibat, CJ 14199), ω-6-fatty acids (e.g., epeleuton), FASN inhibitors (e.g., TVB2640, FT 4101, FT 8225), ANGPTL3 inhibitors (e.g., vupanorsen), PNPLA3 inhibitors (e.g., AZD2693), RAS domain kinase inhibitors (e.g., BioE1115), NTCP inhibitors (e.g., bulevirtide), P2Y13 receptor agonists (e.g., CER-209), ω-3 fatty acids, HSD17β13 inhibitors;Metabolic regulators (FXR agonists (such as Ocaliva (obeticholic acid), IOT022), FGF19 recombinant variants (such as aldafermin), bispecific FGFR1 / KLB antibodies (such as BFKB8488A), mTOT regulators (such as MSDC-0602K), polyethylene glycolylated FGF21 analogs (such as pegbelfermin, BMS-986171), non-bile FXR agonists (such as cilofexor, EDP-305, EYP 001, tropifexor, MET409, AGN-242256, AGN-242266, EDP 297, HPG 1860, MET642, RDX023, TERN 101), ACC inhibitors (such as firsocostat, PF-05221304), hexokinase inhibitors (such as PF-06835919), AMPK activators (such as PXL770, MSTM 101, O304), bile acid regulators (such as Albiero), FGF21 analogs (such as BIO89-100), MOTSc analogs (such as CB4211), cyclophilin inhibitors (such as CRV 431), FGF19 (such as.DEL 30), mitochondrial uncouplers (such as GEN 3026), FXR / GPC dual agonists (such as INT-767), cysteamine derivatives (such as KB-GE-001), amylin and calcitonin dual receptor agonists (such as KBP-089), transient FXR agonists (such as M1217), anti-β-klotho (KLB)-FGFRlc receptor complex mAb (such as MK3655), GDF15 analogs (such as NGM395), cyclophilin inhibitors (such as NV556), LXR regulators (such as PX 329, PX 655, PX 788), LXR inverse agonists (such as PX016), deuterated obeticholic acid (such as ZG 5216)); PPAR regulators (dual PPARα / γ agonists (such as elafibranor), PPAR pan-agonists (such as lanifibranor), PPARα agonists (such as Parmodia), PPARγ agonists (such as CHS 131), MPC inhibitors (such as PXL065), PPARδ / γ agonists (such as T3D 959));RAAS mIM modulators (mineralocorticoid receptor antagonists (e.g., apararenone, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulators, CB1 receptor antagonists (e.g., CRB-4001, IM-102, nimacimab), TPH1 inhibitors (e.g., CU 02), GPR120 agonists (e.g., KBR2001), combinations of cannabinoids and phytocannabinoids (e.g., SCN 002)); PDE modulators (PDE4 inhibitors (e.g., ART 648)); CYP2E1 inhibitors (e.g., SNP-610); cell therapies (e.g., HepaStem) and bromocriptine mesylate and its immediate release formulations; or other drugs beneficial for the prevention or treatment of the above diseases including nitroprusside and diazoxide and free acids, free bases and pharmaceutically acceptable salt forms of the above active agents chemically feasible.;

[0380] The present invention includes pharmaceutically acceptable salts of the compounds defined herein, including pharmaceutically acceptable salts of all structural formulas, embodiments and classes defined herein. A reference to a compound of structural formula (I) includes other general structural formulas, such as compounds of formulas and embodiments falling within the scope of formula (I).

[0381] Dosage of the compound of formula (I)

[0382] If the patient responds or the condition stabilizes after completion of a treatment cycle, the treatment cycle may be repeated at the discretion of a skilled clinician. After completion of a treatment cycle, the patient may continue to receive the same dose of the compound of the present invention as administered in the treatment regimen. This maintenance dose may be continued until the patient's condition progresses or the dose is no longer tolerated (in which case the dose may be reduced and the patient may continue to take the reduced dose).

[0383] Those skilled in the art will recognize that the actual dosage and administration regimen employed in the methods disclosed herein may vary at the discretion of a skilled clinician. The actual dosage used may vary depending on the requirements of the patient and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is within the ability of those skilled in the art. A skilled clinician may decide to vary the dosage and administration regimen after considering factors such as the age, condition and size of the patient, as well as the severity of the condition being treated and the patient's response to the treatment.

[0384] The dosage regimen for using the compounds of the present invention is selected based on various factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound selected for administration; the route of administration; and the renal and hepatic function of the patient. In order to determine the therapeutically effective dose or prophylactically effective dose required to prevent, combat or arrest the progression of the condition, these factors can be fully considered by an ordinary clinician. It should be understood that a specific daily dose can simultaneously be a therapeutically effective amount (e.g., for treating a tumor condition) and a prophylactically effective amount (e.g., for preventing a tumor condition).

[0385] Although individual requirements vary, it is within the ability of those skilled in the art to determine the optimal range of the effective amount of the compounds of the present invention or their pharmaceutically acceptable salts, solvates, prodrugs or polymorphic forms. For example, for administration to humans in the therapeutic or prophylactic treatment of the conditions and disorders identified herein, a typical dose of the compounds of the present invention can be from about 0.05 mg / kg / day to about 50 mg / kg / day, such as at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, which can be, for example, from about 2.5 mg / day (0.5 mg / kg × 5 kg) to about 5000 mg / day (50 mg / kg × 100 kg). For example, the dose of the compound can be from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, from about 0.05 mg / kg / day to about 3 mg / kg / day, from about 0.07 mg / kg / day to about 3 mg / kg / day, from about 0.09 mg / kg / day to about 3 mg / kg / day, from about 0.05 mg / kg / day to about 0.1 mg / kg / day, from about 0.1 mg / kg / day to about 1 mg / kg / day, from about 1 mg / kg / day to about 10 mg / kg / day, from about 1 mg / kg / day to about 5 mg / kg / day, from about 1 mg / kg / day to about 3 mg / kg / day, from about 3 mg / day to about 500 mg / day, from about 5 mg / day to about 250 mg / day, from about 10 mg / day to about 100 mg / day, from about 3 mg / day to about 10 mg / day, or from about 100 mg / day to about 250 mg / day. Such doses can be administered as a single dose or can be divided into multiple doses.

[0386] Pharmaceutical composition

[0387] Compounds of formula I, formula Ib or formula Ic and their pharmaceutically acceptable salts, solvates, prodrugs and polymorphic forms can be administered to animals, preferably mammals, especially humans, either as the drug itself, in admixture with each other or in the form of a pharmaceutical composition. The terms "subject" or "patient" include animals, preferably mammals, especially humans, who use the active agents of the present invention to prevent or treat medical conditions.

[0388] Administering a compound of formula I, formula Ib or formula Ic or a pharmaceutically acceptable salt, solvate, prodrug or polymorphic form thereof to a subject includes self - administration and administration to the patient by another person. The subject may need or wish to treat an existing disease or medical condition, or may need or wish to receive prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a subject who "needs" treatment of an existing condition or prophylactic treatment includes both the need determined by a medical professional and the patient's desire for such treatment.

[0389] If the patient responds or is stable after completing a treatment cycle, the treatment cycle can be repeated at the discretion of a skilled clinician. After completing a treatment cycle, the patient can continue to take the compound of the present invention or a pharmaceutically acceptable salt, solvate, prodrug or polymorphic form thereof at the same dose as administered in the treatment regimen. This maintenance dose can be continued until the patient's condition progresses or the patient can no longer tolerate the dose (in which case the dose can be reduced and the patient can continue to take the reduced dose).

[0390] Those skilled in the art will recognize that the actual doses and administration regimens employed in the methods disclosed herein can vary according to the judgment of a skilled clinician. The actual dose used may vary according to the requirements of the patient and the severity of the condition being treated. Determining an appropriate dose for a particular situation is within the ability of those skilled in the art. A skilled clinician can decide to change the dose and administration regimen after considering factors such as the age, condition and body size of the patient, as well as the severity of the condition being treated and the patient's response to the treatment.

[0391] The dosage and frequency of administration of a compound of formula I, formula Ib or formula Ic and any additional medicaments will be adjusted according to the judgment of the attending clinician (physician) after considering factors such as the age, condition and body size of the patient, as well as the severity of the condition being treated.

[0392] The compounds of the present invention can also be used in the preparation of a medicament for treating NASH and fibrosis.

[0393] The compounds of the present invention can also be used in combination with therapeutic agents, chemotherapeutic agents, and anti-cancer agents for the treatment of hepatocellular carcinoma. Combinations of the presently disclosed compounds with therapeutic agents, chemotherapeutic agents, and anti-cancer agents are all within the scope of the present disclosure. Examples of such agents can be found in Cancer Principles and Practice of Oncology, 9th Edition (May 16, 2011), edited by V.T. DeVita and S. Hellman, published by Lippincott Williams & Wilkins. One of ordinary skill in the art can discern which combination of agents is useful based on the specific characteristics of the drug and the cancer involved. Such agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cell growth inhibitors, anti-proliferatives, isoprenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, cell proliferation and survival signaling inhibitors, bisphosphonates, aromatase inhibitors, siRNA therapeutic agents, gamma-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), and agents that interfere with cell cycle checkpoints.

[0394] The chemotherapeutic agents can be administered according to treatment regimens well known in the art. It will be apparent to those skilled in the art that the administration of chemotherapeutic agents can vary depending on the cancer being treated and the known effects of the chemotherapeutic agent on the disease. Moreover, based on the knowledge of a skilled clinician, the treatment regimen (e.g., dose and administration time) can be altered according to the observed effects of the administered therapeutic agent on the patient and according to the observed response of the cancer to the administered therapeutic agent. The specific choice of chemotherapeutic drugs will depend on the diagnosis of the attending physician and their judgment of the patient's condition and the appropriate treatment regimen.

[0395] The initial administration can be carried out according to established protocols known in the art, and then, based on the observed effects, the dose, mode of administration, and administration time can be modified by a skilled clinician.

[0396] After evaluating the condition being treated and the patient's status, a skilled physician is fully aware of the determination of the order of administration and the number of repetitions of administration of chemotherapeutic agents during the treatment regimen.

[0397] Therefore, based on experience and knowledge, a practicing physician can modify the regimen for each administration of chemotherapeutic drugs according to the needs of the individual patient as the treatment progresses. All such modifications are within the scope of the present disclosure.

[0398] The agent can be administered according to treatment regimens well-known in the art. It will be apparent to those skilled in the art that the administration of the anti-cancer agent can vary depending on the cancer being treated and the known effects of the anti-cancer agent on the disease.

[0399] The initial administration can be carried out according to established protocols known in the art, and then, based on the observed effects, the dose, mode of administration, and time of administration can be modified by a skilled clinician.

[0400] The specific choice of agent will depend on the diagnosis of the attending physician and their judgment of the patient's condition and the appropriate treatment regimen.

[0401] After evaluating the cancer being treated and the patient's condition, a skilled physician is fully aware of determining the order of administration and the number of administration repetitions during the treatment regimen.

[0402] Thus, based on experience and knowledge, a practicing physician can modify the regimen of each administered chemotherapeutic drug according to the needs of an individual patient as the treatment progresses. All such modifications are within the scope of the present disclosure.

[0403] When judging whether the treatment with the administered dose is effective, the attending physician will consider the patient's overall health condition and more specific signs, such as alleviating cancer-related symptoms (such as pain), inhibiting tumor growth, actual shrinkage of the tumor, or inhibiting metastasis. The size of the tumor can be measured by standard methods, such as radiological studies, such as CAT or MRI scans, and serial measurements can be used to judge whether the growth of the tumor has slowed down or even reversed. The alleviation of disease-related symptoms such as pain and the improvement of the overall condition can also be used to help judge the effectiveness of the treatment.

[0404] The compounds, compositions, and methods provided herein can be used to treat cancer. Cancers that can be treated by the compounds, compositions, and methods disclosed herein include, but are not limited to: Liver: Hepatocellular carcinoma (hepatoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

[0405] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL inhibitors include atezolizumab, avelumab, and durvalumab.

[0406] The present invention also relates to a method for treating hepatocellular carcinoma in a human patient, which comprises administering to the patient a compound of the present invention (i.e., a compound of formula I, formula Ib, or formula Ic) and a PD-1 antagonist. The compound of the present invention and the PD-1 antagonist can be administered simultaneously or sequentially.

[0407] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA TM , Merck & Co., Inc., Rahway, NJ, USA), nivolumab (OPDIVO TM , Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO TM , Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab (TECENTRIQ TM , Genentech, San Francisco, CA, USA), durvalumab (IMFINZI TM , AstraZeneca Pharmaceuticals LP, Wilmington, DE) or avelumab (BAVENCIO TM , Merck KGaA, Darmstadt, Germany).

[0408] In some embodiments, the PD-1 antagonist is pembrolizumab. In a specific sub-embodiment, the method comprises administering 200 mg of pembrolizumab to the patient approximately every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to the patient approximately every six weeks.

[0409] In a further sub-embodiment, the method comprises administering 2 mg / kg of pembrolizumab to the patient approximately every three weeks. In a specific sub-embodiment, the patient is a pediatric patient.

[0410] In some embodiments, the PD-1 antagonist is nivolumab. In a specific sub-embodiment, the method comprises administering 240 mg of nivolumab to the patient approximately every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to the patient approximately every four weeks.

[0411] In some embodiments, the PD-1 antagonist is cemiplimab. In a specific embodiment, the method comprises administering 350 mg of cemiplimab to the patient approximately every 3 weeks.

[0412] In some embodiments, the PD-1 antagonist is atezolizumab. In a specific sub-embodiment, the method comprises administering 1200 mg of atezolizumab to the patient approximately every three weeks.

[0413] In some embodiments, the PD-1 antagonist is durvalumab. In a specific sub-embodiment, the method comprises administering 10 mg / kg of durvalumab to the patient approximately every two weeks.

[0414] In some embodiments, the PD-1 antagonist is avelumab. In a specific sub-embodiment, the method comprises administering 800 mg of avelumab to the patient approximately every two weeks.

[0415] The compound of the invention or a pharmaceutically acceptable salt thereof can also be used in combination with the following therapeutic agents for the treatment of cancer: pembrolizumab abarelix (Plenaxis ),aldesleukin aldesleukin Alemtuzumabb alitretinoin allopurinol altretamine amifostine anastrozole arsenic trioxide asparaginase azacitidine bevacuzimab bexarotene capsules bexarotene gel bleomycin bortezomib busulfan intravenous injection oral busulfan calusterone capecitabine carboplatin carmustine carmustine carmustine with polifeprosan 20 implant (Gliadel ), celecoxib cetuximab chlorambucil cisplatin cladribine clofarabine cyclophosphamide cyclophosphamide (Cytoxan ), cyclophosphamide (Cytoxan ), cytarabine liposomal cytarabine dacarbazine dactinomycin, actinomycin D Darbepoetin alfa liposomal daunorubicin daunorubicin, doxorubicin daunorubicin, doxorubicin Denileukindiftitox dexrazoxane docetaxel doxorubicin (Adriamycin ), doxorubicin doxorubicin (Adriamycin PFS ), liposomal doxorubicin drostanolone propionate drostanolone propionate (Masterone ), Elliott B solution (Elliott's B ), epirubicin Epoetin alfa erlotinib estramustine etoposide phosphate etoposide, VP-16 exemestane Filgrastim floxuridine (intra-arterial) Fludarabine Fluorouracil, 5-FU Fulvestrant Gefitinib Gemcitabine Gemtuzumab Ozogamicin Goserelin Acetate (Zoladex ), Goserelin Acetate Histrelin Acetate (Histrelin ), Hydroxyurea Ibritumomab Tiuxetan Idarubicin Ifosfamide Imatinib Mesylate Interferon α2a (Roferon ), Interferon α-2b (Intron ), Irinotecan Lenalidomide Letrozole Leucovorin Leuprolide Acetate Levamisole Lomustine, CCNU Meclorethamine, Nitrogen Mustard Megestrol Acetate Melphalan, L-PAM Mercaptopurine, 6-MP Mesna Mesnex ), Methotrexate Methoxsalen Mitomycin C Mitotane Mitoxantrone Nandrolone phenpropionate Nelarabine Nofetumomab Oprelvekin Oxaliplatin Paclitaxel Paclitaxel Paclitaxel-binding protein particles Palifermin Pamidronate Pegademase (Adagen (Pegademase Bovine) ),Pegaspargase Pegfilgrastim Pemetrexed disodium Pentostatin Pipobroman Plicamycin, mithramycin Porfimer sodium Procarbazine Quinacrine Rasburicase Rituximab Ridaforolimus, sargramostim Sargramostim Sorafenib Streptozocin Sunitinib maleate Talc Tamoxifen Temozolomide Teniposide, VM-26 Testolactone Thioguanine, 6-TG Thiotepa Topotecan Toremifene Tositumomab Tositumomab / I-131 Tositumomab Trastuzumab Tretinoin, ATRA Uracil Mustard ), Valrubicin Vinblastine Vincristine Vinorelbine Vorinostat And zoledronate Or a pharmaceutically acceptable salt thereof.

[0416] Method for preparing the compound of the present invention

[0417] The following examples are provided to more fully understand the present disclosure. Unless otherwise noted, starting materials are commercially available. They should not be construed as limiting the invention in any way.

[0418] Several methods for preparing compounds of formula I or formula Ib are described in the following schemes and examples. Starting materials and intermediates are purchased, prepared by known procedures, or otherwise described. Some of the frequently used routes for preparing compounds of formula I, formula Ib, or formula Ic are also described by the following schemes. In some cases, the order of execution of the various steps in the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. For stereoisomers, enantiomer A refers to the enantiomer that elutes faster / earlier at the point of separation, while enantiomer B refers to the enantiomer that elutes slower / later at the point of separation, and for a given enantiomeric series, this nomenclature remains the same throughout the remaining synthetic sequence, regardless of whether subsequent intermediates and the final compound may have the same or opposite elution order.

[0419] List of abbreviations:

[0420] ACN / MeCN = Acetonitrile

[0421] aq. = Aqueous solution

[0422] ℃ = Degrees Celsius

[0423] B2Pin2 = Bis(pinacolato)diboron

[0424] Boc = tert-Butyloxycarbonyl

[0425] CatAXium A Pd G2 = Chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)

[0426] Cs2CO3 = Cesium carbonate

[0427] CuI = Copper(I) iodide

[0428] DCE = 1,2-Dichloroethane

[0429] DMF = N,N-Dimethylformamide

[0430] DCM = Dichloromethane

[0431] DIPEA = N,N-Diisopropylethylamine

[0432] DMSO = Dimethyl sulfoxide

[0433] dppf = 1,1'-Bis(diphenylphosphino)ferrocene

[0434] Et = Ethyl

[0435] EtOAc = Ethyl acetate

[0436] FA = Formic acid

[0437] RP HPLC = Reverse-phase high performance liquid chromatography

[0438] H or hrs = Hour or hours

[0439] HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0440] HCl = Hydrogen chloride

[0441] HPLC = High performance liquid chromatography

[0442] Hex = Hexane

[0443] IPA = Isopropyl alcohol

[0444] LCMS or LC / MS = Liquid chromatography mass spectrometry

[0445] K2CO3 = Potassium carbonate

[0446] K3PO4 = Potassium phosphate

[0447] KOAc = Potassium acetate

[0448] Me = Methyl

[0449] MeOH = Methanol

[0450] Mn(TMHD)3 = Manganese(III) tris(2,2,6,6 - tetramethyl - 3,5 - heptanedionate)

[0451] MnO2 = Manganese(IV) dioxide

[0452] MsCl = Methanesulfonyl chloride

[0453] NaCl = Sodium chloride

[0454] Na2CO3 = Sodium carbonate

[0455] Na2SO4 = Sodium sulfate

[0456] NBS = N - Bromosuccinimide

[0457] NFSI = N - Fluorobenzenesulfonimide

[0458] NIS = N - Iodosuccinimide

[0459] NMO = N - Methylmorpholine N - oxide

[0460] NMR = Nuclear magnetic resonance

[0461] Rt or RT = Room temperature

[0462] SFC = Supercritical fluid chromatography

[0463] THF = Tetrahydrofuran

[0464] TFA = Trifluoroacetic acid

[0465] TLC = Thin - layer chromatography

[0466] PE or pet. ether = Petroleum ether

[0467] PhSiH3 = Phenylsilane

[0468] Pd2(dba)3 = Tris(dibenzylideneacetone)dipalladium(0)

[0469] Pd(dppf)Cl2 = Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

[0470] Pd(PPh3)2Cl2 = Dichlorobis(triphenylphosphine)palladium(II)

[0471] RuPhos Pd G3 = (2 - Dicyclohexylphosphino - 2′,6′ - diisopropoxy - 1,1′ - biphenyl)[2 - (2′ - amino - 1,1′ - biphenyl)]palladium(II) methanesulfonate

[0472] XPhos Pd G2 = Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

[0473] Zn(OAc)2 = Zinc acetate

[0474] wt.% = Percentage by weight

[0475] x g = Multiple of gravity

[0476] % w / v = Percentage of the weight of the former reagent relative to the volume of the latter reagent.

[0477] Sat. = Saturated

[0478] Soln. = Solution

[0479] LCMS conditions: Column: ACQUITY UPLC-QDa BEH C18, 1.7 mm, 2.1 x 50 mm. Solvent system: A: Water 0.1% FA, B: ACN 0.1% FA

[0480] Gradient conditions: 10 - 90% B, within 1.7 min, total run time 2.4 min

[0481] General synthetic scheme

[0482] Except for the specific embodiments set forth below, many alternatives, modifications, and variations will be apparent to those of ordinary skill in the art. In some cases, the order of execution of steps in the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present disclosure.

[0483] General Scheme 1

[0484]

[0485] Compounds of Formula I, Formula Ib, and Formula Ic are prepared from 1-1 with R 1 -X via SN2, SNAr, or copper-mediated C-O coupling. Saponification of 1-2 provides the corresponding formic acid (1-3) and subsequent amide coupling with a suitable amine (R 2 -NH2) to give the compound of Formula (I) as described in the general scheme. For ease of synthesis, the order of steps in some embodiments can be varied.

[0486] Intermediate

[0487] Intermediate 1

[0488] 5-Chloro-3-(2,2-difluoroethoxy)-2-iodopyridine

[0489]

[0490] Step A: 5-Chloro-3-(2,2-difluoroethoxy)-2-iodopyridine

[0491] At 23 °C, 2,2-difluoroethyl trifluoromethanesulfonate (1.7 mL, 11.6 mmol) was added to a mixture of 5-chloro-2-iodopyridin-3-ol (2.7 g, 10.6 mmol) and K2CO3 (1.9 g, 13.7 mmol) in DMF (8.8 mL). After 1 h, the mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexanes) to give the title compound. LC / MS = 320 [M+1].

[0492] Using procedures similar to those described for INT-1, with appropriate reagents, the following intermediates were synthesized. These intermediates were characterized by LC / MS.

[0493]

[0494]

[0495] Intermediate 9

[0496] (5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate

[0497]

[0498] Step A: (5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol

[0499] At -78 °C, n-butyllithium solution (2.5 M in hexanes, 1.3 mL, 3.3 mmol) was added to a mixture of 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (0.88 g, 2.8 mmol) in toluene (15.3 mL). After 30 min, DMF (0.32 mL, 4.1 mmol) was added at -78 °C. After 1 h, methanol (3.1 mL) was added followed by sodium borohydride (0.21 g, 5.5 mmol) and the resulting mixture was warmed to 23 °C. After 20 min, the mixture was diluted with saturated aqueous NH4Cl and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layer was then dried over MgSO4(s), filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexanes) to give the title compound. LC / MS = 224 [M+1].

[0500] Step B: (5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate

[0501] At -78 °C, methanesulfonyl chloride (48.8 μL, 0.63 mmol) was added to a mixture of (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol (0.10 g, 0.45 mmol) and triethylamine (0.14 mL, 0.98 mmol) in DCM (2.2 mL). After 5 min, the mixture was warmed to 23 °C. After an additional 15 min, the mixture was diluted with saturated aqueous NaCl, and the aqueous layer was extracted once with DCM. The combined organic layers were dried over MgSO4(s), filtered, and concentrated in vacuo to afford the title compound. The crude product was used without further purification. LC / MS = 302 [M+1].

[0502] The following intermediates were synthesized using procedures analogous to those described for INT-9 with appropriate reagents. The intermediates were characterized by LC / MS.

[0503]

[0504] Intermediate 11

[0505] 3-(2,2,2-Trifluoroethoxy)pyridine 1-oxide

[0506]

[0507] Step A: 3-(2,2,2-Trifluoroethoxy)pyridine 1-oxide

[0508] At 23 °C, 3-chloroperoxybenzoic acid (2.18 g, 12.6 mmol) was added to a mixture of 3-(2,2,2-trifluoroethoxy)pyridine (1.86 g, 10.5 mmol) in DCM (21.0 mL). After 24 h, the mixture was diluted with saturated aqueous NaHCO3 and DCM, and the organic layer was washed with water and brine. The organic layer was then dried over MgSO4(s), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 10% methanol / DCM) to afford the title compound. LC / MS = 194 [M+1]. Example

[0509] The following experimental procedures detail the preparation of specific embodiments of the present disclosure. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.

[0510] Example 1

[0511] Example 1: N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0512]

[0513] Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate

[0514] To a stirred mixture of ethyl 5-bromopyrazolo[1,5-a]pyridine-2-carboxylate (2.00 g, 7.43 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (4.25 g, 16.72 mmol), Pd(dppf)Cl2 (272 mg, 372 μmol), and potassium acetate (2.19 g, 22.30 mmol) in 1,4-dioxane (74.3 mL) was added, and the reaction mixture was heated at 100 °C for 2 hrs. The reaction mixture was cooled to RT, water (535 μL, 29.7 mmol) and acetic acid (850 μL, 14.86 mmol) were charged, and the reaction mixture was stirred for 1 hour. Hydrogen peroxide (1.52 mL, 14.86 mmol) was added via syringe, and the reaction mixture was stirred for an additional 16 hours. The reaction mixture was heated at 35 °C for another 2 hrs, and then quenched with sodium thiosulfate (sat. aq. soln.). The crude mixture was dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel using a 0 - 7% methanol / DCM gradient to afford the title compound. LC / MS = 207 [M+1].

[0515] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate Step C: 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylic acid

[0516] To a stirred solution of ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate (600 mg, 2.91 mmol) and 3-(2,2,2-trifluoroethoxy)pyridine 1-oxide (590 mg, 3.06 mmol) in THF (14.5 mL) were added DIPEA (1.53 mL, 8.73 mmol) and tris(pyrrolidin-1-yl)phosphonium bromide hexafluorophosphate (V) (PyBROP) (1.76 g, 3.78 mmol). After 16 hours, the solvent was removed in vacuo, and the crude material was purified by flash column chromatography on silica gel using a 0 - 100% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 382 [M+1].

[0517] Lithium Step D: N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoro

[0518] At 20 °C, lithium hydroxide (37.3 mg, 1.56 mmol) was added to a stirred solution of ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (594 mg, 1.56 mmol) in acetonitrile (8.74 mL) and water (4.37 mL). After 30 minutes, the reaction mixture was concentrated in vacuo and the crude material was used in the subsequent reaction without further purification. LC / MS = 354 [M-5].

[0519] ethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate

[0520] HATU (445 mg, 1.17 mmol) was added to a stirred solution of lithium 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (400 mg, 1.11 mmol), DIPEA (584 μl, 3.34 mmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (234 mg, 1.17 mmol) in DMF (11.1 mL). After 18 hours, the solvent was removed in vacuo and the crude mixture was purified by flash column chromatography on silica gel using a 0-100% ethyl acetate / hexane gradient to give the title compound. LC / MS = 499 [M+1]. 1 1H NMR (500 MHz, DMSO-d6) δ 8.72 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 7.88 (dd, J = 4.8, 1.2 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 8.0, 4.8 Hz, 1H), 6.96–6.86 (m, 2H), 4.93 (q, J = 8.8 Hz, 2H), 3.09 (d, J = 11.6 Hz, 4H), 2.83 (d, J = 14.4 Hz, 2H), 2.03 (t, J = 10.6 Hz, 2H), 1.45 (s, 3H). Human DGAT2 IC 50 = 9.7 nM.

[0521] Using procedures similar to those described in Example 1 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0522]

[0523]

[0524]

[0525]

[0526] Example 19

[0527] Example 21: 3-Methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0528]

[0529] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate

[0530] To a stirred solution of methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (400 mg, 1.09 mmol) in DCE (3.63 mL) was added NIS (294 mg, 1.31 mmol), and the reaction mixture was stirred at 50 °C for 1 hr. The reaction mixture was subjected to flash column chromatography on silica gel using a 0 - 70% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 494 [M+1].

[0531] Step C: Lithium 3-methyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate Step D: 3-Methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoro

[0532] In a screw-cap bottle containing a magnetic stir bar at 20 °C, methyl 3-iodo-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (187 mg, 379 μmol), potassium trifluoro(methyl)-l4-borate (55.5 mg, 455 μmol), RuPhos Pd G3 (29.5 mg, 38 μmol) and Cs2CO3 (445 mg, 1.37 mmol) were charged with toluene (3.45 mL) and water (345 μl) under nitrogen. The reaction mixture was heated to 80 °C for 16 hrs. The reaction mixture was charged again with potassium trifluoro(methyl)-l4-borate (55.5 mg, 455 μmol), Cs2CO3 (445 mg, 1.37 mmol) and CatAXium A Pd G2 (25.4 mg, 38 μmol). The reaction mixture was heated to 80 °C for 16 hrs. The reaction mixture was cooled to RT, diluted with EtOAc, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was subjected to flash column chromatography on silica gel using a 0 - 60% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 382 [M+1].

[0533] ethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate

[0534] At 20 °C, lithium hydroxide (6.85 mg, 286 μmol) was added to a stirred solution of methyl 3-methyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (109 mg, 286 μmol) in THF (1.63 mL), methanol (817 μl), and water (408 μl). After 2 hrs, the reaction mixture was concentrated in vacuo to afford the crude title compound. LC / MS = 368 [M - 5].

[0535] Step B: Lithium 3-fluoro-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine- 2-carboxylate

[0536] HATU (32.1 mg, 84 μmol) was added to a stirred solution of lithium 3-methyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (30 mg, 80 μmol), DIPEA (35.1 μl, 0.20 mmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (16.05 mg, 80 μmol) in DMF (804 μl). After 18 hr, the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (40 - 95% MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 513 [M + 1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 7.6 Hz, 1H), 7.91 (s, 1H), 7.87–7.81 (m, 1H), 7.75–7.68 (m, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.24 (dd, J = 8.0, 4.9 Hz, 1H), 6.86 (dd, J = 7.5, 2.5 Hz, 1H), 4.93 (q, J = 8.8 Hz, 2H), 3.15–3.04 (m, 4H), 2.82 (d, J = 14.0 Hz, 2H), 2.38 (s, 3H), 2.07–1.98 (m, 2H), 1.46 (s, 3H). Human DGAT2 IC 50 = 7.2 nM.

[0537] Using a similar procedure as described in Example 19 with appropriate reagents, the following compounds were synthesized. The compounds were characterized by LC / MS.

[0538]

[0539] Example 21

[0540] Example 23: 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-

[0541] (4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0542]

[0543] Step C: 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,

[0544] At 0 °C, Selectfluor (186 mg, 524 μmol) was added in one portion to a stirred solution of methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (175 mg, 476 μmol) in acetonitrile (2.38 mL). After 1 h, the reaction mixture was warmed to 20 °C and stirred for an additional 4 h. The reaction mixture was filtered through a pad of SiO2, concentrated in vacuo, and purified by flash column chromatography on silica gel using a 0 - 80% ethyl acetate / hexane gradient to afford the desired white solid product. LC / MS = 386 [M+1]. TM At 20 °C, lithium hydroxide (4.60 mg, 192 μmol) was added to a stirred solution of methyl 3-fluoro-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (74 mg, 192 μmol) in acetonitrile (1.60 ml) and water (320 μl). After 30 minutes, the reaction mixture was concentrated in vacuo to give the crude title compound. LC / MS = 378 [M-5].

[0545] 1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide Step A:

[0546]

[0547] Step B: Step C:

[0548] ​At 20 °C, to a stirred solution of lithium 3-fluoro-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (19 mg, 50 μmol), DIPEA (22.00 μl, 126 μmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (10.06 mg, 50 μmol) in DMF (504 μl) was added HATU (20.11 mg, 53 μmol). After 18 hr, the reaction mixture was filtered and the filtrate was purified by reverse-phase HPLC (40 - 80% MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 517 [M+1]. 1 1H NMR (500 MHz, DMSO-d6) δ 8.64 (d, J = 7.6 Hz, 1H), 8.09 (s, 1H), 7.88 (dd, J = 4.8, 1.3 Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 7.28 (dd, J = 8.0, 4.8 Hz, 1H), 6.94 (dd, J = 7.6, 2.6 Hz, 1H), 4.93 (q, J = 8.8 Hz, 2H), 3.16–3.03 (m, 4H), 2.79 (d, J = 14.4 Hz, 2H), 2.03 (t, J = 11.0 Hz, 2H), 1.46 (s, 3H). Human DGAT2 IC 50 = 13 nM.

[0549] Using a similar procedure as described in Example 21 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0550]

[0551]

[0552]

[0553]

[0554]

[0555] Example 41

[0556] 3-Chloro-5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0557]

[0558] Step D: 5-Methoxy-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0559] To a stirred solution of 5-methoxypyrazolo[1,5-a]pyridine-2-carboxylic acid (2000 mg, 10.41 mmol), DIPEA (4544 μl, 26.0 mmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (2078 mg, 10.41 mmol) in DMF (52 mL) was added HATU (4155 mg, 10.93 mmol). After 18 hr, the solvent was removed in vacuo and the reaction mixture was subjected to silica gel flash column chromatography using a 0 - 100% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 338 [M+1].

[0560] Step E: 5-Hydroxy-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0561] To a stirred mixture of 5-methoxy-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (2.00 g, 5.93 mmol) and lithium chloride (2.51 g, 59.3 mmol) in NMP (11.9 mL) was added under a gentle nitrogen stream and the reaction mixture was heated to 160 °C. After 16 hr, the reaction mixture was poured into HCl (1 M aq. soln.) and extracted with DCM. The combined organic fractions were washed with HCl (1 M aq. soln.) and NaCl (sat. aq. soln.), dried over MgSO4, filtered and concentrated in vacuo. The crude residue was subjected to silica gel flash column chromatography using a 0 - 7% methanol / DCM gradient to afford the title compound. LC / MS = 324 [M+1].

[0562] Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate 5-((5-Bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0563] To a stirred solution of 5-hydroxy-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 309 μmol) and CsCO3 (252 mg, 773 μmol) in DMF (1.5 mL) was added 5-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (102 mg, 371 μmol), and the reaction mixture was heated at 60 °C for 16 hrs. The reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography on silica gel using a 0 - 80% EtOAc / hexanes gradient to afford the title compound. LC / MS = 577 [M+1].

[0564] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)-5-vinylpyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine- 5-((5-Cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0565] To a mixture of 5-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (85 mg, 147 μmol), zinc dicyanide (9.51 mg, 81 μmol) and Pd(PPh3)4 (17.01 mg, 15 μmol) in DMF (736 μl) was added, and the reaction mixture was heated at 80 °C for 16 hrs. The reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography on silica gel using a 0 - 80% EtOAc / hexanes gradient to afford the title compound. LC / MS = 524 [M+1].

[0566] 2-carboxylate 3-Chloro-5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0567] To a stirred solution of 5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (30 mg, 57 μmol) in DCE (287 μl) was added 1-chloropyrrolidine-2,5-dione (9.18 mg, 69 μmol), and the reaction mixture was stirred at 70 °C for 6 hrs. After cooling to RT, the reaction mixture was concentrated and purified by silica gel flash column chromatography using a 0 - 70% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 558 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.85 (d, J = 7.5 Hz, 1H), 8.37 (d, J = 1.7 Hz, 1H), 8.27–8.20 (m, 2H), 7.62 (d, J = 2.5 Hz, 1H), 7.11 (dd, J = 7.5, 2.5 Hz, 1H), 5.02 (q, J = 8.7 Hz, 2H), 3.18–3.03 (m, 4H), 2.76 (d, J = 14.6 Hz, 2H), 2.03 (t, J = 11.4 Hz, 2H), 1.47 (s, 3H). Human DGAT2 IC 50 = 5.0 nM.

[0568] Using a similar procedure as described in Example 41 with appropriate reagents, the following compounds were synthesized. The compounds were characterized by LC / MS.

[0569]

[0570] Example 43

[0571] 5-((5-(Cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0572]

[0573] Step C: Lithium 5-((3-(2,2,2-trifluoroethoxy)-5-vinylpyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-

[0574] To a stirred solution of ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate (300 mg, 1.46 mmol) and Cs2CO3 (1.19 g, 3.64 mmol) in DMF (7.3 mL) was added 5-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (598 mg, 2.18 mmol). The reaction mixture was heated to 60 °C for 16 hrs. The reaction mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography on silica gel using a 0 - 80% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 461 [M+1].

[0575] 2-carboxylate Step D: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate

[0576] At 20 °C, a stirred solution of ethyl 5-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (278 mg, 604 μmol), EtOH (4.0 mL) and triethylamine (126 μl, 906 μmol) was flushed with nitrogen for 15 minutes. The flask was charged with Pd(dppf)Cl2 (22.10 mg, 30 μmol), sealed and heated to 85 °C. After 16 hrs, the reaction was filtered through a pad of SiO2 and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel using a 0 - 90% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 408 [M+1].

[0577] ​ ​

[0578] To a stirred solution of ethyl 5-((3-(2,2,2-trifluoroethoxy)-5-vinylpyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (184 mg, 452 μmol) in acetonitrile (6.0 mL) and water (3.0 mL) was added lithium hydroxide (10.82 mg, 452 μmol). After 30 minutes, the reaction mixture was concentrated in vacuo to afford the crude title compound. LC / MS = 386 [M-5].

[0579] ​ ​

[0580] To a stirred solution of lithium 5-((3-(2,2,2-trifluoroethoxy)-5-vinylpyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (87 mg, 226 μmol), DIPEA (99 μl, 565 μmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (45.1 mg, 226 μmol) in DMF (2.3 mL) was added HATU (90 mg, 237 μmol). After 18 hr, the solvent was removed in vacuo and the crude mixture was purified by flash column chromatography on silica gel using a 0 - 80% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 525 [M+1].

[0581] Step E: 5-((5-Formyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1- dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0582] At 0 °C, to a stirred solution of N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)-5-vinylpyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (118 mg, 225 μmol), 2,6-lutidine (52.1 μl, 450 μmol), and potassium osmate(VI) tetrahydrate (2.1 mg, 5.62 μmol) in 1,4-dioxane (1.5 mL) and water (3.0 mL) was added sodium periodate (192 mg, 900 μmol). The reaction mixture was stirred at 20 °C for 3 hrs, then diluted with NaCl (sat. aq. soln.) and extracted with ethyl acetate. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using a 0 - 90% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 527 [M+1].

[0583] Step F: 5-((5-(Cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N- (4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0584] At 0 °C, to a stirred solution of 5-((5-formyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (20 mg, 38 μmol) in THF (380 μl) was added cyclopropylmagnesium bromide (228 μl, 114 μmol). After 6 hrs, the reaction mixture was quenched with NaHCO3 (sat. aq. soln.), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by reverse phase HPLC (20% MeOH / water with 0.1% FA modifier) to afford the title compound. 11H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J = 7.6 Hz, 1H), 7.99 (s, 1H), 7.87 (d, J = 1.5 Hz, 1H), 7.74 (s, 1H), 7.39 (d, J = 2.4 Hz, 1H), 6.94–6.87 (m, 2H), 5.42 (d, J = 4.4 Hz, 1H), 4.93 (q, J = 8.8 Hz, 2H), 4.01 (dd, J = 7.5, 4.5 Hz, 1H), 3.09 (d, J = 11.4 Hz, 4H), 2.83 (d, J = 14.4 Hz, 2H), 2.04 (d, J = 11.3 Hz, 2H), 1.45 (s, 3H), 1.16–1.07 (m, 1H), 0.56–0.33 (m, 4H). EX-43a (fast elution with IB-N column, 20% MeOH / CO2): LC / MS = 569 [M+1]. Human DGAT2 IC 50 = 228 nM. EX-43b (slow elution with IB-N column, 20% MeOH / CO2): LC / MS = 569 [M+1]. Human DGAT2 IC 50 > 9990 nM.

[0585] Using similar procedures as those described in Examples 43a and 43b, with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0586]

[0587]

[0588] Example 46

[0589] 3-Ethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0590]

[0591] Step A: Methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-vinylpyrazolo[1,5-a]py ridine-2-carboxylate

[0592] At 20 °C, a stirred solution of methyl 3-iodo-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (100 mg, 203 μmol), EtOH (1.35 mL), and triethylamine (42 μL, 304 μmol) was purged with nitrogen for 15 minutes. The flask was charged with Pd(dppf)Cl2 (7.42 mg, 10.14 μmol), sealed, and heated at 85 °C. After 16 hrs, the reaction mixture was filtered through a pad of SiO2 and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel using a 0 - 90% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 394 [M+1].

[0593] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate Ethyl ester

[0594] Under nitrogen, hydrogen (balloon) was added to a stirred solution of methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-vinylpyrazolo[1,5-a]pyridine-2-carboxylate (56 mg, 142 μmol) in ethanol (1.4 mL). The reaction mixture was purged with hydrogen for 3 minutes and stirred at 20 °C for 1 hr. The reaction mixture was purged with argon for 5 minutes, diluted with DCM, filtered through celite, and concentrated in vacuo to afford the title compound. LC / MS = 396 [M+1].

[0595] Step C: Lithium 3-ethyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]py ridine-2-carboxylate

[0596] To a stirred solution of methyl 3-ethyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (56 mg, 142 μmol) in acetonitrile (1.9 mL) and water (944 μL) was added lithium hydroxide (3.39 mg, 142 μmol). The reaction mixture was stirred at 40 °C and after 2 hrs, the reaction mixture was concentrated in vacuo to afford the crude title compound. LC / MS = 388 [M-5].

[0597] Step D: 3-Ethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoro ethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0598] To a stirred solution of lithium 3-ethyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (27 mg, 70 μmol), DIPEA (30.4 μl, 174 μmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (13.92 mg, 70 μmol) in DMF (697 μl) was added HATU (27.8 mg, 73 μmol). After 18 h, the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (30 - 70% MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 527 [M+1]. 1 1H NMR (500 MHz, DMSO-d6) δ 8.65 (d, J = 7.6 Hz, 1H), 7.93 (s, 1H), 7.84 (dd, J = 4.8, 1.2 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.24 (dd, J = 8.0, 4.9 Hz, 1H), 6.85 (dd, J = 7.6, 2.6 Hz, 1H), 4.93 (q, J = 8.8 Hz, 2H), 3.14–3.04 (m, 4H), 2.88 (q, J = 7.3 Hz, 2H), 2.82 (d, J = 14.1 Hz, 2H), 2.03 (dt, J = 14.7, 7.2 Hz, 2H), 1.46 (s, 3H), 1.13 (t, J = 7.4 Hz, 3H). Human DGAT2 IC 50 = 17 nM.

[0599] Using procedures similar to those described in Example 46 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0600]

[0601] Examples 49 and 50

[0602] 3-(Difluoromethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (EX-49) and 3-(hydroxymethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (EX-50)

[0603]

[0604] Step A: Methyl 3-formyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]py ridine-2-carboxylate

[0605] At 0 °C, sodium periodate (516 mg, 2.41 mmol) was added to a stirred solution of methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-vinylpyrazolo[1,5-a]pyridine-2-carboxylate (237 mg, 603 μmol), 2,6-dimethylpyridine (140 μl, 1.21 mmol), and potassium osmate tetrahydroxide (5.55 mg, 15 μmol) in 1,4-dioxane (4.0 mL) and water (8.0 mL). The reaction mixture was stirred at 20 °C and after 3 hrs, the reaction mixture was diluted with NaCl (sat. aq. soln.) and extracted with ethyl acetate. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using a 0 - 90% ethyl acetate / hexane gradient to give the title compound. LC / MS = 396 [M+1].

[0606] Step B: Methyl 3-(difluoromethyl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5- a]pyridine-2-carboxylate

[0607] At -70 °C, 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ 4 -sulfanylideneammonium (482 μl, 1.30 mmol) was added to a stirred solution of methyl 3-formyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (234 mg, 592 μmol) in DCM (973 μl). The reaction mixture was warmed to 20 °C and stirred for 1 hr. The reaction temperature was then raised to 40 °C. After 4 hrs, an additional portion of 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ 4 -sulfanylideneammonium (482 μl, 1.30 mmol) was added. After 12 hrs, a further five equivalents of 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ 4 -sulfanylideneammonium (2.41 mL, 6.51 mmol) were added via syringe. After 16 hrs, the reaction mixture was poured into ice and stirred for 20 minutes. The biphasic solution was extracted with DCM, dried over Na2SO4 and Na2CO3, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using a 0 - 70% ethyl acetate / hexane gradient to give the desired product. LC / MS = 418 [M+1].

[0608] Step C: Lithium 3-(difluoromethyl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5- a]pyridine-2-carboxylate

[0609] At 20 °C, lithium hydroxide (9.58 mg, 400 μmol) was added to a stirred solution of methyl 3-(difluoromethyl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (167 mg, 400 μmol) in THF (2.3 mL), MeOH (1.1 mL) and water (572 μl). After 30 minutes, the LCMS reaction mixture was concentrated in vacuo to afford the title compound. LC / MS = 410 [M-5].

[0610] Step D: 3-(Difluoromethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2, 2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (EX-52) and 3-formyl-N-(4- methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyraz olo[1,5-a]pyridine-2-carboxamide

[0611] HATU (32.0 mg, 84 μmol) was added to a stirred solution of lithium 3-(difluoromethyl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (32.8 mg, 80 μmol), DIPEA (35.0 μl, 200 μmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (16.01 mg, 80 μmol) in DMF (802 μl). After 18 hr, the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (50-98% MeCN / water with 0.1% FA modifier) to afford the title compound (EX-49: LC / MS = 549 [M+1]. Human DGAT2 IC 50 = 973 nM and aldehyde by-product (LC / MS = 527 [M+1]).

[0612] Step E: 3-(Hydroxymethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2, 2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0613] Sodium borohydride (1.9 mg, 50 μmol) was added to a stirred solution of 3-formyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (12.6 mg, 24 μmol) in methanol (239 μl). After 1 hr, the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (40-95% MeCN / water with 0.1% FA modifier) to afford the title compound (EX-50). LC / MS = 511 [M-18]. 1HNMR (500 MHz, acetonitrile-d3) δ 8.47 (d, J = 7.6 Hz, 1H), 7.88 (dd, J = 4.8, 1.4 Hz, 1H), 7.55 (dd, J = 8.0, 1.3 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.21 (dd, J = 8.0, 4.9 Hz, 1H), 6.86 (dd, J = 7.6, 2.6 Hz, 1H), 4.81 (s, 2H), 4.67 (q, J = 8.5 Hz, 2H), 4.31 (s, 1H), 3.24–3.13 (m, 2H), 2.98 (d, J = 14.4 Hz, 2H), 2.85 (d, J = 15.0 Hz, 2H), 1.57 (s, 3H). Human DGAT2 IC 50 = 10 nM.

[0614] Example 51

[0615] N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0616]

[0617] Step A: Methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5- a]pyridine-2-carboxylate

[0618] To a stirred solution of methyl 3-iodo-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (150 mg, 304 μmol) and copper(I) iodide (87 mg, 456 μmol) in N-methyl-2-pyrrolidone (3.0 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (116 μl, 912 μmol), and the reaction mixture was heated to 110 °C. After 1 h, the solvent was removed in vacuo. The crude residue was purified by flash column chromatography on silica gel using a 0–80% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 436 [M+1].

[0619] Step B: Lithium 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5- a]pyridine-2-carboxylate

[0620] At 40 °C, lithium hydroxide (6.88 mg, 0.287 mmol) was added to a stirred solution of methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate (125 mg, 287 μmol) in acetonitrile (3.8 mL) and water (1.9 mL). After 30 minutes, the reaction mixture was concentrated in vacuo to afford the title compound. LC / MS = 428 [M - 5].

[0621] Step C: N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy) pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0622] At 20 °C, HATU (29.0 mg, 76 μmol) was added to a stirred solution of lithium 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate (31 mg, 73 μmol), DIPEA (31.7 μl, 181 μmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (14.49 mg, 73 μmol) in DMF (726 μl). After 18 hr, the reaction mixture was filtered and the filtrate was purified by reverse phase HPLC (60 - 90% MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 567 [M + 1]. 1 1H NMR (500 MHz, DMSO-d6) δ 8.96 (d, J = 7.6 Hz, 1H), 8.45 (s, 1H), 7.90 (dd, J = 4.8, 1.3 Hz, 1H), 7.78 (dd, J = 8.1, 1.2 Hz, 1H), 7.39 (s, 1H), 7.32 (dd, J = 8.0, 4.8 Hz, 1H), 7.15 (dd, J = 7.6, 2.5 Hz, 1H), 4.94 (q, J = 8.8 Hz, 2H), 3.09 (s, 4H), 2.71 (d, J = 13.7 Hz, 2H), 2.02 (dt, J = 14.9, 7.7 Hz, 2H), 1.45 (s, 3H). Human DGAT2IC 50 = 828 nM.

[0623] Example 52

[0624] 3-(1-Hydroxyethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0625]

[0626] Step A: Methyl 3-(prop-1-en-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo [1,5-a]pyridine-2-carboxylate

[0627] At 20°C, a stirred mixture of methyl 3-iodo-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (221 mg, 448 μmol), EtOH (3.0 mL), and TEA (94 μL, 672 μmol) was purged with nitrogen for 15 minutes. The vial was charged with Pd(dppf)Cl2 (16 mg, 22 μmol) and heated to 85°C. After 16 hours, the reaction was filtered through a pad of SiO2 and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel using a 0-80% ethyl acetate / hexane gradient to provide the title compound. LC / MS = 408 [M+1].

[0628] Step B: Lithium 3-(prop-1-en-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo [1,5-a]pyridine-2-carboxylate

[0629] To a stirred solution of methyl 3-(prop-1-en-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (182 mg, 448 μmol) in acetonitrile (6.0 mL) and water (3.0 mL) at 40°C was added lithium hydroxide (10.73 mg, 448 μmol). After 2 hours, the reaction mixture was concentrated in vacuo to provide the title compound. LC / MS = 394 [M-5].

[0630] Step C: N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-3-(prop-1-en-2-yl)-5-((3- (2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0631] To a stirred solution of lithium 3-(prop-1-en-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (179 mg, 448 μmol), DIPEA (196 μl, 1.12 mmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (89 mg, 448 μmol) in DMF (4.5 mL) at 20°C was added HATU (179 mg, 470 μmol). After 18 hours, volatiles were removed in vacuo, and the reaction mixture was purified by silica gel flash column chromatography using a 0-70% ethyl acetate / hexane gradient to provide the title compound. LC / MS = 539 [M+1].

[0632] Step D: 3-Acetyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-tri fluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide

[0633] At 0 °C, sodium periodate (238 mg, 1.11 mmol) was added to a stirred solution of N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-3-(prop-1-en-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (150 mg, 279 μmol), 2,6-dimethylpyridine (64.5 μl, 557 μmol), and potassium osmate tetroxide dihydrate (2.57 mg, 6.96 μmol) in 1,4-dioxane (1.9 mL) and water (3.7 mL). The mixture was warmed to 20 °C and after 3 hrs, the reaction mixture was diluted with NaCl (sat. aq. soln.) and extracted with ethyl acetate. The combined organic fractions were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using a 0 - 90% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 541 [M+1].

[0634] Step E: 3-(1-Hydroxyethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2, 2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (Peak 2)

[0635] At 20 °C, NaBH4 (5.88 mg, 155 μmol) was added to a stirred solution of 3-acetyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (40 mg, 74 μmol) in methanol (740 μl). After 1 h, the reaction mixture was quenched with NaHCO3, dried over MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel using a 0 - 100% EtOAc / hexane gradient to afford the crude racemic compound. Chiral resolution by SFC gave the title compound. 1 1H NMR (500 MHz, DMSO-d6) δ 8.67 (d, J = 7.6 Hz, 1H), 8.21 (s, 1H), 7.86 (d, J = 3.5 Hz, 1H), 7.73 (d, J = 7.0 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 8.0, 4.8 Hz, 1H), 6.89 (dd, J = 7.6, 2.6 Hz, 1H), 5.48–5.37 (m, 2H), 4.93 (q, J = 8.7 Hz, 2H), 3.10 (d, J = 3.9 Hz, 4H), 2.79 (s, 2H), 2.04 (dd, J = 14.8, 6.9 Hz, 2H), 1.46 (s, 3H), 1.40 (d, J = 6.2 Hz, 3H).

[0636] EX-52a (rapid elution with AD-H column, 25% MeOH / CO2): LC / MS = 525 [M-18]. Human DGAT2 IC 50 = 1588 nM.

[0637] EX-52b (slow elution with AD-H column, 25% MeOH / CO2). LC / MS = 525 [M-18]. Human DGAT2 IC 50 = 333 nM.

[0638] Example 53

[0639] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(2-hydroxy-2-methylpropyl)-N-

[0640] (4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0641]

[0642] Step A: 5-Bromo-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2- carboxamide

[0643] To a mixture of 5-bromopyrazolo[1,5-a]pyridine-2-carboxylic acid (1.4 g, 5.81 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide dihydrochloride (1.65 g, 6.97 mmol), and DIEA (5.07 mL, 29.0 mmol) in DMF (25 mL) was added HATU (3.31 g, 8.71 mmol). The reaction was stirred at 25 °C for 0.5 h, poured into NH4Cl (300 mL, sat. aq. soln.), and extracted with DCM (100 mL x 3). The combined organic layers were washed with NaCl (100 mL, sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using a 0-80% ethyl acetate / petroleum ether gradient to afford the title compound. LC / MS = 386 [M+1].

[0644] Step B: 5-Hydroxy-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine- 2-carboxamide

[0645] A mixture of 5-bromo-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (2 g, 5.18 mmol), B2Pin2 (3.2 g, 12.60 mmol), KOAc (1.85 g, 18.85 mmol) and Pd(dppf)Cl2 (0.379 g, 518 μmol) in 1,4-dioxane (50 mL) was degassed and backfilled with N2 (three times). The mixture was heated at 90 °C for 13 hrs. After cooling to RT, the mixture was filtered and concentrated in vacuo. The crude (2-((4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)carbamoyl)pyrazolo[1,5-a]pyridin-5-yl)boronic acid (1.82 g, 5.18 mmol) and NMO (1.83 g, 15.62 mmol) in THF (45 mL) was degassed and backfilled with N2 gas (3x). Under N2, the mixture was heated at 80 °C for 3 hrs. The mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using a 0 - 40% ethyl acetate / petroleum ether gradient to afford the title compound. LC / MS = 324 [M+1].

[0646] Step C: 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0647] In a glove box, CuI (71 mg, 373 μmol) was added to a mixture of 5-hydroxy-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (600 mg, 1.86 mmol), 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (670 mg, 2.09 mmol), picolinic acid (54 mg, 439 μmol) and picolinic acid (54 mg, 439 μmol) in DMSO (7 mL). The reaction mixture was stirred at 80 °C. After 15 hrs, the reaction mixture was washed with NH4Cl (100 mL, sat. aq. soln.) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with NaCl (10 mL, sat. aq. soln.), dried over Na2SO4, filtered. The filtrate was concentrated and the crude residue was subjected to flash column chromatography on silica gel using a 0 - 40% EtOAc gradient to afford the title compound. LC / MS = 517 [M+1].

[0648] Step D: 3-Bromo-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1, 1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0649] At 25 °C, NBS (197 mg, 1.11 mmol) was added to a mixture of 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (440 mg, 852 μmol) in THF (10 mL). After 2 h, the reaction mixture was quenched with Na2SO3 (sat. aq. soln.) (30 mL), followed by extraction with EtOAc (30 mL x 3). The combined organic layers were washed with brine (15 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel flash column chromatography using a 0 - 45% EtOAc / petroleum ether gradient to afford the title compound. LC / MS = 597 [M+1].

[0650] Step E: 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-diox otetrahydro-2H-thiopyran-4-yl)-3-(2-methylprop-1-en-1-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0651] Under a N2 atmosphere, Pd(dppf)Cl2 (13 mg, 18 μmol) was added to a mixture of 3-bromo-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 168 μmol), 4,4,5,5-tetramethyl-2-(2-methylprop-1-en-1-yl)-1,3,2-dioxaborolane (62 mg, 341 μmol) and Na2CO3 (54 mg, 509 μmol) in 1,4-dioxane (4 mL) and H2O (0.4 mL). The reaction mixture was stirred at 100 °C. After 5 h, the mixture was poured into sat. NH4Cl (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (7 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using a 0 - 55% ethyl acetate / petroleum ether gradient at 30 mL / min to afford the title compound. LC / MS = 571 [M+1].

[0652] Step F: 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(2-hydroxy-2-methylprop yl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0653] A mixture of 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-3-(2-methylprop-1-en-1-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (40 mg, 70 μmol), Mn(TMHD)3 (10 mg, 17 μmol) and PhSiH3 (40 mg, 0.37 mmol) in DCM (0.5 mL) / i-PrOH (5 mL) was stirred at 30 °C under O2 (15 psi). After 14 h, MeCN (1 mL) was added and the mixture was purified by filtration and reverse phase HPLC (35 - 65% MeCN / water with 10 mM NH4HCO3 modifier) to give the title compound. LC / MS = 589 [M+1]. 1 1H NMR (500 MHz, methanol-d4) δ 8.55 (d, J = 7.63 Hz, 1H), 7.79 (d, J = 2.29 Hz, 1H), 7.64 (dd, J = 2.14, 9.00 Hz, 1H), 7.34 (d, J = 2.14 Hz, 1H), 6.87 (dd, J = 2.21, 7.55 Hz, 1H), 4.74 (q, J = 8.34 Hz, 2H), 3.34 - 3.36 (m, 1H), 3.30 (br s, 1H), 3.11 (s, 2H), 3.03 (br d, J = 13.58 Hz, 2H), 2.90 (brd, J = 14.50 Hz, 2H), 2.21 (br t, J = 13.66 Hz, 2H), 1.57 (s, 3H), 1.22 (s, 6H). Human DGAT2 IC50 = 368 nM.

[0654] Example 54

[0655] 3-Cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0656]

[0657] Step A: 5-Bromo-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2- carboxamide

[0658] Under N2 atmosphere, RuPhos (33 mg, 71 μmol) was added to a stirred mixture of 3-bromo-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (200 mg, 336 μmol), 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (300 mg, 1.79 mmol) and Cs2CO3 (328 mg, 1.01 mmol) in toluene (4 mL) and H2O (0.4 mL). Under N2, the reaction mixture was stirred at 100 °C for 10 hrs. The mixture was concentrated in vacuo and purified by reverse phase HPLC (60 - 80% MeCN / water with 0.1% TFA modifier) to give the title compound. 1 1H NMR (500 MHz, MeCN-d3) δ 8.42 (d, J = 7.63 Hz, 1H), 7.78 (d, J = 2.44 Hz, 1H), 7.46 (dd, J = 2.44, 9.16 Hz, 1H), 7.28 (d, J = 2.44 Hz, 1H), 7.06 (brs, 1H), 6.76 (dd, J = 2.52, 7.55 Hz, 1H), 4.68 (q, J = 8.29 Hz, 2H), 3.12 - 3.23 (m, 2H), 2.94 - 3.03 (m, 2H), 2.78 - 2.90 (m, 2H), 2.15 - 2.21 (m, 3H), 1.55 (s, 3H), 0.92 - 0.98 (m, 2H), 0.72 - 0.78 (m, 2H). LC / MS = 557 [M+1]. Human DGAT2 IC 50 = 48 nM.

[0659] Example 55

[0660] 3-Amino-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0661]

[0662] Step A: 5-Bromo-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2- carboxamide

[0663] At 0 °C, potassium nitrate (12 mg, 119 μmol) was added to a mixture of 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (40 mg, 77 μmol) in H2SO4 (0.5 mL). The mixture was stirred for 2 h. At 0 °C, the mixture was poured into sat. Na2CO3 (40 mL), stirred at 0 °C for 0.2 h, and extracted with DCM (15 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by Pre-TLC (SiO2, ethyl acetate / petroleum ether = 2;1) to give the title compound. LC / MS = 562 [M+1].

[0664] Step B: 3-Amino-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl- 1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0665] Under an N2 atmosphere, Pd-C (5 mg, 47 μmol) and ammonium hydroxide solution (0.1 mL, 27 μmol) were added to 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-3-nitropyrazolo[1,5-a]pyridine-2-carboxamide (15 mg, 27 μmol) in EtOAc (5 mL). The mixture was degassed and backfilled with H2 three times. The resulting mixture was stirred at 25 °C under H2 (15 psi). After 1 h, the mixture was filtered, the filtrate was concentrated in vacuo, and the residue was purified by reverse-phase HPLC (60 - 80% MeCN / water with 0.1% TFA modifier) to give the title compound. LC / MS = 532 [M+1]. 1 1H NMR (500 MHz, methanol-d4) δ 8.63 (br d, J = 7.17 Hz, 1H), 7.85 (d, J = 2.59 Hz, 1H), 7.70 (dd, J = 2.59, 9.00 Hz, 1H), 7.39 (br s, 1H), 7.00 (br d, J = 7.02 Hz, 1H), 4.76 (q, J = 8.34 Hz, 2H), 3.25 - 3.32 (m, 2H), 3.05 (br d, J = 14.04 Hz, 2H), 2.95 (br d, J = 14.80 Hz, 2H), 2.19 - 2.30 (m, 2H), 1.59 (s, 3H). Human DGAT2 IC 50 = 16 nM.

[0666] Example 56

[0667] 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0668]

[0669] Step A: 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a] pyridine-2-carboxylic acid

[0670] A mixture of NFSI (319 mg, 1.012 mmol), Pd2(dba)3 (30.9 mg, 34 μmol), methyl 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (130 mg, 337 μmol) and EtOAc (5 mL) was stirred at 80 °C for 12 hrs. The reaction mixture was concentrated in vacuo and purified by prep-HPLC (TFA conditions) to give the title compound. LC / MS = 404 [M+1].

[0671] Step B: 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a] pyridine-2-carboxylic acid

[0672] To a mixture of water (1 mL) / MeOH (1.0 mL) of methyl 4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (11 mg, 27 μmol) was added LiOH (3 mg, 125 μmol). The reaction mixture was stirred at 20 °C for 1 h, dissolved in H2O and treated with HCl (1N aq. soln.) to pH = 4. The mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with NaCl (20 mL, sat. aq. soln.), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. LC / MS = 390 [M+1].

[0673] Step C: 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1, 1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0674] A mixture of DIPEA (22 μL, 128 μmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (6 mg, 37 μmol), 4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylic acid (10 mg, 26 μmol), and HATU (18 mg, 47 μmol) in DMF (1 mL) was stirred at 20 °C for 2 h. The residue was purified by reverse-phase HPLC (43-63% MeCN / water with 0.1% FA modifier) to give the title compound. LC / MS = 535 [M+1]. 1 HNMR (400 MHz, methanol-d4) δ 8.50 (br d, J = 7.58 Hz, 1H), 7.99 (br s, 1H), 7.66 (d, J = 2.20 Hz, 1H), 7.64 - 7.67 (m, 1H), 7.59 (dd, J = 2.32, 8.93 Hz, 1H), 7.57 - 7.61 (m, 1H), 7.57 - 7.61 (m, 1H), 7.11 (s, 1H), 6.96 (br t, J = 7.34 Hz, 1H), 4.74 (br d, J = 8.31 Hz, 2H), 3.22 - 3.23 (m, 1H), 3.23 (br d, J = 14.18 Hz, 1H), 3.01 (br d, J = 13.69 Hz, 1H), 2.98 - 3.04 (m, 1H), 2.89 (br d, J = 14.92 Hz, 2H), 2.17 - 2.24 (m, 2H), 1.54 (s, 3H). Human DGAT2 IC 50 = 20 nM.

[0675] Example 57

[0676] 6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0677]

[0678] Step A: 4-(Benzyloxy)-2-bromofluoropyridine

[0679] At 0 °C, NaH (60% in oil) (0.156 g, 3.91 mmol) was added to a stirred solution of 2-bromo-5-fluoropyridin-4-ol (0.5 g, 2.60 mmol) in DMF (7 mL). After 30 minutes, (bromomethyl)benzene (0.464 mL, 3.91 mmol) was added and the mixture was warmed to 25 °C. After 2 hours, the reaction mixture was poured into NH4Cl (70 mL, sat. aq. solution) and extracted with DCM (3 x 50 mL). The combined organic layers were washed with NaCl (100 mL, sat. aq. soln.), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using a 0 - 30% EtOAc / petroleum ether gradient to give the title compound. LC / MS = 282.0 and 284.0 [M+H].

[0680] Step B: 4-(Benzyloxy)-5-fluoro-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)py ridine

[0681] In a glove box, CuI (15 mg, 79 μmol) was added to a stirred solution of 4-(benzyloxy)-2-bromo-5-fluoropyridine (100 mg, 0.35 mmol), tetrahydro-2-(2-propynyloxy)-2H-pyran (100 mg, 0.71 mmol), Pd(PPh3)2Cl2 (50 mg, 71 μmol), and TEA (75 mg, 0.74 mmol) in THF (3 mL). The reaction mixture was heated to 70 °C. After 10 hrs, the reaction mixture was poured into NH4Cl (20 mL, sat. aq. soln.) and extracted with DCM (3 x 15 mL). The combined organic layers were washed with NaCl (10 mL, sat. aq. soln.), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using a 0 - 20% EtOAc / petroleum ether gradient to give the title compound. LC / MS = 342.1 [M+H].

[0682] Step C: 1-Amino-4-(benzyloxy)-5-fluoro-2-(3-hydroxyprop-1-yn-1-yl)pyridin-1-ium 2,4,6- trimethylbenzenesulfonate

[0683] To a stirred solution of O-(2,4,6-trimethylbenzenesulfonyl)hydroxylamine) (1.706 g, 7.93 mmol) in DCM (25 mL) was added 4-(benzyloxy)-5-fluoro-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (1.7 g, 4.98 mmol). After 15 hrs, the reaction mixture was concentrated under reduced pressure to give the crude title compound. LC / MS = 273.1 [M+H].

[0684] Step D: (5-(Benzyloxy)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)methanol

[0685] To a stirred solution of 1-amino-4-(benzyloxy)-5-fluoro-2-(3-hydroxyprop-1-yn-1-yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (2.3 g, 4.87 mmol) in DMF (20 mL) was added K2CO3 (4.04 g, 29.2 mmol). After 15 h, the mixture was poured into NH4Cl (200 mL, sat. aq. soln.), and extracted with DCM (50 mL x 3). The combined organic layers were washed with NaCl (40 mL, sat. aq. soln.), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using a 0 - 40% EtOAc / petroleum ether gradient to afford the title compound. LC / MS = 273.1 [M+H].

[0686] Step E: 6-Fluoro-2-(hydroxymethyl)pyrazolo[1,5-a]pyridin-5-ol

[0687] Under N2, to a stirred mixture of (5-(benzyloxy)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)methanol (180 mg, 0.66 mmol) in MeOH (5 mL) and DCM (5 mL) was added Pd - C (50 mg, 0.47 mmol). The mixture was degassed and backfilled with H2 (three times), and then heated to 45 °C under H2 (15 psi). After 1 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (40 - 70% MeCN / water with 0.1% TFA modifier) to afford the title compound. LC / MS = 183.1 [M+H].

[0688] Step F: (6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a] pyridin-2-yl)methanol

[0689] To a stirred solution of K3PO4 (175 mg, 0.82 mmol), picolinic acid (20 mg, 0.16 mmol), 6-fluoro-2-(hydroxymethyl)pyrazolo[1,5-a]pyridin-5-ol (50 mg, 0.27 mmol), and 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (132 mg, 0.41 mmol) in DMSO (2 mL) was added CuI (11 mg, 58 μmol). The reaction mixture was heated to 95 °C. After 15 h, the mixture was filtered, and the filtrate was purified by reverse-phase HPLC (40 - 70% MeCN / water with 0.1% TFA modifier) to afford the title compound. LC / MS = 376.0 [M+H].

[0690] Step G: 6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a] pyridine-2-carbaldehyde

[0691] At 25 °C, MnO2 (17 mg, 0.20 mmol) was added to a stirred solution of (6-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridin-2-yl)methanol (10 mg, 27 μmol) in CHCl3 (1.5 mL). After 1 h, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude title compound. LC / MS = 374.0 [M+H].

[0692] Step H: 6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a] pyridine-2-carboxylic acid

[0693] At 25 °C, KH2PO4 (1 mg, 7.35 μmol) in water (1 mL) and NaClO2 (3 mg, 33 μmol) in water (2 mL) were successively added to a stirred solution of 6-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carbaldehyde (8 mg, 21 μmol) in DMSO (3 mL). After 1 h, the mixture was poured into H2O (10 mL) and lyophilized to give the crude title compound. LC / MS = 390.0 [M+H].

[0694] Step I: 6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1, 1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0695] At 25 °C, HATU (15.63 mg, 41 μmol) was added to a stirred solution of 6-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylic acid (8 mg, 21 μmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide dihydrochloride (10 mg, 42 μmol) and DIPEA (18 μl, 103 μmol) in DMF (2.5 mL). After 30 min, the reaction mixture was filtered and the residue was purified by reverse-phase HPLC (40 - 70% MeCN / water with 0.1% TFA modifier) to give the title compound. LC / MS = 535.1 [M+1]. 1 1H NMR (400 MHz, methanol-d4) δ 8.87 (d, J = 5.48 Hz, 1H), 7.72 (d, J = 2.50 Hz, 1H), 7.64 (dd, J = 2.44, 9.00 Hz, 1H), 7.60 (d, J = 7.87 Hz, 1H), 7.04 (s, 1H), 4.78 (q, J = 8.34 Hz, 2H), 3.22 - 3.30 (m, 2H), 2.99 - 3.10 (m, 2H), 2.85 - 2.97 (m, 2H), 2.18 - 2.30 (m, 2H), 1.57 (s, 3H). Hu DGAT2 IC50 = 1.8 nM.

[0696] Example 58

[0697] 5 - ((5 - Fluoro - 3 - (2,2,2 - trifluoroethoxy)pyridin - 2 - yl)oxy)-4 - methyl - N - (4 - methyl - 1,1 - dioxotetrahydro - 2H - thiopyran - 4 - yl)pyrazolo[1,5 - a]pyridine - 2 - carboxamide

[0698]

[0699] Step A: 4-Chloro-3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine

[0700] In a glove box at 25 °C, to a stirred solution of 2 - bromo - 4 - chloro - 3 - methylpyridine (2 g, 9.69 mmol), 2 - (prop - 2 - yn - 1 - yloxy)tetrahydro - 2H - pyran (2.04 g, 14.53 mmol) and TEA (2.70 mL, 19.37 mmol) in THF (20 mL) was added Pd(PPh3)2Cl (0.68 g, 0.97 mmol) and CuI (0.18 g, 0.97 mmol). The reaction was then sealed and stirred at 60 °C for 16 hrs. The crude product was extracted with EtOAc (40 mL×3) and washed with H2O (50 ml). The combined organic layers were washed with (40 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue purified by flash chromatography on silica gel, eluting with a 13% EtOAc / hexane gradient to give the title compound. LC / MS = 266 [M + 1].

[0701] Step B: 1-Amino-4-chloro-3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1- yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate

[0702] At 0 °C, 4 - chloro - 3 - methyl - 2 - (3 - ((tetrahydro - 2H - pyran - 2 - yl)oxy)prop - 1 - yn - 1 - yl)pyridine (1.5 g, 5.64 mmol) was added to a mixture of O - (2,4,6 - trimethylbenzenesulfonyl)hydroxylamine in DCM (15 mL) (2.048 g, 9.51 mmol). The mixture was then stirred at 20 °C for 15 hrs. The mixture was diluted with MTBE (80 mL). The precipitated crystals were collected by filtration and dried in vacuo to give the title compound for direct use in the next step. LC / MS = 281 [M + + 1].

[0703] Step C: (5-Chloro-4-methylpyrazolo[1,5-a]pyridin-2-yl)methanol

[0704] To a stirred solution of 1-amino-4-chloro-3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (2.0 g, 2.08 mmol) in DMF (20 mL) was added K2CO3 (0.58 g, 4.16 mmol). After 15 hrs, the crude product was extracted with EtOAc (50 mL × 3), washed with H2O (80 mL) and brine (80 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by prep-TLC (SiO2, petroleum ether / EtOAc = 1 / 1) and further purified by reverse-phase column chromatography with 40% MeCN to give the title compound. LC / MS = 197 [M+1].

[0705] Step D: 5-Chloro-4-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde

[0706] To a stirred solution of (5-chloro-4-methylpyrazolo[1,5-a]pyridin-2-yl)methanol (170 mg, 0.87 mmol) in CHCl3 (5 mL) was added manganese(IV) dioxide (1.13 g, 12.97 mmol), and the mixture was heated to 60 °C. After 15 hrs, the mixture was filtered and concentrated to give the title compound. LC / MS = 195 [M+1].

[0707] Step E: 5-Chloro-4-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid

[0708] To a stirred solution of 5-chloro-4-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde (170 mg, 0.87 mmol) in DMSO (2 ml) was added a solution of KH2PO4 (36 mg, 0.27 mmol) in water (0.5 mL) and a solution of NaClO2 (118 mg, 1.31 mmol) in water (1.5 mL). After 15 hrs, the reaction mixture was diluted with 15 mL of water, the pH was adjusted to 10 with NaOH (2 M aq. soln.), the mixture was washed with EtOAc (20 mL × 3), the pH was then adjusted to 4 with HCl (1 N aq. soln.), and the mixture was extracted with EtOAc (20 ml × 3). The combined organic layers were washed with brine (30 ml), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. LC / MS = 211 [M+1].

[0709] Step F: 5-Chloro-4-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a] pyridine-2-carboxamide

[0710] To a stirred solution of 5-chloro-4-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid (170 mg, 0.81 mmol), HATU (460 mg, 1.21 mmol) and DIPEA (0.42 mL, 2.42 mmol) in DMF (3 mL) was added 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (193 mg, 0.97 mmol). After 1 h, the crude product was extracted with EtOAc (20 mL × 3) and washed with H2O (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on SiO2 using EtOAc to give the title compound. LC / MS = 356 [M+1].

[0711] Step G: 4-Methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0712] Under a N2 atmosphere, to a mixture of 5-chloro-4-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (250 mg, 0.70 mmol), B2Pin2 (268 mg, 1.05 mmol), potassium acetate (207 mg, 2.11 mmol) in 1,4-dioxane (2 mL) was added XPhos Pd G2 (55.3 mg, 70 μmol). The mixture was stirred at 85 °C for 12 h. The crude product was extracted with EtOAc (20 mL × 3) and washed with H2O (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using 50% EtOAc / hexanes to give the title compound. LC / MS = 448 [M+1].

[0713] Step H: 5-Hydroxy-4-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5- a]pyridine-2-carboxamide

[0714] At 20 °C, NaBO3·4H2O (114 mg, 1.07 mmol) was added to a suspension of 4-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (160 mg, 0.36 mmol) in THF (2 mL) and water (2 mL). After 3 hrs, the crude product was extracted with EtOAc (20 mL × 3) and washed with H2O (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and filtered. The residue obtained by concentrating the filtrate was purified by prep-TLC (SiO2, petroleum ether / EtOAc = 0 / 1) to give the title compound. LC / MS = 338 [M+1].

[0715] Step I: 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methyl-N-(4-methyl- 1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0716] In a glove box, copper(I) iodide (5 mg, 0.026 mmol) was added to a solution of 5-hydroxy-4-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (80 mg, 0.24 mmol), 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (114 mg, 0.36 mmol), dimethylglycine (5 mg, 0.048 mmol), and K3PO4 (151 mg, 0.711 mmol) in DMSO (2 mL). The reaction mixture was stirred at 95 °C for 15 hrs. The residue obtained by filtering the mixture was purified by reverse-phase HPLC (10 - 90% MeCN / water with 0.1% TFA modifier) to give the title compound. LC / MS = 531 [M+1]. 1 H NMR (400 MHz, methanol-d4) δ 8.46 (d, J = 7.39 Hz, 1H), 7.66 (d, J = 2.50 Hz, 1H), 7.59 (dd, J = 2.44, 9.00 Hz, 1H), 7.04 (br s, 1H), 6.80 (d, J = 7.39 Hz, 1H), 4.76 (q, J = 8.34 Hz, 2H), 3.24 - 3.30 (m, 2H), 3.00 - 3.04 (m, 2H), 2.89 - 2.92 (m, 2H), 2.33 (s, 3H), 2.17 - 2.26 (m, 2H), 1.56 (s, 3H), 1.55 - 1.57 (m, 1H). Human DGAT2 IC 50 = 6.6 nM.

[0717] Example 59

[0718] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0719]

[0720] Step A: 4-Bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine

[0721] In a glove box, TEA (3.89 mL, 27.9 mmol) was added to a stirred solution of 2,4-dibromo-6-methylpyridine (3.5 g, 13.95 mmol), 2-((ethynyloxy)methyl)tetrahydro-2H-pyran (2.35 g, 16.74 mmol), Pd(PPh3)2Cl2 (979 mg, 1.40 μmol), and CuI (266 mg, 1.40 mmol) in THF (40 mL). The reaction mixture was heated to 80 °C. After 16 hrs, the crude product was extracted with EtOAc (50 mL × 3) and washed with H2O (40 ml). The combined organic layers were washed with brine (40 ml), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel using a 0 - 20% EtOAc / petroleum ether gradient to give the title compound. LC / MS = 325 [M].

[0722] Step B: 1-Amino-4-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl) pyridin-1-ium 2,4,6-trimethylbenzenesulfonate

[0723] At 0 °C, O-(2,4,6-trimethylbenzenesulfonyl)hydroxylamine (341 mg, 1.57 mmol) in DCM (15 mL) was added to a stirred mixture of 4-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (200 mg, 645 μmol). Subsequently, the reaction mixture was warmed to 15 °C. After 15 hrs, the mixture was concentrated to give the title compound. LC / MS = 310 [M+1].

[0724] Step C: (5-Bromo-7-methylpyrazolo[1,5-a]pyridin-2-yl)methanol

[0725] At 0 °C, K2CO3 (656 mg, 4.75 mmol) was added to a stirred solution of 1-amino-4-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (832 mg, 1.583 mmol) in DMF (3 mL). The mixture was warmed to 15 °C. After 15 hrs, water (20 mL) was added and the mixture was extracted with EtOAc (30 mL). The combined organic fractions were washed with brine (20 mL), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by Prep-TLC (1:1 petroleum ether / EtOAc) to give the title compound. LC / MS = 241 [M+1].

[0726] Step D: 5-Bromo-7-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde

[0727] MnO2 (72.1 mg, 0.83 mmol) was added to a stirred solution of (5-bromo-7-methylpyrazolo[1,5-a]pyridin-2-yl)methanol (10 mg, 41 μmol) in CHCl3 (2 mL) and the reaction mixture was heated to 60 °C. After 15 hrs, the mixture was filtered and concentrated to give the title compound. LC / MS = 239 [M+1].

[0728] Step E: 5-Bromo-7-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid

[0729] At 15 °C, an aqueous solution (0.1 mL) of KH2PO4 (2 mg, 15 μmol) was added to a stirred solution of 5-bromo-7-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde (9 mg, 38 μmol) in DMSO (0.4 mL), followed by an aqueous solution (0.3 mL) of NaClO2 (5 mg, 55 μmol). After 15 hrs, the reaction mixture was diluted with water and the pH was adjusted to 10 with NaOH (2N aq. soln.). The mixture was washed with EtOAc (2 ml × 3), the pH was adjusted to 4 with HCl (1N aq. soln.), and the resulting solution was extracted with EtOAc (2 ml × 3). The combined organic layers were washed with brine (3 mL), dried over Na2SO4, filtered, and concentrated to give the title compound. LC / MS = 255 [M+1].

[0730] Step F: 5-Bromo-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a] pyridine-2-carboxamide

[0731] At 20 °C, DIPEA (2.26 mL, 12.94 mmol) was added to a stirred solution of 5-bromo-7-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid (1.1 g, 4.31 mmol), HATU (2.46 g, 6.47 mmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (1.1 g, 6.74 mmol) in DMF (20 mL). After 30 minutes, water (100 mL) was added to the solution, and the mixture was extracted with EtOAc (150 mL). The combined organic fractions were washed with brine (120 mL), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 100% EtOAc to give the title compound. LC / MS = 401 [M+1].

[0732] Step G: 7-Methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0733] An 8 mL tube was charged with 5-bromo-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (1.45 g, 3.62 mmol), B2Pin2 (1.84 g, 7.24 mmol), KOAc (1.067 g, 10.87 mmol) and Pd(dppf)Cl2 (265 mg, 362 μmol) in 1,4-dioxane (40 mL) and bubbled with a stream of N2 for 2 min. The tube was sealed and heated to 100 °C. After 3 h, the mixture was cooled to RT, water (10 mL) was added, and the mixture was extracted with EtOAc (15 mL). The combined organic fractions were washed with brine (15 mL), dried (Na2SO4), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with a 0 - 30% EtOAc / petroleum ether gradient to give the title compound.

[0734] Step H: 5-Hydroxy-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5- a]pyridine-2-carboxamide

[0735] At 15 °C, NaBO3·4H2O (1.10 g, 10.33 mmol) was added to a suspension of 7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (1.54 g, 3.44 mmol) in THF (10 mL) and water (10 mL). The mixture was stirred at 15 °C for 2 hrs. The crude product was extracted with EtOAc (20 mL × 3) and washed with H2O (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give the title compound using 100% EtOAc.

[0736] Step I: 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl- 1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0737] In a glove box, CuI (3 mg, 16 μmol) was added to a stirred solution of 5-hydroxy-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (50 mg, 0.15 mmol), 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (95 mg, 296 μmol), K2CO3 (61.4 mg, 445 μmol) and N,N-dimethylglycine (3 mg, 29 μmol) in DMSO (2 mL), and the mixture was heated to 90 °C. After 12 hrs, the mixture was purified by reverse phase HPLC (42-62% MeCN / water with 0.1% FA modifier) to give the title compound. LC / MS = 531 [M+1].

[0738] 1 H NMR (400 MHz, methanol-d4) δ 7.81 (d, J = 2.50 Hz, 1H), 7.64 (dd, J = 2.50, 9.06 Hz, 1H), 7.21 (d, J = 2.38 Hz, 1H), 6.97 (s, 1H), 6.81 (d, J = 1.55 Hz, 1H), 4.73 (q, J = 8.34 Hz, 2H), 3.23 - 3.32 (m, 2H), 3.05 (br d, J = 13.83 Hz, 2H), 2.94 (br d, J = 14.66 Hz, 2H), 2.80 (s, 3H), 2.18 - 2.32 (m, 2H), 1.59 (s, 3H). Human IC 50 = 6.0 nM.

[0739] Example 60

[0740] 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0741]

[0742] Step A: 4-Chloro-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine

[0743] Under N2 atmosphere, Pd(PPh3)2Cl2 (866 mg, 1.23 mmol) and CuI (235 mg, 1.23 mmol) were added to a stirred solution of 2,4-dichloro-5-methylpyridine (2.00 g, 12.34 mmol), 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (2.25 g, 16.05 mmol), and TEA (3.44 mL, 24.69 mmol) in THF (25 mL), and the reaction mixture was heated to 60 °C. After 16 hrs, the crude product was extracted with EtOAc (40 mL × 3), washed with H2O (50 ml) and NaCl (40 mL sat. aq. soln.), dried over Na2SO4, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel using 10% EtOAc / hexane to give the title compound. LC / MS = 266 [M+1].

[0744] Step B: 1-Amino-4-chloro-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl) pyridin-1-ium 2,4,6-trimethylbenzenesulfonate

[0745] At 0 °C, 4-chloro-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (480 mg, 1.806 mmol) was added to a stirred solution of O-(2,4,6-trimethylbenzenesulfonyl)hydroxylamine in DCM (15 mL) (1.706 g, 0.00 mmol), and the reaction mixture was heated to 15 °C. After 15 hrs, the mixture was concentrated to give the crude title compound. LC / MS = 281 [M].

[0746] Step C: (5-Chloro-6-methylpyrazolo[1,5-a]pyridin-2-yl)methanol

[0747] At 20 °C, to a stirred solution of 1-amino-4-chloro-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate (3.81 g, 7.92 mmol) in DMF (10 mL) was added K2CO3 (2.19 g, 15.84 mmol). After 15 h, the crude product was extracted with EtOAc (40 mL × 3), washed with H2O (80 mL) and NaCl (50 mL sat. aq. soln.), dried over Na2SO4, filtered, and the residue obtained by concentration was purified by reverse-phase HPLC (10 - 90% MeCN / water with 0.1% TFA modifier) to give the title compound. LC / MS = 197 [M+1].

[0748] Step D: 5-Chloro-6-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde

[0749] To a stirred solution of (5-chloro-6-methylpyrazolo[1,5-a]pyridin-2-yl)methanol (45 mg, 229 μmol) in CHCl3 (3 mL) was added MnO2 (398 mg, 4.58 mmol), and the mixture was stirred at 60 °C. After 15 hrs, the mixture was filtered, and the filtrate was concentrated to give the title compound. LC / MS = 195 [M+1].

[0750] Step E: 5-Chloro-6-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid

[0751] 5-Chloro-6-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde (35 mg, 180 μmol) was dissolved in DMSO (2 mL). To an aqueous solution (0.5 mL) was added KH2PO4 (8 mg, 59 μmol), followed by an aqueous solution (1.5 mL) of sodium chlorite (25 mg, 276 μmol). The resulting mixture was stirred at 15 °C. After 2 h, the reaction was diluted with water (15 mL), the pH was adjusted to 10 with NaOH (2M aq. soln.), and the mixture was washed with EtOAc (20 mL × 3). The pH of the aqueous layer was adjusted to 4 with HCl (1N aq. soln.), and the mixture was extracted with EtOAc (20 mL × 3). The combined organic layers were washed with NaCl (30 mL sat. aq. soln.), dried over Na2SO4, filtered, and concentrated to give the title compound. LC / MS = 211 [M+1].

[0752] Step F: 5-Chloro-6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a] pyridine-2-carboxamide

[0753] To a stirred solution of 5-chloro-6-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid (30 mg, 142 μmol), HATU (81 mg, 214 μmol) and DIPEA (75 μL, 427 μmol) in DMF (1 mL) was added 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (34.1 mg, 171 μmol). The mixture was stirred at 15 °C. After 1 h, the crude product was extracted with EtOAc (20 mL × 3), washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered. The residue obtained by concentrating the filtrate was purified by prep-TLC (SiO2, petroleum ether / EtOAc = 1 / 1) to give the title compound. LC / MS = 356 [M+1].

[0754] Step G: 6-Methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetra methyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0755] Under N2 atmosphere, to a mixture of 5-chloro-6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (30 mg, 84 μmol), B2Pin2 (32 mg, 126 μmol), potassium acetate (25 mg, 255 μmol) in 1,4-dioxane (2 mL) was added XPhos Pd G2 (7 mg, 8.90 μmol). The mixture was stirred at 85 °C for 12 h. The crude product was extracted with EtOAc (20 mL × 3), washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered. The residue obtained by concentrating the filtrate was purified by prep-TLC (SiO2, petroleum ether / EtOAc = 1 / 2) to give the title compound. LC / MS = 448 [M+1].

[0756] Step H: 5-Hydroxy-6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5- a]pyridine-2-carboxamide

[0757] To a suspension of 6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (25 mg, 56 μmol) in THF (1 mL) and water (1 mL) was added NaBO3·4H2O (18 mg, 169 μmol). The mixture was stirred at 15 °C. After 1 hour, the crude product was extracted with EtOAc (20 mL × 3), washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The residue obtained by concentrating the filtrate was purified by prep-TLC (SiO2, petroleum ether / EtOAc = 0 / 1) to give the title compound. LC / MS = 338 [M+1].

[0758] Step I: 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-6-methyl-N-(4-methyl- 1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide

[0759] In a glove box, to a stirred solution of 5-hydroxy-6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (15 mg, 44 μmol), 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (22 mg, 69 μmol), dimethylglycine (1 mg, 9.70 μmol), and K3PO4 (28 mg, 132 μmol) in DMSO (1 mL) was added CuI (2 mg, 10.50 μmol), and the reaction mixture was heated to 100 °C. After 15 hrs, the mixture was cooled to RT, and the residue obtained by filtration was purified by reverse-phase HPLC (10 - 90% MeCN / water with 0.1% FA modifier) to give the title compound. LC / MS = 531 [M+1]. 1 1H NMR (500 MHz, methanol-d4) δ 8.50 (s, 1H), 7.78 - 7.80 (m, 1H), 7.64 (dd, J = 2.44, 9.16 Hz, 1H), 7.20 (s, 1H), 6.85 (s, 1H), 4.73 (q, J = 8.24 Hz, 2H), 3.23 - 3.30 (m, 2H), 3.00 - 3.03 (m, 2H), 2.87 - 2.90 (m, 2H), 2.25 (s, 3H), 2.17 - 2.24 (m, 2H), 1.55 (s, 3H). Human DGAT2 IC 50 = 3.5 nM.

[0760] Example 61

[0761] 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0762]

[0763] Step A: 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyrimidine-2- carboxylic acid

[0764] To a stirred solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (240 mg, 1.16 mmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (152 mg, 463 μmol), CuI (55 mg, 290 μmol), and K3PO4 (615 mg, 2.90 mmol) in DMSO (5.8 mL) was added 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (777 mg, 2.43 mmol), and the reaction mixture was heated to 90 °C. After 16 h, the reaction mixture was diluted with EtOAc (50 mL) and filtered through Celite. The solution was then washed twice with LiCl (1 N aq. soln.) and NaCl (sat. aq. soln.), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel using a 0 - 100% ethyl acetate / hexane gradient to afford the title compound. LC / MS = 399 [M+1].

[0765] Step B: 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyrimidine-2- carboxylic acid

[0766] At 20 °C, lithium hydroxide (13.66 mg, 0.571 mmol) was added to a stirred solution of ethyl 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyrimidine-2-carboxylate (182 mg, 0.456 mmol) in acetonitrile (3043 μl) and water (1521 μl). After 30 min, the solvent was removed in vacuo to afford the title compound. LC / MS = 371 [M+1].

[0767] Step C: 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxo tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0768] To a stirred solution of lithium 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyrimidine-2-carboxylate (169 mg, 449 μmol), DIPEA (235 μL, 1.35 mmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (94 mg, 471 μmol) in DMF (4.5 μL) was added HATU (179 mg, 471 μmol). After 18 h, the reaction mixture was filtered and the solvent removed in vacuo. The crude residue was purified by SiO2 flash column chromatography using 0 - 100% ethyl acetate / hexanes to afford the title compound. LC / MS = 516 [M+1].

[0769] Step D: 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1- dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0770] At 0 °C, to a stirred solution of 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (86 mg, 167 μmol) in acetonitrile (833 μL) was added a single portion of Selectfluor TM (70.9 mg, 200 μmol). After 1 h, the reaction mixture was warmed to RT and stirred for an additional 24 hrs. The reaction mixture was filtered through a pad of silica gel, concentrated in vacuo, purified by silica gel flash column chromatography using a 0 - 60% ethyl acetate / hexanes gradient, and subsequently by reverse phase HPLC (35 - 70% MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 534 [M+1]. 1 1H NMR (500 MHz, DMSO-d6) δ 9.11 (d, J = 7.7 Hz, 1H), 8.17 (s, 1H), 8.11 (d, J = 2.1 Hz, 1H), 8.04 (d, J = 2.1 Hz, 1H), 7.10 (d, J = 7.5 Hz, 1H), 6.22 (t, J = 53.9 Hz, 1H), 4.47 (td, J = 14.7, 3.2 Hz, 2H), 3.08 (s, 4H), 2.76 (d, J = 13.9 Hz, 2H), 2.03 (d, J = 9.6 Hz, 2H), 1.44 (s, 3H). Human DGAT2 IC 50 = 133 nM.

[0771] The following compounds were synthesized using similar procedures as described in Example 61 with the appropriate reagents. The compounds were characterized by LC / MS.

[0772]

[0773] Example 63

[0774] 7 - ((5 - chloro - 3 - (2,2,2 - trifluoroethoxy)pyridin - 2 - yl)oxy)-N-(4 - methyl - 1,1 - dioxotetrahydro - 2H - thiopyran - 4 - yl)-[1,2,4]triazolo[1,5 - a]pyridine - 2 - carboxamide

[0775]

[0776] Step A: 1,2-Diamino-4-(benzyloxy)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate

[0777] At 20 °C, 4 - (benzyloxy)pyridin - 2 - amine (0.64 g, 3.17 mmol) was added to a mixture of O-(2,4,6 - trimethylbenzenesulfonyl)hydroxylamine in DCM (10 mL) (0.68 g, 3.17 mmol). After 15 hrs, the reaction mixture was concentrated under reduced pressure to give the crude title compound. LC / MS = 216 [M+1]

[0778] Step B: Ethyl 7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0779] Ethyl oxalyl chloride (866 mg, 6.34 mmol) was added to a stirred solution of 1,2 - diamino - 4 - (benzyloxy)pyridin - 1 - ium 2,4,6 - trimethylbenzenesulfonate (1.32 g, 3.17 mmol) in pyridine (20 mL), and the reaction mixture was heated to 100 °C. After two hours, the mixture was poured into Na2CO3 (sat. aq. soln.) (70 mL), and extracted three times with DCM (70 mL). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, using a 0 - 80% ethyl acetate / petroleum ether gradient, to give the title compound. LC / MS = 298 [M+1]

[0780] Step C: Ethyl 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0781] At 25 °C, triethylsilane (1.34 mL, 8.41 mmol) was added dropwise to a stirred solution of 7 - (benzyloxy)-[1,2,4]triazolo[1,5 - a]pyridine - 2 - carboxylate (500 mg, 1.68 mmol), TEA (938 μL, 6.73 mmol), and PdCl2 (149 mg, 841 μmol) in THF (9 mL). After 2 hours, the reaction mixture was filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel, using a 0 - 90% ethyl acetate / petroleum ether gradient, to give the title compound. LC / MS = 208 [M+1]

[0782] Step D: Ethyl 7-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5- a]pyridine-2-carboxylate

[0783] In a glove box, CuI (46.0 mg, 241 μmol) was added to a stirred solution of ethyl 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (250 mg, 1.21 mmol), 2-bromo-5-chloro-3-(2,2,2-trifluoroethoxy)pyridine (456 mg, 1.57 mmol), 1,10-phenanthroline (43.5 mg, 241 μmol), and K2CO3 (500 mg, 3.62 mmol) in DMSO (4 mL). The reaction mixture was heated to 100 °C. After 12 hrs, the mixture was cooled to RT, dried, filtered, and the filtrate was purified by reverse-phase HPLC (43 - 73% ACN / 10 mM NH4HCO3) to give the title compound. LC / MS = 417 [M+1]

[0784] Step E: 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5- a]pyridine-2-carboxylic acid

[0785] To a stirred solution of ethyl 7-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (100 mg, 240 μmol) in MeOH (8 mL) and H2O (0.4 mL) was added LiOH (30 mg, 714 μmol). After 13 hrs, the reaction mixture was concentrated under reduced pressure to give the crude title compound. LC / MS = 389 [M+1]

[0786] Step F: 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxo tetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0787] To a stirred solution of 7-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (30 mg, 77 μmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide dihydrochloride (22 mg, 93 μmol), and HATU (44.0 mg, 116 μM) in DMF (1 mL) was added DIPEA (67 μL, 386 μmol). The mixture was stirred at 25 °C. After 30 minutes, MeCN (1 mL) was added. The mixture was filtered and the filtrate was purified by reverse-phase HPLC (60 - 80% MeCN / water with 0.1% FA modifier) to give the title compound. LCMS = 534 [M+1]. 11H NMR (400 MHz, methanol-d4) δ 8.84 (d, J = 7.58 Hz, 1H), 7.91 (d, J = 2.20 Hz, 1H), 7.81 (d, J = 1.96 Hz, 1H), 7.49 (d, J = 2.20 Hz, 1H), 7.19 (dd, J = 2.45, 7.58 Hz, 1H), 4.74 (q, J = 8.31 Hz, 2H), 3.25 (br d, J = 2.45 Hz, 2H), 3.02 (br d, J = 13.94 Hz, 2H), 2.89 (br d, J = 14.43 Hz, 2H), 2.15 - 2.28 (m, 2H), 1.56 (s, 3H). Human DGAT2IC 50 = 349 nM.

[0788] Using similar procedures as described in Example 63 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0789]

[0790]

[0791] [[ID=

[14] ]]Example 67

[0792] 5 - ((5 - Chloro - 3 - (2,2 - difluoroethoxy)pyridin - 2 - yl)methoxy)-N-(4 - methyl - 1,1 - dioxotetrahydro - 2H - thiopyran - 4 - yl)pyrazolo[1,5 - a]pyrimidine - 2 - carboxamide

[0793]

[0794] Step A: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)pyrazolo[1,5-a]pyrimidine- 2-carboxylic acid

[0795] At 0 °C, (5 - chloro - 3 - (2,2 - difluoroethoxy)pyridin - 2 - yl)methanol (49.6 mg, 0.22 mmol) was added to a stirred solution of sodium hydride (10.64 mg, 0.27 mmol) in THF (1.3 mL). After 10 minutes, ethyl 5 - chloropyrazolo[1,5 - a]pyrimidine - 2 - carboxylate (50 mg, 0.22 mmol) was added and the mixture was warmed to 20 °C. After 2 hrs, LiOH (7.96 mg, 0.33 mmol), MeOH (633 μL) and water (317 μL) were added. After 3 hours, the reaction mixture was acidified with HCl (1 M, aq. soln.), diluted with water and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound. LC / MS = 385 [M+1].

[0796] Step B: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxo tetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide

[0797] To a stirred solution of 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (33 mg, 86 μmol), DIPEA (37 μl, 214 μmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (17 mg, 86 μmol) in DMF (572 μl) was added HATU (33 mg, 86 μmol). After 18 h, the solvent was removed in vacuo and the crude material was purified by flash column chromatography on silica gel using a 0-100% EtOAc / hexanes gradient to afford the title compound. LC / MS = 530 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 8.19 (s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.72 (s, 1H), 6.91 (d, J = 8.7 Hz, 1H), 6.20 (tt, J = 54.7, 3.7 Hz, 1H), 5.64 (s, 2H), 4.44 (td, J = 13.8, 3.6 Hz, 2H), 4.09 (s, 3H), 3.42–3.35 (m, 2H), 3.06–2.95 (m, 2H), 2.93–2.84 (m, 2H), 2.29–2.17 (m, 2H), 1.57 (s, 3H). Human DGAT2 IC 50 = 3.3 nM.

[0798] Using procedures similar to those described in Example 67 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0799]

[0800]

[0801] Assay

[0802] Insect cell expression and membrane preparation

[0803] Sf-9 insect cells were maintained in Grace's insect cell medium containing 10% heat-inactivated fetal bovine serum, 1% Pluronic F-68 and 0.14 μg / ml kanamycin sulfate in a shaking incubator at 27 °C. Cells were harvested 48 hours after infection with an unlabeled baculovirus expressing human DGAT2 (hDGAT2) at a multiplicity of infection (MOI) of 3. The cell pellet was suspended in a buffer containing 10 mM Tris-HCl pH 7.5, 1 mM EDTA, 250 mM sucrose and Complete Protease Inhibitor Cocktail (Sigma Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2000 x g for 15 minutes. Membrane fractions were isolated by ultracentrifugation (100,000 x g), resuspended in the same buffer and frozen (-80 °C) for later use. Protein concentration was determined using the Pierce TM BCA Protein Assay Kit (Thermo Fisher Scientific). Protein levels of expression were analyzed by immunoblotting with rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa 647 (Abcam, ab150075) and then detected using a Typhoon FLA9000 (GE Healthcare).

[0804] LC / MS / MS analysis method

[0805] LC / MS / MS analysis was performed using a LX4-TSQ Vantage system from Thermo Fisher. The system consists of an Agilent binary high performance liquid chromatography (HPLC) pump and a TSQ Vantage triple quadrupole MS / MS instrument. For each sample, 2 μL of the sample from the top organic layer of an in-plate liquid-liquid extraction was injected onto a Thermo Betabasic C4 column (2.1 mm x 20 mm, 5 μm particle size). Samples were then eluted using the following conditions; mobile phase: isopropanol:acetonitrile / 10 mM ammonium formate = 50 / 35 / 15 (v / v / v), flow rate: 0.8 mL / min, temperature: 25 °C. Data were acquired in positive ion mode using a heated electrospray ionization (HESI) interface. The operating parameters of the TSQ Vantage MS / MS instrument were spray voltage 3000 V, capillary temperature 280 °C, vaporizer temperature 400 °C, sheath gas 45 arbitrary units, auxiliary gas 10 arbitrary units, S-lens 165 and collision gas 1.0 mTorr. Data were collected within 33 seconds 13 C 18-Triolein (Q1: 920.8 > Q3: 621.3) and internal standard 13 C 21 -Chromatogram of the standard reference material (SRM) of triolein (Q1: 923.8 > Q3: 617.3). Peak areas were integrated using Xcalibur Quan software. The 13 C 18 Ratio of triolein to the internal standard 13 C 21 -Ratio of triolein was used to generate the percent inhibition and IC 50 values. The percent inhibition of the compound was calculated by the following formula: % Inhibition = 1 - [(Compound reaction - Low control) / (High control - Low control)] x 100%. The effective compounds were titrated and the IC 50 .

[0806] DGAT2 Enzymatic Activity Assay

[0807] Measure the enzyme product using the above membrane preparation 13 C 18 -Amount of triolein ( 13 C-1,2,3-tris(cis-9-octadecenoyl)glycerol) was used to determine DGAT2 activity. The assay was performed in an ABgene 384-well assay plate at rt with a final volume of 25 μL. The assay mixture contained the following: assay buffer (100 mM Tris●Cl, pH 7.0, 20 mM MgCl2, 5% ethanol), 25 μM diolein, 5 μM 13 C oleoyl-CoA and 8 ng / μL DGAT2 membrane.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: X 3 Selected from C(R 3 ) and N; X, Y, and Z are independently selected from N and C(R 4 ); R 1 For (1) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents, or (2)-(C 1-6 )alkyl - heteroaryl, wherein the heteroaryl is a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents; R 2 For (1) a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2)-(C 1-6 )alkyl - heterocyclic group, wherein the heterocyclic group is a 3 - to 6 - membered ring containing 1 or 2 heteroatoms independently selected from N, O, and S (3)-(C 1-6 )alkyl (4)-(C 3-6 )cycloalkyl (5)-(C 1-6 ) hydroxyalkyl, (6)-SO2(C 1-6 )alkyl, or (7)-(C 1-6 )alkyl-NH-SO2-(C 1-6 )alkyl, wherein each alkyl, cycloalkyl, and heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from R 5 ; When present, R 3 is (1) hydrogen, (2) halogen, (3) -NH2, (4)(C 1-6 ) alkyl (5)(C 1-6 )haloalkyl, (6)(C 1-4 ) alkyl hydroxy, or (7)-(C 3-6 ) cycloalkyl; When present, each R 4 is independently (1) hydrogen, (2) halogen, or (3)(C 1-3 ) alkyl; When present, each R 5 is independently (1)-OC 1-6 alkyl (2)-O(C 1-6 ) haloalkyl, (3) halogen, (4) cyano, (5)O-(C 3-6 ) cycloalkyl, optionally substituted by halogen, (6)(C 1-3 ) hydroxyalkyl, (7)(C 1-6 ) haloalkyl-, (8)(C 1-3 ) hydroxyhaloalkyl, or (9)(C 1-6 )alkyl-(C 3-7 )cycloalkyl-OH; When present, each R 6 is independently (1) oxo, (2)(C 1-6 )alkyl, or (3)(C 1-6 ) haloalkyl-.

2. The compound according to claim 1, which has formula Ib, wherein: or a pharmaceutically acceptable salt thereof, wherein: R 1 For (1) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents, or (2)-(C 1-6 )alkyl - heteroaryl, wherein the heteroaryl is a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 R 5 substituents; R 2 For (1) a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2)-(C 1-6 )-alkyl-heterocyclic group, wherein the heterocyclic group is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O, and S (3)-(C 1-6 )alkyl (4)-(C 3-6 ) cycloalkyl (5)-(C 1-6 ) hydroxyalkyl, (6)-SO2(C 1-6 )alkyl, or (7)-(C 1-6 )alkyl-NH-SO2-(C 1-6 )alkyl, wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 6 ; When present, R 3 is (1) hydrogen, (2) halogen, (3) -NH2 (4)(C 1-6 ) alkyl (5)(C 1-6 ) haloalkyl, (6) Hydroxy (C 1-4 ) alkyl, or (7)-(C 3-6 ) cycloalkyl; Each R 4 is independently selected from (1) hydrogen, (2) halogen, or (3)(C 1-3 )alkyl; When present, each R 5 is independently selected from (1)-OC 1-6 alkyl (2)-O(C 1-6 ) haloalkyl (3) halogen, (4) cyano, (5)O-(C 3-6 ) cycloalkyl, optionally substituted by halogen, (6)(C 1-3 ) hydroxyalkyl (7)(C 1-6 ) haloalkyl-, (8)(C 1-3 ) hydroxyhaloalkyl, or (9)(C 1-6 ) hydroxyalkyl-(C 3-7 ) cycloalkyl; When present, each R 6 is independently (1) oxo, (2)(C 1-6 )alkyl, or (3)(C 1-6 ) haloalkyl-.

3. The compound according to claim 1, which has formula Ic, or a pharmaceutically acceptable salt thereof, wherein: X 2 is CH or N; R 2 For (1) a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2)-(C 1-6 )alkyl - heterocyclic group, wherein the heterocyclic group is a 3 - to 6 - membered ring containing 1 or 2 heteroatoms independently selected from N, O, and S (3)-(C 1-6 )alkyl (4)-(C 3-6 ) cycloalkyl (5)-(C 1-6 ) hydroxyalkyl (6)-SO2(C 1-6 )alkyl, or (7)-(C 1-6 )alkyl-NH-SO2-(C 1-6 )alkyl, wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents selected from R 6 ; When present, R 3 is (1) hydrogen, (2) halogen, (3) -NH2 (4)(C 1-6 )alkyl (5)(C 1-6 ) haloalkyl (6) Hydroxy (C 1-4 ) alkyl, or (7)-(C 3-6 ) cycloalkyl; Each R 4 independently is (1) hydrogen, (2) halogen, or (3)(C 1-3 ) alkyl; When present, each R 5a is independently (1)-OC 1-6 alkyl (2)-O(C 1-6 ) haloalkyl, or (3)O-(C 3-6 ) cycloalkyl; When present, each R 5b is independently (1) halogen, (2) cyano, (3)-OC 1-6 alkyl (4)(C 1-3 ) hydroxyalkyl (5)(C 1-3 ) hydroxyhaloalkyl, or (6)(C 1-6 ) hydroxyalkyl-(C 3-7 ) cycloalkyl; When present, each R 6 is independently (1) oxo, (2)(C 1-6 ) alkyl, or (3)(C 1-6 ) haloalkyl-.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 or 2, wherein R 1 is (1) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, OC 1-6 alkyl, O(C 1-6 ) haloalkyl, O-(C 3-6 ) cycloalkyl, cyano, (C 1-6 ) hydroxyalkyl-(C 3-6 ) cycloalkyl and (C 1-3 ) hydroxyhaloalkyl, or (2)-(C 1-6 )alkyl - heteroaryl, wherein the heteroaryl is a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein the heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from halogen, OC 1-6 alkyl and O(C 1-6 )haloalkyl.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 and 4, wherein R 1 is (1) A 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, OC 1-6 alkyl, O(C 1-6 ) haloalkyl, O-(C 3-6 ) cycloalkyl, cyano, (C 1-6 ) hydroxyalkyl-(C 3-6 ) cycloalkyl, (C 1-3 ) hydroxyalkyl and (C 1-3 ) hydroxyhaloalkyl, or (2)-(C 1-6 )-alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing 1 nitrogen heteroatom, and wherein the heteroaryl is unsubstituted or substituted with one or two substituents independently selected from halogen, OC 1-6 -alkyl and O(C 1-6 )-haloalkyl.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 4-5, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, OC 1-6 alkyl, O(C 1-6 )haloalkyl, O-(C 3-6 )cycloalkyl, cyano, (C 1-6 )hydroxyalkyl-(C 3-6 )cycloalkyl, (C 1-3 )hydroxyalkyl and (C 1-3 )hydroxyhaloalkyl.

7. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 4-6, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, OCH2CF3, OCH2CF2H, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH3)OH and CH(CF3)OH.

8. The compound according to any one of claims 1-2, 4-5 or a pharmaceutically acceptable salt thereof, wherein R 1 is -(C 1-3 )alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing 1 nitrogen atom, and the heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from Cl, OCH3, OCH2CH3 and OCH2CHF2.

9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R 2 is (1) A 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted by one, two, three, four or five substituents independently selected from oxo, C 1-3 alkyl or C 1-3 haloalkyl, (2)-(C 3-6 )Naphthenyl, (3)-(C 1-6 ) hydroxyalkyl, or (4)-(C 1-6 )alkyl-NH-SO2-(C 1-6 )alkyl.

10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted by one, two, three, four or five substituents independently selected from oxo, C 1-3 alkyl or C 1-3 haloalkyl.

11. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1 or 2 heteroatoms independently selected from N, O, and S, optionally substituted with one, two, three, four, or five substituents independently selected from oxo, CH3, CHF2, or CH2CF3.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R 2 is C(CH3)2CH2C(CH3)2OH.

13. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 6-membered heterocycle containing 1 nitrogen atom optionally substituted with one or two substituents independently selected from oxo, -(C 1-3 )alkyl, and -(C 1-3 )haloalkyl.

14. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 5-membered heterocycle containing 1 nitrogen atom optionally substituted by one or two substituents independently selected from oxo, -(C 1-3 )alkyl, and -(C 1-3 )haloalkyl.

15. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 2 is -(C 1-6 )alkyl-NH-SO2-(C 1-6 )alkyl.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 or 15, wherein R 2 is CH(CH3)2CH2NHSO2CH3.

17. The compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, halogen, (C 1-6 )alkyl, -(C 1-6 )haloalkyl, -(C 1-6 )hydroxyalkyl, -(C 3-6 )cycloalkyl or -NH2.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-17, wherein R 3 is hydrogen, halogen, CH3, CH2CH3, CH(CH3)2, CH(F2), CH2OH, CF3, CH(OH)CH3, CH2C(OH)(CH3)2, cyclopropyl or -NH2.

19. The compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, halogen or (C 1-6 )alkyl.

20. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-19, wherein R 4 is H, Cl, F or CH3.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 9-20, wherein R 5 is -OC 1-6 alkyl, -O(C 1-6 )haloalkyl, halogen, cyano, O-(C 3-6 )cycloalkyl, (C 1-6 )haloalkyl-, (C 1-3 )hydroxyhaloalkyl, (C 1-3 )hydroxyalkyl or -(C 3-7 )cycloalkylhydroxy.

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 9-21, wherein R 5 is halogen, OCH3, OCH2CH3, OCH2CF3, OCH2CHF2, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH3)OH or CH(CF3)OH.

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 3, 9 - 20, wherein R 5a is OCH2CHF2, OCH2CF3, O - cyclopropyl.

24. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 3, 9-20 or 23, wherein R 5b is halogen, CH(cyclopropyl)OH, CN, CH(CH3)OH, CH(CF3)OH.

25. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2 or 9-22, wherein R 6 is oxo, (C 1-6 )alkyl or (C 1-6 )haloalkyl-.

26. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, 9-22 or 25, wherein R 6 is oxo, CH3, CHF2 or CH2CF3.

27. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4 - 22 or 25 - 26, wherein X is C(R 4 ), Y is C(R 4 ), and Z is C(R 4 ).

28. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4-22 or 25-26, wherein X is N, Y is C(R 4 ), and Z is C(R 4 ).

29. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4-22 or 25-26, wherein X is C(R 4 ), Y is N, and Z is C(R 4 ).

30. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4 - 22 or 25 - 26, wherein X is C(R 4 ) and Y is C(R 4 ), and Z is N.

31. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4-22 or 25-26, wherein X 3 is N.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1, 4-22 or 25-26, wherein X 3 is C(R 3 ).

33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is: N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((3-(2,2,2-Trifluoroethoxy)pyridin-2-yl)oxy)-N-(2,3,3-trimethyl-1,1-dioxoisothiazolidin-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, N-(2-Methyl-1-(methylsulfonamido)propan-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, N-(4-Hydroxy-2,4-dimethylpentan-2-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, N-(2-Oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, N-(3-Methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, (S)-N-(Tetrahydrofuran-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, N-Cyclopentyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((3-cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((3-(2,2-difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((3-cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Methyl-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Fluoro-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-3-Fluoro-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-3-Chloro-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, (S)-3-Chloro-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxotetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-3-fluoro-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((3-(2,2-Difluoroethoxy)pyrazin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3,4-Dichloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Chloro-5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-5-((5-(Cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, (S)-5-((5-(Cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-5-((5-(1-Hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, (S)-5-((5-(1-Hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-N-(3-Methyl-1,1-dioxothietan-3-yl)-5-((5-(2,2,2-trifluoro-1-hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, (S)-N-(3-Methyl-1,1-dioxothietan-3-yl)-5-((5-(2,2,2-trifluoro-1-hydroxyethyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Ethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Ethyl-N-(3-methyl-1,1-dioxothietan-3-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Isopropyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-(Difluoromethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-(Hydroxymethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide, (R)-3-(1-Hydroxyethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, (S)-3-(1-Hydroxyethyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(2-hydroxy-2-methylpropyl)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 3-Amino-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-6-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide, 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-(difluoromethyl)-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(1,1-dioxo-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide 7-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxothietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide 5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide 5-((6-Methoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide 5-((6-Ethoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide, or 5-((3-Chloro-6-methoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide 34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is:

35. The compound or a pharmaceutically acceptable salt thereof according to claim 34, which is 36. A composition for treating a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases, and heart failure, comprising the compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

37. A composition comprising a pharmaceutically acceptable carrier and a compound as claimed in any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

38. A method for treating a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal disease and heart failure, which comprises administering to a patient in need a therapeutically effective amount of a compound as claimed in any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof.

39. Use of a compound as claimed in any one of claims 1 to 35 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal disease and heart failure.

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