Preparation of pyrazolopyridine and triazolopyridine derivatives as novel diacylglyceride O-acyltransferase 2 inhibitors

Abstract

Provided are compounds of Formula I, Ib, or Ic that are DGAT2 inhibitors, as well as pharmaceutically acceptable salts, esters, and prodrugs thereof. Also provided are methods for making compounds of Formula I, Ib, or Ic, pharmaceutical compositions containing compounds of Formula I, Ib, or Ic, and methods for using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure), and related diseases and conditions, comprising administering a compound of Formula I to a patient in need of such treatment. [Formula 1] TIFF2025537517000078.tif26149

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international application claims the benefit of priority to U.S. Provisional Application No. 63 / 421,381, filed November 1, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to novel pharmaceutical compounds that inhibit diacylglyceride O-acyltransferase 2 ("DGAT2") and may be useful in preventing, treating, or acting as reversing agents for hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure) and related diseases and conditions, as well as methods for making such compounds and pharmaceutical compositions comprising such compounds and a pharmaceutical carrier. [Background technology]

[0003] Triacylglycerols ("TGs") serve several functions in the body. One such function of TGs is in energy storage. TGs also play a role in the synthesis of membrane lipids. TG synthesis in cells can protect cells from the potentially toxic effects of excess fatty acids ("FAs"). In enterocytes and hepatocytes, TGs are synthesized for the assembly and secretion of lipoproteins that transport FAs between tissues. TGs play a role in the water barrier at the skin surface, and TGs in adipose tissue provide insulation for the body.

[0004] The glycerol phosphate pathway and the monoacylglycerol pathway are the major pathways for TG biosynthesis. However, the final step in TG synthesis involves the reaction of fatty acyl-CoA with diacylglycerol ("DAG") to form TG. This reaction is catalyzed by the acyl-CoA:diacylglycerol acyltransferase ("DGAT") enzyme. Two DGAT enzymes, DGAT1 and DGAT2, have been identified. Although DGAT1 and DGAT2 catalyze the same reaction, they differ significantly at the DNA and protein sequence levels. DGAT2 can synthesize TG using endogenous fatty acids in in vitro assays, whereas DGAT1 appears to be more dependent on exogenous fatty acids (Yen et al., J. Lipid Research, 2008, 49, 2283). Inactivation of DGAT2 inhibits the growth of cytosolic lipid droplets, whereas inactivation of DGAT1 has the opposite effect (Li et al., Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080).

[0005] DGAT2 is an integral membrane protein of the endoplasmic reticulum and is highly expressed in adipose tissue and liver. DGAT2 is thought to be the major DGAT enzyme controlling TG homeostasis in vivo. DGAT2-deficient mice survive only a few hours after birth, whereas DGAT1-deficient mice are viable (Yen et al., J. Lipid Research, 2008, 49, 2283).

[0006] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 is largely understood from studies using antisense oligonucleotides (ASOs) in rodents. In this setting, knockdown of DGAT2 in ob / ob mice with DGAT2 gene-specific ASOs resulted in a dose-dependent decrease in very low-density lipoprotein (VLDL) and reduced plasma triglycerides, 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 demonstrated a reduction in body weight gain, adipose tissue mass, and hepatic triglyceride content. Ibid. 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 knocking down DGAT2 in rats improved diet-induced hepatic steatosis and insulin resistance. These effects appear to be specific to DGAT2 inhibition, as ASOs against DGAT1 did not produce similar beneficial effects. Although the molecular mechanisms behind these observations remain unclear, collective data suggest that DGAT2 inhibition is associated with decreased expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative / thermogenic genes (CPT1, UCP2) (Choi et al., J. Bio. Chem., 2007, 282, 22678).

[0007] Inhibitors of DGAT2 are useful for treating diseases associated with metabolic syndrome, such as hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure), and related diseases and conditions.

[0008] DGAT2 inhibitor compounds are described in WO2022050749, WO2021133035, WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, WO2013150416, US20150259323, WO2015077299, WO2017011276, WO2018033832, US201801628 and W2003053363. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] WO2022050749 [Patent Document 2] WO2021133035 [Patent Document 3] WO2021064590 [Patent Document 4] WO2016036633 [Patent Document 5] WO2016036636 [Patent Document 6] WO2016036638 [Patent Document 7] WO2018093696 [Patent Document 8] WO2018093698 [Patent Document 9] WO2013150416 [Patent Document 10] US20150259323 [Patent Document 11] WO2015077299 [Patent Document 12] WO2017011276 [Patent Document 13] WO2018033832 [Patent Document 14] US201801628 [Patent Document 15] WO2003053363 [Non-patent literature]

[0010] [Non-Patent Document 1] Yen et al., J. Lipid Research, 2008, 49, 2283 [Non-patent document 2] Li et al., Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080 [Non-patent document 3] Liu, et al., Biochim. Biophys Acta 2008, 1781, 97 [Non-patent document 4] Yu, et al., Hepatology, 2005, 42, 362 [Non-Patent Document 5] Choi et al., J. Bio. Chem., 2007, 282, 22678 Summary of the Invention [Means for solving the problem]

[0011] The present disclosure provides DGAT2 inhibitors, compounds of structural formula I: [ka] and pharmaceutically acceptable salts, esters, and prodrugs thereof. Also provided are methods of making the compounds of Formula I, pharmaceutical compositions containing the compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure), and related diseases and conditions, wherein the method comprises administering a compound of Formula I to a patient in need of such treatment. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure provides compounds of structural formula I: [ka] [During the ceremony, X 3 is C(R 3 ) and N; X, Y and Z are N and C(R 4 ) are independently selected; R 1 teeth, (1) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R 5 ) 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 contains 1, 2, or 3 R 5 (replaced by and; R 2 teeth, (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-heterocyclyl (wherein the heterocyclyl is a 3-6 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 R 6 substituted with 1, 2, 3, 4 or 5 substituents selected from: R 3 teeth, (1) Hydrogen, (2) halogens, (3) -NH2, (4) (C 1-6 ) alkyl, (5) (C 1-6 ) haloalkyl, (6) (C 1-4 ) alkylhydroxy, or (7) -(C 3-6 )Cycloalkyl and; Each R 4 is, independently, (1) Hydrogen, (2) Halogen, or (3) (C 1-3 ) alkyl and; If present, each R 5 is, independently, (1) -OC 1-6 Alkyl, (2) -O(C 1-6 ) haloalkyl, (3) halogens, (4) Cyano, (5) O-(C) optionally substituted with halogen 3-6 ) cycloalkyl, (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 and; If present, each R 6 is, independently, (1) oxo, (2) (C 1-6 ) alkyl, or (3) (C 1-6 )Haloalkyl- is] or a pharmaceutically acceptable salt thereof.

[0013] In a second embodiment of the present disclosure, the compound of formula I or a pharmaceutically acceptable salt thereof is represented by formula Ib: [ka] [During the ceremony, R 1 teeth, (1) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R 5 ) 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 contains 1, 2, or 3 R 5 (replaced by and; R 2 teeth, (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-heterocyclyl (wherein the heterocyclyl is a 3-6 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 R 6 substituted with 1, 2, 3, 4 or 5 substituents selected from: If present, R 3 teeth, (1) Hydrogen, (2) halogens, (3) -NH2, (4) (C 1-6 ) alkyl, (5) (C 1-6 ) haloalkyl, (6) Hydroxy (C 1-4 ) alkyl, or (7) -(C 3-6 )Cycloalkyl and; Each R 4 is, independently, (1) Hydrogen, (2) Halogen, or (3) (C 1-3 ) alkyl and; If present, each R 5 is, independently, (1) -OC 1-6 Alkyl, (2) -O(C 1-6 ) haloalkyl, (3) halogens, (4) Cyano, (5) O-(C) optionally substituted with halogen 3-6 ) cycloalkyl, (6) (C 1-3 ) hydroxyalkyl, (7) (C 1-6 ) haloalkyl-, (8) (C 1-3 ) hydroxyhaloalkyl, or (9) (C 1-6 ) hydroxyalkyl-(C3-7 )Cycloalkyl and; If present, each R 6 is, independently, (1) oxo, (2) (C 1-6 ) alkyl, or (3) (C 1-6 )Haloalkyl- is] or a pharmaceutically acceptable salt thereof.

[0014] In a third embodiment of the present disclosure, the compound of formula I, or a pharmaceutically acceptable salt thereof, is Formula Ic: [ka] [During the ceremony, X 2 is CH or N; R 2 teeth, (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-heterocyclyl (wherein the heterocyclyl is a 3-6 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 R 6 substituted with 1, 2, 3, 4 or 5 substituents selected from: If present, R3 teeth, (1) Hydrogen, (2) halogens, (3) -NH2, (4) (C 1-6 ) alkyl, (5) (C 1-6 ) haloalkyl, (6) Hydroxy (C 1-4 ) alkyl, or (7) -(C 3-6 )Cycloalkyl and; Each R 4 is, independently, (1) Hydrogen, (2) Halogen, or (3) (C 1-3 ) alkyl and; If present, each R 5a is, independently, (1) -OC 1-6 Alkyl, (2) -O(C 1-6 ) haloalkyl, or (3) O-(C 3-6 )Cycloalkyl and; If present, each R 5b is, independently, (1) halogens, (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 and; If present, each R 6 is, independently, (1) oxo, (2) (C 1-6 ) alkyl, or (3) (C1-6 )Haloalkyl- is] or a pharmaceutically acceptable salt thereof.

[0015] Embodiment 4 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, (1) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 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 halogen, OC, 1-6 Alkyl and O(C 1-6 ) substituted with 1, 2, or 3 substituents independently selected from haloalkyl is.

[0016] Embodiment 5 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-4 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, (1) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, OC 1-6 Alkyl, O(C 1-6 ) haloalkyl, O-(C 3-6 ) cycloalkyl, cyano, (C1-6 ) 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 one nitrogen heteroatom, where the heteroaryl is unsubstituted or substituted with halogen, OC 1-6 Alkyl and O(C 1-6 ) substituted with 1 or 2 substituents independently selected from haloalkyl is.

[0017] Embodiment 6 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-5 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 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; and

[0018] Embodiment 7 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-6 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1is a 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, OCHCF, OCHCFH, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH)OH, and CH(CF)OH.

[0019] Embodiment 8 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-7, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing one nitrogen atom, wherein the heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from F, Cl, OCHCF, OCHCFH, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH)OH, and CH(CF)OH.

[0020] Embodiment 9 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, or classes 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, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from Cl, OCH3, OCH2CH3, and OCH2CHF2.

[0021] Embodiment 10 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 9, or classes 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 6-membered heteroaryl containing one nitrogen atom, wherein the heteroaryl is unsubstituted or substituted with one or two substituents independently selected from Cl, OCH3, and OCH2CHF2.

[0022] Embodiment 11 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0023] Embodiment 12 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or any of embodiments 1-11, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S (wherein the heterocyclyl is oxo, C 1-3 Alkyl or C 1-3 haloalkyl), (2) -(C 3-6 ) cycloalkyl, (3) -(C 1-6 ) hydroxyalkyl, or (4) -(C 1-6 ) alkyl-NH-SO2-(C 1-6 ) alkyl is.

[0024] Embodiment 13 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or any of embodiments 1-12, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from oxo, CH, CHF, or CHCF; (2) -(C 3-6 ) cycloalkyl, (3) -(C 1-6 ) hydroxyalkyl, (4) -(C 1-6 ) alkyl-NH-SO2-(C 1-6 ) alkyl is.

[0025] Embodiment 14 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or any of embodiments 1-12, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is selected from oxo, C 1-3 Alkyl or C 1-3 It may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl.

[0026] Embodiment 15 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or any of embodiments 1-14, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from oxo, CH, CHF, or CHCF.

[0027] Embodiment 16 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or any of embodiments 1-15, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2is a 4-membered heterocyclyl containing one sulfur heteroatom, wherein the heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from oxo or CH3.

[0028] Embodiment 17 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-15, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 5-membered heterocyclyl containing one sulfur heteroatom, wherein the heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from oxo or CH3.

[0029] Embodiment 18 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-15, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 6-membered heterocyclyl containing one sulfur heteroatom, wherein the heterocyclyl is optionally substituted with 1, 2, or 3 substituents independently selected from oxo, CH, CHF, or CHCF.

[0030] Embodiment 19 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-13, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 5-membered cycloalkyl.

[0031] Embodiment 20 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-13, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is C(CH3)2CH2C(CH3)2OH.

[0032] Embodiment 21 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-14, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2is a 6-membered heterocycle containing one nitrogen atom, wherein the heterocycle is oxo, -(C 1-3 ) alkyl and -(C 1-3 ) haloalkyl.

[0033] Embodiment 22 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-14, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 5-membered heterocycle containing one nitrogen atom, wherein the heterocycle is oxo, -(C 1-3 ) alkyl and -(C 1-3 ) haloalkyl.

[0034] Embodiment 23 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-13, or classes 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.

[0035] Embodiment 24 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or Embodiments 1-13, or 23, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is CH(CH3)2CH2NHSO2CH3.

[0036] Embodiment 25 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-13, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, [ka] is.

[0037] Embodiment 26 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-25, or classes 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, -(C 1-6 ) hydroxyalkyl, -(C 3-6 ) cycloalkyl or -NH2.

[0038] Embodiment 27 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-26, or classes 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.

[0039] Embodiment 28 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-27, or classes 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.

[0040] Embodiment 29 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-28, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is hydrogen, halogen or (C 1-6 ) alkyl.

[0041] Embodiment 30 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-29, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 4 is H, Cl, F or CH3.

[0042] Embodiment 31 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, or classes 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 1-6 ) haloalkyl-, (C 1-3 ) hydroxyhaloalkyl, (C 1-3 ) hydroxyalkyl or -(C 3-7 ) cycloalkylhydroxy.

[0043] Embodiment 32 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, 31, or classes 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.

[0044] Embodiment 33 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, 31-32, or classes 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.

[0045] Embodiment 34 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, 31-33, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5is F, Cl, OCH3, OCH2CH3, -OCH2CF3, OCH2CHF2, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH3)OH or CH(CF3)OH.

[0046] Embodiment 35 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, 31-34, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5 is OCH2CF3 or OCH2CHF2.

[0047] Embodiment 36 of the present disclosure is a compound of Formula Ic or embodiments 3, 12-30 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5a are OCH2CHF2, OCH2CF3, and O-cyclopropyl.

[0048] Embodiment 37 of the present disclosure is a compound of formula Ic or embodiment 3, 12-30, or 36 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 5b are halogen, CH(cyclopropyl)OH, CN, CH(CH3)OH, CH(CF3)OH.

[0049] Embodiment 38 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-11, 26-37, or classes 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-.

[0050] Embodiment 39 of the present disclosure is a compound of Formula I, Formula Ib, or Formula Ic, or embodiments 1-11, 26-38, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6 is oxo, CH3, CHF2 or CH2CF3.

[0051] Embodiment 40 of the present disclosure is a compound of Formula I or embodiments 1, 4-39 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X 3 is C(R 3 )

[0052] Embodiment 41 of the present disclosure is a compound of Formula I or embodiments 1, 4-39 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X 3 is N.

[0053] Embodiment 42 of the present disclosure is a compound of Formula I or embodiments 1, 4-39 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ) and Y is C(R 4 ) and Z is C(R 4 )

[0054] Embodiment 43 of the present disclosure is a compound of Formula I or embodiments 1, 4-39 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N and Y is C(R 4 ) and Z is C(R 4 )

[0055] Embodiment 44 of the present disclosure is a compound of Formula I or embodiments 1, 4-39 or classes 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 )

[0056] Embodiment 45 of the present disclosure is a compound of Formula I or embodiments 1, 4-39 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ) and Y is C(R 4 ) and Z is N.

[0057] In embodiment 46 of the present invention, the compound of formula I, formula Ib or formula Ic, or a pharmaceutically acceptable salt thereof, is N-(4-methyl-1,1-dioxidetetrahydro-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-dioxideisothiazolidin-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-(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-dioxidothietan-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-dioxidetetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 5-((3-cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 5-((3-cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxidothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 3-Fluoro-N-(3-methyl-1,1-dioxidothietan-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-dioxidetetrahydrothiophen-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydrothiophen-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-dioxidetetrahydrothiophen-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-dioxidothietan-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-dioxidetetrahydrothiophen-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-dioxidothietan-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 3-chloro-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; (R)—N-(3-methyl-1,1-dioxidothietan-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxide-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-dioxidothietan-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-((6-methoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-((6-ethoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; is.

[0058] Embodiment 47, a compound of Formula I, Formula Ib, or Formula Ic, or a pharmaceutically acceptable salt thereof, is [ka] TIFF2025537517000009.tif240163 The file is TIFF2025537517000010.tif35142.

[0059] Embodiment 48. The compound of Formula Ib or a pharmaceutically acceptable salt thereof is [ka] The file is TIFF2025537517000012.tif199149.

[0060] Embodiment 49 is [ka] or a pharmaceutically acceptable salt thereof.

[0061] Embodiment 50 is [ka] or a pharmaceutically acceptable salt thereof.

[0062] Embodiment 51 is [ka] or a pharmaceutically acceptable salt thereof.

[0063] Embodiment 52 is [ka] or a pharmaceutically acceptable salt thereof.

[0064] Embodiment 53 is [ka] or a pharmaceutically acceptable salt thereof.

[0065] Embodiment 54 is [ka] or a pharmaceutically acceptable salt thereof.

[0066] Embodiment 55 is [ka] or a pharmaceutically acceptable salt thereof.

[0067] Embodiment 56 is [ka] or a pharmaceutically acceptable salt thereof.

[0068] Embodiment 57 is [ka] or a pharmaceutically acceptable salt thereof.

[0069] Embodiment 58 is [ka] or a pharmaceutically acceptable salt thereof.

[0070] The present disclosure includes pharmaceutically acceptable salts of the compounds defined herein.

[0071] In one embodiment, the 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.

[0072] The present disclosure further provides pharmaceutical compositions 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.

[0073] The present disclosure also provides pharmaceutical compositions 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).

[0074] The present disclosure also provides pharmaceutical compositions 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.

[0075] 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, or cardiorenal disease (e.g., chronic kidney disease or heart failure), comprising an acceptable carrier and a compound of Formula I, Formula Ib, or Formula Ic, or a pharmaceutically acceptable salt thereof.

[0076] 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, or cardiorenal disease (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.

[0077] 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, or cardiorenal disease (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.

[0078] 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, cardiorenal disease (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.

[0079] 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, cardiorenal disease (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.

[0080] The methods of the disclosure include administering a pharmaceutical composition comprising at least one compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0081] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a compound of Formula I, Formula Ib, or Formula Ic, or a pharmaceutically acceptable salt thereof.

[0082] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a compound of Formula I, Formula Ib, or Formula Ic, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0083] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a composition comprising a compound of Formula I, Formula Ib, or Formula Ic, or a pharmaceutically acceptable salt thereof.

[0084] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a composition comprising a compound of Formula I, Formula Ib, or Formula Ic, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0085] 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 manufacture of a medicament for treating NASH and / or fibrosis.

[0086] In another embodiment, the present disclosure encompasses the use of a compound of Formula I, Formula Ib, or Formula Ic, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of NASH and / or fibrosis.

[0087] "Alkyl," when specified, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. If no number is specified, 1 to 6 carbon atoms is intended for straight-chain alkyl groups, and 3 to 7 carbon atoms for branched-chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, and tert-butyl, pentyl, hexyl, octyl, nonyl, and the like. For example, the term "C 1-6 "Alkyl" means a group having a C 1-4 "C" includes all "alkyl" groups as well as straight or branched alkyl groups having 5 or 6 carbon atoms (including all possible isomers). 1-6"Alkyl" means a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, including all possible isomers, and 1-6 Within the scope of alkyl are included each of the alkyl groups, including each of the hexyl and pentyl isomers, as well as n-, iso-, sec-, and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively "C4 alkyl"; Bu = butyl), n- and i-propyl (propyl, i-propyl, collectively "C3 alkyl"; Pr = propyl), ethyl (Et) and methyl (Me). Commonly used abbreviations for alkyl groups are used throughout the specification, for example, methyl is represented by conventional abbreviations including "Me" or CH3, or by a symbol that is an extended bond as a terminal group, for example: [ka] where ethyl can be represented by "Et" or CH2CH3, propyl can be represented by "Pr" or CH2CH2CH3, and butyl can be represented by "Bu" or CH2CH2CH2CH3. For example, the structure [ka] have equivalent meanings. If no number is specified, 1 to 6 carbon atoms is intended for straight or branched chain alkyl groups.

[0088] "Alkoxy" refers to an alkyl group attached to an oxygen. Examples of alkoxy groups include methoxy, ethoxy, and propoxy.

[0089] "Aryl" refers to a monocyclic or polycyclic aromatic ring moiety containing 6 to 14 ring carbon atoms. In one embodiment, an aryl group contains about 6 to 10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl. Polycyclic rings include, but are not limited to, naphthyl rings and bicyclic rings in which a phenyl is fused to a C5-7 cycloalkyl ring or a C5-7 cycloalkenyl ring. Aryl groups may be substituted with one or more substituents as defined herein. Attachment may be via any carbon atom of either ring.

[0090] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

[0091] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing about 3 to 10 ring carbon atoms. If no number of atoms is specified, 3 to 10 carbon atoms are intended. Cycloalkyls can also be fused to form 1 to 3 carbocyclic rings. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C 1-6 The term "cycloalkyl" refers to a cycloalkyl group having 1 to 6 ring carbon atoms. 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 ring carbon atoms. Thus, for example, "C 3-6 "Cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups are unsubstituted or substituted with one or more ring system substituents, which may be the same or different, as defined herein. When cycloalkyl is a substituent on an alkyl group, the cycloalkyl substituent may be attached to any available carbon within the alkyl group. The following describes -C on an alkyl group: 3-6 An example of a cycloalkyl substituent where the substituent is a bold cyclopropyl: [ka] "Haloalkyl" refers to an alkyl group, as defined herein, in which one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has 1 to 6 carbon atoms. Non-limiting examples of haloalkyl groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2Cl, CH2CF2CH3, and CCl3. The term "C 1-6 Haloalkyl" or "HaloC 1-6 "Alkyl" refers to a haloalkyl group having 1 to 6 carbons.

[0092] "Haloalkoxy", "haloalkyl-O" and derived forms (e.g., "halo(C 1-6 )alkoxy" or O(C 1-6 ")Haloalkyl" are used interchangeably and refer to a halo-substituted alkyl group attached through an oxygen atom. Haloalkoxy includes mono- and multiply halo-substituted alkoxy groups. For example, OCHCF, OCHCHF, OCFCF, and OCFCHF, as well as trifluoromethoxy, chloromethoxy, and bromomethoxy are included.

[0093] "Heterocyclyl," "heterocycle," or "heterocyclic" refers to a monocyclic ring system in which one or more atoms in the ring (heteroatoms) are elements other than carbon. The heteroatom is typically an O, S, or N atom. Heterocycles containing multiple heteroatoms may contain different heteroatoms. Bicyclic ring moieties include fused, spirocyclic, and bridged bicyclic rings, and any of the rings may contain one or more heteroatoms. The ring bonded to the rest of the molecule may or may not contain heteroatoms. Either ring of a bicyclic heterocycle can be saturated, partially unsaturated, or unsaturated. The heterocycle can be bonded to the rest of the molecule through a ring carbon atom, ring oxygen atom, or ring nitrogen atom. Examples of heterocyclyl groups include piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, oxirane, or aziridine.

[0094] "Bicyclic heterocyclyl," "bicyclic heterocycle," or "bicyclic heterocyclic" refers to a heterocyclic ring fused to another ring system, which fusion may be bridged or unbridged.

[0095] 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 the group consisting of O, N, and S. Heteroaryl groups within this definition include, but are not limited to, the following: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazolyl. phenyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline.

[0096] "Oxo" means an oxygen attached to an atom by a double bond. Examples of oxo groups are the double-bonded oxygen in a ketone, sulfoxide, sulfone, sulfate, or the double-bonded oxygen fused to a non-aromatic cycloalkyl or heteroalkyl.

[0097] "Hydroxyalkyl" or "hydroxy(C 1-3 ")Alkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced with a hydroxyl (-OH) group. Examples include CH(OH)CH, CHC(OH)(CH), or CHOH.

[0098] "Hydroxyhaloalkyl" refers to an alkyl group having one or more hydrogen atoms replaced with a hydroxyl (-OH) group and one or more hydrogen atoms replaced with a halogen substituent, such as CH(CF3)OH.

[0099] The term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0100] The term "at least one" means more than one. The meaning of "at least one" with respect to the number of compounds of the invention is independent of its meaning with respect to the number of chemotherapeutic agents.

[0101] The term "chemotherapeutic agent" refers to a drug (medicine or pharmaceutically active ingredient) for treating cancer (i.e., an anti-tumor drug).

[0102] The term "effective amount" means a "therapeutically effective amount." The term "therapeutically effective amount" means that amount of an active compound or drug that elicits the biological or pharmacological response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, medical doctor, or other clinician.

[0103] The terms "treating cancer" or "treatment of cancer" refer to administration to a mammal suffering from a cancerous condition and refer to an effect that alleviates the cancerous condition by killing cancerous cells, as well as an effect that results in the inhibition of cancer growth and / or metastasis.

[0104] Except as otherwise stated herein, the term "carbocycle" (and variations thereof, e.g., "carbocyclic" or "carbocyclyl") as used herein, unless otherwise indicated, refers to a C3-C6 monocyclic ring, e.g., C 3-6Monocyclic carbocyclic rings are shown. The carbocyclic ring can be attached to the rest of the molecule at any carbon atom that results in a stable compound. Saturated carbocyclic rings include, for example, "cycloalkyl" rings, e.g., cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings include, for example, [ka] is included.

[0105] A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged or can remain essentially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0106] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I, Formula Ib, or Formula Ic and embodiments thereof. For example, a particular moiety defined in Formula I, Formula Ib, or Formula Ic may be unsubstituted or substituted, where the latter is intended to encompass substitution patterns (i.e., number and type of substituents) that are chemically possible for that moiety and result in stable compounds.

[0107] The term "substituted" means that one or more hydrogens on the specified atom have been replaced with the indicated group, provided that the replacement does not exceed the normal valence of the specified atom in its existing environment and that the substitution results in a stable compound. When multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted single or multiple times with one or more of the disclosed or claimed substituent moieties. Independently substituted means that the (two or more) substituents can be the same or different. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When a substituent is itself substituted with multiple groups, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results. "Optionally substituted" refers to compounds containing the specified optional substituents and compounds that do not contain such optional substituents.

[0108] Wavy line [ka] As used herein, indicates the point of attachment to the remainder of the compound.

[0109] When a ring atom is represented by a variable moiety such as "X", e.g. [ka] The variables are defined by showing the atom located at the variable position on the ring without showing the ring bond associated with that atom. For example, if X in the ring above is nitrogen, the definition would show "N" and no bond associated with it, e.g., no "=N-" is shown. Similarly, if X is a carbon atom substituted with bromide, the definition would show "C-Br" and no bond associated with it, e.g., [ka] is not displayed.

[0110] The present disclosure also encompasses derivatives of compounds of Formula I, Formula Ib, or Formula Ic that act as prodrugs and solvates. Pharmaceutically acceptable prodrug modifications of compounds of the present invention that are converted in vivo to compounds within the scope of the present invention are also within the scope of the present invention. After administration to a patient, prodrugs are converted to compounds of Formula I, Formula Ib, or Formula Ic in the body by normal metabolic or chemical processes (e.g., hydrolysis in blood). Such prodrugs include those that exhibit enhanced bioavailability, tissue specificity, and / or cellular delivery to improve drug absorption of compounds of Formula I, Formula Ib, or Formula Ic. The effect of such prodrugs can be achieved by altering physicochemical properties (e.g., lipophilicity, molecular weight, charge, and other physicochemical properties that determine the drug's permeation characteristics).

[0111] For example, esters can be prepared by esterification of an available carboxylic acid group, or by forming an ester on an available hydroxy group in the compound, as the case may be. Similarly, amides, which are easily converted, can be made. Pharmaceutically acceptable esters or amides of the compounds of the present invention can be prepared to act as prodrugs, particularly those that can be hydrolyzed in vivo to the acid form (or -COO- form, depending on the pH of the body fluid or tissue where the conversion occurs) or the hydroxy form, and as such are included within the scope of the present invention. Included are esters and acyl groups known in the art for modifying solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 -C substituted with alkyl esters and phenyl esters 1-6 Alkyl, etc.

[0112] "Celite®" (Fluka) diatomaceous earth is diatomaceous earth and is also called "celite."

[0113] Any variable part (e.g., R 1 When a group (e.g., R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 40 , R 41 , R 42 , R 43 , R 4 1 It will be recognized that the substituents (e.g., aryl, heteroaryl, or saturated heterocyclic rings) should be selected based on well-known principles of connectivity and stability of the chemical structure. Unless expressly stated to the contrary, substitution by a named substituent is permissible on any atom within the ring (e.g., an aryl ring, heteroaryl ring, or saturated heterocyclic ring) provided that such ring substitution is chemically permissible and results in a stable compound.

[0114] It should be noted that if there is a discrepancy between a chemical name and a structure, the structure is understood to control.

[0115] Compounds of Formula I, Formula Ib, or Formula Ic can contain one or more asymmetric centers and thus can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereoisomers. Any asymmetric centers present in a compound of Formula I, Formula Ib, or Formula Ic can have, independently of one another, either the S or R configuration. When a bond to a chiral carbon is depicted as a straight line in a structural formula of the invention, it is understood that both the (R) and (S) configurations of that chiral carbon, and thus both enantiomers and mixtures thereof, are encompassed by the formula. Similarly, when a compound name is given without explicitly specifying that a chiral carbon is chiral, it is understood that both the (R) and (S) configurations of that chiral carbon, and thus individual enantiomers and mixtures thereof, are encompassed by the name. The preparation of specific stereoisomers or mixtures thereof can be identified in examples in which such stereoisomers or mixtures are obtained, but this in no way limits the scope of the invention to include all stereoisomers and mixtures thereof.

[0116] The compounds of the present disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers in all ratios (e.g., mixtures of enantiomers and / or diastereomers). Thus, enantiomers in enantiomerically pure form (as both levorotatory and dextrorotatory enantiomers), in the form of racemates, and in the form of mixtures of two enantiomers in all ratios are subject of the present invention. The present disclosure is intended to encompass all such stereoisomeric forms of the compounds of structural formula I, structural formula Ib, or structural formula Ic.

[0117] 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 by chiral chromatography using an optically active stationary phase. In some cases, derivatization can be carried out prior to the separation of stereoisomers. Separation of a mixture of stereoisomers can be carried out at the intermediate stage during the synthesis of a compound of formula I, formula Ib, or formula Ic, or can be carried out on the final racemic product. Absolute stereochemistry can be confirmed by X-ray crystallography of crystalline products or crystalline intermediates, which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer or isomers of a compound 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 present invention includes all such isomers, and salts, solvates (which includes hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0118] If necessary, the racemic mixture of the compound can be separated so that the individual enantiomers are isolated. This 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 diastereomeric mixture, followed by separation of the individual diastereoisomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to a pure enantiomer by cleavage of the added chiral residue. The racemic mixture of the compound can also be directly separated by chromatographic methods utilizing chiral stationary phases, and such methods are well known in the art.

[0119] For compounds of Formula I, Formula Ib, or Formula Ic described herein that contain olefinic double bonds, unless otherwise specified, are intended to include both E and Z geometric isomers.

[0120] Some of the compounds described herein can exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Individual tautomers and mixtures thereof are encompassed by the compounds of Formula I, Formula Ib, or Formula Ic of the present invention.

[0121] In compounds of formula I, formula Ib, or formula Ic, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The invention described and claimed herein is intended to encompass all suitable isotopic variations of compounds of formula I, formula Ib, or formula Ic and embodiments thereof. 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 predominant hydrogen isotope found in nature. Enrichment with deuterium may confer certain therapeutic advantages (e.g., increased in vivo half-life or reduced dosage requirements) or may provide compounds useful as standards for characterizing biological samples. Isotopically enriched compounds within the scope of Formula I, Formula Ib, or Formula Ic can be prepared without undue experimentation by conventional techniques well known to those skilled in the art, or by processes analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0122] It will be understood that the compounds of formula I, formula Ib, or formula Ic can be prepared as pharmaceutically acceptable salts, or as pharmaceutically unacceptable salts when used as the free compounds or precursors to their pharmaceutically acceptable salts or in other synthetic procedures. The compounds of the present invention, including the compounds of the Examples, can also include all salts of compounds of formula I, formula Ib, or formula Ic that are not directly suitable for use in medicine due to poor physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or to prepare physiologically acceptable salts.

[0123] The compounds of the present invention can 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 inorganic acids.

[0124] Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" are non-toxic salts of the compounds of the present invention, generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, and the like. Acid salts include, but are not limited to, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucoate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, valerate, and the like. Furthermore, when a compound of the present invention contains an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, etc. In one embodiment, salts of acidic compounds are as follows: ammonium, calcium, magnesium, potassium, and sodium salts.

[0125] The compounds of Formula I, Formula Ib, or Formula Ic form stable alkali metal salts, alkaline earth metal salts, or optionally substituted ammonium salts using basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides, and ammonia, organic bases, or basic amino acids.

[0126] Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, salts of 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, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Furthermore, basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides, e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, e.g., benzyl and phenethyl bromides, and the like.

[0127] Preparation of pharmacologically acceptable salts from the salt-forming compounds represented by Formula I, Formula Ib, or Formula Ic (including stereoisomers thereof) can be carried out by known methods, for example, by mixing an equivalent amount of the compound of the present invention with a solution containing the desired acid or base, and then recovering the desired salt by filtering the salt or by distilling off the solvent. The compounds of the present invention and their salts can form solvates with solvents such as water, ethanol, or glycerol. The compounds of the present invention can simultaneously form acid addition salts and base salts depending on the type of substituents on the side chain.

[0128] When a compound of formula I, Ib or Ic contains simultaneously an acidic and a basic group in the molecule, the present invention encompasses, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from a compound of formula I, Ib or Ic by conventional methods known to those skilled in the art, for example, by combination with organic or inorganic acids or bases in solvents or dispersants, or by anion or cation exchange from other salts.

[0129] The present invention encompasses compounds of formula I, formula Ib, or formula Ic, as well as salts thereof (particularly pharmaceutically acceptable salts), solvates of said compounds, and solvated salt forms thereof, where such forms are possible unless otherwise indicated.

[0130] Furthermore, the compounds of the present invention can exist in amorphous form and / or one or more crystalline forms, and therefore, all amorphous and crystalline forms of the compounds of Formula I, Formula Ib, or Formula Ic, including the Examples, and mixtures thereof, are intended to be encompassed within the scope of the present invention. Furthermore, some of the compounds of the present invention can form solvates (i.e., hydrates) with water or common organic solvents (e.g., but not limited to, EtOAc). Such solvates and hydrates of the compounds of the present invention (particularly pharmaceutically acceptable solvates and hydrates) are also encompassed within the scope of the present invention, along with unsolvated and anhydrous forms.

[0131] Thus, compounds encompassed by the general structural formulae, specific compounds described in the embodiments and examples, and specific compounds claimed herein include their salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvates and hydrates, and any combination of these forms, as well as their salts, prodrug forms, and salts of their prodrug forms, where such forms are possible unless otherwise indicated.

[0132] The present invention further relates to medicaments containing 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 together with pharmaceutically acceptable vehicles, carriers, additives and / or other active substances and adjuvants.

[0133] The agents according to the invention can be administered orally, by inhalation, rectally or transdermally, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection, with oral administration being preferred.

[0134] The present invention further relates to a method for producing a medicament, which method comprises forming at least one compound of formula I, formula Ib or formula Ic into a suitable dosage form using a pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0135] The present invention further relates to methods for preparing compounds of formula I, formula Ib or formula Ic, which are described below and by which the compounds of the invention can be obtained.

[0136] The term "therapeutically effective (or effective) amount" and similar descriptions, e.g., "therapeutically effective amount," are intended to mean an amount of a pharmaceutical agent that alleviates the symptoms of the disorder, condition, or disease being treated in an animal or human (i.e., a disorder, condition, or disease associated with DGAT2 activity). The term "prophylactically effective (or effective) amount" and similar descriptions, e.g., "prophylactically effective amount," are intended to mean an amount of a pharmaceutical agent that prevents or reduces the symptoms or onset of the disorder, condition, or disease being treated in an animal or human (i.e., a disorder, condition, or disease associated with DGAT2 activity). Dosage regimens utilizing the compounds of the present invention are selected according to various factors, such as the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the potency of the selected compound being administered; the route of administration; and the patient's renal and hepatic function. Consideration of these factors is well within the purview of an ordinarily skilled clinician for the purpose of determining the therapeutically or prophylactically effective dose required to prevent, combat, or arrest the progression of the condition. It is understood that a particular daily dosage amount can be both a therapeutically effective amount (e.g., a therapeutically effective amount for treating hepatic steatosis, diabetes, obesity, hyperlipidemia, hypercholesterolemia) and a prophylactically effective amount (e.g., a prophylactically effective amount for treating NASH) at the same time.

[0137] Disorders, conditions, and diseases that can be treated or prevented by inhibiting DAGT2 with a compound of Formula I, Formula Ib, or Formula Ic include, for example, nonalcoholic steatohepatitis (NASH), liver fibrosis, hyperlipidemia, type I diabetes, type II diabetes, cognitive decline, dementia, coronary heart disease, ischemic stroke, restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial dyslipidemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic nephropathy, Diseases such as glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue disorders, hyperapo B lipoproteinemia, non-alcoholic fatty liver disease, cardiorenal diseases (e.g., chronic kidney disease and heart failure), and related diseases and conditions.

[0138] The compounds of Formula I, Formula Ib, or Formula Ic and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, particularly humans, as pharmaceuticals, either by themselves, in admixture with one another, or in the form of pharmaceutical preparations. The compounds of Formula I, Formula Ib, or Formula Ic and their pharmaceutically acceptable salts can be administered to animals, including dogs and cats, as pharmaceuticals, either by themselves, in admixture with one another, or in the form of pharmaceutical preparations. The term "patient" includes animals, preferably mammals, particularly humans, who use the active agents of the present invention for the prevention or treatment of a medical condition. Administration of a drug to a patient includes both self-administration and administration to the patient by another person. A patient may need or desire treatment for an existing disease or medical condition, or may need or desire prophylactic treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, a patient "in need" of treatment or prophylactic treatment for an existing condition includes both a medical professional's determination of need and the patient's desire for such treatment.

[0139] Furthermore, the subject of the present invention is a pharmaceutical formulation (or pharmaceutical composition) comprising, as active ingredient, a therapeutically effective dose of at least one compound of formula I, formula Ib or formula Ic and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier (i.e., one or more pharmaceutically acceptable carrier substances) and / or excipients.

[0140] Thus, the subject of the present invention is, for example, the said compounds and pharmaceutically acceptable salts thereof for use as medicaments, pharmaceutical preparations comprising said compounds and / or pharmaceutically acceptable salts thereof in a therapeutically effective dose as active ingredient and a customary pharmaceutically acceptable carrier, as well as the use of said compounds and / or pharmaceutically acceptable salts thereof in the treatment or prevention of the above-mentioned syndromes, and their use for preparing medicaments for these purposes.

[0141] The medicaments according to the invention can be administered orally, for example, in the form of pills, tablets, lacquered tablets, dragees, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be parenterally, for example, subcutaneously, intramuscularly or intravenously, in the form of solutions for injection or infusion. Other suitable administration forms are, for example, transdermal 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 administration form depends, for example, on the disease to be treated and its severity.

[0142] For the preparation of pills, tablets, dragees, and hard gelatin capsules, lactose, starch (e.g., corn starch) or starch derivatives, talc, stearic acid, or its salts, can be used. Carriers for soft gelatin capsules and suppositories include, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for preparing solutions (e.g., injectable solutions), emulsions, or syrups include, for example, water, saline, alcohols (e.g., ethanol, glycerin, polyols), sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. Furthermore, the compounds of Formula I, Formula Ib, or Formula Ic and their pharmaceutically acceptable salts can be lyophilized, and the resulting lyophilizates can be used, for example, to prepare preparations for injection or infusion. Suitable carriers for microcapsules, implants, or rods include, for example, glycolic acid and lactic acid copolymers.

[0143] Suitable solid or galenical formulation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, infusions or injection solutions, and formulations with sustained release of active substances, for the preparation of which customary excipients are used, such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners, solubilizers, etc. Commonly 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, such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol, and solvents, such as sterilized water and mono- or polyhydric alcohols (e.g., glycerol).

[0144] In addition to the active compound and carrier, the pharmaceutical formulations may also contain conventional additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, fragrances, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing osmotic pressure, coating agents or antioxidants.

[0145] The dosage of the active compound of Formula I, Formula Ib or Formula Ic and / or its pharmaceutically acceptable salts to be administered will depend on each individual case and, as is customary, should be adapted to the individual circumstances to achieve optimal efficacy, thus depending on the nature and severity of the disorder, condition or disease to be treated, as well as the sex, age, weight and individual response of the human or animal being treated, the potency and duration of action of the compound used, whether the therapy is acute or chronic or prophylactic, or whether other active compounds are administered in addition to the compound of Formula I, Formula Ib or Formula Ic.

[0146] Combination drugs The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents disclosed herein or other suitable agents, depending on the condition being treated. Accordingly, in some embodiments, one or more compounds of the present invention are co-administered with other agents as described herein. When used in combination therapy, the compounds described herein are administered simultaneously with the second agent or separately. This combined administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound of Formula (I) and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of Formula (I) and any of the agents described above can be administered simultaneously, with both agents being present in separate formulations. In another alternative, the compound of Formula (I) can be administered immediately followed by any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, the compound of Formula (I) and any of the agents described above are administered minutes apart, hours apart, or days apart.

[0147] Since one aspect of the present invention contemplates treating a disease / condition with a combination of pharmaceutically active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions, i.e., a compound of Formula (I) and a second pharmaceutical compound. The kit includes a container for housing the separate compositions, such as a divided bottle or a divided foil packet. Further 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 dosage intervals, or when titration of the individual components of the combination by the prescribing medical professional is desired.

[0148] One or more additional pharmacologically active agents can be administered in combination with a compound of Formula I, Formula Ib, or Formula Ic. An additional active agent is intended to mean a pharmaceutically active agent (different from the compound of Formula I, Formula Ib, or Formula Ic, and including the free acid, free base, and pharmaceutically acceptable salts of the additional active agent) that exhibits activity in the body, including prodrugs that are converted into a pharmaceutically active form after administration. Generally, any suitable additional active agent (including, but not limited to, antihypertensive agents, antiobesity agents, anti-inflammatory agents, antifibrotic agents, and antiatherosclerotic agents, such as lipid-modifying compounds, antidiabetic agents, and / or antiobesity agents) can be used in any combination with a compound of Formula I, Formula Ib, or Formula Ic in a single formulation (fixed-dose drug combination), or can be administered to a patient in one or more separate formulations that allow for simultaneous or sequential administration of the active agents (co-administration of separate active agents).

[0149] Examples of additional active agents that may be used 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, cipirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., in combination with losartan, i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan, and hydrochlorothiazide, such as HYZAAR®), any of these drugs that can be used in combination with other drugs; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., di- and tri-peptide urea derivatives, amino acids and derivatives, amino acid chains linked by non-peptide bonds, di- and tri-peptide derivatives, peptidyl aminodiols and peptidyl beta-aminoacyl aminodiol carbamates); and, further, small molecule renin inhibitors such as diol sulfonamides, N-morpholino derivatives, N-heterocyclic alcohols and pyrrolimidazolones;Furthermore, pepstatin derivatives and fluoro- and chloro-derivatives of statin-containing peptides, enalkrein, remikiren, A 65317, terlakiren, ES 1005, ES 8891, SQ 34017, SPP600, SPP630 and SPP635, endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalfil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, gallopamil, niludipine, nimodipine, nicardipine), potassium channel activators (e.g., nicorandil, pi nasidil, cromakalim, minoxidil, aprikalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholytics, beta-adrenergic blocking agents (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartrate), alpha-adrenergic blocking agents (e.g., doxazosin, prazosin, or alpha-methyldopa), central alpha-adrenergic agonists agonists, peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, such as HMG-CoA reductase inhibitors, e.g., simvastatin and lovastatin (which are marketed in lactone prodrug form as ZOCOR® and MEVACOR® and function as inhibitors after administration), and pharmaceutically acceptable salts of dihydroxy open-acid HMG-CoA reductase inhibitors, such as atorvastatin (particularly the calcium salt sold as LIPITOR®), rosuvastatin (particularly the calcium salt sold as CRESTOR®), pravastatin (particularly the sodium salt sold as PRAVACHOL®), fluvastatin (particularly the sodium salt sold as LESCOL®), cerivastatin, and pravastatin;Cholesterol absorption inhibitors, for example, ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid-lowering agent, such as the HMG-CoA reductase inhibitors described above, in particular ezetimibe in combination with simvastatin (VYTORIN®) or atorvastatin calcium; niacin in immediate-release or controlled-release form and / or niacin with an HMG-CoA reductase inhibitor; niacin receptor agonists, for example, acipimox and acifran, and niacin receptor partial agonists; anticholesterol drugs, for example, PCSK9 inhibitors (alirocumab, evolocumab), Nexletol; TM(bempedoic acid, an ACL inhibitor), Vascepa® (icosapent ethyl); metabolic altering agents), such as insulin and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, such as (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, such as (i) PPARα / γ dual agonists (e.g., ZYH2, ZYH1, GFT505, Tiglitazar, muraglitazar, aleglitazar, soderglitazar, and naveglitazar; (2) PPARα agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, and bezafibrate); (3) selective PPARγ modulators (SPPARγMs), (e.g., WO02 / 060388, WO02 / 08188, (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 sustained release formulations thereof, such as Glumetza. TM , Fortamet TM and GlucophageXR TMand (iv) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro, and inhaled formulations of each); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipidamide, amide, 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 mimetics, e.g., 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, e.g., their nasal, 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; drugs intended for use in inflammatory conditions, e.g., aspirin, nonsteroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and Selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (e.g., those disclosed in U.S. Pat. No. 6,730,690 and LY-2523199); CETP inhibitors (e.g., anacetrapib, torcetrapib, and evacetrapib); inhibitors of fructose 1,6-bisphosphatase (e.g., U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748;Nos. 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 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., those disclosed in WO2009 / 001836); neuromedin U receptor agonists (e.g., those disclosed in WO2009 / 042053, e.g., These include, but are not limited to, neuromedin S (NMS); SCD modulators (e.g., aramchol); GPR-105 antagonists (e.g., those disclosed in WO2009 / 000087); glucose pathway modulators, such as SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2, e.g., empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, BI-10773, remogliflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); dual SGLT-1 / 2 inhibitors (e.g., licogliflozin), glucose-6-P dehydrogenase inhibitors (e.g., fluasterone). LAPS glucagon combo (e.g., HM14320), SGLT-1 inhibitors (e.g., SGL5213); inhibitors of acyl-coenzyme A carboxylase (ACC, MK-4074); inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid synthase; inhibitors of acyl-coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2) inhibitors; agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; IL-1b antibodies (e.g., XOMA052 and canakinumab); anti-fibrotic and / or anti-inflammatory drugs (CCR2 / CCR5 dual receptor antagonists (e.g., cenicriviroc));Galectin 3 inhibitors (e.g., belapectin, GB-1107, GB-1211), siRNA against HSP47 (e.g., BMS-986263); NSAIDs derived from pirfenidone (e.g., hydronidone), A3AR agonists (e.g., namodenoson, FM101); TGFTX4 (e.g., nitazoxanide); 5-lipoxygenase inhibitors (e.g., tipelukast), bifunctional urate inhibitors (e.g., ACQT1127), adiponectin receptor agonists (e.g., ALY688), TNF receptor antagonists (e.g., atrocimab), autotaxin inhibitors (e.g., BLD-0409, TJ C0265, TJC0316), CCL24 blocking monoclonal antibodies (e.g., CM101), IL-11 inhibitors (e.g., ENx108A), LPA1 receptor antagonists (e.g., EPGN696), dual JAK1 / 2 inhibitors (e.g., EX76545), GPR antagonists (e.g., GPR91 antagonists), integrin avβ1, avβ3, and avβ6 inhibitors (e.g., IDL2965), NLRP3 antagonists (e.g., IFM-514), inflammasome inhibitors (e.g., JT194, JT349), cell membrane permeability inhibitors (e.g., larazotide), CCR5 antagonists (e.g., leronlimab), TN; F inhibitors (e.g., LIVNate), integrin avβ6 inhibitors (e.g., MORFbeta6), NLRP inflammasome antagonists, siRNA (e.g., OLX701), dual TFGβ / hedgehog inhibitors (e.g., Oxy200), GPR40 agonists / GPR84 antagonists (e.g., PBI-4547), neutrophil elastase inhibitors (e.g., PHP-303), integrin inhibitors (e.g., PLN-1474), TGFβ1 modulators (e.g., PRM-151), CCK receptor antagonists (e.g., proglumide), LOXL2 inhibitors (e.g., PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitors (e.g., cGAS / STING antagonists), kinase inhibitors, RNase, membrane protein mAbs, tumor necrosis factor inhibitors, NRF2 activators (e.g., SCO116), SSAO inhibitors (e.g., TERN201), TRAIL2 agonists (e.g., TLY012), IL-6 receptor antagonists (e.g., TZLS501), AOC3 inhibitors (e.g., UD-014), SSAO / VAP-1 inhibitors, TREM2; antioxidants (e.g., vitamin E); anti-inflammatory Antihypertensives (e.g., norfloxacin, ciprofloxacin, ceftriaxone); coagulation modulating agents (e.g., anticoagulants, antiplatelet agents, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonists (e.g., tirzepeptide); dual GLP-1 / GRA (e.g., cotadutide, ALT-801, DD01, G49, PB-718); dual GLP-1 (e.g., CT868); GLP-1 / GRA / GIP triple agonists (e.g., HM15211); GRP120 stimulators / inflammasome modulators / PPARγ dual agonists ( for example, KDT501); GLP-1 / FGF21 (for example, YH25724); GLP-1 agonists (for example, Ozempic (subcutaneous semaglutide), XW003); selective thyroid hormone receptor beta agonists (for example, resmetirom); apoptosis modulators (JNK-1 inhibitors (for example, CC-90001), peroxidase inhibitors (for example, AZM198), ASK-1 inhibitors (for example, CS-17919, SRT015)); erythropoietin stimulators (erythropoietin receptor agonists (for example, sibinetide)); immunomodulators (TLR4 inhibitors (for example,GBK-233), immunomodulatory polyclonal antibodies (e.g., IMM-124E), TLR4 antagonists (e.g., JKB-122), CD3 monoclonal antibodies (e.g., foralarumab), TLR4 antagonists (e.g., JKB133), TLR4 inhibitors (e.g., mocedipimod), macrophage inhibitors by CD206 targeting (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., ozen Pic (semaglutide sc), XW003), GLP-1 / glucagon dual receptor agonists (e.g., HM12525A), prandial insulin (e.g., ORMD0801); lipid modulators (AMPK activators / glutathione transferase inhibitors (e.g., oltipraz), THR-β agonists (e.g., resmetirom, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN501), IBAT inhibitors (e.g., elobixibat, CJ1419), omega-6 fatty acids (e.g., epereuton (e peleuton), FASN inhibitors (e.g., TVB2640, FT4101, FT8225), ANGPTL3 inhibitors (e.g., bupanorsen), PNPLA3 inhibitors (e.g., AZD2693), RAS domain kinase inhibitors (e.g., BioE1115), NTCP inhibitors (e.g., brevirtide), P2Y13 receptor agonists (e.g., CER-209), omega-3 fatty acids, HSD17β13 inhibitors, metabolic regulators (FXR agonists (e.g., Ocaliva (obeticholic acid), IOT022), recombinant variants of FGF19 (e.g., Aldafermi), ), bispecific FGFR1 / KLB antibodies (e.g., BFKB8488A), mTOT modulators (e.g., MSDC-0602K), pegylated analogs of FGF21 (e.g., pegbelfermin, BMS-986171), non-biliary FXR agonists (e.g., cilofexor, EDP-305, EYP001, tropifexor, MET409, AGN-242256, AGN-242266, EDP297, HPG1860, MET642, RDX023, TERN101), ACC inhibitors (e.g., filsocostat, PF-05221304),Ketohexokinase inhibitors (e.g., PF-06835919), AMPK activators (e.g., PXL770, MSTM101, O304), bile acid modulators (e.g., Albiero), FGF21 analogs (e.g., BIO89-100), MOTSc analogs (e.g., CB4211), cyclophilin inhibitors (e.g., CRV431), FGF19 (e.g., DEL30), mitochondrial uncouplers (e.g., GEN3026), FXR / GPCR dual agonists (e.g., INT-767), cysteamine derivatives (e.g., KB-GE- 001), dual amylin and calcitonin receptor agonists (e.g., KBP-089), transient FXR agonists (e.g., M1217), anti-β-klotho (KLB)-FGFR1c receptor complex mAb (e.g., MK3655), GDF15 mimetics (e.g., NGM395), cyclophilin inhibitors (e.g., NV556), LXR modulators (e.g., PX329, PX655, PX788), LXR inverse agonists (e.g., PX016), deuterated obeticholic acid (e.g., ZG5216); PPAR modulators (dual PPAR α / γ agonists (e.g., elafibranor), PPARpan agonists (e.g., lanifibranor), PPARα agonists (e.g., Palmodia), PPARγ agonists (e.g., CHS131), MPC inhibitors (e.g., PXL065), PPARδ / γ agonists (e.g., T3D959); RAASmIM modulators (mineralocorticoid receptor antagonists (e.g., aparenone, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulators, including CB1 receptor antagonists (e.g., CRB-4001, IM-102, nimasimab), TPH1 inhibitors (e.g., CU02), GPR120 agonists (e.g., KBR2001), and combinations of cannabinoids and botanical anti-inflammatory compounds (e.g., SCN002); PDE modulators (PDE4 inhibitors (e.g., ART648)); CYP2E1 inhibitors (e.g., SNP-610); cell therapy (e.g., HepaStem), and bromocriptine mesylate and its rapid-release formulations; or nitroprusside and diazoxide.Combination with other drugs useful in the prevention or treatment of the above diseases (where chemically possible, the free acid, free base and pharmaceutically acceptable salt forms of the above active drugs).

[0150] 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. Reference to a compound of structural formula (I) includes compounds of other general structural formulas, such as formulas and embodiments falling within the scope of formula (I).

[0151] Dosage of Compound of Formula (I) After completion of a treatment cycle, if the patient is responding or stable, the treatment cycle can be repeated according to the judgment of a skilled clinician. After completion of a treatment cycle, the patient can continue to receive the compound of the present invention at the same dose administered in the treatment protocol. This maintenance dose can be continued until the patient progresses or is no longer able to tolerate the dose (in which case the dose can be reduced and the patient can continue on the reduced dose).

[0152] Those skilled in the art will recognize that the actual dosages and administration protocols used in the methods of the present invention may be varied according to the judgment of a skilled clinician. The actual dosage used may vary depending on the needs of the patient and the severity of the condition being treated. Determination of the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. The decision to vary the dosage and administration protocol may be made by a skilled clinician 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 treatment.

[0153] Dosage regimens utilizing the compounds of the present invention are selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the potency of the compound selected for administration; the route of administration; and the patient's renal and hepatic function. Consideration of these factors is within the skill of the clinician in determining the therapeutically or prophylactically effective dose required to prevent, inhibit, or inhibit the progression of the condition. It is understood that a particular daily dosage may simultaneously be both a therapeutically effective amount (e.g., a therapeutically effective amount for treating an oncological condition) and a prophylactically effective amount (e.g., a prophylactically effective amount for preventing an oncological condition).

[0154] While individual needs vary, determination of optimal ranges for effective amounts of the compounds of the invention is within the skill of one in the art. For example, when administered to humans in the therapeutic or prophylactic treatment of the conditions and disorders identified herein, a typical dosage of a compound of the invention will be from about 0.05 mg / kg / day to about 50 mg / kg / day, e.g., 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 not more than 50 mg / kg, 40 mg / kg, 30 mg / kg, 20 mg / kg, or 10 mg / kg, which may be, for example, from about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dosage of the compound may be about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.05 mg / kg / day to about 10 mg / kg / day, about 0.05 mg / kg / day to about 5 mg / kg / day, about 0.05 mg / kg / day to about 3 mg / kg / day, about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / kg / day, or about 0.05 mg / kg / day to about 0.1 mg / kg / day. g / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses can be administered in a single dose or can be divided into multiple doses.

[0155] Pharmaceutical Composition The compounds of Formula I, Formula Ib, or Formula Ic and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, and particularly humans, as pharmaceuticals on their own, mixed with each other, or in the form of pharmaceutical compositions. The term "subject" or "patient" includes animals, preferably mammals, and particularly humans, who use the active agents to prevent or treat a medical condition.

[0156] Administration of a compound of Formula I, Formula Ib, or Formula Ic to a subject includes both self-administration and administration to the patient by another person. The subject may need or desire treatment for an existing disease or medical condition, or may need or desire prophylactic treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, a subject "in need" of treatment for an existing condition or prophylactic treatment includes both identification of the need by a medical professional and the patient's desire for such treatment.

[0157] After completion of a treatment cycle, if the patient is responding or stable, the treatment cycle can be repeated according to the judgment of a skilled clinician. After completion of a treatment cycle, the patient can continue to receive the compound of the present invention at the same dose administered in the treatment protocol. This maintenance dose can be continued until the patient progresses or is no longer able to tolerate the dose (in which case the dose can be reduced and the patient can continue on the reduced dose).

[0158] Those skilled in the art will recognize that the actual dosages and administration protocols used in the methods of the present invention may be varied according to the judgment of a skilled clinician. The actual dosage used may vary depending on the needs of the patient and the severity of the condition being treated. Determination of the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. The decision to vary the dosage and administration protocol may be made by a skilled clinician 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 treatment.

[0159] The dosage and frequency of administration of the compound of Formula I, Formula Ib, or Formula Ic and the additional agent will be regulated according to the judgment of the attending clinician (physician), taking into account factors such as the age, condition, and size of the patient, and the severity of the condition being treated.

[0160] The compounds of the present invention are further useful in the preparation of a medicament useful in the treatment of NASH and fibrosis.

[0161] The compounds of the present invention are also useful in combination with therapeutic, chemotherapeutic, and anticancer drugs for treating hepatocellular carcinoma. Combinations of the compounds of the present disclosure with therapeutic, chemotherapeutic, and anticancer drugs are within the scope of the present invention. Examples of such drugs can be found in "Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 9th edition (May 16, 2011), Lippincott Williams & Wilkins Publishers." A skilled artisan will be able to identify which combinations of drugs are useful based on the specific properties of the drugs and the cancer involved. Such agents include 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 / cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other anti-angiogenesis agents, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, gamma-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), and agents that interfere with cell cycle checkpoints.

[0162] The chemotherapeutic agent can be administered according to treatment protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent can be varied depending on the cancer being treated and the known effects of the chemotherapeutic agent on that disease. Furthermore, according to the knowledge of a skilled clinician, the treatment protocol (e.g., dosage and frequency of administration) can be modified taking into account the observed effects of the administered therapeutic agent on the patient and the observed response of the cancer to the administered therapeutic agent. The particular choice of chemotherapeutic agent depends on the diagnosis of the attending physician and their judgment of the patient's condition and the appropriate treatment protocol.

[0163] Initial administration can be according to established protocols known in the art, after which the dose, mode of administration and frequency of administration can be modified by a skilled clinician based on the observed effects.

[0164] The determination of the sequence of administration of chemotherapeutic agents and the number of repetitions of administration during a treatment protocol is within the knowledge of a skilled physician after evaluation of the condition being treated and the condition of the patient.

[0165] Thus, according to experience and knowledge, the practitioner may modify each protocol for the administration of chemotherapy drugs according to the needs of the individual patient as treatment progresses, and all such modifications are within the scope of the present invention.

[0166] The agents can be administered according to treatment protocols 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 that disease.

[0167] Initial administration can be according to established protocols known in the art, after which the dose, mode of administration and frequency of administration can be modified by a skilled clinician based on the observed effects.

[0168] The particular choice of medication will depend on the attending physician's diagnosis and their judgment of the patient's condition and the appropriate treatment protocol.

[0169] The determination of the order of administration of agents and the number of repetitions of administration during a treatment protocol is within the knowledge of a skilled physician after evaluation of the cancer being treated and the condition of the patient.

[0170] Thus, according to experience and knowledge, the practitioner may modify each protocol for administration of anticancer drugs according to the needs of the individual patient as treatment progresses, and all such modifications are within the scope of the present invention.

[0171] In determining whether treatment is effective at a given dosage, the attending physician will consider not only the patient's general health, but also more specific signs such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Tumor size can be measured by standard methods, such as radiological tests (e.g., CAT or MRI scans), and serial measurements can be used to determine whether tumor growth is slowing or reversing. Relief of disease-related symptoms (e.g., pain) and improvement in overall condition can also help determine the effectiveness of treatment.

[0172] The compounds, compositions, and methods provided herein are useful for treating cancer. Cancers that may be treated by the compounds, compositions, and methods disclosed herein include, but are not limited to, the following: Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

[0173] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL inhibitors include atezolizumab, avelumab, and durvalumab.

[0174] The present invention further relates to a method of treating hepatocellular carcinoma in a human patient, comprising 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.

[0175] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody or antigen-binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody or 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).

[0176] In some embodiments, the PD-1 antagonist is pembrolizumab. In certain subembodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In other subembodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.

[0177] In a further subembodiment, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every 3 weeks. In a particular subembodiment, the patient is a pediatric patient.

[0178] In some embodiments, the PD-1 antagonist is nivolumab. In certain subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other subembodiments, the method comprises administering 480 mg of nivolumab to the patient about every four weeks.

[0179] In some embodiments, the PD-1 antagonist is cemiplimab. In certain embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.

[0180] In some embodiments, the PD-1 antagonist is atezolizumab. In certain subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every 3 weeks.

[0181] In some embodiments, the PD-1 antagonist is durvalumab. In particular subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every two weeks.

[0182] In some embodiments, the PD-1 antagonist is avelumab. In certain subembodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks.

[0183] The compounds of the invention, or pharmaceutically acceptable salts thereof, may also be useful in treating cancer in combination with the following therapeutic agents: Pembrolizumab (Keytruda®), abarelix (Plenaxisdepot®); aldesleukin (Prokine®); aldesleukin (Proleukin®); alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene Gel (Targretin®); Bleomycin (Blenoxane®); Bortezomib (Velcade®); Busulfan intravenous (Busulfex®); Busulfan oral (Myleran®); Calsterone (Methosarb®); Capecitabine (Xeloda®); Carboplatin (Paraplatin®); Carmustine (BCNU®, BiCNU®); Carmustine (Gliadel®); Carmustine and polifeprosan 20 Implants (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);Dactinomycin, Actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); Daunorubicin liposomal (DanuoXome®); Daunorubicin, daunomycin (Daunorubicin®); Daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); Dexrazoxane (Zinecard®); Docetaxel (Taxotere®); Doxorubicin (Adriamycin PFS®); Doxorubicin (Adriamycin®, Rubex®); Doxorubicin (Adriamycin PFS Injection®); Doxorubicin Liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone injection®); Elliott's B Solution®; epirubicin (Ellence®); epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestane (Aromasin®); filgrastim (Neupogen®); floxuridine (intra-arterial) (FUDR®); fludarabine (Fludara) (registered trademark); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelinimplant®); hydroxyurea (Hydrea®); ibritumomab tiusetan (Zevalin®);Idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alpha-2a (RoferonA®); interferon alpha-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); leucovorin acetate Prolide (Eligard®); Levamisole (Ergamisol®); Lomustine, CCNU (CeeBU®); Mechlorethamine, Nitrogen Mustard (Mustargen®); Megestrol Acetate (Megace®); Melphalan, L-PAM (Alkeran®); Mercaptopurine, 6-MP (Purinethol®); Mesna (Mesnex®); Mesna (Mesnextabs®); Methotrexate (Methotrex®) ate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); nofetumomab (Verluma®); opelvequin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®) paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargas (Oncaspar®); pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);Pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); rasuburicase (Elitek®); rituximab (Rituxan®); ridaforolimus; sargramostim (Leukine®); sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®) trademark); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); tositumomab (Bexxar®); tositumomab / I-131 tositumomab (Bexxar®); trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); uracil mustard (Uracil Mustard Capsules®; valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®), and zoledronate (Zometa®), or pharmaceutically acceptable salts thereof;

[0184] Methods for Producing the Compounds of the Invention The following examples are provided so that the present invention might be more fully understood. Unless otherwise indicated, starting materials were commercially available. They should not be construed as limiting the invention in any way.

[0185] Several methods for preparing compounds of the present invention are illustrated in the following schemes and examples. Starting materials and intermediates are either commercially available, prepared from known procedures, or as otherwise described. Some frequently used routes to compounds of Formula I, Formula Ib, or Formula Ic are also illustrated by the schemes below. In some cases, the order in which the steps of the reaction schemes are carried out can be varied to facilitate the reaction or to avoid undesired reaction products. With respect to stereoisomers, Enantiomer A refers to the enantiomer that elutes faster / earlier upon separation, and Enantiomer B refers to the enantiomer that elutes slower / later upon separation; this nomenclature is maintained throughout the remaining synthetic procedures for a given enantiomeric series, regardless of whether subsequent intermediates and final compounds may have the same or opposite elution order. [Table 1] TIFF2025537517000031.tif234166LCMS 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).

[0186] Gradient conditions: 10-90% B in 1.7 min, total run time 2.4 min.

[0187] General synthetic scheme In addition to the specific examples given below, many alternatives, modifications, and variations thereof will be apparent to those skilled in the art. In some cases, the order of carrying out the steps of the reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. All such alternatives, modifications, and variations are intended to be within the spirit and scope of the present invention.

[0188] General Scheme 1 [ka] Compounds of Formula I, Ib, or Ic can be prepared by coupling 1-1 with R via SN2, SNAr, or copper-mediated CO coupling. 1 -X. Saponification of 1-2 gave the corresponding carboxylic acid (1-3), followed by the addition of the appropriate amine (R 2 Amide coupling with 4-( ... [Example]

[0189] Intermediates Intermediate 1 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine [ka] Step A: 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine To a mixture of 5-chloro-2-iodopyridin-3-ol (2.7 g, 10.6 mmol) and KCO (1.9 g, 13.7 mmol) in DMF (8.8 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (1.7 mL, 11.6 mmol) at 23 °C. After 1 h, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to give the title compound.

[0190] LC / MS = 320 [M+1]. Using the appropriate reagents and procedures similar to those described in INT-1, the following intermediates were synthesized and characterized by LC / MS. [Table 2] Intermediate 9 (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate [ka] Step A: (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol To a mixture of 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (0.88 g, 2.8 mmol) in toluene (15.3 mL) was added n-butyllithium solution (2.5 M in hexanes, 1.3 mL, 3.3 mmol) at −78° C. After 30 min, DMF (0.32 mL, 4.1 mmol) was added at −78° C. After 1 h, methanol (3.1 mL) was added sequentially, followed by sodium borohydride (0.21 g, 5.5 mmol), and the resulting mixture was then 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 under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound.

[0191] LC / MS = 224 [M+1] Step B: (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate 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) was added MsCl (48.8 μL, 0.63 mmol) at −78 °C. After 5 min, the mixture was allowed to warm 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 MgSO(s), filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0192] LC / MS = 302 [M+1] Using the appropriate reagents and procedures similar to those described in INT-9, the following intermediates were synthesized and characterized by LC / MS. [Table 3] Intermediate 11 3-(2,2,2-trifluoroethoxy)pyridine 1-oxide [ka] Step A: 3-(2,2,2-trifluoroethoxy)pyridine 1-oxide To a mixture of 3-(2,2,2-trifluoroethoxy)pyridine (1.86 g, 10.5 mmol) in DCM (21.0 mL) was added 3-chloroperbenzoic acid (2.18 g, 12.6 mmol) at 23 °C. After 24 h, the mixture was diluted with saturated aqueous NaHCO and DCM, and the organic layer was washed with water and brine. The organic layer was then dried over MgSO(s), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-10% methanol in DCM) to provide the title compound.

[0193] LC / MS = 194 [M+1] Example The following experimental procedures detail the preparation of certain examples of the present disclosure, which are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.

[0194] Example 1 Example 1: N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate 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'-bi(1,3,2-dioxaborolane) (4.25 g, 16.72 mmol), Pd(dppf)Cl (272 mg, 372 μmol), and potassium acetate (2.19 g, 22.30 mmol) was added dioxane (74.3 mL), and the reaction mixture was heated to 100° C. for 2 hours. The reaction mixture was cooled to room temperature, and water (535 μL, 29.7 mmol) and acetic acid (850 μL, 14.86 mmol) were added, 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 h. The reaction mixture was heated to 35° C. for an additional 2 h and subsequently quenched with sodium thiosulfate (saturated aqueous solution). The crude mixture was dried over MgSO, filtered, and concentrated. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-7% methanol in DCM to afford the title compound.

[0195] LC / MS = 207 [M+1] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate 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 bromotri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (PyBROP) (1.76 g, 3.78 mmol) sequentially. After 16 h, the solvent was removed under reduced pressure, and the crude material was subjected to silica gel flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to provide the title compound.

[0196] LC / MS = 382 [M+1] Step C: Lithium 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate 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) was added lithium hydroxide (37.3 mg, 1.56 mmol) at 20° C. After 30 min, the reaction mixture was concentrated under reduced pressure, and the crude material was used in the next reaction without further purification.

[0197] LC / MS = 354 [M-5] Step D: N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirring 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) was added HATU (445 mg, 1.17 mmol). After 18 h, the solvent was removed under reduced pressure, and the crude mixture was subjected to silica gel flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to provide the title compound.

[0198] LC / MS = 499 [M+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 Using the appropriate reagents, the following compounds were synthesized using procedures similar to those described in Example 1. The compounds were characterized by LC / MS. [Table 4] TIFF2025537517000040.tif227166TIFF2025537517000041.tif14166 Example 19 Example 21: 3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate To a stirring 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 h. The reaction mixture was subjected to silica gel flash column chromatography using a gradient of 0-70% ethyl acetate in hexane to provide the title compound.

[0199] LC / MS = 494 [M+1] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate To a screw-cap vial containing a magnetic stir bar, methyl 3-iodo-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (187 mg, 379 μmol), trifluoro(methyl)-14-borane potassium salt (55.5 mg, 455 μmol), RuPhos Pd G3 (29.5 mg, 38 μmol), and CsCO3 (445 mg, 1.37 mmol) was charged with toluene (3.45 mL) and water (345 μL) under nitrogen at 20 °C. The reaction mixture was heated to 80 °C for 16 h. The reaction mixture was again charged with trifluoro(methyl)-14-borane, potassium salt (55.5 mg, 455 μmol), CsCO (445 mg, 1.37 mmol), and CatAXium A Pd G (25.4 mg, 38 μmol). The reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc, dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-60% ethyl acetate in hexanes to provide the title compound.

[0200] LC / MS = 382 [M+1] Step C: Lithium 3-methyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate 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) was added lithium hydroxide (6.85 mg, 286 μmol) at 20° C. After 2 h, the reaction mixture was concentrated under reduced pressure to give the crude title compound.

[0201] LC / MS = 368 [M-5] Step D: 3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide 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) was added HATU (32.1 mg, 84 μmol). After 18 h, the reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (40-95% MeCN / water with 0.1% FA modifier) ​​to provide the title compound.

[0202] 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. Using the appropriate reagents and procedures similar to those described in Example 19, the following compounds were synthesized and characterized by LC / MS. [Table 5] Example 21 Example 23: 3-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate Methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate (175 mg, 476 μmol) was dissolved in acetonitrile (2.38 mL) and stirred. TM (186 mg, 524 μmol) was added in one portion at 0° C. 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 plug of SiO, concentrated under reduced pressure, and subjected to silica gel flash column chromatography using a gradient of 0-80% ethyl acetate in hexanes to give the desired product as a white solid.

[0203] LC / MS = 386 [M+1]. Step B: Lithium 3-fluoro-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate 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) was added lithium hydroxide (4.60 mg, 192 μmol) at 20° C. After 30 minutes, the reaction mixture was concentrated under reduced pressure to give the crude title compound.

[0204] LC / MS = 378 [M-5] Step C: 3-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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) at 20° C. After 18 h, the reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (40-80% MeCN / water with 0.1% FA modifier) ​​to provide the title compound.

[0205] LC / MS = 517 [M+1]. 1 H 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 Using the appropriate reagents, the following compounds were synthesized using procedures similar to those described in Example 21. The compounds were characterized by LC / MS. [Table 6] TIFF2025537517000046.tif221166TIFF2025537517000047.tif88166 Example 41 3-chloro-5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 5-Methoxy-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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 h, the solvent was removed under reduced pressure, and the reaction mixture was subjected to silica gel flash column chromatography using a gradient of 0-100% ethyl acetate in hexane to give the title compound.

[0206] LC / MS = 338 [M+1] Step B: 5-hydroxy-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirring mixture of 5-methoxy-N-(4-methyl-1,1-dioxidetetrahydro-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) was added NMP (11.9 mL), and the reaction mixture was heated to 160 °C under a gentle stream of nitrogen. After 16 h, the reaction mixture was poured into HCl (1 M aqueous solution) and extracted with DCM. The combined organic fractions were washed with HCl (1 M aqueous solution) and NaCl (saturated aqueous solution), dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-7% methanol in DCM to give the title compound.

[0207] LC / MS = 324 [M+1] Step C: 5-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirring solution of 5-hydroxy-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (100 mg, 309 μmol) and CsCO (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 to 60° C. for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography using a gradient of 0-80% EtOAc in hexanes to provide the title compound.

[0208] LC / MS = 577 [M+1] Step D: 5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirring mixture of 5-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (85 mg, 147 μmol), dicyanozinc (9.51 mg, 81 μmol), and Pd(PPh) (17.01 mg, 15 μmol) was added DMF (736 μL), and the reaction mixture was heated to 80° C. for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography using a gradient of 0-80% EtOAc in hexanes to provide the title compound.

[0209] LC / MS = 524 [M+1] Step E: 3-chloro-5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirring solution of 5-((5-cyano-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-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 hours. After cooling to room temperature, the reaction mixture was concentrated and subjected to silica gel flash column chromatography using a gradient of 0-70% ethyl acetate in hexane to provide the title compound.

[0210] 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 Using the appropriate reagents and procedures similar to those described in Example 41, the following compounds were synthesized and characterized by LC / MS. [Table 7] Example 43 5-((5-(cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate To a stirring solution of ethyl 5-hydroxypyrazolo[1,5-a]pyridine-2-carboxylate (300 mg, 1.46 mmol) and CsCO (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), and the reaction mixture was heated to 60° C. for 16 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography using a gradient of 0-80% ethyl acetate in hexanes to provide the title compound.

[0211] LC / MS = 461 [M+1] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)-5-vinylpyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate 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 sparged with nitrogen for 15 minutes at 20° C. The vial was charged with Pd(dppf)Cl (22.10 mg, 30 μmol), sealed, and heated at 85° C. After 16 h, the reaction was filtered through a plug of SiO and concentrated under reduced pressure. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-90% ethyl acetate in hexanes to provide the title compound.

[0212] LC / MS = 408 [M+1]. Step C: Lithium 5-((3-(2,2,2-trifluoroethoxy)-5-vinylpyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate To a stirring 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 under reduced pressure to provide the crude title compound.

[0213] LC / MS = 386 [M-5] Step D: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate To a stirring 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 h, the solvent was removed under reduced pressure, and the crude mixture was subjected to silica gel flash column chromatography using a gradient of 0-80% ethyl acetate in hexanes to provide the title compound.

[0214] LC / MS = 525 [M+1] Step E: 5-((5-formyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide Sodium periodate (192 mg, 900 μmol) was added to a stirred solution of N-(4-methyl-1,1-dioxidetetrahydro-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-dimethylpyridine (52.1 μL, 450 μmol), and potassium tetrahydroxydioxide osmium (2.1 mg, 5.62 μmol) in 1,4-dioxane (1.5 mL) and water (3.0 mL) at 0° C. The reaction mixture was stirred at 20° C. for 3 h, then diluted with NaCl (sat. aq.) and extracted with ethyl acetate. The combined organic fractions were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was subjected to silica gel flash column chromatography using a gradient of 0-90% ethyl acetate in hexanes to afford the title compound.

[0215] LC / MS = 527 [M+1] Step F: 5-((5-(cyclopropyl(hydroxy)methyl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirring solution of 5-((5-formyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-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) at 0° C. After 6 h, the reaction mixture was quenched with NaHCO (sat. aq.), dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by reverse-phase HPLC (20% MeOH / water with 0.1% FA modifier) ​​to provide the title compound.

[0216] 1 H 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 (IB-N column, faster elution with 20% MeOH / CO2): LC / MS = 569 [M+1]. Human DGAT2 IC 50 = 228 nM. EX-43b (IB-N column, slower elution with 20% MeOH / CO2): LC / MS = 569 [M+1]. Human DGAT2 IC 50 >9990 nM. Using the appropriate reagents and procedures similar to those described in Examples 43a and 43b, the following compounds were synthesized and characterized by LC / MS. [Table 8] Example 46 3-Ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-vinylpyrazolo[1,5-a]pyridine-2-carboxylate 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 sparged with nitrogen for 15 minutes at 20°C. The vial was charged with Pd(dppf)Cl (7.42 mg, 10.14 μmol), sealed, and heated at 85°C. After 16 hours, the reaction mixture was filtered through a plug of SiO and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography using a gradient of 0-90% ethyl acetate in hexanes to provide the title compound.

[0217] LC / MS = 394 [M+1] Step B: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate To a stirring 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) under nitrogen was added hydrogen (balloon). The reaction mixture was sparged with hydrogen for 3 minutes and stirred at 20° C. for 1 hour. The reaction mixture was sparged with argon for 5 minutes, diluted with DCM, filtered through Celite, and concentrated under reduced pressure to provide the title compound.

[0218] LC / MS = 396 [M+1]. Step C: Lithium 3-ethyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate To a stirring 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), and the reaction mixture was stirred at 40° C. After 2 h, the reaction mixture was concentrated under reduced pressure to provide the crude title compound.

[0219] LC / MS = 388 [M-5]. Step D: 3-ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide 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 provide the title compound.

[0220] LC / MS = 527 [M+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 = Human DGAT2 IC 50 = 17 nM Using the appropriate reagents and procedures similar to those described in Example 46, the following compounds were synthesized and characterized by LC / MS. [Table 9] Examples 49 and 50 3-(Difluoromethyl)-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (EX-50) [ka] Step A: Methyl 3-formyl-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate 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 tetrahydroxydiosmium oxide (5.55 mg, 15 μmol) in 1,4-dioxane (4.0 mL) and water (8.0 mL) at 0°C. The reaction mixture was stirred at 20°C. After 3 h, the reaction mixture was diluted with NaCl (sat. aq.) and extracted with ethyl acetate. The combined organic fractions were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was subjected to silica gel flash column chromatography using a gradient of 0-90% ethyl acetate in hexanes to afford the title.

[0221] LC / MS = 396 [M+1]. Step B: Methyl 3-(difluoromethyl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate A 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) was stirred and added with 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ 4 -sulfanamine (482 μL, 1.30 mmol) was added. The reaction mixture was warmed to 20° C. and stirred for 1 hour. The reaction temperature was increased to 40° C. After 4 hours, additional 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ 4 -sulfanamine (482 μL, 1.30 mmol) was added. After 12 h, an additional 5 equivalents of 1,1,1-trifluoro-N,N-bis(2-methoxyethyl)-λ 4-sulfanamine (2.41 mL, 6.51 mmol) was added via syringe. After 16 h, the reaction mixture was poured into ice and stirred for 20 min. The biphasic solution was extracted with DCM, dried over Na2SO4 and Na2CO3, filtered, and concentrated under reduced pressure. The crude material was subjected to silica gel flash column chromatography using a gradient of 0-70% ethyl acetate in hexanes to give the desired product.

[0222] LC / MS = 418 [M+1]. Step C: Lithium 3-(difluoromethyl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate To a stirring 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) was added lithium hydroxide (9.58 mg, 400 μmol) at 20° C. After 30 min, LCMS showed the reaction mixture was concentrated under reduced pressure to provide the title compound.

[0223] LC / MS = 410 [M-5] Step D: 3-(Difluoromethyl)-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide 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) was added HATU (32.0 mg, 84 μmol). After 18 h, the reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (50-98% MeCN / water with 0.1% FA modifier) ​​to obtain the title compound (EX-49: LC / MS = 549 [M+1]. Human DGAT2 IC 50 = 973 nM) and a by-product aldehyde (LC / MS = 527 [M+1]).

[0224] Step E: 3-(hydroxymethyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirred solution of 3-formyl-N-(4-methyl-1,1-dioxidetetrahydro-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) was added NaBH (1.9 mg, 50 μmol). After 1 h, the reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (40-95% MeCN / water with 0.1% FA modifier) ​​to give the title compound (EX-50).

[0225] LC / MS = 511 [M-18]. 1 H NMR (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. Example 51 N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Methyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate To a stirring 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-pyrrolidinone (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 under reduced pressure. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-80% ethyl acetate in hexanes to provide the title compound.

[0226] LC / MS = 436 [M+1]. Step B: Lithium 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxylate 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) was added lithium hydroxide (6.88 mg, 0.287 mmol) at 40° C. After 30 min, the reaction mixture was concentrated under reduced pressure to give the title product.

[0227] LC / MS = 428 [M-5] Step C: N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)pyrazolo[1,5-a]pyridine-2-carboxamide 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) was added HATU (29.0 mg, 76 μmol) at 20° C. After 18 h, the reaction mixture was filtered, and the filtrate was purified by reverse-phase HPLC (60-90% MeCN / water with 0.1% FA modifier) ​​to provide the title compound.

[0228] LC / MS = 567 [M+1]. 1 H 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 DGAT2 IC 50 = 828 nM. Example 52 3-(1-hydroxyethyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] 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 A stirred solution 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 sparged with nitrogen for 15 minutes at 20° C. The vial was charged with Pd(dppf)Cl (16 mg, 22 μmol) and heated to 85° C. After 16 hours, the reaction was filtered through a plug of SiO and concentrated under reduced pressure. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-80% ethyl acetate in hexanes to provide the title compound.

[0229] LC / MS = 408 [M+1] 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 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) was added lithium hydroxide (10.73 mg, 448 μmol) at 40° C. After 2 h, the reaction mixture was concentrated under reduced pressure to provide the title compound.

[0230] LC / MS = 394 [M-5]. Step C: N-(4-methyl-1,1-dioxidetetrahydro-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 To a stirring 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) was added HATU (179 mg, 470 μmol) at 20° C. After 18 h, the volatiles were removed under reduced pressure, and the reaction mixture was subjected to silica gel flash column chromatography using a gradient of 0-70% ethyl acetate in hexanes to provide the title compound.

[0231] LC / MS = 539 [M+1]. Step D: 3-acetyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide Sodium periodate (238 mg, 1.11 mmol) was added to a stirred solution of N-(4-methyl-1,1-dioxidetetrahydro-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 tetrahydroxydioxide osmium (2.57 mg, 6.96 μmol) in 1,4-dioxane (1.9 mL) and water (3.7 mL) at 0° C., and the mixture was allowed to warm to 20° C. After 3 h, the reaction mixture was diluted with NaCl (saturated aqueous solution) and extracted with ethyl acetate. The combined organic fractions were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was subjected to silica gel flash column chromatography using a gradient of 0-90% ethyl acetate in hexanes to afford the title compound.

[0232] LC / MS = 541 [M+1] Step E: 3-(1-hydroxyethyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxamide (Peak 2) To a stirring solution of 3-acetyl-N-(4-methyl-1,1-dioxidetetrahydro-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) was added NaBH (5.88 mg, 155 μmol) at 20 °C. After 1 h, the reaction mixture was quenched with NaHCO, dried over MgSO, filtered, and concentrated. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-100% EtOAc in hexanes to afford the crude racemic compound. SFC chiral resolution afforded the title compound.

[0233] 1 H 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). EX-52a (AD-H column, faster elution with 25% MeOH / CO2): LC / MS = 525 [M-18]. Human DGAT2 IC 50 = 1588 nM EX-52b (AD-H column, slower elution with 25% MeOH / CO2). LC / MS = 525 [M-18]. Human DGAT2 IC 50 = 333 nM. Example 53 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(2-hydroxy-2-methylpropyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 5-Bromo-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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, saturated aqueous solution), and extracted with DCM (100 mL × 3). The combined organic layers were washed with NaCl (100 mL, saturated aqueous solution), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using a 0-80% ethyl acetate / petroleum ether gradient to provide the title compound.

[0234] LC / MS = 386 [M+1] Step B: 5-hydroxy-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide A mixture of 5-bromo-N-(4-methyl-1,1-dioxidetetrahydro-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)Cl (0.379 g, 518 μmol) in dioxane (50 mL) was degassed and backfilled with N (three times). The mixture was heated to 90 °C for 13 h. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. Crude (2-((4-methyl-1,1-dioxidetetrahydro-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 N gas (3 times). The mixture was heated to 80° C. under N for 3 h. The mixture was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography using a gradient of 0-40% ethyl acetate / petroleum ether to provide the title compound.

[0235] LC / MS = 324 [M+1]. Step C: 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a mixture of 5-hydroxy-N-(4-methyl-1,1-dioxidetetrahydro-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), and picolinic acid (54 mg, 439 μmol) in DMSO (7 mL) was added CuI (71 mg, 373 μmol) in a glove box, and the reaction mixture was stirred at 80 °C. After 15 h, the reaction mixture was washed with NH4Cl (100 mL, saturated aqueous solution) and extracted with EtOAc (60 mL × 3). The combined organic layers were washed with NaCl (10 mL, saturated aqueous solution), dried over Na2SO4, and filtered. The filtrate was concentrated and the crude residue was subjected to silica gel flash column chromatography using a gradient of 0-40% EtOAc to afford the title compound.

[0236] LC / MS = 517 [M+1] Step D: 3-bromo-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (440 mg, 852 μmol) in THF (10 mL) at 25° C. After 2 h, the reaction mixture was quenched with NaSO (saturated aqueous solution) (30 mL) and then extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (15 mL), dried over NaSO, filtered, concentrated, and subjected to silica gel flash column chromatography using a gradient of 0–45% EtOAc / petroleum ether to give the title compound.

[0237] LC / MS = 597 [M+1] Step E: 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-(2-methylprop-1-en-1-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a mixture of 3-bromo-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-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 NaCO (54 mg, 509 μmol) in dioxane (4 mL) and HO (0.4 mL) was added Pd(dppf)Cl (13 mg, 18 μmol) under a N atmosphere. The reaction mixture was stirred at 100 °C. After 5 h, the mixture was poured into saturated NH4Cl (10 mL) and extracted with DCM (10 mL × 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 (30 mL / min) to give the title compound.

[0238] LC / MS = 571 [M+1] Step F: 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(2-hydroxy-2-methylpropyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide A mixture of 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-(2-methylprop-1-en-1-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (40 mg, 70 μmol), Mn(TMHD) (10 mg, 17 μmol), and PhSiH (40 mg, 0.37 mmol) in DCM (0.5 mL) / i-PrOH (5 mL) was stirred under O (15 psi) at 30 °C. After 14 h, MeCN (1 mL) was added, and the mixture was filtered and purified by reverse-phase HPLC (35-65% MeCN / water with 10 mM NHHCO modifier) ​​to give the title compound.

[0239] LC / MS = 589 [M+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 (br d, 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 Example 54 3-Cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 5-Bromo-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 3-bromo-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-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 CsCO (328 mg, 1.01 mmol) in toluene (4 mL) and HO (0.4 mL) under N was added RuPhos (33 mg, 71 μmol). The reaction mixture was stirred at 100° C. under N for 10 h. The mixture was concentrated under reduced pressure and purified by reverse phase HPLC (60-80% MeCN / water with 0.1% TFA modifier) ​​to provide the title compound.

[0240] 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 (br s, 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 Example 55 3-Amino-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 5-Bromo-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a mixture of 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (40 mg, 77 μmol) in HSO (0.5 mL) was added potassium nitroperoxous acid (12 mg, 119 μmol) at 0 °C, and the mixture was stirred for 2 h. The mixture was poured into saturated NaCO (40 mL) at 0 °C, stirred at 0 °C for 0.2 h, and extracted with DCM (15 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by pre-TLC (SiO, ethyl acetate / petroleum ether = 2:1) to give the title compound.

[0241] LC / MS = 562 [M+1] Step B: 3-amino-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a solution of 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3-nitropyrazolo[1,5-a]pyridine-2-carboxamide (15 mg, 27 μmol) in EtOAc (5 mL) was added Pd—C (5 mg, 47 μmol) and ammonium hydroxide solution (0.1 mL, 27 μmol) under a N atmosphere. The mixture was degassed and filled with H (3 times). The resulting mixture was stirred under H (15 psi) at 25° C. After 1 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase HPLC (60-80% MeCN / water with 0.1% TFA modifier) ​​to provide the title compound.

[0242] LC / MS = 532 [M+1]. 1 H 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 Example 56 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylic acid A mixture of NFSI (319 mg, 1.012 mmol), Pd(dba) (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 h. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC (TFA condition) to give the title compound.

[0243] LC / MS = 404 [M+1]. Step B: 4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylic acid To a mixture 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) in water (1 mL) / MeOH (1.0 mL) was added LiOH (3 mg, 125 μmol). The reaction mixture was stirred at 20 °C for 1 h, dissolved in HO, and treated with HCl (1 N aq.) until pH = 4. The mixture was extracted with EtOAc (10 mL × 3). The combined organic layers were washed with NaCl (20 mL, saturated aq.), dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0244] LC / MS = 390 [M+1]. Step C: 4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide A mixture of DIPEA (22 μL, 128 μmol), 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 for 2 h at 20° C. The residue was purified by reverse-phase HPLC (43-63% MeCN / water with 0.1% FA modifier) ​​to provide the title compound.

[0245] LC / MS = 535 [M+1]. 1 H NMR (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 Human DGAT2 IC 50 = 20 nM Example 57 6-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 4-(benzyloxy)-2-bromo-5-fluoropyridine To a stirred solution of 2-bromo-5-fluoropyridin-4-ol (0.5 g, 2.60 mmol) in DMF (7 mL) was added NaH (60% in oil) (0.156 g, 3.91 mmol) at 0 °C. After 30 min, (bromomethyl)benzene (0.464 mL, 3.91 mmol) was added, and the mixture was allowed to warm to 25 °C. After 2 h, the reaction mixture was poured into NH Cl (70 mL, saturated aqueous solution) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with NaCl (100 mL, saturated aqueous solution), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient of 0–30% EtOAc in petroleum ether to provide the title compound.

[0246] LC / MS = 282.0 and 284.0 [M+H] Step B: 4-(benzyloxy)-5-fluoro-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine To a stirring 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(PPh)Cl (50 mg, 71 μmol), and TEA (75 mg, 0.74 mmol) in THF (3 mL) was added CuI (15 mg, 79 μmol) in a glovebox. The reaction mixture was heated to 70 °C. After 10 h, the reaction mixture was poured into NH Cl (20 mL, saturated aqueous solution) and extracted with DCM (3 × 15 mL). The combined organic layers were washed with NaCl (10 mL, saturated aqueous solution), dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using a 0–20% EtOAc / petroleum ether gradient to provide the title compound.

[0247] LC / MS=342.1 [M+H] Step C: 1-amino-4-(benzyloxy)-5-fluoro-2-(3-hydroxyprop-1-yn-1-yl)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate To a stirred solution of O-(mesitylsulfonyl)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 h, the reaction mixture was concentrated under reduced pressure to give the crude title compound.

[0248] LC / MS = 273.1 [M+H] Step D: (5-(benzyloxy)-6-fluoropyrazolo[1,5-a]pyridin-2-yl)methanol 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 KCO (4.04 g, 29.2 mmol). After 15 h, the mixture was poured into NHCl (200 mL, saturated aqueous solution) and extracted with DCM (50 mL × 3). The combined organic layers were washed with NaCl (40 mL, saturated aqueous solution), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient of 0-40% EtOAc in petroleum ether to provide the title compound.

[0249] LC / MS=273.1 [M+H] Step E: 6-Fluoro-2-(hydroxymethyl)pyrazolo[1,5-a]pyridin-5-ol To a stirring solution 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) under N. The mixture was degassed, filled with H (3 times), and warmed to 45° C. under H (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 provide the title compound.

[0250] LC / MS = 183.1 [M+H] Step F: (6-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridin-2-yl)methanol K3P O4To a stirred solution of 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), and 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 provide the title compound.

[0251] LC / MS = 376.0 [M+H] Step G: 6-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carbaldehyde To a stirring 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 CHCl (1.5 mL) was added MnO (17 mg, 0.20 mmol) at 25° C. After 1 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound.

[0252] LC / MS = 374.0 [M+H] Step H: 6-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylic acid 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) was added KHPO (1 mg, 7.35 μmol) in water (1 mL) and NaClO (3 mg, 33 μmol) in water (2 mL) at 25° C. After 1 h, the mixture was poured into HO (10 mL) and lyophilized to give the crude title compound.

[0253] LC / MS = 390.0 [M+H] Step I: 6-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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) was added HATU (15.63 mg, 41 μmol) at 25° C. 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 provide the title compound.

[0254] LC / MS = 535.1 [M+1]. 1 H 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 IC 50 = 1.8 nM. Example 58 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 4-chloro-3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine 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(PPh)Cl (0.68 g, 0.97 mmol) and CuI (0.18 g, 0.97 mmol) in a glove box at 25 °C. The reaction was then sealed and stirred at 60 °C for 16 h. The crude product was extracted with EtOAc (40 mL × 3) and washed with HO (50 mL). The combined organic layers were washed with brine (40 mL), dried over NaSO, and filtered. The filtrate was concentrated to give a residue which was purified by silica gel flash chromatography using a gradient of 13% EtOAc in hexanes to give the title compound.

[0255] LC / MS = 266 [M+1] 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 To a mixture of O-(mesitylsulfonyl)hydroxylamine (2.048 g, 9.51 mmol) in DCM (15 mL) at 0° C. was added 4-chloro-3-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (1.5 g, 5.64 mmol), and the mixture was stirred at 20° C. for 15 h. The mixture was diluted with MTBE (80 mL). The precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound, which was used directly in the next step.

[0256] LC / MS = 281 [M++1] Step C: (5-chloro-4-methylpyrazolo[1,5-a]pyridin-2-yl)methanol 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 KCO (0.58 g, 4.16 mmol). After 15 h, the crude product was extracted with EtOAc (50 mL × 3), washed with HO (80 mL) and brine (80 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (SiO, petroleum ether / EtOAc = 1 / 1) and further purified by reverse-phase column chromatography using 40% MeCN to give the title compound.

[0257] LC / MS = 197 [M+1] Step D: 5-chloro-4-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde Manganese(IV) oxide (1.13 g, 12.97 mmol) was added to a stirring solution of (5-chloro-4-methylpyrazolo[1,5-a]pyridin-2-yl)methanol (170 mg, 0.87 mmol) in CHCl (5 mL), and the mixture was heated to 60° C. After 15 h, the mixture was filtered and concentrated to provide the title compound.

[0258] LC / MS = 195 [M+1] Step E: 5-chloro-4-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid 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 KHPO (36 mg, 0.27 mmol) in water (0.5 mL) and NaClO (118 mg, 1.31 mmol) in water (1.5 mL), sequentially. After 15 h, the reaction mixture was diluted with 15 mL of water, the pH was adjusted to pH 10 with NaOH (2 M aqueous solution), and the mixture was washed with EtOAc (20 mL × 3). The pH was then adjusted to pH 4 with HCl (1 N aqueous solution) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0259] LC / MS = 211 [M+1] Step F: 5-chloro-4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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 HO (30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was subjected to SiO flash column chromatography using EtOAc to give the title compound.

[0260] LC / MS = 356 [M+1] Step G: 4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a mixture of 5-chloro-4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (250 mg, 0.70 mmol), B2Pin2 (268 mg, 1.05 mmol), and potassium acetate (207 mg, 2.11 mmol) in 1,4-dioxane (2 mL) was added XPhos Pd G2 (55.3 mg, 70 μmol) under a N2 atmosphere. The mixture was stirred at 85 °C for 12 h. The crude product was extracted with EtOAc (20 mL × 3) and washed with HO (30 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel flash column chromatography using 50% EtOAc in hexane to give the title compound.

[0261] LC / MS = 448 [M+1] Step H: 5-hydroxy-4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a suspension of 4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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) was added NaBO*4HO (114 mg, 1.07 mmol) at 20 °C. After 3 h, the crude product was extracted with EtOAc (20 mL × 3) and washed with HO (30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and filtered. The filtrate was concentrated to give a residue, which was purified by prep-TLC (SiO, petroleum ether / EtOAc = 0 / 1) to give the title compound.

[0262] LC / MS = 338 [M+1] Step I: 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirred solution of 5-hydroxy-4-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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 KPO (151 mg, 0.711 mmol) in DMSO (2 mL) was added copper(I) iodide (5 mg, 0.026 mmol) in a glove box, and the reaction mixture was stirred at 95° C. for 15 h. The mixture was filtered to give a residue that was purified by reverse-phase HPLC (10-90% MeCN / water with 0.1% TFA modifier) ​​to give the title compound.

[0263] 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 Example 59 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 4-Bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine 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(PPh)Cl (979 mg, 1.40 μmol), and CuI (266 mg, 1.40 mmol) in THF (40 mL) was added TEA (3.89 mL, 27.9 mmol) in a glove box. The reaction mixture was heated to 80 °C. After 16 h, the crude product was extracted with EtOAc (50 mL × 3) and washed with HO (40 mL). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography using a gradient of 0-20% EtOAc in petroleum ether to afford the title compound.

[0264] LC / MS = 325 [M] 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 To a stirring mixture of O-(mesitylsulfonyl)hydroxylamine (341 mg, 1.57 mmol) in DCM (15 mL) was added 4-bromo-2-methyl-6-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (200 mg, 645 μmol) at 0° C., and the reaction mixture was then warmed to 15° C. After 15 h, the mixture was concentrated to provide the title compound.

[0265] LC / MS = 310 [M+1] Step C: (5-bromo-7-methylpyrazolo[1,5-a]pyridin-2-yl)methanol 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) was added K2CO3 (656 mg, 4.75 mmol) at 0 °C. The mixture was allowed to warm to 15 °C. After 15 h, 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 provide the title compound.

[0266] LC / MS = 241 [M+1] Step D: 5-Bromo-7-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde To a stirring solution of (5-bromo-7-methylpyrazolo[1,5-a]pyridin-2-yl)methanol (10 mg, 41 μmol) in CHCl (2 mL) was added MnO (72.1 mg, 0.83 mmol), and the reaction mixture was heated to 60° C. After 15 h, the mixture was filtered and concentrated to give the title compound.

[0267] LC / MS = 239 [M+1] Step E: 5-Bromo-7-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid To a stirred solution of 5-bromo-7-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde (9 mg, 38 μmol) in DMSO (0.4 mL) was added KH2PO4 (2 mg, 15 μmol) in water (0.1 mL) at 15 °C, followed by NaClO2 (5 mg, 55 μmol) in water (0.3 mL). After 15 h, the reaction mixture was diluted with water and the pH was adjusted to pH 10 with NaOH (2 N aqueous solution). The mixture was washed with EtOAc (2 mL × 3), the pH was adjusted to pH 4 with HCl (1 N aqueous solution), 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.

[0268] LC / MS = 255 [M+1] Step F: 5-bromo-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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) was added DIPEA (2.26 mL, 12.94 mmol) at 20 °C. After 30 min, water (100 mL) was added, and the mixture was extracted with EtOAc (150 mL). The combined organic fractions were washed with brine (120 mL), dried (NaSO), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography using 100% EtOAc to provide the title compound.

[0269] LC / MS = 401 [M+1] Step G: 7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide An 8 mL tube was charged with 5-bromo-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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)Cl (265 mg, 362 μmol) in dioxane (40 mL), and a stream of N was bubbled through for 2 min. The tube was sealed and heated to 100 °C. After 3 h, the mixture was cooled to room temperature, 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 (NaSO), filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient of 0-30% EtOAc in petroleum ether to afford the title compound.

[0270] Step H: 5-hydroxy-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a suspension of 7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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) was added NaBO*4HO (1.10 g, 10.33 mmol) at 15 °C. The mixture was stirred at 15 °C for 2 h. The crude product was extracted with EtOAc (20 mL × 3) and washed with HO (30 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using 100% EtOAc to provide the title compound.

[0271] Step I: 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirred solution of 5-hydroxy-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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), KCO (61.4 mg, 445 μmol), and N,N-dimethylglycine (3 mg, 29 μmol) in DMSO (2 mL) was added CuI (3 mg, 16 μmol) in a glovebox, and the mixture was heated to 90 °C. After 12 h, the mixture was purified by reverse-phase HPLC (42-62% MeCN / water with 0.1% FA modifier) ​​to provide the title compound.

[0272] LC / MS = 531 [M+1]. 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. Example 60 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 4-chloro-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine 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) was added Pd(PPh)Cl (866 mg, 1.23 mmol) and CuI (235 mg, 1.23 mmol) under a N atmosphere, and the reaction mixture was warmed to 60 °C. After 16 h, the crude product was extracted with EtOAc (40 mL × 3), washed with HO (50 mL) and NaCl (40 mL saturated aqueous solution), dried over NaSO, filtered, and concentrated. The crude residue was subjected to silica gel flash column chromatography using 10% EtOAc in hexane to give the title compound.

[0273] LC / MS = 266 [M+1] 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 To a stirred solution of O-(mesitylsulfonyl)hydroxylamine (1.706 g, 0.00 mmol) in DCM (15 mL) was added 4-chloro-5-methyl-2-(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)pyridine (480 mg, 1.806 mmol) at 0° C., and the reaction mixture was allowed to warm to 15° C. After 15 h, the mixture was concentrated to give the crude title compound.

[0274] LC / MS = 281 [M] Step C: (5-chloro-6-methylpyrazolo[1,5-a]pyridin-2-yl)methanol To a stirring 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 KCO (2.19 g, 15.84 mmol) at 20 °C. After 15 h, the crude product was extracted with EtOAc (40 mL × 3), washed with HO (80 mL) and NaCl (50 mL saturated aqueous solution), dried over NaSO, filtered, and concentrated to give a residue that was purified by reverse-phase HPLC (10-90% MeCN / water with 0.1% TFA modifier) ​​to give the title compound.

[0275] LC / MS = 197 [M+1] Step D: 5-chloro-6-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde To a solution of (5-chloro-6-methylpyrazolo[1,5-a]pyridin-2-yl)methanol (45 mg, 229 μmol) in CHCl (3 mL) was added MnO (398 mg, 4.58 mmol), and the mixture was stirred at 60° C. After 15 h, the mixture was filtered, and the filtrate was concentrated to give the title compound.

[0276] LC / MS = 195 [M+1] Step E: 5-chloro-6-methylpyrazolo[1,5-a]pyridine-2-carboxylic acid 5-Chloro-6-methylpyrazolo[1,5-a]pyridine-2-carbaldehyde (35 mg, 180 μmol) was dissolved in DMSO (2 mL). KH2PO4 (8 mg, 59 μmol) in water (0.5 mL) was added, followed by sodium chloride (25 mg, 276 μmol) in water (1.5 mL), and the mixture was stirred at 15 °C. After 2 h, the reaction was diluted with water (15 mL), the pH was adjusted to pH 10 with NaOH (2 M aqueous solution), and the mixture was washed with EtOAc (20 mL × 3). The pH of the aqueous layer was adjusted to pH 4 with HCl (1 N aqueous solution) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with NaCl (30 mL saturated aqueous solution), dried over Na2SO4, filtered, and concentrated to provide the title compound.

[0277] LC / MS = 211 [M+1]. Step F: 5-chloro-6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide 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 HO (30 mL) and brine (30 mL), dried over NaSO, and filtered. The filtrate was concentrated to give a residue, which was purified by prep-TLC (SiO, petroleum ether / EtOAc = 1 / 1) to give the title compound.

[0278] LC / MS = 356 [M+1] Step G: 6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a mixture of 5-chloro-6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide (30 mg, 84 μmol), B2Pin2 (32 mg, 126 μmol), and potassium acetate (25 mg, 255 μmol) in 1,4-dioxane (2 mL) was added XPhos Pd G2 (7 mg, 8.90 μmol) under a N2 atmosphere. The mixture was stirred at 85 °C for 12 h. The crude product was extracted with EtOAc (20 mL × 3), washed with HO (30 mL) and brine (30 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to give a residue, which was purified by prep-TLC (SiO2, petroleum ether / EtOAc = 1 / 2) to give the title compound.

[0279] LC / MS = 448 [M+1]. Step H: 5-hydroxy-6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a suspension of 6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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 NaBO*4HO (18 mg, 169 μmol). The mixture was stirred at 15 °C. After 1 h, the crude product was extracted with EtOAc (20 mL × 3), washed with HO (30 mL) and brine (30 mL), dried over NaSO, and filtered. The filtrate was concentrated to give a residue that was purified by prep-TLC (SiO, petroleum ether / EtOAc = 0 / 1) to give the title compound.

[0280] LC / MS = 338 [M+1] Step I: 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide To a stirred solution of 5-hydroxy-6-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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 KPO (28 mg, 132 μmol) in DMSO (1 mL) was added CuI (2 mg, 10.50 μmol) in a glovebox, and the reaction mixture was heated to 100 °C. After 15 h, the mixture was cooled to room temperature and filtered to give a residue that was purified by reverse-phase HPLC (10-90% MeCN / water with 0.1% FA modifier) ​​to give the title compound.

[0281] LC / MS = 531 [M+1]. 1 H 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 Example 61 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide [ka] Step A: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 5-Chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (777 mg, 2.43 mmol) was added 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), and the reaction mixture was heated to 90 °C. After 16 h, the reaction mixture was diluted with 50 mL of EtOAc and filtered through Celite. The solution was then washed twice with LiCl (1 N aq.), washed with NaCl (sat. aq.), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was subjected to silica gel flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to afford the title compound.

[0282] LC / MS = 399 [M+1] Step B: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid 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) was added lithium hydroxide (13.66 mg, 0.571 mmol) at 20° C. After 30 minutes, the solvent was removed under reduced pressure to provide the title compound.

[0283] LC / MS = 371 [M+1] Step C: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide To a stirring 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 under reduced pressure. The crude residue was subjected to SiO flash column chromatography using 0-100% ethyl acetate in hexanes to provide the title compound.

[0284] LC / MS = 516 [M+1] Step D: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-fluoro-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide A solution of 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide (86 mg, 167 μmol) in acetonitrile (833 μL) was stirred and added with Selectfluor TM (70.9 mg, 200 μmol) was added in one portion at 0° C. After 1 h, the reaction mixture was allowed to warm to room temperature and stirred for an additional 24 h. The reaction mixture was filtered through a plug of silica gel, concentrated under reduced pressure, and subjected to silica gel flash column chromatography using a gradient of 0-60% ethyl acetate in hexanes, followed by reverse-phase HPLC (35-70% MeCN / water (with 0.1% FA modifier)) to provide the title compound.

[0285] LC / MS = 534 [M+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 Using the appropriate reagents and procedures similar to those described in Example 61, the following compounds were synthesized and characterized by LC / MS. [Table 10] Example 63 7-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 1,2-Diamino-4-(benzyloxy)pyridin-1-ium 2,4,6-trimethylbenzenesulfonate To a mixture of O-(mesitylsulfonyl)hydroxylamine (0.68 g, 3.17 mmol) in DCM (10 mL) was added 4-(benzyloxy)pyridin-2-amine (0.64 g, 3.17 mmol) at 20° C. After 15 h, the reaction mixture was concentrated under reduced pressure to give the crude title compound.

[0286] LC / MS = 216 [M+1] Step B: Ethyl 7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate 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 2 h, the mixture was poured into NaCO (saturated aqueous solution) (70 mL) and extracted three times with DCM (70 mL). The combined organic layers were washed with brine (60 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography using a gradient of 0-80% ethyl acetate in petroleum ether to provide the title compound.

[0287] LC / MS = 298 [M+1] Step C: Ethyl 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirring 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 PdCl (149 mg, 841 μmol) in THF (9 mL) was added triethylsilane (1.34 mL, 8.41 mmol) dropwise at 25° C. After 2 h, the reaction mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography using a gradient of 0-90% ethyl acetate in petroleum ether to provide the title compound.

[0288] LC / MS = 208 [M+1] 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 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 KCO (500 mg, 3.62 mmol) in DMSO (4 mL) was added CuI (46.0 mg, 241 μmol) in a glove box, and the reaction mixture was heated to 100 °C. After 12 h, the mixture was cooled to room temperature, filtered, and the filtrate was purified by reverse-phase HPLC (43-73% ACN / 10 mM NHHCO) to provide the title compound.

[0289] LC / MS = 417 [M+1] 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 To a stirring 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 HO (0.4 mL) was added LiOH (30 mg, 714 μmol). After 13 h, the reaction mixture was concentrated under reduced pressure to give the crude title compound.

[0290] LC / MS = 389 [M+1] Step F: 7-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide 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), and the mixture was stirred at 25 °C. After 30 min, 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 provide the title compound.

[0291] LCMS = 534 [M+1]. 1 H 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, 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 DGAT2 IC 50 = 349 nM Using the appropriate reagents and procedures similar to those described in Example 63, the following compounds were synthesized and characterized by LC / MS. [Table 11] Example 67 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide [ka] Step A: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid To a stirred solution of sodium hydride (10.64 mg, 0.27 mmol) in THF (1.3 mL) was added (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol (49.6 mg, 0.22 mmol) at 0 °C. After 10 min, ethyl 5-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate (50 mg, 0.22 mmol) was added, and the mixture was allowed to warm to 20 °C. After 2 h, LiOH (7.96 mg, 0.33 mmol), MeOH (633 μL), and water (317 μL) were added. After 3 h, the reaction mixture was acidified with HCl (1 M, aq), diluted with water, and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq.), dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0292] LC / MS = 385 [M+1] Step B: 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide To a stirring 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 under reduced pressure, and the crude material was subjected to silica gel flash column chromatography using a gradient of 0-100% EtOAc in hexanes to provide the title compound.

[0293] LC / MS = 530 [M+1]. 1H 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. Using the appropriate reagents and procedures similar to those described in Example 67, the following compounds were synthesized and characterized by LC / MS. [Table 12] Assay Insect cell expression and membrane preparation 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 at 27°C in a shaking incubator. Cells were harvested after infection with an untagged baculovirus expressing human DGAT2 (hDGAT2) at a multiplicity of infection (MOI) of 3 for 48 hours. The cell pellet was suspended in a buffer containing 10 mM Tris-HCl (pH 7.5), 1 mM EDTA, 250 mM sucrose, and a complete protease inhibitor cocktail (Sigma-Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2,000 × g for 15 minutes. Membrane fractions were isolated by ultracentrifugation (100,000 × g), resuspended in the same buffer, and frozen (−80°C) for later use. Protein concentrations were measured using the Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific). Protein expression was analyzed by immunoblotting with rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa Fluor® 647 (Abcam, ab150075), followed by detection using a Typhoon FLA9000 (GE Healthcare).

[0294] LC / MS / MS analysis method LC / MS / MS analysis was performed using a Thermal Fisher LX4-TSQ Vantage system. This system consisted 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 sample from the upper organic layer of the in-plate liquid-liquid extraction was injected onto a Thermo Betabasic C4 column (2.1 mm × 20 mm, 5 μm particle size). The sample was 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 mode using a heated electrospray ionization (HESI) interface. The operating parameters for the TSQ Vantage MS / MS instrument were as follows: spray voltage 3000 V, capillary temperature 280°C, vaporizer temperature 400°C, sheath gas 40 arbitrary units, auxiliary gas 10 arbitrary units, S-lens 165, and collision gas 1.0 mTorr. 13 C 18 - Triolein (Q1: 920.8>Q3: 621.3) and internal standard 13 C 21 - Standard Reference Material (SRM) chromatograms of triolein (Q1: 923.8>Q3: 617.3) were collected for 33 seconds. Peak areas were integrated using Xcalibur Quan software. 13 C 18 -Triolein and internal standard 13 C 21 The ratio between the 100% ATP spiked with 100% triolein and that spiked with 100% triolein was used to obtain the percent inhibition and IC50 values. The percent compound inhibition was calculated by the following formula: % Inhibition = 1 - [(compound response - low control) / (high control - low control)] x 100%.

[0295] Potent compounds were titrated and IC 50 was calculated by a four-parameter sigmoidal curve fitting equation.

[0296] DGAT2 enzyme activity assay Using the membrane preparation described above, the enzyme product 13 C 18 -Triolein ( 13 DGAT2 activity was determined by measuring the amount of C-1,2,3-tri(cis-9-octadecenoyl)glycerol. The assay was performed in an ABgene 384-well assay plate at room temperature in a final volume of 25 μL. The assay mixture contained the following: assay buffer (100 mM Tris Cl, pH 7.0, 20 mM MgCl, 5% ethanol), 25 μM diolein, 5 μM C-oleoyl-CoA, and 8 ng / μL DGAT2 membranes.

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, X ３ is C(R ３ ) and N; X, Y and Z are N and C(R ４ ) independently selected from; R １ teeth, (1) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R ５ substituted with (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 contains 1, 2, or 3 R ５ (replaced by and R ２ teeth, (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-heterocyclyl, wherein the heterocyclyl is a 3-6 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) -SO ２ (C １－６ ) alkyl, or (7) -(C １－６ ) alkyl-NH-SO ２ -(C １－６ ) alkyl wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or R ５ substituted with 1, 2, 3, 4 or 5 substituents selected from: If present, R ３ teeth, (1) hydrogen, (2) halogens, (3) -NH ２ 、 (4) (C １－６ ) alkyl, (5) (C １－６ ) haloalkyl, (6) (C １－４ ) alkylhydroxy, or (7) -(C ３－６ ) cycloalkyl and If present, each R ４ is, independently, (1) hydrogen, (2) Halogen, or (3) (C １－３ ) alkyl and If present, each R ５ is, independently, (1) -OC １－６ Alkyl, (2) -O(C １－６ ) haloalkyl, (3) halogens, (4) cyano, (5) O—(C) optionally substituted with halogen ３－６ ) cycloalkyl, (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 and If present, each R ６ is, independently, (1) oxo, (2) (C １－６ ) alkyl, or (3) (C １－６ ) haloalkyl- is] or a pharmaceutically acceptable salt thereof.

2. Formula Ib: 【Chemistry 2】 [During the ceremony, R １ teeth, (1) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R ５ substituted with (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 contains 1, 2, or 3 R ５ (replaced by and R ２ teeth, (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-heterocyclyl, wherein the heterocyclyl is a 3-6 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) -SO ２ (C １－６ ) alkyl, or (7) -(C １－６ ) alkyl-NH-SO ２ -(C １－６ ) alkyl wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or R ６ substituted with 1, 2, 3, 4 or 5 substituents selected from: If present, R ３ teeth, (1) hydrogen, (2) halogens, (3) -NH ２ 、 (4) (C １－６ ) alkyl, (5) (C １－６ ) haloalkyl, (6) Hydroxy (C １－４ ) alkyl, or (7) -(C ３－６ ) cycloalkyl and Each R ４ is, independently, (1) hydrogen, (2) Halogen, or (3) (C １－３ ) alkyl Selected from: If present, each R ５ is, independently, (1) -OC １－６ Alkyl, (2) -O(C １－６ ) haloalkyl, (3) halogens, (4) cyano, (5) O—(C) optionally substituted with halogen ３－６ ) cycloalkyl, (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 Selected from: If present, each R ６ is, independently, (1) oxo, (2) (C １－６ ) alkyl, or (3) (C １－６ ) haloalkyl- is] The compound according to claim 1, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof.

3. Formula Ic: 【Transformation 3】 [During the ceremony, X ２ is CH or N; R ２ teeth, (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-heterocyclyl, wherein the heterocyclyl is a 3-6 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) -SO ２ (C １－６ ) alkyl, or (7) -(C １－６ ) alkyl-NH-SO ２ -(C １－６ ) alkyl wherein each alkyl, cycloalkyl and heterocycle is unsubstituted or R ６ substituted with 1, 2, 3, 4 or 5 substituents selected from: If present, R ３ teeth, (1) hydrogen, (2) halogens, (3) -NH ２ 、 (4) (C １－６ ) alkyl, (5) (C １－６ ) haloalkyl, (6) Hydroxy (C １－４ ) alkyl, or (7) -(C ３－６ ) cycloalkyl and Each R ４ is, independently, (1) hydrogen, (2) Halogen, or (3) (C １－３ ) alkyl and If present, each R ５ａ is, independently, (1) -OC １－６ Alkyl, (2) -O(C １－６ ) haloalkyl, or (3) O-(C ３－６ ) cycloalkyl and If present, each R ５ｂ is, independently, (1) halogens, (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 and If present, each R ６ is, independently, (1) oxo, (2) (C １－６ ) alkyl, or (3) (C １－６ ) haloalkyl- is] The compound according to claim 1, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof.

4. R １ teeth, (1) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 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 halogen, OC １－６ Alkyl and O(C １－６ ) substituted with 1, 2, or 3 substituents independently selected from haloalkyl 3. The compound according to claim 1 or 2, wherein:

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

6. R １ is a 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 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 6. The compound according to any one of claims 1 to 2, 4 to 5, or a pharmaceutically acceptable salt thereof, which is substituted with 1, 2 or 3 substituents independently selected from hydroxyhaloalkyl.

7. R １ is a 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, OCH ２ CF ３ , OCH ２ CF ２ H, O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH ３ )OH and CH(CF ３ 7. The compound according to any one of claims 1 to 2, 4 to 6, or a pharmaceutically acceptable salt thereof, which is substituted with 1, 2 or 3 substituents independently selected from: ) OH.

8. R １ is -(C １－３ ) alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing one nitrogen atom, wherein the heteroaryl is unsubstituted or is selected from the group consisting of Cl, OCH ３ , OCH ２ CH ３ and OCH ２ CHF ２ 6. The compound according to any one of claims 1-2, 4-5, or a pharmaceutically acceptable salt thereof, which is substituted with 1, 2, or 3 substituents independently selected from:

9. R ２ teeth, (1) A 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is oxo, C １－３ Alkyl or C １－３ and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkyl. (2) -(C ３－６ ) cycloalkyl, (3) -(C １－６ ) hydroxyalkyl, or (4) -(C １－６ ) alkyl-NH-SO ２ -(C １－６ ) alkyl 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein:

10. R ２ is a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is oxo, C １－３ Alkyl or C １－３ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from haloalkyl.

11. R ２ is a 4- to 7-membered heterocyclyl containing one or two heteroatoms independently selected from N, O and S, wherein the heterocyclyl is oxo, CH ３ , CHF ２ or CH ２ CF ３ 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from:

12. R ２ is C(CH ３ ) ２ CH ２ C(CH ３ ) ２ 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R is OH.

13. R ２ is a 6-membered heterocycle containing one nitrogen atom, wherein the heterocycle is oxo, -(C １－３ ) alkyl and -(C １－３ 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 or 2 substituents independently selected from: haloalkyl.

14. R ２ is a 5-membered heterocycle containing one nitrogen atom, wherein the heterocycle is oxo, -(C １－３ ) alkyl and -(C １－３ 11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, optionally substituted with 1 or 2 substituents independently selected from: haloalkyl.

15. R ２ is -(C １－６ ) alkyl-NH-SO ２ -(C １－６ 10. The compound of claim 1, wherein R is 1 or 2. 11.) alkyl, or a pharmaceutically acceptable salt thereof.

16. R ２ is CH(CH ３ ) ２ CH ２ NHSO ２ CH ３ 16. The compound according to any one of claims 1 to 9 or 15, or a pharmaceutically acceptable salt thereof, wherein:

17. R ３ is hydrogen, halogen, (C １－６ ) alkyl, -(C １－６ ) haloalkyl, -(C １－６ ) hydroxyalkyl, —(C ３－６ ) cycloalkyl or —NH ２ 17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein:

18. R ３ is hydrogen, halogen, CH ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , CH(F ２ ), C.H. ２ OH, CF ３ , CH(OH)CH ３ , C.H. ２ C(OH)(CH ３ ) ２ , cyclopropyl or —NH ２ 18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein:

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

20. R ４ is H, Cl, F or CH ３ 20. The compound according to any one of claims 1 to 19, wherein:

21. 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 21. The compound according to any one of claims 1 to 2, 9 to 20, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

22. R ５ is a halogen, OCH ３ , OCH ２ CH ３ , -OCH ２ CF ３ , OCH ２ CHF ２ , O-cyclopropyl, CN, CH(cyclopropyl)OH, CH(CH ３ )OH or CH(CF ３ 22. The compound according to any one of claims 1 to 2, 9 to 21, or a pharmaceutically acceptable salt thereof, wherein:

23. R ５ａ is OCH ２ CHF ２ , OCH ２ CF ３ 21. The compound according to any one of claims 3, 9 to 20, or a pharmaceutically acceptable salt thereof, wherein R is O-cyclopropyl.

24. R ５ｂ is halogen, CH(cyclopropyl)OH, CN, CH(CH ３ ) OH, CH(CF ３ 24. The compound of any one of claims 3, 9-20 or 23, or a pharmaceutically acceptable salt thereof, wherein:

25. R ６ is oxo, (C １－６ ) alkyl or (C １－６ 23. The compound of any one of claims 1-2 or 9-22, or a pharmaceutically acceptable salt thereof, wherein:

26. R ６ is oxo, CH ３ , CHF ２ or CH ２ CF ３ 26. The compound according to any one of claims 1 to 2, 9 to 22 or 25, or a pharmaceutically acceptable salt thereof, wherein

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

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

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

30. X is C(R ４ ) and Y is C(R ４ ) and Z is N, or a pharmaceutically acceptable salt thereof.

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

32. X ３ is C(R ３ 27. The compound according to any one of claims 1, 4-22, or 25-26, or a pharmaceutically acceptable salt thereof, wherein

33. below, N-(4-methyl-1,1-dioxidetetrahydro-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-dioxideisothiazolidin-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-dioxidothietan-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-dioxidetetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 5-((3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 5-((3-cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 5-((3-cyclopropoxy-5-fluoropyridin-2-yl)oxy)-N-(3-methyl-1,1-dioxidothietan-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydrothiophen-3-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 3-fluoro-N-(3-methyl-1,1-dioxidothietan-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-dioxidetetrahydrothiophen-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydrothiophen-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-dioxidetetrahydrothiophen-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-dioxidothietan-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-dioxidetetrahydrothiophen-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-dioxidothietan-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; 3-chloro-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyridine-2-carboxamide; (R)—N-(3-methyl-1,1-dioxidothietan-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidothietan-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxidetetrahydro-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-dioxide-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-dioxidothietan-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-((6-methoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 5-((6-ethoxypyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-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-dioxidetetrahydro-2H-thiopyran-4-yl)pyrazolo[1,5-a]pyrimidine-2-carboxamide; 2. The compound of claim 1, wherein:

34. below, 【Chemistry 4】 【change】 【change】 2. The compound of claim 1, wherein:

35. below, 【Transformation 5】 35. The compound of claim 34, wherein:

36. 36. A composition for treating a condition selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease, and heart failure, comprising a compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

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

38. 36. A method for treating a condition selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease and heart failure, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any of claims 1 to 35, or a pharmaceutically acceptable salt thereof.

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

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