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

Abstract

Provided are compounds of Formula I that are DGAT2 inhibitors, as well as pharmaceutically acceptable salts, esters, and prodrugs thereof. Also provided are methods of making compounds of Formula I, pharmaceutical compositions containing 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, comprising administering a compound of Formula I to a patient in need of such treatment. [Formula 1] TIFF2025537516000053.tif31163

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international application claims the benefit of priority to U.S. Provisional Application No. 63 / 421,375, 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, 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 4 ) 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 4 (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) 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N or O; (3) -(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 or O; (4) -(C 1-6 ) alkyl-aryl, (5) -(C 3-6 ) cycloalkyl, (6) -(C 1-6 ) hydroxyalkyl, or (7) -SO2(C 1-6 ) alkyl and wherein each alkyl, aryl, cycloalkyl, heteroaryl, and heterocycle is unsubstituted or contains one, two, or three R 6 is replaced by; Each R 3 teeth, (1) Hydrogen, (2) Halogen, or (3) (C 1-3 ) alkyl are independently selected from; If present, each R 4 is, independently, (1) -OC 1-6 Alkyl, (2) -O(C 1-6 ) haloalkyl, (3) Halogen, or (4) OC optionally substituted with halogen 1-6 Alkyl-(C 3-7 )Cycloalkyl and; If present, each R 6 is, independently, (1) halogens, (2) Hydroxy, (3) Cyano, (4) oxo, (5) (C 1-6 ) alkyl, (6) (C 1-3 ) alkylhydroxy, (7) (C 1-6 ) haloalkyl-, (8) -O(C 1-6 ) alkyl, or (9) -O(C 1-6 ) Haloalkyl is] or a pharmaceutically acceptable salt thereof.

[0013] Embodiment 2 of the present disclosure is a compound of Formula I or embodiment 1 or a class 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 contains one, two, or three R 4 ) or (2) -(C 1-6 ) alkyl-heteroaryl (wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 nitrogen atoms, where the heteroaryl is unsubstituted or contains 1, 2, or 3 R 4 (replaced by is.

[0014] Embodiment 3 of the present disclosure is a compound of Formula I or Embodiments 1-2 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 ) OC optionally substituted with haloalkyl or halogen 1-6 Alkyl-(C 3-7 ) substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; or (2) -(C 1-6 ) alkyl-heteroaryl (wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 nitrogen atoms, where the heteroaryl is unsubstituted or substituted with halogen, -OC 1-6 Alkyl, O-(C 1-6 ) OC optionally substituted with haloalkyl or halogen 1-6 Alkyl-(C 3-7 ) substituted with 1, 2, or 3 substituents independently selected from cycloalkyl is.

[0015] Embodiment 4 of the present disclosure is a compound of Formula I or embodiments 1-3 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, -OC 1-6 Alkyl, O-(C 1-6 ) OC optionally substituted with haloalkyl or halogen 1-6 Alkyl-(C 3-7 ) substituted with 1, 2, or 3 substituents independently selected from cycloalkyl;

[0016] Embodiment 5 of the present disclosure is a compound of Formula I or embodiments 1-4 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from F, Cl, OCHCF, OCHCH, OCHCHF, OCH-cyclopropyl-F, or OCHCFCH.

[0017] Embodiment 6 of the present disclosure is a compound of Formula I or embodiments 1-3 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-6 ) alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, -OC 1-6 Alkyl, -O(C 1-6 ) OC optionally substituted with haloalkyl or halogen 1-6 Alkyl-(C 3-7 ) substituted with 1, 2, or 3 substituents independently selected from cycloalkyl;

[0018] Embodiment 7 of the present disclosure is a compound of Formula I or embodiments 1-3 or 6 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-6 ) 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 halogen and -O(C 1-6 ) substituted with 1 or 2 substituents independently selected from haloalkyl.

[0019] Embodiment 8 of the present disclosure is a compound of Formula I or embodiments 6-7 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-6 ) 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 halogen, OCH2CH3, OCH2CF3, or OCH2CHF2.

[0020] Embodiment 9 of the present disclosure is a compound of Formula I or embodiment 6-7 or 6 or a class thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-6 ) 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 F, Cl, OCHCF, or OCHCHF.

[0021] Embodiment 10 of the present disclosure is a compound of Formula I or any one of Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0022] Embodiment 11 of the present disclosure is a compound of Formula I or any one of embodiments 1-10, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (2) -(C 3-6 )Cycloalkyl wherein each cycloalkyl or heterocycle is unsubstituted or contains 1, 2, or 3 R 6 is replaced by .

[0023] Embodiment 12 of the present disclosure is a compound of Formula I or any of Embodiments 1-11, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (2) -(C 3-6 )Cycloalkyl wherein each cycloalkyl or heterocycle is unsubstituted or is selected from the group consisting of hydroxy, halogen, (C 1-6 ) Alkyl, OC 1-6 Alkyl, (C 1-6 ) substituted with 1, 2, or 3 substituents independently selected from haloalkyl- or oxo.

[0024] Embodiment 13 of the present disclosure is a compound of Formula I or any one of embodiments 1-12, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (2) -(C 3-6 )Cycloalkyl wherein each cycloalkyl or heterocycle is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from OH, F, oxo, CH, OCH, CF, or CHCF.

[0025] Embodiment 14 of the present disclosure is a compound of Formula I or any one of Embodiments 1-11, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocycle is unsubstituted or contains 1, 2 or 3 R 6 is replaced by .

[0026] Embodiment 15 of the present disclosure is a compound of Formula I or any one of embodiments 1-12 or 14, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocycle is unsubstituted or is substituted with halogen, hydroxy, (C 1-6 ) alkyl, oxo, -O(C 1-6 ) alkyl or (C 1-6 ) haloalkyl-substituted with 1, 2, or 3 substituents independently selected from

[0027] Embodiment 16 of the present disclosure is a compound of Formula I or any one of embodiments 1-12, 14, or 15, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocycle is unsubstituted or is substituted with halogen, hydroxy, (C 1-6 ) alkyl, oxo or (C 1-6 ) haloalkyl-substituted with 1, 2, or 3 substituents independently selected from

[0028] Embodiment 17 of the present disclosure is a compound of Formula I or any one of embodiments 1-12 or 14-16, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocycle containing one heteroatom independently selected from O and S, wherein the heterocycle is unsubstituted or 1-6 ) alkyl, oxo or (C 1-6 ) haloalkyl-substituted with 1, 2, or 3 substituents independently selected from

[0029] Embodiment 18 of the present disclosure is a compound of Formula I or any one of embodiments 1-17, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-7 membered heterocycle containing one heteroatom independently selected from O and S, wherein the heterocycle is unsubstituted or substituted with one, two or three substituents independently selected from CH, oxo or CHCF.

[0030] Embodiment 19 of the present disclosure is a compound of Formula I or any one of embodiments 1-11, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -(C 3-6 ) cycloalkyl, wherein the cycloalkyl is unsubstituted or has one, two, or three R 6 is replaced by .

[0031] Embodiment 20 of the present disclosure is a compound of Formula I or any one of embodiments 1-11 or 19, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -(C 3-6 ) cycloalkyl, wherein the cycloalkyl is unsubstituted or is substituted with hydroxy, halogen, (C 1-6 ) Alkyl, OC 1-6 Alkyl or (C 1-6) haloalkyl-substituted with 1, 2, or 3 substituents independently selected from

[0032] Embodiment 21 of the present disclosure is a compound of Formula I or any one of embodiments 1-11 or 19-20, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -(C 3-6 ) cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from OH, F, CH3, OCH3, or CF3.

[0033] Embodiment 22 of the present disclosure is a compound of Formula I or any one of embodiments 1-11, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, [ka] is.

[0034] Embodiment 23 of the present disclosure is a compound of Formula I or embodiments 1-22 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, halogen or C 1-3 alkyl.

[0035] Embodiment 24 of the present disclosure is a compound of Formula I or embodiments 1-23 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 are independently selected from hydrogen, halogen, or CH3.

[0036] Embodiment 25 of the present disclosure is a compound of Formula I or embodiments 1-24 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 are independently selected from hydrogen, F, or CH3.

[0037] Embodiment 26 of the present disclosure is a compound of Formula I or embodiments 1-1-2, 11-25 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 is halogen, -OC 1-6 Alkyl, O-(C 1-6 ) OC optionally substituted with haloalkyl or halogen 1-6 Alkyl-(C 3-7 ) cycloalkyl.

[0038] Embodiment 27 of the present disclosure is a compound of Formula I or embodiments 1-2, 11-27 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 is halogen, OCH2CF3, OCH2CH3, OCH2CHF2, OCH2-cyclopropyl-F or OCH2CF2CH3.

[0039] Embodiment 28 of the present disclosure is a compound of Formula I or embodiments 1-2, 11-27 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 is F, Cl, OCH2CF3, OCH2CH3, OCH2CHF2, OCH2-cyclopropyl-F or OCH2CF2CH3.

[0040] Embodiment 29 of the present disclosure is a compound of Formula I or embodiments 1-11, 14, 19, 23-28 or a class thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 6 is halogen, hydroxy, (C 1-6 ) Alkyl, oxo, -OC 1-6 Alkyl or (C 1-6 ) haloalkyl-.

[0041] Embodiment 30 of the present disclosure is a compound of Formula I or embodiments 1-11, 14, 19, 23-29 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 6are independently selected from halogen, hydroxy, CH3, oxo, OCH3, CF3, or CH2CF3.

[0042] Embodiment 31 of the present disclosure is a compound of Formula I or embodiments 1-11, 14, 19, 23-30 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 6 are independently selected from F, hydroxy, CH3, oxo, OCH3, CF3, or CH2CF3.

[0043] In embodiment 32 of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof is 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; N-(4,4-difluoro-1-methyl-cyclohexyl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; N-(3,3-difluoro-1-methyl-cyclobutyl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 5,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 8-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[3-(2,2-difluoroethoxy)pyrazin-2-yl]oxy-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; or 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; is.

[0044] In embodiment 33 of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof is [ka] The file is TIFF2025537516000007.tif134130.

[0045] Embodiment 34 is [ka] or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 35 is [ka] or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 36 is [ka] or a pharmaceutically acceptable salt thereof.

[0048] Embodiment 37 is [ka] or a pharmaceutically acceptable salt thereof.

[0049] Embodiment 38 is [ka] or a pharmaceutically acceptable salt thereof.

[0050] Embodiment 39 is [ka] or a pharmaceutically acceptable salt thereof.

[0051] The present disclosure includes pharmaceutically acceptable salts of the compounds defined herein.

[0052] In one embodiment, the disclosure is a composition comprising an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof.

[0053] The present disclosure further provides pharmaceutical compositions comprising an effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0054] The present disclosure further provides pharmaceutical compositions comprising an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and an effective amount of at least one other pharmaceutically active ingredient (e.g., a chemotherapeutic agent).

[0055] The present disclosure also provides pharmaceutical compositions comprising an effective amount of at least one compound of Formula I 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.

[0056] 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 or a pharmaceutically acceptable salt thereof.

[0057] 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 or a pharmaceutically acceptable salt thereof.

[0058] 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 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0059] 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 or a pharmaceutically acceptable salt thereof.

[0060] 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 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0061] 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.

[0062] 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 or a pharmaceutically acceptable salt thereof.

[0063] 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, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0064] 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 or a pharmaceutically acceptable salt thereof.

[0065] 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 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0066] In another embodiment, the present disclosure provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating NASH and / or fibrosis.

[0067] In another embodiment, the present disclosure encompasses the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of NASH and / or fibrosis.

[0068] "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 1-6Within 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 are intended for straight or branched chain alkyl groups.

[0069] "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.

[0070] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

[0071] "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.

[0072] "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.

[0073] "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.

[0074] 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.

[0075] "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.

[0076] "Hydroxyalkyl" or "-hydroxy(C 1-3 ")Alkyl" means an alkyl group in which one or more hydrogen atoms have been replaced with a hydroxyl (-OH) group.

[0077] 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.

[0078] 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.

[0079] The term "chemotherapeutic agent" refers to a drug (medicine or pharmaceutically active ingredient) for treating cancer (i.e., an anti-tumor drug).

[0080] 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.

[0081] 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.

[0082] 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 3-6 Monocyclic 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.

[0083] 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).

[0084] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I and its embodiments. For example, a particular moiety defined in Formula I can be unsubstituted or substituted, where the latter is intended to encompass any substitution pattern (i.e., number and type of substituents) that is chemically possible for that moiety and results in a stable compound.

[0085] 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.

[0086] Wavy line [ka] As used herein, indicates the point of attachment to the remainder of the compound.

[0087] 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.

[0088] The present disclosure also encompasses derivatives of compounds of Formula I 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 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. The effects of such prodrugs can be achieved by altering physicochemical properties (e.g., lipophilicity, molecular weight, charge, and other physicochemical properties that determine the permeation characteristics of a drug).

[0089] 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.

[0090] "Celite®" (Fluka) diatomaceous earth is diatomaceous earth and is also called "celite."

[0091] Any variable part (e.g., R 1 When a group (e.g., R ) occurs more than one time in any constituent or in formula I or other general formulae herein, its definition at each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In selecting compounds of the present invention, those of ordinary skill in the art will recognize that various substituents (i.e., R 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.

[0092] It should be noted that if there is a discrepancy between a chemical name and a structure, the structure is understood to control.

[0093] Compounds of structural formula I may contain one or more asymmetric centers and may therefore exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereoisomers. All asymmetric centers present in compounds of formula I may 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 present 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 stating 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 may be identified in examples in which such stereoisomers or mixtures are obtained, but this in no way limits the scope of the present invention to include all stereoisomers and mixtures thereof.

[0094] 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.

[0095] Compounds of structural formula I 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 separation of the stereoisomers. Separation of a mixture of stereoisomers can be carried out at the stage of an intermediate during the synthesis of a compound of formula I, or it 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 can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. The present invention includes all such isomers, as well as salts, solvates (including hydrates), and solvated salts of such racemates, enantiomers, diastereomers, and tautomers, and mixtures thereof.

[0096] 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.

[0097] For compounds of Formula I described herein that contain olefinic double bonds, unless otherwise specified, they are intended to include both E and Z geometric isomers.

[0098] Some of the compounds described herein may 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. Both the individual tautomers and mixtures thereof are encompassed by the compounds of Formula I of the present invention.

[0099] In compounds of structural formula I, the atoms may exhibit their natural isotopic abundance, 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 structural formula I 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 structural formula I 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.

[0100] It will be understood that the compounds of structural formula I can be prepared as pharmaceutically acceptable salts, or as pharmaceutically unacceptable salts when used as 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 that are not directly suitable for use in medicine due to poor physiological compatibility, but which can be used, for example, as intermediates in chemical reactions or to prepare physiologically acceptable salts.

[0101] 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.

[0102] 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.

[0103] The compounds of formula I form stable alkali metal salts, alkaline earth metal salts or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia, organic bases or basic amino acids.

[0104] 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.

[0105] Preparation of pharmacologically acceptable salts from the salt-forming compound represented by formula I (including its stereoisomers) 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 evaporating the solvent. The compound of the present invention and its salts can form solvates with solvents such as water, ethanol, or glycerol. The compound of the present invention can simultaneously form acid addition salts and base salts, depending on the type of substituents on the side chain.

[0106] If the compound of formula I contains simultaneously an acidic and a basic group in the molecule, the present invention also encompasses, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compound of formula I 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.

[0107] The present invention encompasses compounds of structural formula I, 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.

[0108] Additionally, 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, including the Examples, and mixtures thereof, are intended to be encompassed within the scope of the present invention. Additionally, some of the compounds of the present invention can form solvates (i.e., hydrates) with water or common organic solvents (such as, but not limited to, EtOAc). Such solvates and hydrates (particularly pharmaceutically acceptable solvates and hydrates) of the compounds of the present invention, along with unsolvated and anhydrous forms, are also encompassed within the scope of the present invention.

[0109] 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.

[0110] The present invention further relates to medicaments containing at least one compound of formula I and / or a pharmaceutically acceptable salt of a compound of formula I and / or optionally a stereoisomeric form of a compound of formula I or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of formula I together with pharmaceutically acceptable vehicles, carriers, additives and / or other active substances and adjuvants.

[0111] 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.

[0112] The present invention further relates to a method for producing a medicament, which method comprises bringing at least one compound of formula I into a suitable dosage form using a pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0113] The present invention further relates to methods for preparing compounds of formula I, which are described below and by which the compounds of the invention can be obtained.

[0114] 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.

[0115] Disorders, conditions, and diseases that can be treated or prevented by inhibiting DAGT2 with compounds of Formula I 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, and glomerulosclerosis. , chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue disorders, hyperapo B lipoproteinemia, non-alcoholic fatty liver disease, cardiorenal diseases (e.g., chronic kidney disease and heart failure), and related diseases and conditions.

[0116] The compounds of formula I and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, particularly humans, as pharmaceuticals, either by themselves, in admixture with each other, or in the form of pharmaceutical preparations. The compounds of formula I and their pharmaceutically acceptable salts can be administered to animals, including dogs and cats, as pharmaceuticals, either by themselves, in admixture with each other, 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.

[0117] 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 and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier (i.e., one or more pharmaceutically acceptable carrier substances) and / or additives.

[0118] 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.

[0119] 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.

[0120] 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 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.

[0121] 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).

[0122] 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.

[0123] The dosage of the active compound of formula I and / or its pharmaceutically acceptable salt to be administered will depend on each individual case and, as is customary, should be adapted to the individual circumstances to achieve optimal efficacy. It will therefore depend 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.

[0124] 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.

[0125] 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.

[0126] One or more additional pharmacologically active agents can be administered in combination with a compound of Formula I. An additional active agent is intended to mean a pharmaceutically active agent (different from the compound of Formula I, and including free acids, free bases, and pharmaceutically acceptable salts of the additional active agent) that is active in the body, including prodrugs that are converted to 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 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).

[0127] 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, aliskiren, 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., nicola 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 blocking agents phospholipid 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) , TJC0265, 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., Leron; limab), TNF 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), LOX L2 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 drugs (e.g., norfloxacin, ciprofloxacin, ceftriaxone); coagulation modulating drugs (e.g., anticoagulants, antiplatelet drugs, 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 (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonists (e.g., Ozempic (subcutaneous semaglutide), XW003); selective thyroid hormone receptor beta agonists (e.g., resmetirom); apoptosis modulators (JNK-1 inhibitors (e.g., CC-90001), peroxidase inhibitors (e.g., AZM198), ASK-1 inhibitors (e.g., CS-17919, SRT015)); erythropoietin stimulators (erythropoietin receptor agonists (e.g., sibinetide)); immunomodulators (TLR4 inhibitors (e.g.,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).

[0128] 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).

[0129] Dosage of Compound of Formula (I) After the treatment cycle is completed, the patient may continue to receive the compounds of this invention at the same dose as administered in the treatment protocol. This maintenance dose may continue until the patient progresses or is no longer able to tolerate the dose (in which case the dose may be reduced and the patient may continue on the reduced dose).

[0130] 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.

[0131] 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).

[0132] 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.

[0133] Pharmaceutical Composition The compounds of formula I 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.

[0134] Administration of a compound of Formula I 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 said 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.

[0135] 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).

[0136] 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.

[0137] The dosage and frequency of administration of the compound of Formula I 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.

[0138] The compounds of the present invention are further useful in the preparation of a medicament useful in the treatment of NASH and fibrosis.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL inhibitors include atezolizumab, avelumab, and durvalumab.

[0152] 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) and a PD-1 antagonist. The compound of the present invention and the PD-1 antagonist can be administered simultaneously or sequentially.

[0153] 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).

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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.

[0159] 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.

[0160] 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.

[0161] 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;

[0162] 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.

[0163] 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 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] TIFF2025537516000022.tif109167LCMS 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).

[0164] Gradient conditions: 10-90% B in 1.7 min, total run time 2.4 min.

[0165] 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.

[0166] General Scheme 1 [ka] Compounds of formula I 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]

[0167] Intermediates Intermediate 1 3-ethoxy-2-fluoropyridine [ka] Step A: 3-ethoxy-2-fluoropyridine Iodoethane (6.4 mL, 80 mmol) was added to a stirring solution of 2-fluoropyrid-3-ol (5.0 g, 44 mmol) and KCO (9.8 g, 71 mmol) in DMF (45 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-10% EtOAc / PE) to give the title compound.

[0168] LC / MS = 142 [M+1] Using the appropriate reagents, the following intermediates were synthesized using a procedure similar to that described for Intermediate 1. These intermediates were characterized by LC / MS. [Table 2] Intermediate 10 (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 stirred solution 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, N,N-dimethylformamide (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 mixture was allowed to warm to room temperature. 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, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound.

[0169] LC / MS = 224 [M+1] Step B: (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate To a solution 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 methanesulfonyl chloride (48.8 μL, 0.63 mmol) at −78 °C. After 5 min, the mixture was allowed to warm to room temperature. After an additional 15 min, the mixture was diluted with saturated aqueous NaCl, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without further purification.

[0170] LC / MS = 302 [M+1] Using the appropriate reagents, the following intermediates were synthesized using a procedure similar to that described for Intermediate 10. The intermediates were characterized by LC / MS. [Table 3] 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.

[0171] Example 1 Example 1: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Ethyl 6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirred solution of ethyl 6-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.00 g, 70 mmol), KOAc (1.09 g, 11.1 mmol), and B2Pin2 (2.12 g, 8.33 mmol) in 1,4-dioxane (18.5 mL) was added Pd(dppf)Cl2 (271 mg, 0.370 mmol) at room temperature. The resulting mixture was heated to 105 °C for 1 hour, cooled to room temperature, and then acetic acid (0.424 mL, 7.41 mmol) and water (0.50 mL) were added. The resulting solution was stirred at room temperature for an additional 1 hour. The reaction mixture was cooled to 0 °C, and hydrogen peroxide (0.756 mL, 7.41 mmol) was added. The reaction was then stirred at room temperature for 18 hours. The mixture was concentrated directly onto silica gel and purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to afford the title compound.

[0172] LC / MS = 208 [M+1] Step B: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Sodium hydride (60.0 mg, 1.48 mmol, 60 wt%) was added to a stirred solution of ethyl 6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (255 mg, 1.23 mmol) in DMF (3.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (339 mg, 1.48 mmol) was added. The resulting reaction mixture was heated to 100° C. for 18 hours, then cooled to room temperature and directly purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0173] LC / MS = 418 [M+1] Step C: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (95.3 mg, 0.229 mmol) in MeOH (0.10 mL), water (0.050 mL), and THF (0.30 mL) at room temperature was added lithium hydroxide monohydrate (9.60 mg, 0.229 mmol). The resulting mixture was stirred at room temperature for 18 hours and then lyophilized to provide the title compound.

[0174] LC / MS = 389 [M+1] Step D: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (20.0 mg, 0.0510 mmol) and HATU (39.1 mg, 0.103 mmol) in DMF (1.00 mL) was added DIPEA (27.0 μL, 0.302 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (11.3 mg, 0.0570 mmol). The resulting mixture was stirred at room temperature for 1 hour and then directly purified by mass-triggered reverse-phase HPLC (C18, 10→60% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0175] 1 H NMR (500 MHz, methanol-d4) δ 9.09 - 8.90 (m, 1H), 7.91 (d, J = 9.7 Hz, 1H), 7.84 - 7.64 (m, 3H), 4.79 (q, J = 8.3 Hz, 2H), 3.30 (m, 2H), 3.05 (d, J = 13.6 Hz, 2H), 2.93 (d, J = 14.4 Hz, 2H), 2.25 (t, J = 12.4 Hz, 2H), 1.59 (s, 3H). LC / MS = 534 [M+1]. Human DGAT2 IC 50 = 3.0 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] TIFF2025537516000030.tif54162 Example 13 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 1,6-diamino-3-bromo-2-methylpyridin-1-ium O-Diphenylphosphinylhydroxylamine (46.8 g, 200 mmol) was added to a stirred solution of 5-bromo-6-methylpyridin-2-amine (25.0 g, 134 mmol) in THF (300.0 mL) at room temperature. The resulting mixture was stirred at 45° C. for 18 hours. The reaction mixture was then cooled to room temperature and filtered. The isolated solid was washed with MTBE and dried under reduced pressure to provide the title compound.

[0176] LC / MS = 218 [M+1] Step B: Ethyl 6-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Ethyl 2-chloro-2-oxoacetate (31.9 mL, 286 mmol) was added dropwise to a stirred solution of 1,6-diamino-3-bromo-2-methylpyridin-1-ium diphenylphosphinate (40.0 g, 95.0 mmol) in ACN (280.0 mL) and pyridine (96.0 mL, 1190 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 18 h. The reaction mixture was then cooled to 0 °C, and HCl (4 M in water, 309 mL, 1.24 mol) was added. The solution was allowed to warm to room temperature and extracted with DCM. The combined organic layers were washed with 4 wt% aqueous KCO, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0177] LC / MS = 285 [M+1] Step C: Ethyl 6-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirred solution of ethyl 6-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (23.0 g, 81.0 mmol), B2Pin2 (37.0 g, 146 mmol), and KOAc (15.9 g, 162 mmol) in 1,4-dioxane (230.0 mL) and water (32.2 mL) was added [(1,3,5,7-tetramethyl-6-phenyl-2,4,6-trioxa-6-phosphaadamantane)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (0.820 g, 1.24 mmol) at room temperature. The resulting mixture was stirred at 85 °C for 18 h and then cooled to room temperature. Acetic acid (27.8 mL, 486 mmol) was added and the solution was stirred at room temperature for an additional 0.5 h. The reaction was cooled to 0° C., and then hydrogen peroxide (16.5 mL, 162 mmol) and water (32.2 mL) were added. The reaction was stirred at 0° C. for 1 h. The mixture was filtered, and the isolated solid was washed with MTBE and water and dried under reduced pressure to provide the title compound.

[0178] LC / MS = 222 [M+1] Step D: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Sodium hydride (1.52 g, 38.0 mmol, 60 wt%) was added to a stirred solution of ethyl 6-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (7.00 g, 31.6 mmol) in DMF (158 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (8.72 g, 38.0 mmol) was added. The resulting reaction mixture was heated to 100° C. for 18 hours. The solution was then cooled to room temperature, concentrated directly onto silica gel, and purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0179] LC / MS = 431 [M+1] Step E: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (12.6 g, 29.3 mmol) in MeOH (34.4 mL), water (13.8 mL), and THF (68.8 mL) at room temperature was added lithium hydroxide monohydrate (1.23 g, 29.3 mmol). The resulting mixture was stirred at room temperature for 18 hours and then lyophilized to provide the title compound.

[0180] LC / MS = 403 [M+1] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (11.80 g, 29.3 mmol) and HATU (22.3 g, 58.6 mmol) in DMF (98.0 mL) was added DIPEA (15.4 mL, 88.0 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (6.44 g, 32.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then directly purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0181] 1 H NMR (500 MHz, methanol-d4) δ 7.85 - 7.59 (m, 4H), 4.81 (q, J = 8.4 Hz, 2H), 3.35 (m, 2H), 3.06 (d, J = 13.7 Hz, 2H), 2.95 (d, J = 14.6 Hz, 2H), 2.73 (s, 3H), 2.26 (t, J = 13.6 Hz, 2H), 1.61 (s, 3H). LC / MS = 548 [M+1]. Human DGAT2 IC 50 = 7.6 nM. Using the appropriate reagents and procedures similar to those described in Example 13, the following compounds were synthesized and characterized by LC / MS. [Table 5] TIFF2025537516000033.tif42163 Example 22 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 1,2-diamino-5-bromo-4-methylpyridin-1-ium At 0° C., tert-butyl ((mesitylsulfonyl)oxy)carbamate (5.60 g, 17.8 mmol) was added to TFA (32.8 mL, 426 mmol). The resulting mixture was stirred at 0° C. for 1 h, then ice water (100 mL) was added, and the solution was stirred at 0° C. for an additional 1 h. The precipitated solid was then isolated by filtration and washed with ice water. The solid was dissolved in DCM (50 mL) and stirred with NaSO at 0° C. for 15 min. The NaSO was removed by filtration, and the filtrate was added to a stirring solution of 5-bromo-4-methylpyridin-2-amine (3.32 g, 17.8 mmol) dissolved in DCM (10 mL). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated under reduced pressure to a solid that was washed with EtO to provide the title compound.

[0182] LC / MS = 203 [M+1] Step B: Methyl 6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Methyl 2-chloro-2-oxoacetate (8.57 mL, 93.0 mmol) was added dropwise to a stirred solution of 1,2-diamino-5-bromo-4-methylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (7.14 g, 17.8 mmol) in pyridine (89.0 mL) at room temperature. The resulting mixture was stirred at 100° C. for 18 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The crude residue was dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0183] LC / MS = 271 [M+1] Step C: Methyl 6-hydroxy-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirred solution of methyl 6-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.60 g, 5.91 mmol), B2Pin2 (3.38 g, 13.31 mmol), and KOAc (1.74 g, 17.7 mmol) in 1,4-dioxane (29.6 mL) was added Pd(dppf)Cl (0.433 g, 0.591 mmol) at room temperature. The resulting mixture was heated to 105 °C for 1 h. The mixture was cooled to room temperature, and then acetic acid (0.677 mL, 11.8 mmol) and water (0.60 mL) were added. The resulting solution was stirred at room temperature for an additional 1 h. The reaction mixture was cooled to 0 °C, and hydrogen peroxide (1.21 mL, 11.8 mmol) was added. The reaction was then stirred at room temperature for 18 h. The mixture was concentrated directly onto silica gel and purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to afford the title compound.

[0184] LC / MS = 208 [M+1] Step D: Methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Sodium hydride (27.8 mg, 0.695 mmol, 60 wt%) was added to a stirred solution of methyl 6-hydroxy-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (120.0 mg, 0.579 mmol) in DMF (5.80 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (160.0 g, 0.695 mmol) was added. The resulting reaction mixture was heated to 100° C. for 18 hours. The solution was then cooled to room temperature, concentrated directly onto silica gel, and purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0185] LC / MS = 417 [M+1]. Step E: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (33.9 mg, 0.0810 mmol) in MeOH (47.9 μL), water (19.1 μL), and THF (96.0 μL) at room temperature was added lithium hydroxide monohydrate (3.41 mg, 0.0810 mmol). The resulting mixture was stirred at room temperature for 18 hours and then lyophilized to provide the title compound.

[0186] LC / MS = 403 [M+1] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (16.1 mg, 0.0400 mmol) and HATU (30.4 mg, 0.0800 mmol) in DMF (1.00 mL) was added DIPEA (0.0210 mL, 0.120 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (8.79 mg, 0.0440 mmol). The resulting mixture was stirred at room temperature for 1 hour and then directly purified by mass-triggered reverse-phase HPLC (C18, 5→50% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0187] 1 H NMR (500 MHz, methanol-d4) δ 8.91 (s, 1H), 7.88 - 7.67 (m, 3H), 4.81 (q, J = 8.4 Hz, 4H), 3.33 - 3.24 (m, 1H), 3.05 (d, J = 13.5 Hz, 2H), 2.92 (d, J = 14.0 Hz, 2H), 2.36 (s, 3H), 2.25 (t, J = 13.2 Hz, 2H), 1.59 (s, 3H). LC / MS = 548 [M+1]. Human DGAT2 IC 50 = 31 nM Using the appropriate reagents and procedures similar to those described in Example 22, the following compounds were synthesized and characterized by LC / MS. [Table 6] Example 24 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 1,6-diamino-3-bromo-2,4-dimethylpyridin-1-ium At 0° C., tert-butyl ((mesitylsulfonyl)oxy)carbamate (16.9 g, 53.7 mmol) was added to TFA (50.0 mL, 649 mmol). The resulting mixture was stirred at 0° C. for 1 h, then ice water (100.0 mL) was added, and the solution was stirred at 0° C. for an additional 1 h. The precipitated solid was then isolated by filtration and washed with ice water. The solid was dissolved in DCM (100.0 mL) and stirred with NaSO at 0° C. for 15 min. The NaSO was removed by filtration, and the filtrate was added to a stirred solution of 5-bromo-4,6-dimethylpyridin-2-amine (8.00 g, 39.8 mmol) in DCM (10.0 mL). The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was then concentrated under reduced pressure to a solid that was washed with EtO to provide the title compound.

[0188] LC / MS = 218 [M+1]. Step B: Methyl 6-bromo-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Methyl 2-chloro-2-oxoacetate (14.7 mL, 159 mmol) was added dropwise to a stirred solution of 1,6-diamino-3-bromo-2,4-dimethylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (16.6 g, 39.8 mmol) in pyridine (133 mL) at room temperature. The resulting mixture was stirred at 100° C. for 1.5 hours and then at room temperature for 18 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and concentrated under reduced pressure. The crude residue was purified by silica flash column chromatography (0-10% MeOH / DCM) to provide the title compound.

[0189] LC / MS = 286 [M+2]. Step C: Methyl 6-hydroxy-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirred solution of methyl 6-bromo-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (5.00 g, 17.6 mmol), B2Pin2 (6.70 g, 26.4 mmol), and KOAc (5.18 g, 52.8 mmol) in 1,4-dioxane (70.4 mL) was added Pd(dppf)Cl (0.773 g, 1.06 mmol) at room temperature. The resulting mixture was heated to 100 °C for 18 hours. The mixture was cooled to 0 °C, and then acetic acid (3.02 mL, 52.8 mmol) and water (3.00 mL) were added. The resulting solution was stirred at 0 °C for an additional 1 hour. Hydrogen peroxide (4.21 mL, 44.0 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 1.5 hours. MgSO4 was then added to the solution, and the mixture was filtered through Celite and washed with DCM. The filtrate was concentrated, and the crude material was purified by silica flash column chromatography (0-10% MeOH / DCM) to give the title compound.

[0190] LC / MS = 222 [M+1] Step D: Methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Sodium hydride (43.4 mg, 1.09 mmol, 60 wt%) was added to a stirred solution of methyl 6-hydroxy-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (200.0 mg, 0.904 mmol) in DMF (3.62 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (249 mg, 1.09 mmol) was added. The resulting reaction mixture was heated to 100° C. for 48 hours. The solution was then cooled to room temperature, concentrated directly onto silica gel, and purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to provide the title compound.

[0191] LC / MS = 431 [M+1] Step E: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (65.0 mg, 0.151 mmol) in water (750 μL) and ACN (750 μL) at room temperature was added lithium hydroxide monohydrate (9.50 mg, 0.226 mmol). The resulting mixture was stirred at room temperature for 0.5 hours and then lyophilized to provide the title compound.

[0192] LC / MS = 417 [M+1] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (60.0 mg, 0.144 mmol) and HATU (65.7 mg, 0.173 mmol) in DMF (1.00 mL) was added DIPEA (88.0 μL, 0.504 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (34.5 mg, 0.173 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then directly purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to provide the title compound.

[0193] 1H NMR (500 MHz, methanol-d4) δ 7.79 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 2.0 Hz, 1H), 7.66 (s, 1H), 4.87 - 4.81 (m, 2H), 3.31 (m, J = 2.8 Hz, 1H), 3.05 (d, J = 13.8 Hz, 2H), 2.94 (d, J = 14.6 Hz, 2H), 2.29 (s, 3H), 2.25 (d, J = 12.4 Hz, 2H), 1.60 (s, 3H). LC / MS = 562 [M+1]. Human DGAT2 IC 50 = 181 nM Using the appropriate reagents and procedures similar to those described in Example 24, the following compounds were synthesized and characterized by LC / MS. [Table 7] Example 26 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-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-5-chloro-3-fluoropyridin-1-ium 2,4,6-trimethylbenzenesulfonate At 0° C., tert-butyl ((mesitylsulfonyl)oxy)carbamate (2.00 g, 6.34 mmol) was added to TFA (20.0 mL, 261 mmol). The resulting mixture was stirred at 0° C. for 1.5 hours, and then ice water (15.0 g) was added. The precipitated solid was then isolated by filtration and washed with ice water. The solid was dissolved in DCM (15.0 mL) and stirred with NaSO at 0° C. for 15 minutes. The NaSO was removed by filtration, and the filtrate was added to a stirred solution of 5-chloro-3-fluoropyridin-2-amine (0.95 g, 6.48 mmol) in DCM (10.0 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure to provide the title compound.

[0194] LC / MS = 162 [M+1] Step B: Ethyl 6-chloro-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Ethyl oxalyl chloride (1.80 g, 13.18 mmol) was added dropwise to a stirred solution of 1,2-diamino-5-chloro-3-fluoropyridin-1-ium 2,4,6-trimethylbenzenesulfonate (2.29 g, 6.34 mmol) in pyridine (30.0 mL) at room temperature. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature and poured into saturated aqueous Na2CO3. The mixture was extracted with DCM, and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0195] LC / MS = 244 [M+2] Step C: (2-(ethoxycarbonyl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)boronic acid To a stirred solution of ethyl 6-chloro-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (0.70 g, 2.87 mmol), B2Pin2 (1.20 g, 4.73 mmol), and KOAc (46.0 mg, 8.62 mmol) in 1,4-dioxane (15.0 mL) was added X-Phos G2 Pd (226 mg, 0.287 mmol) at room temperature. The resulting mixture was heated to 90 °C for 13 h, after which the mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound.

[0196] LC / MS = 254 [M+1] Step D: Ethyl 8-fluoro-6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirred suspension of NaBO3.4H2O (913 mg, 8.62 mmol) in THF (15.0 mL) and water (6.0 mL) at room temperature was added (2-(ethoxycarbonyl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)boronic acid (727 mg, 2.87 mmol). The resulting mixture was stirred at room temperature for 16 h. The reaction was then quenched with saturated aqueous NH4Cl. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0197] LC / MS = 226 [M+1] Step E: 8-Fluoro-6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of ethyl 8-fluoro-6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (90.0 mg, 0.400 mmol) in MeOH (4.0 mL) and water (0.4 mL) at room temperature was added lithium hydroxide monohydrate (40.0 mg, 0.952 mmol). The resulting mixture was stirred at room temperature for 13 hours and then concentrated under reduced pressure to provide the title compound.

[0198] LC / MS = 198 [M+1] Step F: 8-Fluoro-6-hydroxy-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 8-fluoro-6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (79.0 mg, 0.401 mmol) and HATU (229 mg, 0.601 mmol) in DMF (4.00 mL) was added DIPEA (0.350 mL, 2.00 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (109 mg, 0.461 mmol) at room temperature. The resulting mixture was stirred at room temperature for 0.5 h. The mixture was then poured into saturated aqueous NH₄Cl. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude residue was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0199] LC / MS = 343 [M+1] Step G: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-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 8-fluoro-6-hydroxy-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (120 mg, 0.351 mmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (81.0 mg, 0.245 mmol), 5-chloro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (177 mg, 0.526 mmol), and potassium phosphate tribasic (223 mg, 1.05 mmol) in DMSO (2.0 mL) was added copper(I) iodide (17.0 mg, 0.089 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 14 h. The mixture was then filtered and the filtrate was directly purified by mass-triggered reverse phase HPLC (C18, ACN in water, 0.1% NH4HCO3 modifier) ​​to give the title compound.

[0200] 1H NMR (500 MHz, methanol-d4) δ 8.92 (d, J = 0.83 Hz, 1H), 7.82 (d, J = 2.03 Hz, 1H), 7.77 (d, J = 2.03 Hz, 1H), 7.72 (dd, J = 1.85, 10.55 Hz, 1H), 4.79 (q, J = 8.34 Hz, 2H), 3.30 (br s, 2H), 3.05 (br d, J = 13.95 Hz, 2H), 2.93 - 2.95 (m, 2H), 2.22 - 2.31 (m, 2H), 1.59 (s, 3H). LC / MS = 552 [M+1]. Human DGAT2 IC 50 = 9.5 nM. Example 27 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-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-5-bromo-4-fluoropyridin-1-ium At 0° C., tert-butyl ((mesitylsulfonyl)oxy)carbamate (14.2 g, 45.0 mmol) was added to TFA (50.0 mL, 649 mmol). The resulting mixture was stirred at 0° C. for 1 hour, then ice water (100.0 mL) was added, and the solution was stirred at 0° C. for an additional 1 hour. The precipitated solid was then isolated by filtration and washed with ice water. The solid was dissolved in DCM (100.0 mL) and stirred with NaSO at 0° C. for 15 minutes. The NaSO was removed by filtration, and the filtrate was added to a stirring solution of 5-bromo-4-fluoropyridin-2-amine (5.73 g, 30.0 mmol) dissolved in DCM (10.0 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure to a solid and washed with EtO to provide the title compound.

[0201] LC / MS = 208 [M+1] Step B: Methyl 6-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Methyl 2-chloro-2-oxoacetate (14.5 mL, 158 mmol) was added dropwise to a stirred solution of 1,2-diamino-5-bromo-4-fluoropyridin-1-ium 2,4,6-trimethylbenzenesulfonate (12.2 g, 30.0 mmol) in pyridine (100.0 mL) at room temperature. The resulting mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica flash column chromatography (0-10% MeOH / DCM) to provide the title compound.

[0202] LC / MS = 297 [M+Na] Step C: Methyl 6-hydroxy-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirred solution of methyl 6-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (1.43 g, 5.22 mmol), B2Pin2 (6.70 g, 26.4 mmol), and KOAc (5.18 g, 52.8 mmol) in 1,4-dioxane (26.1 mL) was added Pd(dppf)Cl (2.98 g, 11.8 mmol) at room temperature. The resulting mixture was heated to 100 °C for 18 hours. The mixture was cooled to room temperature, and then acetic acid (0.598 mL, 10.4 mmol) and water (0.600 mL) were added. The resulting solution was stirred at room temperature for an additional hour. The reaction mixture was cooled to 0 °C, and then hydrogen peroxide (1.07 mL, 10.4 mmol) was added. The reaction was stirred at room temperature for 18 hours. The mixture was concentrated directly onto silica gel and purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to afford the title compound.

[0203] LC / MS = 212 [M+1] Step D: Methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Sodium hydride (40.0 mg, 1.00 mmol, 60 wt%) was added to a stirred solution of methyl 6-hydroxy-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (0.177 mg, 0.836 mmol) in DMF (3.00 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (0.230 g, 1.00 mmol) was added. The resulting reaction mixture was heated to 100° C. for 18 hours. The solution was then cooled to room temperature, concentrated directly onto silica gel, and purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0204] LC / MS = 421 [M+1] Step E: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (3.90 mg, 9.27 μmol) in MeOH (6.00 μL), water (2.00 mL), and THF (11.0 mL) at room temperature was added lithium hydroxide monohydrate (0.389 mg, 9.27 μmol). The resulting mixture was stirred at room temperature for 0.5 hours and then lyophilized to provide the title compound.

[0205] LC / MS = 407 [M+1] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (3.77 mg, 9.27 μmol) and HATU (7.05 mg, 0.0190 mmol) in DMF (1.00 mL) was added DIPEA (4.86 μL, 0.0280 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (2.04 mg, 10.2 μmol). The resulting mixture was stirred at room temperature for 1 hour and then directly purified by mass-triggered reverse-phase HPLC (C18, 45→85% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0206] 1 H NMR (500 MHz, methanol-d4) δ 9.15 (d, J = 6.6 Hz, 1H), 7.84 - 7.72 (m, 3H), 4.81 (q, J = 8.3 Hz, 2H), 3.28 (s, 1H), 3.05 (d, J = 13.5 Hz, 2H), 2.94 (d, J = 24.4 Hz, 2H), 2.25 (t, J = 13.2 Hz, 2H), 1.59 (s, 3H). LC / MS = 552 [M+1]. Human DGAT2 IC 50 = 7.2 nM Example 28 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: 1,2-diamino-5-bromo-3-fluoro-6-methylpyridin-1-ium At 0° C., tert-butyl ((mesitylsulfonyl)oxy)carbamate (15.9 g, 50.5 mmol) was added to TFA (50.0 mL, 649 mmol). The resulting mixture was stirred at 0° C. for 1 hour, then ice water (100.0 mL) was added, and the solution was stirred at 0° C. for an additional 1 hour. The precipitated solid was then isolated by filtration and washed with ice water. The solid was dissolved in DCM (100.0 mL) and stirred with NaSO at 0° C. for 15 minutes. The NaSO was removed by filtration, and the filtrate was added to a stirring solution of 5-bromo-3-fluoro-6-methylpyridin-2-amine (9.00 g, 43.9 mmol) dissolved in DCM (191 mL). The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure to a solid and washed with EtO to provide the title compound.

[0207] LC / MS = 223 [M+2]. Step B: Methyl 6-bromo-8-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Methyl 2-chloro-2-oxoacetate (12.1 mL, 132 mmol) was added dropwise to a stirred solution of 1,2-diamino-5-bromo-3-fluoro-6-methylpyridin-1-ium 2,4,6-trimethylbenzenesulfonate (18.5 g, 43.9 mmol) in pyridine (146 mL) at room temperature. The resulting mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude residue was purified by silica flash column chromatography (0-10% MeOH / DCM) to provide the title compound.

[0208] LC / MS = 290 [M+2] Step C: Methyl 8-fluoro-6-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate To a stirred solution of methyl 6-bromo-8-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (5.50 g, 19.1 mmol), B2Pin2 (7.27 g, 28.6 mmol), and KOAc (5.62 g, 57.3 mmol) in 1,4-dioxane (76.0 mL) was added Pd(dppf)Cl (0.838 g, 1.15 mmol) at room temperature. The resulting mixture was heated to 100 °C for 18 hours, cooled to 0 °C, and then acetic acid (3.28 mL, 57.3 mmol) and water (3.30 mL) were added. The resulting solution was stirred at 0 °C for an additional 1 hour. Hydrogen peroxide (4.57 mL, 47.7 mmol) was added at 0 °C, and the reaction was stirred at room temperature for 1.5 hours. MgSO4 was then added to the solution, and the mixture was filtered through Celite and washed with DCM. The filtrate was concentrated, and the crude material was purified by silica flash column chromatography (0-10% MeOH / DCM) to give the title compound.

[0209] LC / MS = 226 [M+1] Step D: Methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate Sodium hydride (53.3 mg, 1.33 mmol, 60 wt%) was added to a stirred solution of methyl 8-fluoro-6-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (250.0 mg, 1.11 mmol) in DMF (4.44 mL) at 0° C. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (306 mg, 1.33 mmol) was added. The resulting reaction mixture was heated to 100° C. for 18 hours. The solution was then cooled to room temperature, concentrated directly onto silica gel, and purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0210] LC / MS = 435 [M+1] Step E: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (79.0 mg, 0.182 mmol) in water (1.00 mL) and ACN (1.00 mL) at room temperature was added lithium hydroxide monohydrate (11.4 mg, 0.273 mmol). The resulting mixture was stirred at room temperature for 0.5 hours and then lyophilized to provide the title compound.

[0211] LC / MS = 421 [M+1] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (40.0 mg, 0.0950 mmol) and HATU (43.4 mg, 0.114 mmol) in DMF (475 μL) was added DIPEA (58.1 μL, 0.333 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (22.8 mg, 0.114 mmol). The resulting mixture was stirred at room temperature for 1 hour and then directly purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to provide the title compound.

[0212] 1H NMR (500 MHz, methanol-d4) δ 7.76 (dd, J = 10.2, 2.0 Hz, 2H), 7.68 (d, J = 10.4 Hz, 1H), 4.81 (q, J = 8.3 Hz, 2H), 3.36 (m, J = 20.2 Hz, 1H), 3.05 (d, J = 13.8 Hz, 2H), 2.95 (d, J = 14.7 Hz, 2H), 2.70 (s, 3H), 2.27 (t, J = 13.5 Hz, 2H), 1.60 (s, 3H). LC / MS = 566 [M+1]. Human DGAT2 IC 50 = 12 nM Using the appropriate reagents and procedures similar to those described in Example 28, the following compounds were synthesized and characterized by LC / MS. [Table 8] TIFF2025537516000042.tif41162 Example 35 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide [ka] Step A: Ethyl 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate CsCO (0.385 g, 1.18 mmol) was added to a stirred solution of ethyl 6-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (0.174 g, 0.787 mmol) and (5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl methanesulfonate (0.358 g, 1.18 mmol) in DMF (5.00 mL) at room temperature. The resulting mixture was heated to 60 °C for 18 h. The reaction was cooled to room temperature, the mixture was filtered, and the filtrate was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0213] LC / MS = 429 [M+1] Step B: 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate (140.0 mg, 0.326 mmol) in MeOH (0.163 mL), water (0.163 mL), and THF (0.326 mL) at room temperature was added lithium hydroxide monohydrate (14.0 mg, 0.326 mmol). The resulting mixture was stirred at room temperature for 2 hours and then lyophilized to provide the title compound.

[0214] LC / MS = 401 [M+1] Step C: 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide To a mixture of 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (130.0 mg, 0.326 mmol) and HATU (248 mg, 0.652 mmol) in DMF (2.00 mL) was added DIPEA (0.171 mL, 0.978 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (71.6 mg, 0.359 mmol). The resulting mixture was stirred at room temperature for 3 hours and then directly purified by mass-triggered reverse-phase HPLC (C18, 65→98% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0215] 1H NMR (500 MHz, methanol-d4) δ 8.20 (s, 1H), 7.88 (d, J = 9.7 Hz, 1H), 7.72 (d, J = 9.7 Hz, 1H), 7.59 (d, J = 10.0 Hz, 1H), 5.35 (s, 2H), 4.76 (q, J = 8.3 Hz, 2H), 3.29 (m, 1H), 3.04 (d, J = 13.7 Hz, 2H), 2.93 (d, J = 14.8 Hz, 2H), 2.69 (s, 3H), 2.25 (t, J = 13.5 Hz, 2H), 1.59 (s, 3H). LC / MS = 566 [M+1]. Human DGAT2 IC 50 = 1683 nM. Using the appropriate reagents and procedures similar to those described in Example 35, the following compounds were synthesized and characterized by LC / MS. [Table 9] 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).

[0216] 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%.

[0217] Potent compounds were titrated and IC 50 was calculated by a four-parameter sigmoidal curve fitting equation.

[0218] 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, 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 ４ 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, wherein the heteroaryl is unsubstituted or contains 1, 2, or 3 R ４ (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) 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N or O; (3) -(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 or O; (4) -(C １－６ ) alkyl-aryl, (5) -(C ３－６ ) cycloalkyl, (6) -(C １－６ ) hydroxyalkyl, or (7) -SO ２ (C １－６ ) alkyl and wherein each alkyl, aryl, cycloalkyl, heteroaryl, and heterocycle is unsubstituted or contains one, two, or three R ６ is replaced by; Each R ３ teeth, (1) hydrogen, (2) Halogen, or (3) (C １－３ ) alkyl are independently selected from If present, each R ４ is, independently, (1) -OC １－６ Alkyl, (2) -O(C １－６ ) haloalkyl, (3) Halogen, or (4) O—C optionally substituted with halogen １－６ Alkyl-(C ３－７ ) cycloalkyl and If present, each R ６ is, independently, (1) halogens, (2) hydroxy, (3) cyano, (4) oxo, (5) (C １－６ ) alkyl, (6) (C １－３ ) alkylhydroxy, (7) (C １－６ ) haloalkyl-, (8) -OC １－６ Alkyl, or (9) -O(C １－６ ) haloalkyl is] or a pharmaceutically acceptable salt thereof.

2. 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 ４ 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, wherein the heteroaryl is unsubstituted or contains 1, 2, or 3 R ４ (replaced by 2. The compound of claim 1, wherein:

3. 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 optionally substituted with halogen １－６ Alkyl-(C ３－７ ) cycloalkyl), or (2) -(C １－６ ) alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, —OC １－６ Alkyl, O—(C １－６ ) O—C optionally substituted with haloalkyl or halogen １－６ Alkyl-(C ３－７ ) substituted with 1, 2, or 3 substituents independently selected from cycloalkyl; The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein:

4. 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 ) O—C optionally substituted with haloalkyl or halogen １－６ Alkyl-(C ３－７ 4. The compound according to claim 1, wherein the aryl group is substituted with one, two, or three substituents independently selected from cycloalkyl, or a pharmaceutically acceptable salt thereof.

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

6. R １ is -(C １－６ ) alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing one nitrogen atom, wherein the heteroaryl is unsubstituted or is substituted with halogen or —O(C １－６ 4. The compound according to claim 1, wherein the compound is substituted with one or two substituents independently selected from haloalkyl, or a pharmaceutically acceptable salt thereof.

7. R １ is -(C １－６ ) alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing one nitrogen atom, wherein the heteroaryl is unsubstituted or substituted with halogen, OCH ２ CF ３ or OCH ２ CHF ２ 7. The compound according to any one of claims 1 to 3 or 6, or a pharmaceutically acceptable salt thereof, substituted with one or two substituents independently selected from:

8. R ２ teeth, (1) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (2) -(C ３－６ ) cycloalkyl wherein each cycloalkyl or heterocycle is unsubstituted or contains 1, 2, or 3 R ６ The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, substituted with:

9. R ２ teeth, (1) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (2) -(C ３－６ ) cycloalkyl wherein each cycloalkyl or heterocycle is unsubstituted or is selected from the group consisting of hydroxy, halogen, (C １－６ ) alkyl, O.C. １－６ Alkyl, (C １－６ 9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is substituted with 1, 2 or 3 substituents independently selected from haloalkyl- or oxo.

10. R ２ teeth, (1) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (2) -(C ３－６ ) cycloalkyl wherein each cycloalkyl or heterocycle is unsubstituted or is selected from the group consisting of OH, F, oxo, CH ３ , OCH ３ , C.F. ３ or CH ２ CF ３ 10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, substituted with 1, 2 or 3 substituents independently selected from:

11. R ２ is a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocycle is unsubstituted or contains 1, 2 or 3 R ６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, substituted with:

12. R ２ is a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocycle is unsubstituted or is substituted with halogen, hydroxy, (C １－６ ) alkyl, oxo or (C １－６ 12. The compound according to any one of claims 1 to 9 or 11, or a pharmaceutically acceptable salt thereof, which is substituted with 1, 2 or 3 substituents independently selected from: haloalkyl-;

13. R ２ is a 4-7 membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocycle is unsubstituted or ３ , oxo or CH ２ CF ３ 13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, substituted with 1, 2 or 3 substituents independently selected from:

14. R ２ is -(C ３－６ ) cycloalkyl, wherein the cycloalkyl is unsubstituted or has one, two, or three R ６ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, substituted with:

15. R ２ is -(C ３－６ ) cycloalkyl, wherein the cycloalkyl is unsubstituted or is substituted with hydroxy, halogen, (C １－６ ) alkyl, O.C. １－６ Alkyl or (C １－６ 15. The compound of any one of claims 1 to 9 or 14, or a pharmaceutically acceptable salt thereof, which is substituted with 1, 2 or 3 substituents independently selected from: haloalkyl-;

16. R ２ is -(C ３－６ ) cycloalkyl, wherein the cycloalkyl is unsubstituted or is selected from the group consisting of OH, F, CH ３ , OCH ３ Or CF ３ 16. The compound according to any one of claims 1 to 9 or 14 to 15, or a pharmaceutically acceptable salt thereof, substituted with 1, 2 or 3 substituents independently selected from:

17. R ３ is hydrogen, halogen or C １－３ 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R is independently selected from alkyl;

18. R ３ is hydrogen, halogen or CH ３ 18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, independently selected from:

19. If present, each R ４ is a halogen, -OC １－６ Alkyl, O—(C １－６ ) O—C optionally substituted with haloalkyl or halogen １－６ Alkyl-(C ３－７ 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

20. If present, each R ４ is a halogen, OCH ２ CF ３ , OCH ２ CH ３ , OCH ２ CHF ２ , OCH ２ -cyclopropyl-F or OCH ２ CF ２ CH ３ 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

21. If present, each R ６ is a halogen, hydroxy, (C １－６ ) alkyl, oxo, —OC １－６ Alkyl or (C １－６ 15. The compound of any one of claims 1 to 8, 11 or 14, or a pharmaceutically acceptable salt thereof, wherein each of the groups is independently selected from: ) haloalkyl-;

22. If present, each R ６ is halogen, hydroxy, CH ３ , oxo, OCH ３ , C.F. ３ or CH ２ CF ３ 22. The compound according to any one of claims 1 to 8, 11, 14 or 21, or a pharmaceutically acceptable salt thereof, independently selected from:

23. below, 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; N-(4,4-difluoro-1-methyl-cyclohexyl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; N-(3,3-difluoro-1-methyl-cyclobutyl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 5,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 8-fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-[3-(2,2-difluoroethoxy)pyrazin-2-yl]oxy-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; or 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide; 2. The compound of claim 1, wherein:

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

25. below, 【Transformation 3】 25. The compound of claim 24, wherein:

26. below, 【Chemistry 4】 25. The compound of claim 24, wherein:

27. below, 【Transformation 5】 25. The compound of claim 24, wherein:

28. below, 【Transformation 6】 25. The compound of claim 24, wherein:

29. below, 【Transformation 7】 25. The compound of claim 24, wherein:

30. 30. 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 of claims 1 to 29, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

31. A composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

32. 30. 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 29, or a pharmaceutically acceptable salt thereof.

33. 30. Use of a compound according to any one of claims 1 to 29, 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.

Images