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

Abstract

The present disclosure provides compounds of Formula I and pharmaceutically acceptable salts, esters, and prodrugs thereof, which are DGAT2 inhibitors. The present disclosure also provides methods of preparing the compounds of Formula I, pharmaceutical compositions comprising the compounds of formula I and the use of these compounds in the treatment of hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, decline in cognitive ability, dementia, diabetes mellitus, diabetes mellitus, diabetes mellitus, diabetes mellitus, diabetes mellitus, diabetes mellitus, and the like. Methods of treating heart and kidney diseases, such as chronic kidney disease and heart failure, and related diseases and disorders, comprising administering to a patient in need thereof a compound of Formula I. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This international application claims the benefit of priority of U.S. Provisional Application No. 63 / 421,375, filed on November 1, 2022, the entire content of which is incorporated herein by reference. Technical field

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

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

[0005] The glycerol - 3 - phosphate and monoacylglycerol pathways are the major pathways for the biosynthesis of TG. However, the last step in TG synthesis involves the reaction of fatty acyl - CoA and diacylglycerol (“DAG”) to form TG. This reaction is catalyzed by acyl - CoA: diacylglycerol acyltransferase (“DGAT”). Two DGAT enzymes, DGAT1 and DGAT2, have been identified. Although DGAT1 and DGAT2 catalyze the same reaction, they are significantly different at the levels of DNA and protein sequences. In in vitro tests, DGAT2 is able to utilize endogenous fatty acids to synthesize TG, while DGAT1 seems to be more dependent on exogenous fatty acids (Yen et al., J. Lipid Research, 2008, 49, 2283). Inactivation of DGAT2 attenuates cytoplasmic lipid droplet growth, while inactivation of DGAT1 has the opposite effect. (Li et al., Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080).

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

[0007] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been mainly understood through attempts to utilize antisense oligonucleotides (ASO) in rodents. In this context, in ob / ob mice with DGAT2 gene-specific ASO, DGAT2 knockdown resulted in a dose-dependent decrease in very low density lipoprotein (“VLDL”) and decreases in plasma TG, total cholesterol, and ApoB (Liu et al., Biochim. Biophys Acta 2008, 1781, 97). In the same study, treatment of ob / ob mice with DGAT2 antisense oligonucleotides showed decreases in body weight gain, fat mass, and liver TG 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 diet-induced hepatic steatosis and insulin resistance in rats were improved by knocking down DGAT2. These effects appear to be specific to DGAT2 inhibition, as ASO against DGAT1 did not produce similar beneficial effects. Although the molecular mechanisms underlying these observations are uncertain, the combined data suggest that inhibition of DGAT2 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).

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

[0009] The DGAT2 inhibitor compounds are described in WO2022050749, WO2021133035, WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, WO2013150416, US20150259323, WO2015077299, WO2017011276, WO2018033832, US201801628 and WO2003053363. Summary of the Invention

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

[0011]

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

[0013] The present disclosure relates to compounds having Structural Formula I:

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] R

[0017] ,

[0018] ,

[0016] , 4 ,

[0019] , 4 ,

[0020] , , , , 2 , , 1-6 , 1 , is

[0017] (1) a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein said heteroaryl is unsubstituted or substituted with 1, 2 or 3 R 4 substituents, or

[0018] (2) -(C 1-6 )alkyl-heteroaryl, wherein said heteroaryl is a 5-membered or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein said heteroaryl is unsubstituted or substituted with 1, 2 or 3 R 4 substituents,

[0019] R 2 is

[0020] (1) A 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0021] (2) A 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N or O,

[0022] (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,

[0023] (4)-(C 1-6 )alkyl - aryl,

[0024] (5)-(C 3-6 )cycloalkyl,

[0025] (6)-(C 1-6 )hydroxyalkyl, or

[0026] (7)-SO2(C 1-6 )alkyl,

[0027] wherein each alkyl, aryl, cycloalkyl, heteroaryl and heterocycle is unsubstituted or substituted by 1, 2 or 3 R 6 substituents;

[0028] Each R 3 is independently selected from

[0029] (1) hydrogen,

[0030] (2) halogen, or

[0031] (3)(C 1-3 )alkyl,

[0032] When present, each R 4 is independently

[0033] (1)-OC 1-6 alkyl,

[0034] (2)-O(C 1-6 )haloalkyl,

[0035] (3) halogen, or

[0036] (4)O-C 1-6 alkyl-(C 3-7 )cycloalkyl, optionally substituted by halogen,

[0037] When present, each R 6 is independently

[0038] (1) halogen,

[0039] (2) hydroxy,

[0040] (3) Cyano,

[0041] (4) Oxo,

[0042] (5) (C 1-6 ) alkyl,

[0043] (6) (C 1-3 ) alkylhydroxy,

[0044] (7) (C 1-6 ) haloalkyl-,

[0045] (8) -O(C 1-6 ) alkyl, or

[0046] (9) -O(C 1-6 ) haloalkyl.

[0047] In Embodiment 2 of the present disclosure, it 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 is

[0048] (1) A six-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 4 substituents, or

[0049] (2) -(C 1-6 ) alkyl-heteroaryl, wherein the heteroaryl is a five- or six-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, and the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 4 substituents.

[0050] In Embodiment 3 of the present disclosure, it is a compound of Formula I or Embodiments 1-2, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0051] (1) A six-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, -OC 1-6 alkyl, O-(C 1-6 ) haloalkyl or O-C optionally substituted by halogen 1-6 alkyl-(C 3-7 ) cycloalkyl, or

[0052] (2) -(C 1-6 ) alkyl-heteroaryl, wherein the heteroaryl is a five- or six-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, and the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, -OC 1-6 alkyl, O-(C1-6 ) a haloalkyl or an optionally halogen-substituted O-C 1-6 alkyl-(C 3-7 ) substituted by a cycloalkyl substituent.

[0053] In Embodiment 4 of the present disclosure, it is a compound of Formula I or Embodiments 1-3, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, -OC 1-6 alkyl, O-(C 1-6 ) a haloalkyl or an optionally halogen-substituted O-C 1-6 alkyl-(C 3-7 ) substituted by a cycloalkyl substituent.

[0054] In Embodiment 5 of the present disclosure, it is a compound of Formula I or Embodiments 1-4, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from F, Cl, OCH2CF3, OCH2CH3, OCH2CHF2, OCH2-cyclopropyl-F or OCH2CF2CH3.

[0055] In Embodiment 6 of the present disclosure, it is a compound of Formula I or Embodiments 1-3, 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 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, -OC 1-6 alkyl, -O(C 1-6 ) a haloalkyl or an optionally halogen-substituted O-C 1-6 alkyl-(C 3-7 ) substituted by a cycloalkyl substituent.

[0056] In Embodiment 7 of the present disclosure, it is a compound of Formula I or Embodiments 1-3 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 1 nitrogen atom, wherein the heteroaryl is unsubstituted or substituted by one or two substituents independently selected from halogen or -O(C 1-6 ) a haloalkyl substituent.

[0057] Embodiment 8 of the present disclosure is a compound of Formula I or Embodiments 6-7, 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 1 nitrogen atom, and the heteroaryl is unsubstituted or substituted by one or two substituents independently selected from halogen, OCH2CH3, OCH2CF3 or OCH2CHF2.

[0058] Embodiment 9 of the present disclosure is a compound of Formula I or Embodiments 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 1 nitrogen atom, and the heteroaryl is unsubstituted or substituted by one or two substituents independently selected from F, Cl, OCH2CF3 or OCH2CHF2.

[0059] 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 is

[0060]

[0061] 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 is

[0062] (1) a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0063] (2)-(C 3-6 )cycloalkyl,

[0064] wherein each cycloalkyl or heterocycle is unsubstituted or substituted by 1, 2 or 3 R 6 substituents.

[0065] Embodiment 12 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

[0066] (1) a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0067] (2)-(C 3-6 )cycloalkyl,

[0068] wherein each cycloalkyl or heterocycle is unsubstituted or substituted by one, two or three independently selected from hydroxy, halogen, (C 1-6 )alkyl, OC 1-6 Alkyl, (C 1-6 ) is substituted with a haloalkyl- or oxo-substituent.

[0069] In embodiment 13 of the present disclosure, there 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 for

[0070] (1) a 4- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or

[0071] (2)-(C 3-6 )cycloalkyl,

[0072] wherein each cycloalkyl or heterocycle is unsubstituted or substituted with one, two or three substituents independently selected from OH, F, oxo, CH3, OCH3, CF3 or CH2CF3.

[0073] In 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 unsubstituted or replaced by one, two or three R 6 Substituted 4- to 7-membered heterocycle.

[0074] In 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 unsubstituted or replaced by one, two or three independently selected heteroatoms selected from halogen, hydroxy, (C 1-6 )alkyl, oxo, -O(C 1-6 )alkyl or (C 1-6 ) a 4- to 7-membered heterocyclic ring substituted with a haloalkyl-substituent.

[0075] In 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 unsubstituted or replaced by one, two or three independently selected heteroatoms selected from halogen, hydroxy, (C 1-6 )alkyl, oxo or (C 1-6 ) a 4- to 7-membered heterocyclic ring substituted with a haloalkyl-substituent.

[0076] In Embodiment 17 of the present disclosure, it 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 an unsubstituted or substituted by one, two or three substituents independently selected from (C 1-6 )alkyl, oxo or (C 1-6 )haloalkyl- 4- to 7-membered heterocycle containing 1 heteroatom independently selected from O and S.

[0077] In Embodiment 18 of the present disclosure, it 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 an unsubstituted or substituted by one, two or three substituents independently selected from CH3, oxo or CH2CF3 4- to 7-membered heterocycle containing 1 heteroatom independently selected from O and S.

[0078] In Embodiment 19 of the present disclosure, it 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 an unsubstituted or substituted by one, two or three R 6 substituted -(C 3-6 )cycloalkyl.

[0079] In Embodiment 20 of the present disclosure, it 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 an unsubstituted or substituted by one, two or three substituents independently selected from hydroxy, halogen, (C 1-6 )alkyl, OC 1-6 alkyl or (C 1-6 )haloalkyl- substituted -(C 3-6 )cycloalkyl.

[0080] In Embodiment 21 of the present disclosure, it 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 an unsubstituted or substituted by one, two or three substituents independently selected from OH, F, CH3, OCH3 or CF3 substituted -(C 3-6 )cycloalkyl.

[0081] In Embodiment 22 of the present disclosure, it 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

[0082]

[0083] Embodiment 23 of the present disclosure is a compound of formula I or any one of Embodiments 1-22, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is independently selected from hydrogen, halogen or C 1-3 alkyl.

[0084] Embodiment 24 of the present disclosure is a compound of formula I or any one of Embodiments 1-23, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is independently selected from hydrogen, halogen or CH3.

[0085] Embodiment 25 of the present disclosure is a compound of formula I or any one of Embodiments 1-24, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is independently selected from hydrogen, F or CH3.

[0086] Embodiment 26 of the present disclosure is a compound of formula I or any one of Embodiments 1-1-2, 11-25, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 [[ID=S19]]is halogen, -OC 1-6 alkyl, O-(C 1-6 ) haloalkyl or optionally halogen-substituted O-C 1-6 alkyl-(C 3-7 ) cycloalkyl.

[0087] Embodiment 27 of the present disclosure is a compound of formula I or any one of Embodiments 1-2, 11-27, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is halogen, OCH2CF3, OCH2CH3, OCH2CHF2, OCH2-cyclopropyl-F or OCH2CF2CH3.

[0088] Embodiment 28 of the present disclosure is a compound of formula I or any one of Embodiments 1-2, 11-27, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is F, Cl, OCH2CF3, OCH2CH3, OCH2CHF2, OCH2-cyclopropyl-F or OCH2CF2CH3.

[0089] Embodiment 29 of the present disclosure is a compound of formula I or any one of Embodiments 1-11, 14, 19, 23-28, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 6 is independently selected from halogen, hydroxy, (C 1-6 ) alkyl, oxo, -OC 1-6alkyl or (C 1-6 ) haloalkyl-.

[0090] In Embodiment 30 of the present disclosure, it is a compound of Formula I or any one of Embodiments 1-11, 14, 19, 23-29, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 6 is independently selected from halogen, hydroxy, CH3, oxo, OCH3, CF3, or CH2CF3.

[0091] In Embodiment 31 of the present disclosure, it is a compound of Formula I or any one of Embodiments 1-11, 14, 19, 23-30, or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 6 is independently selected from F, hydroxy, CH3, oxo, OCH3, CF3, or CH2CF3.

[0092] In Embodiment 32 of the present invention, the compound of Formula I or its pharmaceutically acceptable salt is:

[0093] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0094] 6-[(3-ethoxy-2-pyridinyl)oxy]-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0095] 6-[(3-ethoxy-2-pyridinyl)oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0096] 6-[(3-ethoxy-2-pyridinyl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0097] 6-[(3-ethoxy-2-pyridinyl)oxy]-N-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0098] 6-[(3-ethoxy-2-pyridinyl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0099] N-(4-Methyl-1,1-dioxido-tetrahydro-thiopyran-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-pyridinyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0100] N-(3,3-Difluoro-1-methyl-cyclobutyl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0101] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[(5-chloro-3-ethoxy-2-pyridinyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-N-[1,1-dioxido-4-(2,2,2-trifluoroethyl)tetrahydrothiophen-4-yl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0102] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0103] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0104] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0105] 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0106] 5,7-dimethyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0107] 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0108] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0109] 8-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0110] 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0111] 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0112] 6-[3-(2,2-difluoroethoxy)pyrazin-2-yl]oxy-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide,

[0113] 6-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, or

[0114] 6-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide.

[0115] In Embodiment 33 of the present invention, the compound of Formula I or a pharmaceutically acceptable salt thereof is:

[0116]

[0117] Embodiment 34 is selected from:

[0118] of the compounds, or a pharmaceutically acceptable salt thereof.

[0119] Embodiment 35 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0120]

[0121] Embodiment 36 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0122]

[0123] Embodiment 37 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0124]

[0125] Embodiment 38 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0126]

[0127] Embodiment 39 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0128]

[0129] The present disclosure includes pharmaceutically acceptable salts of the compounds defined therein.

[0130] In one embodiment, the present disclosure is a composition comprising an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

[0131] The present disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0132] The present disclosure also provides a pharmaceutical composition 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).

[0133] The present disclosure also provides a pharmaceutical composition 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.

[0134] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases such as chronic kidney disease or heart failure, comprising a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt thereof.

[0135] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases such as chronic kidney disease or heart failure, comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0136] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases such as chronic kidney disease or heart failure, comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0137] In one embodiment, the present disclosure provides a method for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases such as chronic kidney disease or heart failure in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

[0138] In one embodiment, the present disclosure provides a method for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases such as chronic kidney disease 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.

[0139] The method of the present disclosure comprises administering a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0140] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, comprising administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof.

[0141] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, which comprises administering to a patient in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0142] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, which comprises administering to a patient in need thereof a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0143] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, which comprises administering to a patient in need thereof a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0144] In another embodiment, the present disclosure provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH and / or fibrosis.

[0145] In another embodiment, the present invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH and / or fibrosis.

[0146] "Alkyl" means a branched and straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms when mentioned. If no number is specified, 1-6 carbon atoms are intended for straight-chain alkyl, and 3-7 carbon atoms are intended for branched-chain alkyl. Examples of alkyl include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, octyl, nonyl, etc. For example, the term "C 1-6 alkyl" includes all "C 1-4 alkyl" as defined below, plus straight-chain or branched-chain alkyl having 5 or 6 carbon atoms, including all possible isomers. "C 1-6 alkyl" means a straight-chain or branched-chain alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms, including all possible isomers, and includes each alkyl within C 1-6 alkyl, including each hexyl and pentyl isomer, as well as n-butyl, isobutyl, sec-butyl and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively referred to as "C4 alkyl"; Bu = butyl), n-propyl and isopropyl (propyl, i-propyl, collectively referred to as "C3 alkyl"; Pr = propyl), ethyl (Et) and methyl (Me). The common abbreviations of alkyl are used throughout the specification. For example, methyl can be represented by conventional abbreviations including "Me" or CH3 or the symbol of an extended bond as a terminal group (e.g., ) indicates that ethyl can be represented by "Et" or CH2CH3, propyl can be represented by "Pr" or CH2CH2CH3, butyl can be represented by "Bu" or CH2CH2CH2CH3, and so on. For example, the structure has the same meaning. If no number is specified, 1 - 6 carbon atoms are intended for straight-chain or branched alkyl groups.

[0147] "Aryl" refers to an aromatic monocyclic or polycyclic ring moiety containing 6 to 14 ring carbon atoms. In one embodiment, aryl contains about 6 to 10 ring carbon atoms. Monocyclic aromatic rings include, but are not limited to, phenyl. Polycyclic rings include, but are not limited to, naphthalene rings and bicyclics where a phenyl is fused to a C 5-7 cycloalkyl or a C 5-7 cycloalkenyl ring. Aryl may optionally be substituted with one or more substituents as defined herein. The bonding can occur through any carbon atom of any ring.

[0148] "Halogen", "halo" or "halo group" includes fluorine, chlorine, bromine and iodine.

[0149] "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 - 10 carbon atoms are intended. Cycloalkyl can also be fused to form 1 - 3 carbon rings. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. The term "C 1-6 cycloalkyl" refers to a cycloalkyl having 1 to 6 ring carbon atoms. The term "C 3-6 cycloalkyl" refers to a cycloalkyl having 3 to 6 ring carbon atoms. Thus, for example, "C 3-6 cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl is unsubstituted or substituted with one or more ring system substituents, which may be the same or different and as defined herein. When cycloalkyl is a substituent on an alkyl, the cycloalkyl substituent can be bonded to any available carbon in the alkyl. The following is an illustration of a -C 3-6 cycloalkyl substituent on an alkyl, where the substituent is cyclopropyl, shown in bold:

[0150] "Haloalkyl" refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl have been replaced by halogen. In one embodiment, haloalkyl has 1 to 6 carbon atoms. Non-limiting examples of haloalkyl include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2Cl, CH2CF2CH3 and CCl3. The term "C 1-6 haloalkyl" or "halo-C 1-6"Alkyl" means a haloalkyl having 1 to 6 carbons.

[0151] "Haloalkoxy", "haloalkyl - O" and derivatives such as "halo(C 1-6 )alkoxy" or "O(C 1-6 )haloalkyl" are used interchangeably and mean an alkyl substituted by a halo group linked through an oxygen atom. Haloalkoxy includes both mono - substituted and poly - halogen - substituted alkoxy. For example, it includes trifluoromethoxy, chloromethoxy and bromomethoxy, as well as OCH2CF3, OCH2CHF2, OCF2CF3 and OCF2CHF2.

[0152] "Heterocyclic group", "heterocycle" or "heterocyclic" refers to a monocyclic structure in which one or more atoms in the ring (i.e., one or more heteroatoms) are elements other than carbon. Heteroatoms are typically O, S or N atoms. A heterocycle containing more than one heteroatom may contain different heteroatoms. Bicyclic moieties include fused bicyclics, spiro bicyclics and bridged bicyclics, and may contain one or more heteroatoms in either ring. The ring attached to the rest of the molecule may or may not contain heteroatoms. Either ring of a bicyclic heterocycle may be saturated, partially unsaturated or unsaturated. The heterocycle may be attached to the rest of the molecule through a ring carbon atom, a ring oxygen atom or a ring nitrogen atom. Examples of heterocyclic groups include: piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, ethylene oxide or aziridine, etc.

[0153] Unless otherwise specified, the term "heteroaryl" as used herein refers to a stable monocyclic, bicyclic or tricyclic having at most 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. Heteroaryls within this definition include, but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzpyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, dihydroindolyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, oxazolyl and tetrahydroquinoline.

[0154] "Oxo" means oxygen attached to an atom by a double bond. Examples of oxo groups are the double-bonded oxygen in ketones, sulfoxides, sulfones, and sulfates, or the double-bonded oxygen fused to a non-aromatic cycloalkyl or heteroalkyl group.

[0155] "Hydroxyalkyl" or "hydroxy(C 1-3 )alkyl" means an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy (-OH) group.

[0156] The term "composition" is intended to cover a product containing a specified amount of a specified ingredient, as well as any product directly or indirectly resulting from the combination of the specified amounts of the specified ingredients.

[0157] The term "at least one" means one or more than one. The meaning of "at least one" referring to the number of compounds of the present invention is independent of the meaning of referring to the number of chemotherapeutic agents.

[0158] The term "chemotherapeutic agent" means a drug (medication or pharmaceutically active ingredient) used for the treatment of cancer (i.e., an anti-tumor agent).

[0159] The term "effective amount" means "therapeutically effective amount". The term "therapeutically effective amount" means the amount of an active compound or agent that elicits the biological or pharmaceutical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, or human.

[0160] The term "treating cancer" or "treatment of cancer" refers to administering to a mammal suffering from a cancerous disorder, and means reducing the effects of the cancerous disorder by killing cancer cells, and also means causing an effect that inhibits the growth and / or metastasis of the cancer.

[0161] Unless otherwise specified herein, the term "carbocyclic" (and its variants, such as "carbocyclic" or "carbocyclic group"), unless otherwise indicated, refers to a C3 to C6 monocyclic ring, e.g., C 3-6 monocyclic carbocycle. The carbocycle can be attached to the rest of the molecule at any carbon atom, resulting in a stable compound. Saturated carbocycles include, for example, "cycloalkyl" rings, e.g., cyclopropyl, cyclobutyl, etc. Unsaturated carbocycles include, for example

[0162] A "stable" compound is a compound that can be prepared and isolated, and whose structure and properties remain or can remain substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutically or prophylactically administered to a subject).

[0163] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I and its embodiments. For example, certain moieties as defined in Formula I may be unsubstituted or substituted, and the latter is intended to cover substitution patterns (i.e., the number and types of substituents) that are chemically possible for the moiety and result in stable compounds.

[0164] The term "substituted" means that one or more hydrogens on the specified atom are replaced by a group selected from the groups shown, provided that in the given circumstances, it does not exceed the normal valence of the specified atom, and the substitution results in a stable compound. In cases where multiple substituent moieties are disclosed or claimed, the substituted compounds may be mono- or poly-substituted independently by one or more of the disclosed or claimed substituent moieties. Independently substituted means that the (two or more) substituents may be the same or different. Combinations of substituents and / or variables are permitted only if such combinations result in stable compounds. If a substituent itself is substituted by more than one group, it should be understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure is produced. Optionally substituted means compounds containing the specified optional substituent and compounds not containing the optional substituent.

[0165] As used herein, a wavy line indicates the point of attachment to the remainder of the compound.

[0166] In cases where a ring atom is represented by a variable such as "X", for example, the variable defines the atom located at the variable ring position without depicting the ring bonds associated with that atom. For example, when X in the above ring is nitrogen, the definition will show "N", and the bonds associated with it will not be depicted. For example, "=N-" will not be shown. Similarly, when X is a carbon atom substituted with bromine, the definition will show "C-Br", and the bonds associated with it will not be depicted. For example,

[0167] The present disclosure also includes derivatives of the compounds of Formula I as prodrugs and solvates. Any pharmaceutically acceptable prodrug modification of the compounds of the present invention that results in in vivo conversion to a compound within the scope of the present invention is also within the scope of the present invention. After administration to a patient, the prodrug is converted in vivo to a compound of Formula I by normal metabolic or chemical processes, such as hydrolysis in the blood. Such prodrugs include those that exhibit enhanced bioavailability, tissue specificity, and / or cellular delivery to improve the drug absorption of the compounds of Formula I. The effects of such prodrugs may be produced by modification of physicochemical properties (such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine drug permeability properties).

[0168] For example, esters can optionally be prepared by esterifying available carboxylic acid groups or by forming esters on available hydroxyl groups in the compound. Similarly, labile amides can be made. Pharmaceutically acceptable esters or amides of the compounds of the invention can be prepared as prodrugs that can be hydrolyzed in vivo, in particular, back to the acid (or -COO-, depending on the pH of the liquid or tissue in which the conversion occurs) or hydroxyl form, and are thus encompassed within the scope of the invention. Those esters and acyl groups known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations are included. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 alkyl esters and -C 1-6 alkyl substituted with phenyl esters.

[0169] (Fluka) Diatomite is diatomaceous earth and can be referred to as "celite".

[0170] When any variable (e.g., R 1 etc.) appears more than once in any component or in Formula I or other general formulas herein, its definition at each occurrence is independent of its definition at each other occurrence. Such combinations are permitted only if the combination of substituents and / or variables results in a stable compound. In selecting the compounds of the invention, one of ordinary skill in the art will recognize that the various substituents, i.e., R 1 etc., are selected in accordance with well-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substituents designated on any atom in a ring (e.g., aryl, heteroaryl ring or saturated heterocycle) are permitted, provided that such ring substitution is chemically allowed and results in a stable compound.

[0171] It should be noted that if there is a difference between the chemical name and the structure, the structure is considered to be dominant.

[0172] Compounds of Structural Formula I may contain one or more asymmetric centers and can therefore exist in the form of racemates and racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. The asymmetric centers present in the compounds of Formula I can each independently have the S configuration or the R configuration. When the bonds to a chiral carbon are depicted as straight lines in the structural formulas of the present invention, it is to be understood that the (R) and (S) configurations of the chiral carbon and thus the enantiomers and their mixtures are included in these formulas. Similarly, when a compound name is listed without chiral designation for a chiral carbon, it is to be understood that the (R) and (S) configurations of the chiral carbon and thus the individual enantiomers and their mixtures are encompassed by that name. The generation of specific stereoisomers or mixtures thereof can be identified in the examples in which such stereoisomers or mixtures are obtained, but this in no way limits the inclusion of all stereoisomers and their mixtures within the scope of the present invention.

[0173] The compounds of the present disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers in all proportions. Accordingly, enantiomers in enantiomerically pure form, both as the levorotatory enantiomer and as the dextrorotatory enantiomer, in racemic form, and in the form of mixtures of the two enantiomers in all proportions are the subject of the present invention. In the case of cis / trans isomerism, the present invention includes cis and trans and mixtures of these forms in all proportions. The present invention is meant to cover all such stereoisomeric forms of the compounds of Structural Formula I.

[0174] The compounds of Structural Formula I can be separated into their respective diastereomers, for example, by fractional crystallization from a suitable solvent (such as MeOH or EtOAc or a mixture thereof), or by chiral chromatography using an optically active stationary phase. Optionally, derivatization can be carried out prior to the separation of the stereoisomers. The separation of the stereoisomeric mixture can be carried out at an intermediate step during the synthesis of the compounds of Formula I, or can be carried out on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, optionally using a reagent containing an asymmetric center of known absolute configuration for derivatization. Alternatively, any stereoisomer or isomer of the compounds 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 these racemates, enantiomers, diastereomers, and tautomers and their mixtures.

[0175] If desired, the racemic mixture of the compound can be separated to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, for example, coupling the racemic mixture of the compound with an enantiomerically pure compound to form a diastereomeric mixture, and then separating the individual diastereomers by standard methods (such as fractional crystallization or chromatography). The coupling reaction is usually the formation of a salt using an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to the pure enantiomer by cleaving the added chiral residue. The racemic mixture of the compound can also be directly separated by chromatographic methods using a chiral stationary phase, which are well known in the art.

[0176] For the compounds of formula I containing an alkenyl double bond as described herein, unless otherwise specified, it is meant to include both E and Z geometric isomers.

[0177] Some of the compounds described herein can exist as tautomers, which have different hydrogen attachment points accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The compounds of formula I of the present invention encompass individual tautomers and mixtures thereof.

[0178] In the compounds of structural formula I, the atoms can exhibit their natural isotope abundances, or one or more atoms can be artificially enriched in a specific isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly present in nature. The present invention, as described and claimed herein, is intended to include all suitable isotopic variants of the compounds of structural formula I and their embodiments. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H, also denoted as D herein). Protium is the predominant hydrogen isotope in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as increased in vivo half-life or reduced dose requirements, or can provide compounds that can be used as standards for the characterization of biological samples. The isotopically enriched compounds in structural formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by methods similar to those described in the protocols and examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0179] It should be understood that when the compounds of structural formula I are used as precursors of free compounds or their pharmaceutically acceptable salts or in other synthetic operations, they can be prepared as pharmaceutically acceptable salts or non-pharmaceutically acceptable salts. The compounds of the present invention, including the compounds of the examples, can also include all salts of the compounds of formula I, which are not directly suitable for use in drugs due to low physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically acceptable salts.

[0180] 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 bases or organic bases as well as inorganic acids or organic acids.

[0181] Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present invention, which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate (camphorsulfonate), camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, ethanedisulfonate, etidronate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxy-naphthoate, iodide, isothiocyanate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (pamoate), palmitate, pantothenate, phosphate / hydrogenphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, toluenesulfonate, triethiodide, valerate, etc. In addition, in the case where the compounds of the present invention carry acidic moieties, their suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases (including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, etc.). In one embodiment, the salts of acidic compounds are as follows, ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts.

[0182] Using basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia, organic bases or alternatively basic amino acids, the compounds of formula I form stable alkali metal salts, alkaline earth metal salts or optionally substituted ammonium salts.

[0183] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexylamine, and basic ion exchange resins (such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.). In addition, it also includes basic nitrogen-containing groups that can be quaternized with reagents such as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl; and dipentyl sulfates, long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides, aralkyl halides such as benzyl and phenethyl bromides, etc.

[0184] The preparation of pharmaceutically acceptable salts from the compounds of formula I capable of forming salts, including their stereoisomeric forms, is carried out by known methods. For example, by mixing the compound of the present invention with an equivalent amount of the compound and a solution containing the required acid, base, etc., and then collecting the required salt by filtering the salt or distilling off the solvent. The compounds of the present invention and their salts can form solvates with solvents such as water, ethanol, or glycerol. Depending on the type of side-chain substituents, the compounds of the present invention can form acid addition salts and salts with bases simultaneously.

[0185] If the compound of formula I contains both acidic and basic groups in the molecule, the present invention includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The salts can be obtained from the compounds of formula I by conventional methods known to those skilled in the art, such as by combination with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

[0186] The present invention includes the compounds of structural formula I and their salts, especially pharmaceutically acceptable salts, solvates of such compounds, and solvated salt forms, and such forms are possible unless otherwise stated.

[0187] In addition, the compounds of the present invention can exist in amorphous form and / or one or more crystalline forms. Accordingly, all amorphous and crystalline forms of the compounds of formula I (including the examples), as well as mixtures thereof, are intended to be included within the scope of the present invention. Further, some of the compounds of the present invention can form solvates with water (i.e., hydrates) or common organic solvents (such as, but not limited to, EtOAc). Such solvates and hydrates of the compounds of the present invention, particularly pharmaceutically acceptable solvates and hydrates, as well as the unsolvated and anhydrous forms, are equally encompassed within the scope of the present invention.

[0188] Accordingly, the compounds described in the examples and the general structural formulas, embodiments, and specific compounds claimed herein encompass their salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms, and any combination of these forms, as well as their salts, prodrug forms, and salts of prodrug forms, which are possible unless otherwise indicated.

[0189] The present invention also relates to a medicament comprising 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, and a pharmaceutically acceptable vehicle, carrier, additive, and / or other active substances and adjuvants.

[0190] The medicament according to the present invention can be administered orally, by inhalation, rectally, or transdermally, or by subcutaneous, intra-articular, intraperitoneal, or intravenous injection. Oral administration is preferred.

[0191] The present invention also relates to a method for producing a medicament, which comprises bringing at least one compound of formula I into a suitable form for administration using a pharmaceutically acceptable carrier and, optionally, other suitable active substances, additives, or adjuvants.

[0192] The present invention also relates to a method for preparing the compounds of formula I, which is described below and by which the compounds of the present invention can be obtained.

[0193] The terms "therapeutically effective (or efficacious) amount" and similar descriptions, such as "amount effective for treatment", are intended to mean an amount of a drug that will relieve the symptoms of a disorder, condition or disease (i.e., a disorder, condition or disease associated with DGAT2 activity) in the animal or human being being treated. The terms "preventively effective (or efficacious) amount" and similar descriptions, such as "amount effective for prevention", are intended to mean an amount of a drug that will prevent or reduce the symptoms or occurrence of a disorder, condition or disease (i.e., a disorder, condition or disease associated with DGAT2 activity) in the animal or human being being treated. The dosing regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound selected for administration; the route of administration; and the renal and hepatic function of the patient. The consideration of these factors for the purpose of determining the therapeutically effective or preventively effective dose required to prevent, combat or arrest the progression of a condition is well within the scope of the ordinary clinician. It should be understood that a particular daily dose can be both a therapeutically effective amount (e.g., for treating hepatic steatosis, diabetes, obesity, hyperlipidemia, hypercholesterolemia) and a preventively effective amount (e.g., for treating NASH).

[0194] Disorders, conditions and diseases that can be treated or prevented by inhibiting DGAT2 with a compound of formula I are, for example, diseases such as non-alcoholic 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 lipemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hyperglycerolemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue diseases, hyperapolipoprotein B lipoproteinemia, non-alcoholic hepatic steatosis, cardio-renal diseases such as chronic kidney disease and heart failure, and related diseases and conditions.

[0195] The compounds of formula I and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals and especially to humans, as the drug itself, in mixtures 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 the drug itself, in mixtures with each other or in the form of pharmaceutical preparations. The term "patient" includes animals, preferably mammals and especially humans, using the present active agent for the prevention or treatment of a medical condition. Administering a drug to a patient includes self - administration and administration to the patient by another person. A patient may require or desire treatment of an existing disease or medical condition or may require or desire prophylactic treatment to prevent or reduce the risk of occurrence of the disease or medical condition. As used herein, a patient "in need" of treatment or prophylactic treatment of an existing condition encompasses both the determination of need by a medical professional and the patient's desire for such treatment.

[0196] Furthermore, a subject of the invention is a pharmaceutical preparation (or pharmaceutical composition) comprising a therapeutically effective dose of at least one compound of formula I and / or its pharmaceutically acceptable salt as an active ingredient and conventional pharmaceutically acceptable carriers, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0197] Accordingly, a subject of the invention is, for example, the use of the said compounds and their pharmaceutically acceptable salts as drugs, pharmaceutical preparations, which comprise a therapeutically effective dose of the said compounds and / or their pharmaceutically acceptable salts as active ingredients and conventional pharmaceutically acceptable carriers, and the use of the said compounds and / or their pharmaceutically acceptable salts in the treatment or prevention of the syndromes mentioned above and their use in the manufacture of a drug for these purposes.

[0198] The drugs according to the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar - coated tablets, 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 carried out parenterally in the form of solutions for injection or infusion, for example subcutaneously, intramuscularly or intravenously. Other suitable forms of administration are, for example, transdermal or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred form of administration depends, for example, on the disease to be treated and its severity.

[0199] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, starch (such as corn starch) or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural oils or hardened oils, etc. Suitable carriers for the preparation of solutions (such as solutions for injection) or emulsions or syrups are, for example, water, physiological sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of formula I and their pharmaceutically acceptable salts and use the resulting lyophilizates, for example, for the preparation of preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0200] Suitable solid or galenic preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, fruit juices, suspensions, emulsions, drops or injectable solutions and preparations with extended release of the active substance, in the preparation of which conventional excipients are used such as vehicle, disintegrant, binder, coating agent, swelling agent, glidant or lubricant, flavoring agent, sweetening agent and solubilizer. Frequently used auxiliaries that can 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 sterile water and monoalcohols or polyols such as glycerol.

[0201] In addition to the active compound and the carrier, the pharmaceutical preparation may also contain conventional additives, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweetening agents, colorants, flavoring agents, fragrances, thickeners, diluents, buffering substances, solvents, solubilizers, reagents for achieving a depot effect, salts for changing the osmotic pressure, coating agents or antioxidants.

[0202] The dose of the active compound of formula I and / or its pharmaceutically acceptable salt to be administered depends on the specific circumstances and, as a rule, will be adapted to the specific circumstances to achieve the best effect. Thus, it depends on the nature and severity of the disorder, condition or disease to be treated, also on the sex, age, weight and individual reactivity of the human or animal to be treated, on the efficacy and duration of action of the compound used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to the compound of formula I.

[0203] Combination agent

[0204] Depending on the condition being treated, the compounds of the present invention can be administered alone or in combination with one or more other therapeutic agents or other suitable agents disclosed herein. Thus, in some embodiments, one or more compounds of the present invention will be co-administered with other agents as described herein. When used in combination therapy, the compounds described herein are administered simultaneously with or separately from the second agent. This combination administration can include administering the two agents simultaneously in the same dosage form, simultaneously in separate dosage forms, and separately. That is, the compound of formula (I) and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of formula (I) and any of the above agents can be administered simultaneously, where the two agents are present in separate formulations. In another alternative, the compound of formula (I) can be administered, followed immediately by administering any of the above agents, or vice versa. In some embodiments of the separate administration scenario, the compound of formula (I) and any of the above agents are administered at intervals of minutes, or hours, or days.

[0205] Since one aspect of the present invention contemplates treating diseases / conditions with combinations of pharmaceutically active compounds that can be administered alone, the present invention further relates to a combination of separate pharmaceutical compositions in the form of a kit. The kit contains two separate pharmaceutical compositions: the compound of formula (I) and a second pharmaceutical compound. The kit contains containers for holding the separate compositions, such as separate bottles or separate foil packages. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit contains instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, parenteral; IV, transdermal, and subcutaneous), at different dosing intervals, or when the prescribing healthcare professional needs to titrate the separate components of the combination.

[0206] One or more other pharmaceutically active agents can be co-administered with the compound of formula I. One (or more) other active agents is intended to mean one (or more) pharmaceutically active agents that are active in the body, including prodrugs that are converted to a pharmaceutically active form after administration, which are different from the compound of formula I, and also includes the free acids, free bases, and pharmaceutically acceptable salts of said other active agents. Generally, any suitable one or more other active agents, including but not limited to anti-hypertensive agents, anti-obesity agents, anti-inflammatory agents, anti-fibrotic agents, and anti-atherosclerotic agents such as lipid-modifying compounds, anti-diabetic agents, and / or anti-obesity agents, can be used in any combination with the compound of formula I in a single dosage formulation (fixed-dose drug combination), or can be administered to a patient in one or more separate dosage formulations, which allows for simultaneous or sequential administration of the active agents (co-administering the separate active agents).

[0207] Examples of other active agents that can be used include, but are not limited to, angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, cilazapril, ceronapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., losartan, i.e., valsartan, candesartan, olmesartan, telmisartan, and any of these drugs used in combination with hydrochlorothiazide, e.g., ); neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., urea derivatives of dipeptides and tripeptides, amino acids and derivatives, amino acid chains linked by non-peptide bonds, dipeptide and tripeptide derivatives, peptidyl amino diols and peptidyl β-aminoacyl amino diol carbamates; and, also including small molecule renin inhibitors, including sulfondiols and N-morpholino derivatives, N-heterocyclic alcohols and pyrrolimidazolones; also including pepsin inhibitor derivatives and fluoro and chloro derivatives of peptides containing statone, enalkiren, remikiren, A 65317, terlakiren, ES1005, ES 8891, SQ 34017, aliskiren, SPP600, SPP630, and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, gallopamil, niludipine, nimodipine, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, apricarin, cloprazolam), diuretics (e.g., hydrochlorothiazide), sympathomimetics, β-adrenergic blockers (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartrate), α-adrenergic blockers (e.g., doxazosin, prazosin, or methyldopa), central α-adrenergic agonists, peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, e.g., HMG-CoA reductase inhibitors, e.g., simvastatin and lovastatin, which are marketed in the form of lactone prodrugs and as inhibitors after administration of and and pharmaceutically acceptable salts of dihydroxy open-ring acid HMG-CoA reductase inhibitors, e.g., atorvastatin (especially the calcium salt marketed as ), rosuvastatin (especially the calcium salt marketed as ), pravastatin (especially the calcium salt marketed as the sodium salts sold), fluvastatin (especially the sodium salts sold), cerivastatin, and pitavastatin; cholesterol absorption inhibitors such as ezetimibe and combinations of ezetimibe with any other lipid-lowering agent (such as the above-mentioned HMG-CoA reductase inhibitors, especially with simvastatin or atorvastatin calcium); niacin in immediate-release or controlled-release form, and / or used in combination with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, and niacin receptor partial agonists; anti-cholesterol agents such as PCSK9 inhibitors (amroubicinab, evolocumab), Nexletol TM (bepexid acid, ACL inhibitor) and (eicosapentaenoic acid ethyl ester); metabolic modifiers, including insulin and insulin mimetics (such as, degludec insulin, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (such as, sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, including (i) β-klotho / FGFR1 activating monoclonal antibodies (such as, MK-3655), pan-FGFR1-4 / KLB modulators, FGF19 analogs (such as, Aldafermin), (ii) PPARγ agonists such as glitazones (such as, pioglitazone, AMG 131, mitoglitazone, lobeglitazone, rosiglitazone, and balaglitazone), and other PPAR ligands, including (1) PPARα / γ dual agonists (such as, ZYH2, ZYH1, GFT505, ciglitazar, moglitazar, aleglitazar, soleglitazar, and naglitazar); (2) PPARα agonists such as fenofibric acid derivatives (such as, gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARγ modulators (SPPARγM) (such as, those disclosed in WO 02 / 060388, WO 02 / 08188, WO2004 / 019869, WO 2004 / 020409, WO 2004 / 020408, and WO 2004 / 066963); (4) PPARγ partial agonists, (5) PPARα / δ dual agonists (such as, Elafibranor); (iii) biguanides such as metformin and its pharmaceutically acceptable salts, especially, metformin hydrochloride, and its sustained-release formulations such as Glumetza TM 、Fortamet TM and GlucophageXR TM; and (iv) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., detemir insulin, lispro insulin, degludec insulin, glargine insulin, lispro insulin, and inhalable formulations thereof); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylureas and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glibenclamide, glipizide, glimepiride, mitiglinide, meglitinide, 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, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof), bile acid sequestering agents (e.g., colestilan, colestimide, colesevelam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of cross-linked dextran); acyl coenzyme A: cholesterol acyltransferase inhibitors (e.g., avasimibe); anti-obesity compounds; agents for inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKA) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (e.g., those disclosed in U.S. Patent No. 6,730,690 and LY-2523199); CETP inhibitors (e.g., anacetrapib, torcetrapib, and evacetrapib); inhibitors of fructose 1,6-bisphosphatase (e.g., those disclosed in U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); inhibitors of acetyl coenzyme A carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated protein kinase (AMPK) agonists; 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 WO 2009 / 001836);Neuregulin U receptor agonists (e.g., those disclosed in WO2009 / 042053, including but not limited to Neuregulin S (NMS)); SCD modulators (e.g., Aramchol); GPR-105 antagonists (e.g., those disclosed in WO 2009 / 000087); Glucose pathway modulators such as SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2 such as 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., fluoristerone); LAPS glucagon combo (e.g., HM14320); SGLT-1 inhibitors (e.g., SGL5213); Inhibitors of acyl-CoA carboxylase (ACC, MK-4074); Inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); Inhibitors of fatty acid synthase; Inhibitors of acyl-CoA:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); Agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); Inhibitors of ileal bile acid transporter; 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 agents (CCR2 / CCR5 dual receptor antagonists (e.g., cenicriviroc); Galectin-3 inhibitors (e.g., belapectin, GB-1107, GB-1211), siRNA agonist HSP 47 (e.g., BMS-986263); Pyrfenidone-derived NSAIDs (e.g., oxymetazoline); 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., atrosimab), autotoxin inhibitors (e.g., BLD-0409, TJC 0265, TJC 0316), CCL24-blocking monoclonal antibodies (e.g., CM101), IL-11 inhibitors (e.g., ENx 108A), LPA1 receptor antagonists (e.g., EPGN 696), dual JAK1 / 2 inhibitors (e.g., EX 76545), GPR antagonists (e.g., GPR91 antagonists), integrin avβ1, avβ3, and avβ6 inhibitors (e.g., IDL 2965), NLRP3 antagonists (e.g., IFM-514), inflammasome inhibitors (e.g., JT194, JT349), cell membrane permeability inhibitors (e.g., larixol), CCR5 antagonists (e.g., Ieronlimab), TNF inhibitors (e.g., LIVNate), integrin avβ6 inhibitors (e.g., MORFβ6), NLRP inflammasome antagonists, siRNA (e.g., OLX701), dual TFGβ / Hedgehog inhibitors (e.g., Oxy 200), GPR40 agonist / GPR84 antagonist (e.g., PBI-4547), neutrophil elastase inhibitors (e.g., PHP-303), integrin inhibitors (e.g., PLN-1474), TGFβ1 regulators (e.g., PRM-151), CCK receptor antagonists (e.g., proglumide), LOXL2 inhibitors (e.g., PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitors (e.g., cGAS / STING antagonists), kinase-inhibitory ribonucleases (RNase), membrane protein mAbs, tumor necrosis factor inhibitors, NRF2 activators (e.g., SCO 116), SSAO inhibitors (e.g., TERN 201), 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 agents (e.g., norfloxacin, ciprofloxacin, ceftriaxone); blood coagulation regulators (e.g., anticoagulants, antiplatelet agents, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonists (e.g., tirzepatide); dual GLP-1 / GRA (e.g., cotadutide, ALT-801, DD 01, G49, PB-718); dual GLP-1 (e.g., CT 868);GLP-1 / GIP / TRIPLE AGONIST (e.g., HM15211); GRP120 STIMULATOR / INFLAMMASOME REGULATOR PPARγ DUAL AGONIST (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 AGONIST (e.g., SEMAGLUTIDE (SEMAGLUTIDE sc), XW003); SELECTIVE THYROID HORMONE RECEPTOR-β AGONIST (e.g., RESMETIROM); APOPTOSIS REGULATOR (JNK-1 INHIBITOR (e.g., CC-90001), PEROXIDASE INHIBITOR (e.g., AZM198), ASK-1 INHIBITOR (e.g., CS-179S9, SRT015)); ERYTHROPOIETIN STIMULATOR (ERYTHROPOIETIN RECEPTOR AGONIST (e.g., CIPIROTIDE)); IMMUNE REGULATOR (TLR4 INHIBITOR (e.g., GBK-233), IMMUNOMODULATORY POLYCLONAL ANTIBODY (e.g., IMM-124E), TLR4 ANTAGONIST (e.g., JKB-122), CD3 MONOCLONAL ANTIBODY (e.g., FRESOLUTUMAB), TLR4 ANTAGONIST (e.g., JKB 133), TLR4 INHIBITOR (e.g., MOSMOLD), MACROPHAGE INHIBITOR TARGETED BY CD206 (e.g., MT2002), TLR2 / 4 ANTAGONIST (e.g., VB-201, VB-703), IMMUNOMODULATORY POLYCLONAL ANTIBODY (e.g., IMM-124E)); INCRETIN-BASED THERAPY (GLP-1 AGONIST (e.g., SEMAGLUTIDE (SEMAGLUTIDE sc), XW 003), GLP-1 / GLUCAGON DUAL RECEPTOR AGONIST (e.g., HM12525A), MEALTIME INSULIN (e.g., ORMD 0801)); LIPID REGULATOR (AMPK ACTIVATOR / GLUTATHIONE TRANSFERASE (e.g., OLTIPRAZ), THR-β AGONIST (e.g., RESMETIROM, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN 501), IBAT INHIBITOR (e.g., ELUXADOLAT, CJ 14199), ω-6-FATTY ACID (e.g., EPELEUTON), FASN INHIBITOR (e.g., TVB2640, FT 4101, FT 8225), ANGPTL3 INHIBITOR (e.g., VUPANORSEN), PNPLA3 INHIBITOR (e.g., AZD2693), RAS DOMAIN KINASE INHIBITOR (e.g., BIOE1115), NTCP INHIBITOR (e.g., BULEVIRTIDE), P2Y13 RECEPTOR AGONIST (e.g., CER-209), ω-3 FATTY ACID, HSD17β13 INHIBITOR;Metabolic regulators (FXR agonists (e.g., Ocaliva (obeticholic acid), IOT022), recombinant variants of FGF19 (e.g., aldafermin), bispecific FGFR1 / KLB antibodies (e.g., BFKB8488A), mTOT regulators (e.g., MSDC-0602K), pegylated analogs of FGF21 (e.g., pegbelfermin, BMS-986171), non-bile FXR agonists (e.g., cilofexor, EDP-305, EYP 001, tropifexor, MET409, AGN-242256, AGN-242266, EDP297, HPG 1860, MET642, RDX023, TERN 101), ACC inhibitors (e.g., firsocostat, PF-05221304), ketohexokinase inhibitors (e.g., PF-06835919), AMPK activators (e.g., PXL770, MSTM 101, O304), bile acid regulators (e.g., Albiero), FGF21 analogs (e.g., BIO89-100), MOTSc analogs (e.g., CB4211), cyclophilin inhibitors (e.g., CRV 431), FGF19 (e.g., DEL 30), mitochondrial uncouplers (e.g., GEN 3026), 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., M 1217), anti-β-klotho (KLB)-FGFR1c receptor complex mAb (e.g., MK3655), GDF-15 analogs (e.g., NGM395), cyclophilin inhibitors (e.g., NV556), LXR regulators (e.g., PX 329, PX 655, PX 788), LXR inverse agonists (e.g., PX016), deuterated obeticholic acid (e.g., ZG 5216)); PPAR regulators (dual PPARα / γ agonists (e.g., elafibranor), PPAR pan-agonists (e.g., ranilano), PPARα agonists (e.g., Parmodia), PPARγ agonists (e.g., CHS131), MPC inhibitors (e.g., PXL065), PPARδ / γ agonists (e.g., T3D 959)); RAAS mIM regulators (mineralocorticoid receptor antagonists (e.g., apararenone, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium));Neurotransmitter modulators (cannabinoid receptor modulators, CB1 receptor antagonists (e.g., CRB-4001, IM-102, nemadectin), TPH1 inhibitors (e.g., CU 02), GPR120 agonists (e.g., KBR2001), combinations of cannabinoids and phytocannabinoids (e.g., SCN 002)); PDE modulators (PDE4 inhibitors (e.g., ART 648)); CYP2E1 inhibitors (e.g., SNP-610); cell therapies (e.g., HepaStem) and bromocriptine mesylate and its immediate release formulations; or used in combination with other drugs beneficial for the prevention or treatment of the above diseases, including sodium nitroprusside and dinitrogen oxide, and, where chemically possible, in the form of free acids, free bases and pharmaceutically acceptable salts of the above active agents.;

[0208] 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. References to compounds of structural formula (I) include compounds of other general structural formulas, such as formulas and embodiments falling within the scope of formula (I).

[0209] Dosage of the compound of formula (I)

[0210] After completion of the treatment cycle, the patient may continue to take the compounds of the present invention at the same dose as administered in the treatment regimen. 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 to take the reduced dose).

[0211] Those skilled in the art will recognize that the actual dosage and regimen of administration used in the methods of the present invention may vary according to the judgment of a skilled clinician. The actual dosage used may vary according to the needs of the patient and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is within the skill of the art. Decisions to change the dosage and regimen of administration may be made after a skilled clinician has considered factors such as the age, condition and physical build of the patient, and the severity of the condition being treated and the patient's response to treatment.

[0212] The dosage regimen utilizing the compounds of the present invention is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the disease to be treated; the potency of the compound selected for administration; the route of administration; and the renal and hepatic function of the patient. Consideration of these factors for the purpose of determining a therapeutically effective or prophylactically effective dose required to prevent, combat or arrest the progression of the condition is entirely within the scope of the ordinary clinician. It should be understood that a particular daily dose may simultaneously be a therapeutically effective amount (e.g., for treating a neoplastic condition) and a prophylactically effective amount (e.g., for preventing a neoplastic condition).

[0213] Although individual requirements may vary, the determination of the optimal range of an effective amount of the compounds of the present invention is within the skill of the art. For administration to humans in the therapeutic or prophylactic treatment of the conditions and disorders identified herein, for example, a typical dose of the compounds of the present invention can be from about 0.05 mg / kg / day to about 50 mg / kg / day, such as at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less or 10 mg / kg or less. For example, it can be 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 dose of the compound can be from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, from about 0.05 mg / kg / day to about 3 mg / kg / day, from about 0.07 mg / kg / day to about 3 mg / kg / day, from about 0.09 mg / kg / day to about 3 mg / kg / day, from about 0.05 mg / kg / day to about 0.1 mg / kg / day, from about 0.1 mg / kg / day to about 1 mg / kg / day, from about 1 mg / kg / day to about 10 mg / kg / day, from about 1 mg / kg / day to about 5 mg / kg / day, from about 1 mg / kg / day to about 3 mg / kg / day, from about 3 mg / day to about 500 mg / day, from about 5 mg / day to about 250 mg / day, from about 10 mg / day to about 100 mg / day, from about 3 mg / day to about 10 mg / day or from about 100 mg / day to about 250 mg / day. Such doses can be administered as a single dose or can be divided into multiple doses.

[0214] Pharmaceutical composition

[0215] The compounds of formula I and their pharmaceutically acceptable salts can be administered to animals as the drug itself, as mixtures with each other or in the form of pharmaceutical compositions, preferably to mammals and especially to humans. The terms "subject" or "patient" include animals, preferably mammals and especially humans, which are using the active agent for the prevention or treatment of a medical condition.

[0216] Administering a compound of formula I to a subject includes self - administration and administration to the patient by another person. The subject may be in need of or desirous of treatment for an existing disease or medical condition, or may be in need of or desirous of prophylactic treatment to prevent or reduce the risk of occurrence of the disease or medical condition. As used herein, a subject "in need of" treatment for an existing condition or prophylactic treatment encompasses both the determination of need by a medical professional and the patient's desire for such treatment.

[0217] If the patient responds or stabilizes after completion of a treatment cycle, the treatment cycle can be repeated at the discretion of a skilled clinician. After completion of a treatment cycle, the patient can continue to take the compound of the invention at the same dose as that administered in the treatment regimen. This maintenance dose can continue 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 to take the reduced dose).

[0218] Those skilled in the art will recognize that the actual dosage and administration regimen used in the methods of the invention can vary according to the discretion of a skilled clinician. The actual dosage used can vary according to the needs of the patient and the severity of the condition being treated. Determining the appropriate dosage for a particular situation is within the skill of the art. A decision to change the dosage and regimen of administration can be made after a skilled clinician has considered factors such as the age, condition and physical build of the patient, and the severity of the condition being treated and the patient's response to the treatment.

[0219] The amount and frequency of administration of the compound of formula I and any other medicament will be adjusted according to the judgment of the attending clinician (physician), taking into account factors such as the age, condition and physical build of the patient and the severity of the condition being treated.

[0220] The compounds of the invention can also be used in the preparation of a medicament useful for the treatment of NASH and fibrosis.

[0221] The compounds of the present invention can also be combined with therapeutic agents, chemotherapeutic agents, and anti-cancer agents for the treatment of hepatocellular carcinoma. Combinations of the presently disclosed compounds with therapeutic agents, chemotherapeutic agents, and anti-cancer agents are within the scope of the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology, V.T. Devita and S. Hellman (eds.), 9th Edition (May 16, 2011), Lippincott Williams & Wilkins Publishers. Those of ordinary skill in the art will be able to discern which combinations of agents are useful based on the particular characteristics of the drug and the cancer involved. Such agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents / cytostatic agents, anti-proliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapies, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), and agents that interfere with cell cycle checkpoints.

[0222] Chemotherapeutic agents can be administered according to well-known treatment regimens in the art. It will be apparent to those skilled in the art that the administration of chemotherapeutic agents can vary depending on the cancer being treated and the known effects of the chemotherapeutic agent on the disease. In addition, based on the knowledge of a skilled clinician, the treatment regimen (e.g., the dose and timing of administration) can vary depending on the observed effects of the administered therapeutic agent on the patient and the observed response of the cancer to the administered therapeutic agent. The specific choice of chemotherapeutic agent will depend on the diagnosis of the attending physician and their judgment of the patient's condition, as well as the appropriate treatment regimen.

[0223] The initial administration can be carried out according to established protocols known in the art, and then, based on the observed effects, the dose, mode of administration, and timing of administration can be modified by a skilled clinician.

[0224] After evaluating the condition being treated and the patient's status, the determination of the order of administration and the number of repeated administrations of chemotherapeutic agents during the treatment regimen is entirely within the knowledge of a skilled physician.

[0225] Thus, based on experience and knowledge, as the treatment progresses, a practicing physician can modify each regimen for the administration of chemotherapeutic agents according to the needs of the individual patient. All such modifications are within the scope of the present invention.

[0226] Agents can be administered according to treatment regimens well-known in the art. It will be apparent to those skilled in the art that the administration of the anti-cancer agent can be varied depending on the cancer being treated and the known effects of the anti-cancer agent on the disease.

[0227] Initial administration can be carried out according to established protocols known in the art, and then, based on the observed effects, the dose, mode of administration, and time of administration can be modified by a skilled clinician.

[0228] The specific choice of agent will depend on the diagnosis of the attending physician and their judgment of the patient's condition, as well as the appropriate treatment regimen.

[0229] After assessing the cancer being treated and the patient's condition, the determination of the order of administration and the number of repeated administrations of the agent during the treatment regimen is entirely within the knowledge of a skilled physician.

[0230] Thus, based on experience and knowledge, as the treatment progresses, the practicing physician can modify each regimen for the administration of the anti-cancer agent according to the needs of the individual patient. All such modifications are within the scope of the present invention.

[0231] When judging whether the treatment with the administered dose is effective, the attending clinician will consider the patient's overall health status and more specific signs, such as the alleviation of cancer-related symptoms (e.g., pain), the inhibition of tumor growth, the actual shrinkage of the tumor, or the inhibition of metastasis. The size of the tumor can be measured by standard methods, such as radiological studies, e.g., CAT or MRI scans, and serial measurements can be used to determine whether the growth of the tumor is retarded or even reversed. The alleviation of disease-related symptoms (e.g., pain) and the improvement of the overall condition can also be used to help judge the effectiveness of the treatment.

[0232] The compounds, compositions, and methods provided herein can be used to treat cancer. Cancers that can be treated by the compounds, compositions, and methods disclosed herein include, but are not limited to: Liver: Hepatocellular carcinoma (hepatoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

[0233] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL-inhibitors include atezolizumab, avelumab, and durvalumab.

[0234] The present invention also relates to a method for treating hepatocellular carcinoma in a human patient, which comprises administering to the patient a compound of the present invention (i.e., a compound of formula I) and a PD-1 antagonist. The compound of the present invention and the PD-1 antagonist can be administered simultaneously or sequentially.

[0235] In a specific embodiment, the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof. In an alternative embodiment, the PD-1 antagonist is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA TM , Merck & Co., Inc., Rahway, NJ, USA), nivolumab (OPDIVO TM , Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO TM , Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab (TECENTRIQ TM , Genentech, San Francisco, CA, USA), durvalumab (IMFINZI TM , AstraZeneca Pharmaceuticals LP, Wilmington, DE) or avelumab (BAVENCIO TM , Merck KGaA, Darmstadt, Germany).

[0236] In some embodiments, the PD-1 antagonist is pembrolizumab. In a specific sub-embodiment, the method comprises administering 200 mg of pembrolizumab to a patient approximately every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to a patient approximately every six weeks.

[0237] In a further sub-embodiment, the method comprises administering 2 mg / kg of pembrolizumab to a patient approximately every three weeks. In a specific sub-embodiment, the patient is a pediatric patient.

[0238] In some embodiments, the PD-1 antagonist is nivolumab. In a specific sub-embodiment, the method comprises administering 240 mg of nivolumab to a patient approximately every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to a patient approximately every four weeks.

[0239] In some embodiments, the PD-1 antagonist is cemiplimab. In a specific embodiment, the method comprises administering 350 mg of cemiplimab to a patient approximately every three weeks.

[0240] In some embodiments, the PD-1 antagonist is atezolizumab. In a specific sub-embodiment, the method comprises administering 1200 mg of atezolizumab to a patient approximately every three weeks.

[0241] In some embodiments, the PD-1 antagonist is durvalumab. In a specific sub-embodiment, the method comprises administering 10 mg / kg durvalumab to a patient approximately every two weeks.

[0242] In some embodiments, the PD-1 antagonist is avelumab. In a specific sub-embodiment, the method comprises administering 800 mg avelumab to a patient approximately every two weeks.

[0243] The compounds of the invention or pharmaceutically acceptable salts thereof may also be used in the treatment of cancer in combination with the following therapeutic agents: pembrolizumab abarelix (Plenaxis );aldesleukin aldesleukin alemtuzumab alitretinoin allopurinol altretamine amifostine anastrozole arsenic trioxide asparaginase azacitidine bevacizumab bexarotene capsules bexarotene gel bleomycin bortezomib busulfan intravenous busulfan oral calusterone capecitabine carboplatin carmustine carmustine carmustine with polifeprosan 20 implant (Gliadel );celecoxib cetuximab chlorambucil cisplatin cladribine clofarabine cyclophosphamide cyclophosphamide (Cytoxan );cyclophosphamide (Cytoxan );cytarabine cytarabine liposome dacarbazine actinomycin, actinomycin D darbepoetin alfa daunorubicin liposome daunorubicin, doxorubicin Daunomycin, Doxorubicin Denileukin Diftitox Dexrazoxane Docetaxel Doxorubicin (Adriamycin );Doxorubicin Doxorubicin (Adriamycin PFS );Doxorubicin Liposome Drostanolone Propionate Drostanolone Propionate (Masterone );Elliott's B Solution (Elliott's B );Epirubicin Epoetin Alfa Erlotinib Estramustine Etoposide Phosphate Etoposide, VP-16 Exemestane Filgrastim Floxuridine (Intra-arterial) Fludarabine Fluorouracil, 5-FU Fulvestrant Gefitinib Gemcitabine Gemtuzumab Ozogamicin Goserelin Acetate (Zoladex );Goserelin Acetate Histrelin Acetate (Histrelin );Hydroxycarbamide Ibritumomab Idarubicin Ifosfamide Imatinib Mesylate Interferon Alfa-2a (Roferon );Interferon Alfa-2b (Intron );Irinotecan Lenalidomide Letrozole Leucovorin Leuprorelin Acetate Levamisole Lomustine, CCNU Mechlorethamine, Nitrogen Mustard Megestrol Acetate Melphalan, L-PAM Mercaptopurine, 6-MP Mesna Mesna ); Methotrexate Methoxsalen Mitomycin C Mitotane Mitoxantrone Nandrolone Phenylpropionate Nelarabine Nofetumomab Oprelvekin Oxaliplatin Paclitaxel Paclitaxel Paclitaxel Protein-Bound Particles Palifermin Pamidronate Pegaspargase (Adagen (Pegademase Bovine) ); Pegaspargase Pegfilgrastim Pemetrexed Disodium Pentostatin Piperbromide Plicamycin, Mithramycin Porfimer Sodium Procarbazine Quinacrine Rasburicase Rituximab Denileukin Diftitox; Sargramostim Sargramostim Sorafenib Streptozocin Sunitinib Malate Talc Tamoxifen Temozolomide Teniposide, VM-26 Testolactone Tioguanine, 6-TG Thiotepa Topotecan Toremifene Tositumomab Tositumomab / I- 131 Tositumomab Trastuzumab Tretinoin, ATRA Uracil Mustard ); Valrubicin Vinblastine Vincristine Vinorelbine Vorinostat and zoledronic acid or a pharmaceutically acceptable salt thereof.

[0244] Method for preparing the compound of the present invention

[0245] The following examples are provided so that the invention may be more fully understood. Starting materials are commercially available unless otherwise noted. It should not be construed as limiting the invention in any way.

[0246] Several methods for preparing the compounds of the present invention are described in the following schemes and examples. Starting materials and intermediates were purchased, made by known procedures, or otherwise specified. Some common routes for the compounds of Formula I are also described by the following schemes. In some cases, the order of steps in the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. For stereoisomers, enantiomer A refers to the enantiomer that elutes faster / earlier at the point of separation, while enantiomer B refers to the enantiomer that elutes slower / later, and this nomenclature is maintained throughout the remainder of the synthetic sequence of a given enantiomeric series, regardless of the possibility that subsequent intermediates and the final compound may have the same or opposite elution order.

[0247] List of abbreviations:

[0248] Ac = acetyl

[0249] ACN = acetonitrile

[0250] aq. = aqueous

[0251] B2Pin 2＝ bis(pinacolato)diboron

[0252] °C = degrees Celsius

[0253] DMF = dimethylformamide

[0254] DCM = dichloromethane

[0255] DCE = 1,2 - dichloroethane

[0256] DIPEA = N,N - diisopropylethylamine

[0257] DMSO = dimethyl sulfoxide

[0258] Et = ethyl

[0259] EtOAc = ethyl acetate

[0260] FA = formic acid

[0261] RP HPLC = reverse - phase high - performance liquid chromatography

[0262] H or hrs = hour

[0263] HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0264] HCl = Hydrogen chloride

[0265] HOAc = Acetic acid

[0266] HPLC = High performance liquid chromatography

[0267] LCMS or LC / MS = Liquid chromatography mass spectrometry

[0268] Me = Methyl

[0269] mCPBA = meta-Chloroperoxybenzoic acid

[0270] MgSO4 = Magnesium sulfate

[0271] MTBE = Methyl tert-butyl ether

[0272] RT or rt = Room temperature

[0273] NBS = N-Bromosuccinimide

[0274] NCS = N-Chlorosuccinimide

[0275] NIS = N-Iodosuccinimide

[0276] NMR = Nuclear magnetic resonance

[0277] rt or RT = Room temperature

[0278] SFC = Supercritical fluid chromatography

[0279] PE or pet. ether = Petroleum ether

[0280] PdCl2(dppf) or Pd(dppf)Cl2 = Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

[0281] THF = Tetrahydrofuran

[0282] TFA = Trifluoroacetic acid

[0283] TLC = Thin layer chromatography

[0284] wt. % = Weight percentage

[0285] x g = Multiple of gravity

[0286] % w / v = Percentage of the weight of the former reagent relative to the volume of the latter reagent

[0287] Sat. = Saturated

[0288] Soln. = Solution

[0289] XPhos Pd G2 = Chloro(2 - dicyclohexylphosphino - 2′,4′,6′ - triisopropyl - 1,1′ - biphenyl)[2 - (2′ - amino - 1,1′ - biphenyl)]palladium(II)

[0290] LCMS Conditions: Column: ACQUITY UPLC - QDa BEH C18, 1.7 mm, 2.1 x 50 mm. Solvent System: A: Water 0.1% FA, B: ACN 0.1% FA

[0291] Gradient Conditions: 10 - 90% B, within 1.7 min, total run time 2.4 min

[0292] General synthetic scheme

[0293] Except for the specific embodiments set forth below, many substitutions, modifications, and variations will be apparent to those of ordinary skill in the art. In some cases, the order of steps in the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. All such substitutions, modifications, and variations are intended to fall within the spirit and scope of the present invention.

[0294] General Scheme 1

[0295]

[0296] The compound of formula I is prepared from 1 - 1 with R 1 -X via SN2, SNAr, or copper - mediated C - O coupling. Saponification of 1 - 2 provides the corresponding formic acid (1 - 3), and subsequent amide coupling with a suitable amine (R 2 -NH2) provides the compound of formula (I) as described in the general scheme. The order of steps in some embodiments can be varied to facilitate the synthesis.

[0297] Intermediate

[0298] Intermediate 1

[0299] 3 - Ethoxy - 2 - fluoropyridine

[0300]

[0301] Step A: 3-Ethoxy-2-fluoropyridine

[0302] At RT, iodoethane (6.4 mL, 80 mmol) was added to a stirred solution of 2-fluoropyridin-3-ol (5.0 g, 44 mmol) and K2CO3 (9.8 g, 71 mmol) in DMF (45 mL), and the reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to RT, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 10% EtOAc / PE) to afford the title compound. LC / MS = 142 [M+1].

[0303] The following intermediates were synthesized using procedures similar to those described for Intermediate 1 with appropriate reagents. These intermediates were characterized by LC / MS.

[0304]

[0305]

[0306] Intermediate 10

[0307] Methyl (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanesulfonate

[0308]

[0309] Step A: (5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol

[0310] At -78 °C, n-butyllithium solution (2.5 M in hexanes, 1.3 mL, 3.3 mmol) was added to a stirred solution of 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (0.88 g, 2.8 mmol) in toluene (15.3 mL). 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 followed by sodium borohydride (0.21 g, 5.5 mmol), and the resulting mixture was warmed to RT. After 20 min, the mixture was diluted with saturated aqueous NH4Cl solution, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 224 [M+1].

[0311] Step B: Methyl (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanesulfonate

[0312] At -78 °C, methanesulfonyl chloride (48.8 μL, 0.63 mmol) was added to a stirred 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). After 5 min, the mixture was warmed to RT. After an additional 15 min, the mixture was diluted with saturated aqueous NaCl solution and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 302 [M+1].

[0313] The following intermediates were synthesized using procedures similar to those described for Intermediate 10 with appropriate reagents. The intermediates were characterized by LC / MS.

[0314]

[0315] Example

[0316] The following experimental procedures detail the preparation of specific embodiments of the present disclosure. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.

[0317] Example 1

[0318] Example 1: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0319]

[0320] Step A: Ethyl 6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0321] At RT, Pd(dppf)Cl2 (271 mg, 0.370 mmol) was added 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). The resulting mixture was heated to 105 °C for 1 h. The mixture was cooled to RT, and then acetic acid (0.424 mL, 7.41 mmol) and water (0.50 mL) were added. The resulting solution was stirred for an additional 1 h at RT. 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 RT for 18 h. The mixture was directly concentrated onto silica gel and purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes, then 0 - 10% MeOH / DCM) to afford the title compound. LC / MS = 208 [M+1].

[0322] 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

[0323] At RT, 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). The resulting mixture was stirred at RT for 5 min, 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 h, then cooled to RT, and purified directly by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 418 [M+1].

[0324] 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

[0325] At RT, lithium hydroxide monohydrate (9.60 mg, 0.229 mmol) was added 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). The resulting mixture was stirred at RT for 18 h, then lyophilized to afford the title compound. LC / MS = 389 [M+1].

[0326] Step D: 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxotetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0327] At RT, 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 addition of 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (11.3 mg, 0.0570 mmol). The resulting mixture was stirred at RT for 1 h and then purified directly by reversed-phase HPLC triggered by mass spectrometry (C18, 10 to 60% ACN / water, 0.1% FA modifier) to afford the title compound. 1 1H 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.

[0328] The following compounds were synthesized using procedures similar to those described in Example 1 with appropriate reagents. These compounds were characterized by LC / MS.

[0329]

[0330]

[0331] Example 13

[0332] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0333]

[0334] Step A: 1,6-Diamino-3-bromo-2-methylpyridin-1-ium

[0335] At RT, O-diphenylphosphorylhydroxylamine (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). The resulting mixture was stirred at 45 °C for 18 h. The reaction mixture was then cooled to RT and filtered. The separated solid was washed with MTBE and dried in vacuo to afford the title compound. LC / MS = 218 [M+1].

[0336] Step B: Ethyl 6-bromo-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0337] At RT, 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 diphenylphosphine (40.0 g, 95.0 mmol) in ACN (280.0 mL) and pyridine (96.0 mL, 1190 mmol). The resulting mixture was stirred at 85 °C for 18 h. The reaction mixture was then cooled to 0 °C, and HCl (4 M aqueous solution, 309 mL, 1.24 mol) was added. The solution was warmed to RT and extracted with DCM. The combined organic layers were washed with 4 wt% aqueous K2CO3, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. LC / MS = 285 [M+1].

[0338] Step C: Ethyl 6-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0339] At RT, [(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) was added 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). The resulting mixture was stirred at 85 °C for 18 h, then cooled to RT. Acetic acid (27.8 mL, 486 mmol) was added, and the solution was stirred at RT for an additional 0.5 h. The reaction was cooled to 0 °C, 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 separated solid was washed with MTBE and water and dried in vacuo to afford the title compound. LC / MS = 222 [M+1].

[0340] 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

[0341] At 0 °C, 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). The resulting mixture was stirred at RT for 5 min, 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 h. The solution was then cooled to RT, concentrated directly onto silica gel, and purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 431 [M+1].

[0342] 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

[0343] At RT, lithium hydroxide monohydrate (1.23 g, 29.3 mmol) was added 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). The resulting mixture was stirred at RT for 18 h, then lyophilized to afford the title compound. LC / MS = 403 [M+1].

[0344] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5-methyl-N-(4-methyl- 1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0345] At RT, DIPEA (15.4 mL, 88.0 mmol) was added 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), then 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (6.44 g, 32.2 mmol) was added. The resulting mixture was stirred at RT for 1 h, then purified directly by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. 11H 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.

[0346] The following compounds were synthesized using procedures similar to those described in Example 13 with appropriate reagents. These compounds were characterized by LC / MS.

[0347]

[0348]

[0349]

[0350] Example 22

[0351] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0352]

[0353] Step A: 1,2-Diamino-5-bromo-4-methylpyridin-1-ium

[0354] At 0 °C, tert-butyl ((mesitylenesulfonyl)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 (100.0 mL) was added and the solution was stirred at 0 °C for an additional 1 h. The precipitated solid was then separated by filtration and washed with ice water. The solid was dissolved in DCM (50.0 mL) and stirred with Na2SO4 at 0 °C for 15 min. The Na2SO4 was removed by filtration and the filtrate was added to a stirred solution of 5-bromo-4-methylpyridin-2-amine (3.32 g, 17.8 mmol) in DCM (10.0 mL). The resulting mixture was stirred at RT for 18 h. The reaction mixture was then concentrated to a solid in vacuo and washed with Et2O to afford the title compound. LC / MS = 203 [M+1].

[0355] Step B: Methyl 6-bromo-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0356] At RT, 2-chloro-2-oxoacetic acid methyl ester (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). The resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was then cooled to RT and concentrated in vacuo. The crude residue was dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. LC / MS = 271 [M+1].

[0357] Step C: Methyl 6-hydroxy-7-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0358] At RT, Pd(dppf)Cl2 (0.433 g, 0.591 mmol) was added 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). The resulting mixture was heated to 105 °C for 1 h. The mixture was cooled to RT, then acetic acid (0.677 mL, 11.8 mmol) and water (0.60 mL) were added. The resulting solution was stirred at RT 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 RT for 18 h. The mixture was directly concentrated onto silica gel and purified by flash column chromatography on silica gel (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to afford the title compound. LC / MS = 208 [M+1].

[0359] 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

[0360] At 0 °C, 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). The resulting mixture was stirred at RT for 5 min, 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 h. The solution was then cooled to RT, concentrated directly onto silica gel, and purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 417 [M+1].

[0361] 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

[0362] At RT, lithium hydroxide monohydrate (3.41 mg, 0.0810 mmol) was added 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). The resulting mixture was stirred at RT for 18 h, then lyophilized to afford the title compound. LC / MS = 403 [M+1].

[0363] Step F: 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl- 1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0364] At RT, DIPEA (0.0210 mL, 0.120 mmol) was added 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), then 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (8.79 mg, 0.0440 mmol) was added. The resulting mixture was stirred at RT for 1 h, then purified directly by mass spectrometry-triggered reverse-phase HPLC (C18, 5 to 50% ACN / water, 0.1% FA modifier) to afford the title compound. 1HNMR (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.

[0365] The following compound was synthesized using procedures similar to those described in Example 22 with appropriate reagents. The compound was characterized by LC / MS.

[0366]

[0367] Example 24

[0368] 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0369]

[0370] Step A: 1,6-Diamino-3-bromo-2,4-dimethylpyridin-1-ium

[0371] At 0 °C, tert-Butyl ((mesitylenesulfonyl)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 separated by filtration and washed with ice water. The solid was dissolved in DCM (100.0 mL) and stirred with Na2SO4 at 0 °C for 15 min. The Na2SO4 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 RT for 18 h. The reaction mixture was then concentrated to a solid in vacuo and washed with Et2O to afford the title compound. LC / MS = 218 [M+1].

[0372] Step B: Methyl 6-bromo-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0373] At RT, 2-chloro-2-oxoacetic acid methyl ester (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). The resulting mixture was stirred at 100 °C for 1.5 h, then at RT for 18 h. The reaction mixture was cooled to RT, filtered through Celite, and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (0 - 10% MeOH / DCM) to afford the title compound. LC / MS = 286 [M+2].

[0374] Step C: Methyl 6-hydroxy-5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0375] At RT, Pd(dppf)Cl2 (0.773 g, 1.06 mmol) was added 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). The resulting mixture was heated to 100 °C for 18 h. The mixture was cooled to 0 °C, 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 h. At 0 °C, hydrogen peroxide (4.21 mL, 44.0 mmol) was added and the reaction was stirred at RT for 1.5 h. MgSO4 was then added to the solution and the mixture was filtered through Celite, washed with DCM. The filtrate was concentrated and the crude material was purified by flash column chromatography on silica gel (0 - 10% MeOH / DCM) to afford the title compound. LC / MS = 222 [M+1].

[0376] 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

[0377] At 0 °C, 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). The resulting mixture was stirred at RT for 5 min, 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 h. The solution was then cooled to RT, concentrated directly onto silica gel, and purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes, then 0 - 10% MeOH / DCM) to afford the title compound. LC / MS = 431 [M+1].

[0378] 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

[0379] At RT, lithium hydroxide monohydrate (9.50 mg, 0.226 mmol) was added 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). The resulting mixture was stirred at RT for 0.5 h, then lyophilized to afford the title compound. LC / MS = 417 [M+1].

[0380] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5,7-dimethyl-N-(4-meth yl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0381] At RT, DIPEA (88.0 μL, 0.504 mmol) was added 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), then 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (34.5 mg, 0.173 mmol) was added. The resulting mixture was stirred at RT for 1 h, then purified directly by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes, then 0 - 10% MeOH / DCM) to afford the title compound. 11H 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.

[0382] The following compound was synthesized using procedures similar to those described in Example 24 with appropriate reagents. The compound was characterized by LC / MS.

[0383]

[0384] Example 26

[0385] 6 - ((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0386]

[0387] Step A: 1,2-Diamino-5-chloro-3-fluoropyridin-1-ium 2,4,6-trimethylbenzenesulfonate

[0388] At 0 °C, tert-butyl ((mesitylenesulfonyl)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 h, and then ice water (15.0 g) was added. The precipitated solid was then separated by filtration and washed with ice water. The solid was dissolved in DCM (15.0 mL) and stirred with Na2SO4 at 0 °C for 15 min. Na2SO4 was removed by filtration, and the precipitate 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 RT for 18 h. The reaction mixture was then concentrated in vacuo to afford the title compound. LC / MS = 162 [M+1].

[0389] Step B: Ethyl 6-chloro-8-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0390] At RT, oxalyl chloride monoethyl ester (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). The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to RT 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 in vacuo. The crude residue was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 244 [M+2].

[0391] Step C: (2-(Ethoxycarbonyl)-8-fluoro-[1,2,4]triazolo[1,5-a]pyridin-6-yl)boronic acid

[0392] At RT, X-Phos G2 Pd (226 mg, 0.287 mmol) was added 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). The resulting mixture was heated to 90 °C for 13 h; then the mixture was filtered, and the filtrate was concentrated in vacuo to afford the title compound. LC / MS = 254 [M+1].

[0393] Step D: Ethyl 8-fluoro-6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0394] At RT, to a stirred suspension of NaBO3 . 4H2O (913 mg, 8.62 mmol) in THF (15.0 mL) and water (6.0 mL) 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 RT for 16 h; then the reaction was 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 in vacuo. The crude residue was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 226 [M+1].

[0395] Step E: 8-Fluoro-6-hydroxy-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid

[0396] At RT, lithium hydroxide monohydrate (40.0 mg, 0.952 mmol) was added 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). The resulting mixture was stirred at RT for 13 h and then concentrated in vacuo to afford the title compound. LC / MS = 198 [M+1].

[0397] Step F: 8-Fluoro-6-hydroxy-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triaz olo[1,5-a]pyridine-2-carboxamide

[0398] At RT, DIPEA (0.350 mL, 2.00 mmol) was added 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), followed by the addition of 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (109 mg, 0.461 mmol). The resulting mixture was stirred at RT for 0.5 h; then the mixture was 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 in vacuo. The crude residue was purified by flash column chromatography on silica gel (0-100% EtOAc / hexanes) to afford the title compound. LC / MS = 343 [M+1].

[0399] Step G: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-N-(4-methyl-1, 1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0400] At RT, copper(I) iodide (17.0 mg, 0.089 mmol) was added to a solution of 8-fluoro-6-hydroxy-N-(4-methyl-1,1-dioxotetrahydro-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 (8l.0 mg, 0.245 mmol), 5-chloro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (177 mg, 0.526 mmol), and tripotassium phosphate (223 mg, 1.05 mmol) in DMSO (2.0 mL). The resulting mixture was stirred at 90 °C for 14 h; then the mixture was filtered and the filtrate was purified directly by mass spectrometry-triggered reverse-phase HPLC (C18, aqueous solution of ACN, 0.1% NH4HCO3 modifier) to afford the title compound. 11H 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.

[0401] Example 27

[0402] 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0403]

[0404] Step A: 1,2-Diamino-5-bromo-4-fluoropyridin-1-ium

[0405] At 0 °C, tert-butyl ((mesitylenesulfonyl)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 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 separated by filtration and washed with ice water. The solid was dissolved in DCM (100.0 mL) and stirred with Na2SO4 at 0 °C for 15 min. The Na2SO4 was removed by filtration and the filtrate was added to a stirred solution of 5-bromo-4-fluoropyridin-2-amine (5.73 g, 30.0 mmol) in DCM (10.0 mL). The resulting mixture was stirred at RT for 18 h. The reaction mixture was then concentrated to a solid in vacuo and washed with Et2O to afford the title compound. LC / MS = 208 [M+1].

[0406] Step B: Methyl 6-bromo-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0407] At RT, 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). The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to RT and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (0 - 10% MeOH / DCM) to afford the title compound. LC / MS = 297 [M+Na].

[0408] Step C: Methyl 6-hydroxy-7-fluoro-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0409] At RT, Pd(dppf)Cl2 (2.98 g, 11.8 mmol) was added 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). The resulting mixture was heated to 100 °C for 18 h. The mixture was cooled to RT, then acetic acid (0.598 mL, 10.4 mmol) and water (0.600 mL) were added. The resulting solution was stirred for an additional 1 h at RT. The reaction mixture was cooled to 0 °C, then hydrogen peroxide (1.07 mL, 10.4 mmol) was added. The reaction was stirred at RT for 18 h. The mixture was directly concentrated onto silica gel and purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes, then 0 - 10% MeOH / DCM) to afford the title compound. LC / MS = 212 [M+1].

[0410] 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

[0411] At 0 °C, 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). The resulting mixture was stirred at RT for 5 min, 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 h. The solution was then cooled to RT, directly concentrated onto silica gel and purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 421 [M+1].

[0412] 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

[0413] At RT, lithium hydroxide monohydrate (0.389 mg, 9.27 μmol) was added 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). The resulting mixture was stirred at RT for 0.5 h and then lyophilized to afford the title compound. LC / MS = 407 [M+1].

[0414] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1, 1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0415] At RT, DIPEA (4.86 μL, 0.0280 mmol) was added 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), followed by the addition of 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (2.04 mg, 10.2 μmol). The resulting mixture was stirred at RT for 1 h and then purified directly by reversed-phase HPLC triggered by mass spectrometry (C18, aqueous solution of 45 to 85% ACN, 0.1% FA modifier) to afford the title compound. 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.

[0416] Example 28

[0417] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0418]

[0419] Step A: 1,2-diamino-5-bromo-3-fluoro-6-methylpyridin-1-ium

[0420] At 0 °C, tert-butyl ((mesitylenesulfonyl)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 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 separated by filtration and washed with ice water. The solid was dissolved in DCM (100.0 mL) and stirred with Na2SO4 at 0 °C for 15 min. The Na2SO4 was removed by filtration, and the filtrate was added to a stirred solution of 5-bromo-3-fluoro-6-methylpyridin-2-amine (9.00 g, 43.9 mmol) in DCM (191 mL). The resulting mixture was stirred at RT for 18 h. The reaction mixture was then concentrated to a solid in vacuo and washed with Et2O to afford the title compound. LC / MS = 223 [M+2].

[0421] Step B: Methyl 6-bromo-8-fluoro-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0422] At RT, 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). The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to RT and concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (0-10% MeOH / DCM) to afford the title compound. LC / MS = 290 [M+2].

[0423] Step C: Methyl 8-fluoro-6-hydroxy-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylate

[0424] At RT, Pd(dppf)Cl2 (0.838 g, 1.15 mmol) was added 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). The resulting mixture was heated to 100 °C for 18 h. The mixture was 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 h. At 0 °C, hydrogen peroxide (4.57 mL, 47.7 mmol) was added, and the reaction was stirred at RT for 1.5 h. MgSO4 was then added to the solution, and the mixture was filtered through diatomaceous earth and washed with DCM. The filtrate was concentrated, and the crude material was purified by flash column chromatography on silica gel (0 - 10% MeOH / DCM) to afford the title compound. LC / MS = 226 [M+1].

[0425] 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

[0426] At 0 °C, 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). The resulting mixture was stirred at RT for 5 min, 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 h. The solution was then cooled to RT, concentrated directly onto silica gel, and purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 435 [M+1].

[0427] 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

[0428] At RT, lithium hydroxide monohydrate (11.4 mg, 0.273 mmol) was added 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). The resulting mixture was stirred at RT for 0.5 h and then lyophilized to afford the title compound. LC / MS = 421 [M+1].

[0429] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-8-fluoro-5-methyl-N-(4- methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0430] 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-ammonium 1,1-dioxide chloride (22.8 mg, 0.114 mmol) at RT. The resulting mixture was stirred at RT for 1 h and then purified directly by flash column chromatography on silica gel (0-100% EtOAc / hexanes followed by 0-10% MeOH / DCM) to give the title compound. 1 H 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 =12nM.

[0431] The following compounds were synthesized with appropriate reagents using procedures similar to those described in Example 28. These compounds were characterized by LC / MS.

[0432]

[0433]

[0434] Example 35

[0435] 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0436]

[0437] Step A: Ethyl 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-[1,2,4]tri azolo[1,5-a]pyridine-2-carboxylate

[0438] At RT, Cs2CO3 (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 methyl (5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanesulfonate (0.358 g, 1.18 mmol) in DMF (5.00 mL). The resulting mixture was heated to 60 °C for 18 h. The reaction was cooled to RT, the mixture was filtered, and the filtrate was purified by silica gel flash column chromatography (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 429 [M+1].

[0439] Step B: 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-[1,2,4]tri azolo[1,5-a]pyridine-2-carboxylic acid

[0440] At RT, lithium hydroxide monohydrate (14.0 mg, 0.326 mmol) was added 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). The resulting mixture was stirred at RT for 2 h and then lyophilized to afford the title compound. LC / MS = 4***[M+1].

[0441] Step C: 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methoxy)-5-methyl-N-(4-methyl-1, 1-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide

[0442] At RT, DIPEA (0.171 mL, 0.978 mmol) was added to a stirred 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, 0.6**2 mmol) in DMF (2.00 mL), followed by the addition of 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (71.6 mg, 0.359 mmol). The resulting mixture was stirred at RT for 3 h and then purified directly by mass spectrometry-triggered reversed-phase HPLC (C18, 65 to 98% aqueous solution of ACN, 0.1% FA modifier) to afford the title compound. 11H 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.

[0443] The following compound was synthesized using procedures similar to those described in Example 35 with appropriate reagents. The compound was characterized by LC / MS.

[0444]

[0445] Determination

[0446] Insect cell expression and membrane preparation

[0447] Sf-9 insect cells were maintained at 27 °C in a shaking incubator in Grace's insect cell medium containing 10% heat-inactivated fetal bovine serum, 1% Pluronic F-68, and 0.14 μg / ml kanamycin sulfate. Cells were harvested 48 hours after infection with an unlabeled baculovirus expressing human DGAT2 (hDGAT2) at a multiplicity of infection (MOI) of 3. The cell pellet was resuspended in a buffer containing 10 mM Tris-HCl pH 7.5, 1 mM EDTA, 250 mM sucrose, and a complete protease inhibitor mixture (Sigma-Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2000 x g for 15 minutes. The membrane fraction was isolated by ultracentrifugation (100,000 x g), resuspended in the same buffer, and frozen (-80 °C) for later use. Protein concentration was determined using the Pierce TM BCA Protein Assay Kit (Thermo Fisher Scientific). Protein level expression was analyzed by immunoblotting with a rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa 647 (Abcam, ab150075) followed by detection using a Typhoon FLA9000 (GE Healthcare).

[0448] LC / MS / MS analysis method

[0449] LC / MS / MS analysis was performed using a LX4-TSQ Vantage system from Thermo Fisher. The system consists of an Agilent binary high performance liquid chromatography (HPLC) pump and a TSQ Vantage triple quadrupole MS / MS instrument. For each sample, 2 μL of the sample from the top organic layer of the in-plate liquid-liquid extraction was injected into a Thermo Betabasic C4 column (2.1 mm x 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 was acquired in positive mode using a heated electrospray ionization (HESI) interface. The operating parameters of the TSQ Vantage MS / MS instrument were spray voltage 3000 V, capillary temperature 280 °C, vaporizer temperature 400 °C, sheath gas 45 arbitrary units, auxiliary gas 10 arbitrary units, S-lens 165, and collision gas 1.0 mTorr. Collect 13 C 18 -triolein (Q1: 922.8 > Q3: 621.3) and the internal standard 13 C 21 -triolein (Q1: 923.8 > Q3: 617.3) standard reference material (SRM) chromatograms for 33 seconds. The peak areas were integrated using Xcalibur Quan software. The 13 C 18 triolein produced in the reaction and the incorporated internal standard 13 C 21 -triolein ratio was used to generate the percent inhibition and IC 50 values. The percent inhibition of the compound was calculated using the following formula: % Inhibition = 1 - [(Compound reaction - Low control) / (High control - Low control)] x 100%. The effective compounds were titrated and the IC 50 .

[0450] DGAT2 Enzymatic Activity Assay

[0451] DGAT2 activity was measured by using the above membrane preparation to measure the enzymatic product 13 C 18 -triolein ( 13Determined by the amount of C-1,2,3-tris(cis-9-octadecenoyl)glycerol). The assay was performed at room temperature in an ABgene 384-well assay plate with a final volume of 25 μL. The assay mixture contained the following: assay buffer (100 mM Tris●Cl, pH 7.0, 20 mM MgCl2, 5% ethanol), 25 μM diolein, 5 μM 13 C oleoyl-CoA and 8 ng / μL DGAT2 membrane.

Claims

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

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 is (1) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 4 substituents, or (2)-(C 1-6 )alkyl - heteroaryl, wherein the heteroaryl is a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, and wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 R 4 substituents.

3. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-2, wherein R 1 is (1) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, -OC 1-6 alkyl, O-(C 1-6 ) haloalkyl and optionally halogen-substituted O-C 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, and wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from halogen, - OC 1-6 -alkyl, O-(C 1-6 )-haloalkyl or O - C 1-6 -alkyl-(C 3-7 )-cycloalkyl which is optionally substituted by halogen.

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

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from F, Cl, OCH2CF3, OCH2CH3, OCH2CHF2, OCH2-cyclopropyl-F or OCH2CF2CH3.

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

7. The compound according to any one of claims 1-3 or 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is -(C 1-6 )alkyl-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing 1 nitrogen atom, and wherein the heteroaryl is unsubstituted or substituted with one or two substituents independently selected from halogen, OCH2CF3 or OCH2CHF2.

8. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-7, wherein R 2 is (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 Each of the cycloalkyl or heterocyclic rings is unsubstituted or substituted by 1, 2 or 3 Rs 6 substituents.

9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R 2 is (1) a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or (2)-(C 3-6 )Naphthenyl, wherein each cycloalkyl or heterocyclic ring is unsubstituted or substituted by one, two or three substituents independently selected from hydroxy, halogen, (C 1-6 )alkyl, OC 1-6 alkyl, (C 1-6 )haloalkyl- or oxo.

10. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9, wherein R 2 is (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 )Naphthenyl, wherein each cycloalkyl or heterocycle is unsubstituted or substituted by one, two or three substituents independently selected from OH, F, oxo, CH3, OCH3, CF3 or CH2CF3.

11. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R 2 is an unsubstituted or mono-, di- or tri-substituted R 6 4- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S.

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

13. The compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 7-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S, which is unsubstituted or substituted by one, two or three substituents independently selected from CH3, oxo or CH2CF3.

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

15. The compound according to any one of claims 1-9 or 14, or a pharmaceutically acceptable salt thereof, wherein R 2 is unsubstituted or substituted by one, two or three substituents independently selected from hydroxy, halogen, (C 1-6 )alkyl, OC 1-6 alkyl or (C 1-6 )haloalkyl-substituted -(C 3-6 )cycloalkyl.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-9 or 14-15, wherein R 2 is an unsubstituted or substituted by one, two or three substituents independently selected from OH, F, CH3, OCH3 or CF3 of -(C 3-6 ) cycloalkyl.

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

18. The compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected from hydrogen, halogen or CH3.

19. The compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein each R, when present, 4 is halogen, -OC 1-6 alkyl, O-(C 1-6 ) haloalkyl or O-C 1-6 alkyl-(C 3-7 ) cycloalkyl optionally substituted by halogen.

20. The compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof, wherein when present, each R 4 is halogen, OCH2CF3, OCH2CH3, OCH2CHF2, OCH2-cyclopropyl-F or OCH2CF2CH3.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, 11 or 14, wherein each R, when present, 6 is independently selected from halogen, hydroxy, (C 1-6 )alkyl, oxo, -OC 1-6 alkyl or (C 1-6 )haloalkyl-.

22. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-8, 11, 14 or 21, wherein when present, each R 6 is independently selected from halogen, hydroxy, CH3, oxo, OCH3, CF3 or CH2CF3.

23. The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[(3-ethoxy-2-pyridinyl)oxy]-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[(3-ethoxy-2-pyridinyl)oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[(3-ethoxy-2-pyridinyl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[(3-ethoxy-2-pyridinyl)oxy]-N-[(3R)-tetrahydrofuran-3-yl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[(3-ethoxy-2-pyridinyl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-pyridinyl]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-pyridinyl]oxy]-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[(5-Chloro-3-ethoxy-2-pyridinyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-tetrahydrothiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-N-[1,1-dioxido-4-(2,2,2-trifluoroethyl)tetrahydrothiopyran-4-yl]-5-methyl-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 5,7-Dimethyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-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-dioxotetrahydro-2H-thiopyran-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(3-methyl-1,1-dioxo-thietane-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 8-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-tetrahydrothiophen-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-dioxotetrahydrothiophen-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-dioxotetrahydrothiophen-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-dioxotetrahydrothiophen-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-dioxotetrahydro-2H-thiophen-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-dioxotetrahydro-2H-thiophen-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide.

24. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is:

25. The compound or a pharmaceutically acceptable salt thereof according to claim 24, which is 26. The compound or a pharmaceutically acceptable salt thereof according to claim 24, which is 27. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, which is 28. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, which is 29. The compound according to claim 24 or a pharmaceutically acceptable salt thereof, which is 30. A composition for treating a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases, and heart failure, the composition comprising a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

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

32. A method for treating a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases, and heart failure, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

33. Use of the compound according to any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases and heart failure.

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