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

Abstract

Compounds of Formula I, as well as pharmaceutically acceptable salts, esters, and prodrugs thereof, are invented that are DGAT2 inhibitors. Also provided are methods for making compounds of Formula I, pharmaceutical compositions containing compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases, such as chronic kidney disease and heart failure, and related diseases and conditions, comprising administering a compound of Formula I to a patient in need of treatment. [Formula 1] TIFF2023545741000135.tif29138

Description

[Technical field]

[0001] The present invention relates to novel pharmaceutical compounds that inhibit diacylglyceride O-acyltransferase 2 ("DGAT2") and may be useful in preventing, treating, or acting as ameliorators of hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal disease (e.g., chronic kidney disease and heart failure), and related diseases and conditions, as well as methods for making such compounds and pharmaceutical compositions comprising such compounds and a pharmaceutical carrier. [Background technology]

[0002] Triacylglycerols ("TG") serve several functions in living organisms. One such function of TGs is in energy storage. TGs also have a role in membrane lipid synthesis. TG synthesis in cells can protect the cells from the possible toxic effects of excess fatty acids ("FAs"). In intestinal and hepatic cells, TGs are synthesized for assembly and secretion of lipoproteins that transport FAs between tissues. TGs have a role in the skin surface water barrier, and TGs in adipose tissue provide insulation for life.

[0003] The glycerol phosphate pathway and the monoacylglycerol pathway are the major pathways for TG biosynthesis. However, the final step in TG synthesis involves the reaction of fatty acyl-CoA and diacylglycerol ("DG") to form TG. The reaction is catalyzed by acyl-CoA:diacylglycerol acyltransferase ("DGAT") enzymes. To date, two DGAT enzymes, DGAT1 and DGAT2, have been identified. Although DGAT1 and DGAT2 catalyze the same reaction, they differ significantly at the DNA and protein sequence levels. DGAT2 can synthesize TG using endogenous fatty acids in in vitro assays, whereas DGAT1 appears to be more dependent on exogenous fatty acids (Yen et al., J. Lipid Research, 2008, 49, 2283). Inactivation of DGAT2 impairs the growth of cytoplasmic lipid droplets, whereas inactivation of DGAT1 exerts the opposite effect (Li et al., Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080).

[0004] DGAT2 is an integral membrane protein of the reticulum and is strongly expressed in adipose tissue and liver. DGAT2 appears to be the predominant DGAT enzyme controlling TG homeostasis in vivo. DGAT2-deficient mice survive only a few hours after birth, whereas DGAT1-deficient mice are viable (Yen et al., J. Lipid Research, 2008, 49, 2283).

[0005] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been understood, mostly through attempts to utilize antisense oligonucleotides (ASOs) in rodents. In this context, knockdown of DGAT2 in ob / ob mice with DGAT2 gene-specific ASOs resulted in a dose-dependent reduction in very low density lipoprotein ("VLDL") and in plasma TG, total cholesterol and ApoB (Liu, et al., Biochim. Biophys Acta 2008, 1781, 97). In the same study, DGAT2 antisense oligonucleotide treatment of ob / ob mice showed reduced body weight gain, adipose weight and hepatic TG content (ibid.). In another study, antisense treatment of ob / ob mice improved hepatic steatosis and hyperlipidemia (Yu, et al., Hepatology, 2005, 42, 362). In another study, knockdown of DGAT2 in rats was shown to improve diet-induced hepatic steatosis and insulin resistance. These effects appear to be specific to inhibition of DGAT2, since ASOs against DGAT1 did not produce similar beneficial effects. Although the molecular mechanisms behind these findings are not yet known, collected 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).

[0006] In view of the above, inhibitors of DGAT2 are useful in treating diseases associated with the spectrum of metabolic syndrome, such as hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure) and related diseases and conditions.

[0007] DGAT2 inhibitor compounds are described in WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, WO2013150416, US20150259323, WO2015077299, W02017011276, WO2018033832, US201801628, W02003053363. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Yen et al.,J.Lipid Research,2008,49,2283 [Non-Patent Document 2] Li et al., Arterioscler. Thromb.Vasc.Biol.2015,35,1080 [Non-Patent Document 3] Liu,et al.,Biochim.Biophys Acta 2008,1781,97 [Non-Patent Document 4] Yu,et al.,Hepatology,2005,42,362 [Non-Patent Document 5] Choi et al.,J.Bio.Chem.,2007,282,22678 Summary of the Invention

[0009] The present invention relates to compounds represented by formula I, which are DGAT2 inhibitors: [ka]

[0010] and pharma- ceutically acceptable salts, esters, and prodrugs thereof. Also provided are methods for making compounds of formula I, pharmaceutical compositions containing compounds of formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal disease (e.g., chronic kidney disease and heart failure) and related diseases and conditions, comprising administering a compound of formula I to a patient in need of treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Formula I The present disclosure relates to compounds having the following structural formula I: or a pharma- ceutically acceptable salt thereof: [ka]

[0012] During the ceremony, X, Y, and Z are independently N or C(R 5 ) are selected from; R 1 teeth, (1) Unsubstituted or 1, 2 or 3 R 6 phenyl substituted with (2) 5- or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or has 1, 2, or 3 R 6 is replaced by ], or (3) 8-10 membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or has 1, 2, or 3 R 6 has been replaced by .] and; R 2 teeth, (1) Unsubstituted or 1, 2 or 3 R 7 phenyl substituted with (2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or has 1, 2 or 3 R 7 ], (3) C which may be unsubstituted or mono- or di-substituted with halogen, OH, CF3, or -CN. 1-6 Alkyl, (4) Is it unsubstituted? 1-3 It may be mono- or di-substituted with alkyl, halogen, OH, CF3, or CN (C 3-6 ) cycloalkyl, (5)-(C 3-6 ) alkylC(O)NH2, (6) A 4- to 6-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S, wherein the heterocycle is unsubstituted or has 1, 2, or 3 R 7 ], (7) Unsubstituted or 1, 2 or 3 R 7 -CH2-aryl substituted by (8) Unsubstituted or 1, 2 or 3 R 7 -SO2(C 1-6 ) alkyl, or (9) Unsubstituted or 1, 2 or 3 R 7 -SO2-aryl substituted with and; R 3 teeth, (1) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (2) 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (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, O, and S; (4)-(C 1-6 ) alkyl-aryl, (5)-(C 1-6 ) alkyl-heterocycle [the heterocycle is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O, and S], (6)-(C 1-6 ) alkyl, (7)-(C 3-6 ) cycloalkyl, (8)-(C 1-6 ) hydroxyalkyl, (9)-(C 1-6 )Alkyl-S(O)2-NR 8a R 8b or (10)-(C 1-6 )Alkyl-S(O)2-(C 1-3 ) Alkyl and Each aryl, heteroaryl, cycloalkyl, or heterocycle is unsubstituted or has 1, 2, or 3 R 9 each alkyl is unsubstituted or substituted with 1, 2 or 3 R 10 is replaced by; R 4 teeth, (1) Hydrogen, or (2)(C 1-3 ) Alkyl and or R 3 and R 4 together with the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from N, O and S, said heterocycle being unsubstituted or containing 1, 2 or 3 R 11 is replaced by If present, each R 5 teeth, (1) Hydrogen, (2)(C 1-6 ) alkyl, (3)(C 3-6 ) cycloalkyl, (4)(C 1-6 ) haloalkyl, (5) cyano, or (6) Halogen is selected from If present, each R 6 is independently (1) Cyano, (2) halogens, (3)-OC 1-6 Alkyl, (4) Halogen, C 1-3 Alkyl, C 1-6 Optionally substituted with haloalkyl or OH (C 3-6 ) cycloalkyl, (5) -C(=O)NH2, (6)-O(C 3-6 ) cycloalkyl [wherein the cycloalkyl is halogen, C 1-3 may be substituted with alkyl or OH. (7) Hydroxy, (8)N(R 11 )2, (9)(C 1-6 ) haloalkyl-, (10)-O(C 1-6 ) haloalkyl, (11)-SO2(C 1-6 ) alkyl, (12)-SO2NH(C 1-6 ) alkyl, (13)-SC 1-6 Alkyl, (14)N(R 11 )C(O)R 11 , (15)-SC 1-6 haloalkyl, or (16)(C 1-6 ) Alkyl Selected from; If present, each R 7 is independently (1)(C 1-3 ) alkyl, (2) halogens, (3)(C 1-6 ) alkoxy-, (4)(C 1-6 ) haloalkyl-, or (5) Hydroxy Selected from; If present, R 8a and R 8b is independently (1) Hydrogen, (2)(C 1-3 ) alkyl, or (3)(C 3-7 )Cycloalkyl Selected from; If present, each R 9 is independently (1)(C 1-3 ) alkyl, (2)(C 1-3 ) haloalkyl-, (3) oxo, (4)(C 3-6 ) cycloalkyl, (5) N(R 11 )2, (6) Hydroxy, (7)(C 1-3 ) alkoxyl-, (8) cyano, or (9) Halogen Selected from; If present, R 10 is independently (1)(C 1-3 ) alkoxy-, (2) Hydroxy, (3) halogens, (4)(C 1-3 ) haloalkyl-, or (5) N(R 11 )2 Selected from; R 11 If present, (1) Hydrogen, or (2)(C 1-3 ) Alkyl It is.

[0013] In the first embodiment of the present disclosure, R 1 but, a) Independently, halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, OC1-3 Alkyl, OC 1-3 Haloalkyl, OC 3-6 Cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-3 phenyl optionally substituted with 1 to 3 substituents selected from alkyl, wherein the cycloalkyl may be substituted with halogen or OH; b) independently halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, OC 1-3 Alkyl, OC 1-3 Haloalkyl, OC 3-6 6-membered heteroaryl containing 1 or 2 nitrogen atoms, optionally substituted with 1 to 3 substituents selected from cycloalkyl or CN, wherein when the cycloalkyl is cyclopropyl, the cyclopropyl may be substituted with halogen or OH; c) independently halogen, (C 1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents selected from alkyl; or d) 8-10 membered fused heteroaryl containing 1, 2, 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with halogen, (C 1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 substituted with alkyl, or a pharma- ceutically acceptable salt of either of the foregoing.

[0014] In the second embodiment of the present disclosure, R 1 is not alkyl; or a compound of formula I, or a compound of embodiment 1, or a pharma- ceutically acceptable salt of any of the foregoing.

[0015] In embodiment 3a of the present disclosure, R 1 but, a) Halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, CN, NHC(O)C 1-3 Alkyl, NC 1-3 Alkyl, C(O)NH2, SC 1-3 Alkyl, S(O)2NHC 1-3 Alkyl, S(O)2C 1-3 Alkyl, OC 1-3 Alkyl or OC 1-3 Phenyl which may be substituted with haloalkyl, wherein the cycloalkyl may further be substituted with halogen. ]; b) Independently halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, OC 1-3 Alkyl or OC 1-3 pyridyl optionally substituted by 1 to 3 substituents selected from haloalkyl; c) independently halogen, (C 1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents selected from alkyl; or d) 8-10 membered fused heteroaryl containing 1, 2, 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with halogen, (C 1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 substituted with alkyl. or any one of embodiments 1-2, or a pharma- ceutically acceptable salt of any of the foregoing.

[0016] In embodiment 3b of the present disclosure, R 1 but, e) Halogens, C 1-3 Alkyl, C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, OC 1-3 Alkyl or OC 1-3 phenyl optionally substituted with haloalkyl, wherein the cycloalkyl may further be substituted with halogen; f) Independently halogen, C 1-3 Alkyl, C 3-6 Cycloalkyl, OC 1-3 Alkyl or OC 1-3 pyridyl optionally substituted by 1 to 3 substituents selected from haloalkyl; g) independently halogen, (C 1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents selected from alkyl; or h) 8-10 membered fused heteroaryl containing 1, 2, 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with halogen, (C 1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 substituted with alkyl. or any one of embodiments 1-2, or a pharma- ceutically acceptable salt of any of the foregoing.

[0017] In embodiment 4a of the present disclosure, R 1 but, a) phenyl optionally substituted with 1 to 3 substituents independently selected from F, CF3, CN, N(CH3)2, C(O)NH2, SCH3, S(O)2NHCH3, S(O)2CH3, OCH2CH3, OCH(CH3)2, OCHF2, OCH2CHF2, OCF3, OCF2CHF2, NHC(O)CH3, cyclopropyl, and O-cyclopropyl [the cyclopropyl may be further substituted with 1 to 3 F]; b) pyridyl optionally substituted by 1 to 3 substituents independently selected from OC(F)2(CH3), OCH2CH3, OCH(CH3)2, OCHF2, OCH2CHF2, OCF3, OCF2CHF2, OCF2CHF2, or cyclopropyl; c) independently halogen, (C 1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents selected from alkyl; or d) 8- to 10-membered condensed heteroaryl containing 1 to 3 heteroatoms selected from N, O, or S atoms, which may be substituted with CH3. or any one of embodiments 1-3, or a pharma- ceutically acceptable salt of any of the foregoing.

[0018] In embodiment 4b of the present disclosure, R 1 but, a) phenyl optionally substituted with 1 to 3 substituents independently selected from F, OCH2CH3, OCH(CH3)2, OCHF2, OCH2CHF2, OCF3, OCF2CHF2, cyclopropyl, and O-cyclopropyl [the cyclopropyl may be further substituted with 1 to 3 F]; b) pyridyl optionally substituted by 1 to 3 substituents independently selected from OC(F)2(CH3), OCH2CH3, OCHF2, OCH2CHF2, OCF3, OCF2CHF2, or cyclopropyl; c) independently halogen, (C1-3 ) alkyl, (C 3-6 ) cycloalkyl, (C 1-3 ) haloalkyl-, OH or OC 1-3 a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms selected from N, O, and S, optionally substituted with 1 to 2 substituents independently selected from alkyl; or d) 8- to 10-membered condensed heteroaryl containing 1 to 3 heteroatoms selected from N, O, or S atoms. or any one of embodiments 1-3, or a pharma- ceutically acceptable salt of any of the foregoing.

[0019] In embodiment 5a of the present disclosure, R 1 but [ka]

[0020] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0021] In embodiment 5b of the present disclosure, R 1 but, [ka]

[0022] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0023] In embodiment 6a of the present disclosure, R 1is a compound of Formula I, or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing, wherein:

[0024] In embodiment 6b of the present disclosure, R 1 is phenyl unsubstituted or substituted with one, two or three substituents independently selected from F, OCHF2, OCF3, OCH(CH3)(CH3), OCF2CHF2, OCH2CHF2, OCH2CH3, cyclopropyl, or O-cyclopropyl, said cyclopropyl being optionally further substituted with one to three halogen atoms; or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0025] In embodiment 7a of the present disclosure, R 1 is a 5- or 6-membered heteroaryl containing one N, said heteroaryl being unsubstituted or substituted with one, two or three substituents independently selected from OCHF2, OCH2CH3, OCF2CHF2, OCH(CH3)2, OCH2CHF2, OCF2CH3, F, or cyclopropyl; or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0026] In embodiment 7b of the present disclosure, R 1is a 5- or 6-membered heteroaryl containing one N, said heteroaryl being unsubstituted or substituted with one, two or three substituents independently selected from OCHF, OCHCH, F, or cyclopropyl; or any one of the preceding embodiments, or a pharma- ceutically acceptable salt thereof.

[0027] In embodiment 8 of the present disclosure, R 1 but [ka]

[0028] or a pharma- ceutically acceptable salt thereof.

[0029] In embodiment 9 of the present disclosure, R 1 but [ka]

[0030] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0031] In a tenth embodiment of the present disclosure, R 1 but [ka]

[0032] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0033] In an eleventh embodiment of the present disclosure, R 1 but [ka]

[0034] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0035] In embodiment 12 of the present disclosure, R 1 but [ka]

[0036] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0037] In embodiment 13 of the present disclosure, R 1 but [ka]

[0038] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0039] In the fourteenth embodiment of the present disclosure, R 1 but [ka]

[0040] or any one of embodiments 1-4, or a pharma- ceutically acceptable salt of any of the foregoing.

[0041] In embodiment 15a of the present disclosure, R 2 but (1) Halogen, C 1-3 Haloalkyl, C 1-3 alkyl, or a 4-6 membered heteroaryl containing 0-1 oxygen atom and / or 0-2 nitrogen atom, which may be mono- or di-substituted with OH; (2) Unsubstituted or halogen, OH, CF3, or (C 3-6) C, which may be mono-, di- or tri-substituted with cycloalkyl, phenyl, or C(O)NH2 1-6 Alkyl, (3) C 1-6 C, which may be mono-, di- or tri-substituted with alkyl, halogen, OH, or CF 3-6 Cycloalkyl, (4) Halogen, C 1-3 Haloalkyl, C 1-3 a 4-6 membered heterocycle containing 0-1 oxygen atom and / or 0-2 nitrogen atom, which may be mono- or di-substituted with alkyl or OH; (5) C 1-6 Phenyl optionally substituted with alkyl or halogen, or (6)S(O)2C 1-6 Alkyl, or S(O)2-phenyl or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0042] In embodiment 15b of the present disclosure, R 2 but, (1) Halogen, C 1-3 Haloalkyl, C 1-3 alkyl, or a 4-6 membered heteroaryl containing 0-1 oxygen atom and / or 0-2 nitrogen atom, which may be mono- or di-substituted with OH; (2) Unsubstituted or halogen, OH, CF3, or (C 3-6 ) C, which may be mono-, di- or tri-substituted by cycloalkyl 1-6 Alkyl, (3) C 1-6 C, which may be mono-, di- or tri-substituted with alkyl, halogen, OH, or CF 3-6 Cycloalkyl, (4) Halogen, C 1-3 Haloalkyl, C 1-3 a 4-6 membered heterocycle containing 0-1 oxygen atom and / or 0-2 nitrogen atom, which may be mono- or di-substituted with alkyl or OH; (5) C 1-6phenyl optionally substituted with alkyl or halogen, or (6)S(O)2C 1-6 Alkyl or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0043] In embodiment 16a of the present disclosure, R 2 but, (1) C 1-3 a 5- or 6-membered heteroaryl containing two N atoms, optionally substituted with alkyl or halogen; (2) phenyl substituted with halogen; (3) C 1-6 Alkyl or C 3-6 Cycloalkyl [each alkyl or cycloalkyl is C 1-6 may be mono-, di- or tri-substituted with alkyl, halogen, C(O)NH2, OH, CF3, or CN; (4) a 5-membered saturated heterocycle containing one oxygen atom which may be substituted by OH; (5) Halogen, C 1-3 Haloalkyl or C 1-3 a 6-membered saturated heterocycle containing 0 or 1 oxygen atom and 0 or 1 nitrogen atom, optionally mono- or di-substituted with alkyl; or (6)S(O)2C 1-6 Alkyl or S(O)2-phenyl or any one of embodiments 1-15 or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0044] In embodiment 16b of the present disclosure, R 2 but, (1) C 1-3 a 5- or 6-membered heteroaryl containing two N atoms, optionally substituted with alkyl or halogen; (2) phenyl substituted with halogen; (3) C 1-6 Alkyl or C 3-6Cycloalkyl [each alkyl or cycloalkyl is C 1-6 may be mono-, di- or tri-substituted with alkyl, halogen, OH, CF3, or CN; (4) a 5-membered saturated heterocycle containing one oxygen atom which may be substituted by OH; (5) Halogen, C 1-3 Haloalkyl, or C 1-3 a 6-membered saturated heterocycle containing 0 or 1 oxygen atom and 0 or 1 nitrogen atom, optionally mono- or di-substituted with alkyl; or (6)S(O)2C 1-6 Alkyl or any one of embodiments 1-15 or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0045] In embodiment 17 of the present disclosure, R 2 but, (1) phenyl substituted with halogen; (2) C 1-6 Alkyl or C 3-6 Cycloalkyl [each alkyl or cycloalkyl is C 1-6 may be mono-, di- or tri-substituted with alkyl, halogen, OH, CF3; or (3) Halogen, C 1-3 Haloalkyl, or C 1-3 A compound of formula I, or embodiments 1-16, or a class thereof, wherein R is a 6-membered saturated heterocycle containing 0 or 1 oxygen atom and 0 or 1 nitrogen atom, optionally mono- or di-substituted with alkyl, or a pharma- ceutically acceptable salt of any of the foregoing.

[0046] In embodiment 18a of the present disclosure, R 2 But, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, Phenyl, C 3-6 Heterocycle, C 3-6AlkylC(O)NH2, S(O)2-phenyl, C 1-6 A compound of formula I, or embodiments 1-16, or a class thereof, wherein R is alkyl-phenyl, wherein said alkyl is optionally substituted with 1-3 halogen or CF3, and said phenyl is optionally substituted with halogen, or a pharma- ceutically acceptable salt of any of the foregoing.

[0047] In embodiment 18b of the present disclosure, R 2 But, C 1-6 Alkyl, C 3-6 Cycloalkyl, C 1-6 AlkylOH, C 1-6 Haloalkyl, Phenyl, C 3-6 and said alkyl is optionally substituted with 1-3 halogen or CF3, and said phenyl is optionally substituted with halogen, a compound of formula I, or embodiments 1-16 or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0048] In embodiment 19 of the present disclosure, R 2 is phenyl substituted with halogen; or a pharma- ceutically acceptable salt of any of the foregoing.

[0049] In embodiment 20 of the present disclosure, R 2 C 1-6 alkyl, or a pharma- ceutically acceptable salt of any of the foregoing.

[0050] In embodiment 21 of the present disclosure, R 2 C may be substituted with 1 to 3 halogens or OH. 1-6 alkyl, or a pharma- ceutically acceptable salt of any of the foregoing.

[0051] In embodiment 22 of the present disclosure, R 2 C 1-6haloalkyl; a compound of formula I, or any of embodiments 1-16 or a class thereof; or a pharma- ceutically acceptable salt of any of the foregoing.

[0052] In embodiment 23 of the present disclosure, R 2 C 1-6 alkyl-OH. A compound of formula I, or any of embodiments 1-16 or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0053] In embodiment 24 of the present disclosure, R 2 C 3-6 cycloalkyl; or a compound of formula I, or any of embodiments 1-16 or a class thereof; or a pharma- ceutically acceptable salt of any of the foregoing.

[0054] In embodiment 25 of the present disclosure, R 2 but [ka]

[0055] or a pharma- ceutically acceptable salt of any of the foregoing.

[0056] In embodiment 26 of the present disclosure, R 2 but [ka]

[0057] or a pharma- ceutically acceptable salt of any of the foregoing.

[0058] In embodiment 27 of the present disclosure, R 2 but [ka]

[0059] or a pharma- ceutically acceptable salt of any of the foregoing.

[0060] In embodiment 28 of the present disclosure, R 2 but [ka]

[0061] or any one of embodiments 1-16, or a pharma- ceutically acceptable salt of any of the foregoing.

[0062] In embodiment 29 of the present disclosure, R 3 but, (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, O, and S; (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, O and S; (4)-(C 1-6 ) alkyl-aryl, (5)-(C 1-6 ) alkyl-heterocycle [the heterocycle is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O, and S], (6)-(C 1-6 ) alkyl, (7)-(C 3-6 ) cycloalkyl, or (8)(C 1-6 ) Hydroxyalkyl and Each aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or has 1, 2 or 3 R 9 each alkyl is unsubstituted or substituted with 1, 2 or 3 R 10or any one of embodiments 1-25, or a pharma- ceutically acceptable salt of any of the foregoing, wherein the compound of formula I is substituted with

[0063] In embodiment 30 of the present disclosure, R 3 but, (1) a 4- to 6-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from N, O and S; (2)-(C 3-6 ) cycloalkyl, (3)(C 1-6 ) Hydroxyalkyl or Each aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or has 1, 2 or 3 R 9 each alkyl is unsubstituted or substituted with 1, 2 or 3 R 10 or any one of embodiments 1-26, or a pharma- ceutically acceptable salt of any of the foregoing, wherein R is substituted with R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17

[0064] In embodiment 31 of the present disclosure, R 3 but, (1) Halogen, OH, C 1-6 Alkyl or C 0-6 4- to 6-membered cycloalkyl which may be mono-, di- or tri-substituted with alkyl(OH); (2) Halogen, C 1-3 Alkyl, C 1-3 a 4- to 6-membered heterocycle containing one sulfur atom or one oxygen atom, which may be mono-, di- or tri-substituted with alkyl (OH) or oxo; (3) C 1-6 Alkyl, wherein the alkyl may be mono-, di- or tri-substituted with halogen or OH. or any one of embodiments 1-27, or a pharma- ceutically acceptable salt of any of the foregoing.

[0065] In embodiment 32 of the present disclosure, R 3 but, (1) 4- to 6-membered cycloalkyl optionally mono-, di- or tri-substituted with F or OH, (2) a 4- to 6-membered heterocycle containing one sulfur atom which may be mono-, di- or tri-substituted with oxo, CHF2, or CH3; (3) a 5- or 6-membered heterocycle containing one oxygen atom, which may be mono-, di- or trisubstituted by CH3 or OH; (4) C 1-6 alkyl-heterocycle, wherein the heterocycle is a 5-membered heterocycle containing one oxygen atom, which may be mono-, di- or tri-substituted with OH; (5) C 1-6 alkyl-heteroaryl, wherein the heteroaryl contains two nitrogen atoms and may be mono-, di- or tri-substituted with CH2CH3; (6) a 5-membered heteroaryl containing two nitrogen atoms and one sulfur atom, which may be mono-, di- or tri-substituted with CH3; or (7) C 1-6 Alkyl, wherein the alkyl may be mono-, di- or tri-substituted with halogen or OH. or any one of embodiments 1-28, or a pharma- ceutically acceptable salt of any of the foregoing.

[0066] In embodiment 33 of the present disclosure, R 3 but, (1) 4- to 6-membered cycloalkyl optionally substituted with F or OH, (2) a 4- to 6-membered heterocycle containing one sulfur atom which may be mono-, di- or tri-substituted by oxo or CH3; (3) a 5- or 6-membered heterocycle containing one oxygen atom, which may be mono-, di- or trisubstituted by CH3 or OH; or (4) C 1-6 Alkyl, wherein the alkyl may be mono-, di- or tri-substituted with halogen or OH. or any one of embodiments 1-28, or a pharma- ceutically acceptable salt of any of the foregoing.

[0067] In embodiment 34a of the present disclosure, R 3 but, (1) 4- to 6-membered cycloalkyl optionally mono-, di- or tri-substituted with F or OH, (2) a 4- to 6-membered heterocycle containing one sulfur atom which may be mono-, di- or tri-substituted with oxo, CHF2, or CH3; (3) a 5- or 6-membered heterocycle containing one oxygen atom, which may be mono-, di- or trisubstituted by CH3 or OH; (4) C containing one oxygen atom, which may be mono-, di- or trisubstituted with OH 1-6 Alkyl-heterocycles, (5) C 0-6 alkyl-heteroaryl, wherein the heteroaryl contains 2 nitrogen atoms and 0-1 sulfur atoms and may be mono-, di- or tri-substituted with CH3, CH2CH3; or (6) C 1-6 Alkyl, wherein the alkyl may be mono-, di- or tri-substituted with halogen or OH. or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0068] In embodiment 34b of the present disclosure, R 3 but, (1) 4- to 6-membered cycloalkyl optionally mono-, di- or tri-substituted with F or OH, (2) a 4- to 6-membered heterocycle containing one sulfur atom which may be mono-, di- or tri-substituted by oxo or CH3; (3) a 5- or 6-membered heterocycle containing one oxygen atom, which may be mono-, di- or trisubstituted by CH3 or OH; or (4) C 1-6 Alkyl, wherein the alkyl may be mono-, di- or tri-substituted with halogen or OH. or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0069] In embodiment 35a of the present disclosure, R 3 but [ka]

[0070] or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0071] In embodiment 35b of the present disclosure, R 3 but, [ka]

[0072] or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0073] In embodiment 36 of the present disclosure, R 3 but [ka]

[0074] or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0075] In embodiment 37 of the present disclosure, R 3 but [ka]

[0076] or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0077] In embodiment 38 of the present disclosure, R 3 but [ka]

[0078] or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0079] In embodiment 39 of the present disclosure, R 3 but [ka]

[0080] or any one of embodiments 1-29, or a pharma- ceutically acceptable salt of any of the foregoing.

[0081] In embodiment 40 of the present disclosure, R 4 is H; or a pharma- ceutically acceptable salt of any of the foregoing.

[0082] In embodiment 41 of the present disclosure, R 5 is H, halogen or CN; or a pharma- ceutically acceptable salt of any of the foregoing.

[0083] In embodiment 42 of the present disclosure, R 5 is H, F, Cl or CN, or any pharma- ceutically acceptable salt of any of the foregoing.

[0084] In embodiment 43 of the present disclosure, R 6 but (1) Cyano, (2) halogens, (3)-OC 1-6 Alkyl, (4) Halogen, C 1-3 Alkyl, C1-6 Optionally substituted with haloalkyl or OH (C 3-6 ) cycloalkyl, (5) -C(=O)NH2, (6)-O(C 3-6 ) cycloalkyl [wherein the cycloalkyl is halogen, C 1-3 may be substituted with alkyl or OH. (7) Hydroxy, (8)N(R 11 )2, (9)(C 1-6 ) haloalkyl-, (10)-O(C 1-6 ) haloalkyl-, (11)-SO2(C 1-6 ) alkyl, (12)-SO2NH(C 1-6 ) alkyl, (13)-SC 1-6 Alkyl, (14)-SC 1-6 haloalkyl, or (15)(C 1-6 Alkyl) or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0085] In embodiment 44a of the present disclosure, R 6 is halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, OC 1-3 Alkyl, OC 1-3 Haloalkyl, OC 3-6 Cycloalkyl, S(O)C 1-3 Alkyl, NHC(O)C 1-3 Alkyl, NC 1-6 Alkyl, C(O)NH2, SC 1-6 Alkyl, S(O)2NHC 1-6wherein cycloalkyl is optionally substituted with halogen; or a compound of formula I, or any of embodiments 15-42, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0086] In embodiment 44b of the present disclosure, R 6 is halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, OC 1-3 Alkyl, OC 1-3 Haloalkyl, OC 3-6 Cycloalkyl, S(O)C 1-3 wherein cycloalkyl is optionally substituted with halogen; or a compound of formula I, or any of embodiments 15-42, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0087] In embodiment 45 of the present disclosure, R 6 C 1-3 Alkyl, C 3-6 Cycloalkyl, OC 3-6 Cycloalkyl, OC 1-3 Alkyl, OC 1-3 Haloalkyl, or S(O)2C 1-3 wherein cycloalkyl is optionally further substituted with 1 to 3 F; or a compound of formula I, or embodiments 15 to 42, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0088] In embodiment 46a of the present disclosure, R 6 is F, CF3, OCHF2, OCF3, OCH2CH3, OCH(CH3)2, OCF2CHF2, OCH2CHF2, cyclopropyl, or O-cyclopropyl, CN, N(CH3)2, C(O)NH2, SCH3, S(O)2NHCH3, NHC(O)CH3, OH, OCF2CHF2, S(O)2CH3, wherein said cyclopropyl is optionally further substituted with one to three halogen atoms, or a compound of formula I, or any of embodiments 15-42, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0089] In embodiment 46b of the present disclosure, R 6 is F, OCHF2, OCF3, OCH2CH3, OCH(CH3)2, OCF2CHF2, OCH2CHF2, cyclopropyl, or O-cyclopropyl, said cyclopropyl being optionally further substituted with one to three halogen atoms, or a compound of formula I, or any of embodiments 15-42, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0090] In embodiment 47 of the present disclosure, R 7 is halogen, C 1-6 haloalkyl, or OH; or a compound of formula I, or embodiments 1-15 and 29-46, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0091] In embodiment 48 of the present disclosure, R 7 is F, CF3, or OH, or any of the preceding pharma- ceutically acceptable salts of any of the preceding.

[0092] In embodiment 49 of the present disclosure, R 8a is H; or a pharma- ceutically acceptable salt of any of the foregoing.

[0093] In embodiment 50 of the present disclosure, R 8b is H; or a pharma- ceutically acceptable salt of any of the foregoing.

[0094] In embodiment 51 of the present disclosure, R 9 =O, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, or C 1-6 is alkylOH; or a compound of formula I, or embodiments 1-30, 40-50, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0095] In embodiment 52 of the present disclosure, R 9 O2, =O, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 is alkylOH; or a compound of formula I, or embodiments 1-30, 40-50, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0096] In embodiment 53a of the present disclosure, R 9 is O2, =O, OH, CH3, CH2CH3, F, CF3, CHF2, or CH2OH, or any of embodiments 1-30, 40-50, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0097] In embodiment 53b of the present disclosure, R 9 is =O, OH, CH3, CH2CH3, F, CF3, or CH2OH; or any pharma- ceutically acceptable salt thereof; or a compound of formula I, or embodiments 1-30, 40-50, or a class thereof, wherein

[0098] In embodiment 54 of the present disclosure, R 10 =O, OH, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 is alkylOH; or a compound of formula I, or embodiments 1-30, 40-53, or a class thereof, or a pharma- ceutically acceptable salt of any of the foregoing.

[0099] In embodiment 55 of the present disclosure, R 10 is =O, OH, CH3, CH2CH3, F, CF3, or CH2OH; or any pharma- ceutically acceptable salt thereof; or a compound of formula I, or any of embodiments 1-30, 40-53, or a class thereof, wherein

[0100] In embodiment 56 of the present disclosure, X is N and Y is C(R 5 ), and Z is C(R 5or any one of embodiments 1-51, or a pharma- ceutically acceptable salt of any of the foregoing.

[0101] In embodiment 57 of the present disclosure, X is C(R 5 ), Y is N, and Z is C(R 5 or any one of embodiments 1-51, or a pharma- ceutically acceptable salt of any of the foregoing.

[0102] In embodiment 58 of the present disclosure, X is C(R 5 ), and Y is C(R 5 ) and Z is N; or any one of embodiments 1-51, or a pharma- ceutically acceptable salt of any of the foregoing.

[0103] In embodiment 59 of the present disclosure, X, Y and Z are C(R 5 or any one of embodiments 1-51, or a pharma- ceutically acceptable salt of any of the foregoing.

[0104] In embodiment 60 of the present disclosure, X is N, Y is N, and Z is C(R 5 or any one of embodiments 1-51, or a pharma- ceutically acceptable salt of any of the foregoing.

[0105] In embodiment 61 of the present disclosure, X is N and Y is C(R 5 ) and Z is N; or any one of embodiments 1-51, or a pharma- ceutically acceptable salt of any of the foregoing.

[0106] In embodiment 62 of the present disclosure, X is C(R 5 ), Y is N and Z is N; or any one of embodiments 1-51, or a pharma- ceutically acceptable salt of any of the foregoing.

[0107] In embodiment 63, the present invention provides a compound according to any one of Examples 1 to 129 below, or a pharma- ceutically acceptable salt thereof.

[0108] In embodiment 64, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0109] or a pharma- ceutically acceptable salt thereof.

[0110] In embodiment 65, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0111] or a pharma- ceutically acceptable salt thereof.

[0112] In embodiment 66, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0113] or a pharma- ceutically acceptable salt thereof.

[0114] In embodiment 67, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0115] In embodiment 68, the present invention provides a method for producing a composition comprising: [ka]

[0116] or a pharma- ceutically acceptable salt thereof.

[0117] In embodiment 69, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0118] or a pharma- ceutically acceptable salt thereof.

[0119] In embodiment 70, the present invention provides a method for producing a pharmaceutical composition comprising: [ka]

[0120] or a pharma- ceutically acceptable salt thereof.

[0121] In embodiment 71, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0122] or a pharma- ceutically acceptable salt thereof.

[0123] In embodiment 72, the present invention provides a method for producing a composition comprising: [ka]

[0124] or a pharma- ceutically acceptable salt thereof.

[0125] In embodiment 73, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0126] or a pharma- ceutically acceptable salt thereof.

[0127] In embodiment 74, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0128] or a pharma- ceutically acceptable salt thereof.

[0129] In embodiment 75, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0130] or a pharma- ceutically acceptable salt thereof.

[0131] In embodiment 76, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0132] or a pharma- ceutically acceptable salt thereof.

[0133] In embodiment 77, the present invention provides a method for producing a composition comprising: [ka]

[0134] or a pharma- ceutically acceptable salt thereof.

[0135] In embodiment 78, the present invention provides a method for producing a composition comprising the steps of: [ka]

[0136] or a pharma- ceutically acceptable salt thereof.

[0137] In embodiment 79 of the invention, the compound of formula I or a pharma- ceutically acceptable salt thereof is [ka] TIFF0007604636000038.tif224158TIFF0007604636000039.tif221155TIFF0007604636000040.tif224165TIFF0007604636000041.tif226155TIFF0007604636000042.tif114155.

[0138] In embodiment 80 of the present invention, the compound of formula I or a pharma- ceutically acceptable salt thereof is (R)-1,3-bis(4-fluorophenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]benzimidazole-5-carboxamide, 1-(3-isopropoxyphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]benzimidazole-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-(3-ethoxyphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]benzimidazole-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[4-(difluoromethoxy)-2-pyridyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-(3-cyclopropylphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(cyclopropoxy)phenyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(2,2-difluorocyclopropyl)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-(2-hydroxy-1,2-dimethyl-propyl)-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1S,2S)-2-hydroxycyclopentyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-1-[3-(difluoromethoxy)phenyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1R,2R)-2-hydroxycyclohexyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-cyclobutyl-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-cyclopentyl-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-ethyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-cyclopropyl-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-(1,1-difluoropropan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-3-(1,1-difluoropropan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-(sec-butyl)-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(sec-butyl)-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(sec-butyl)-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-(2-hydroxy-2-methylpropyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidethietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-(difluoromethoxy)pyridin-3-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-cyclopropylpyridin-3-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-3-[3-(trifluoromethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-3-[3-(trifluoromethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-isopropoxyphenyl)-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-isopropoxyphenyl)-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[5-(difluoromethoxy)-2-fluoro-phenyl]-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[5-(difluoromethoxy)-2-fluoro-phenyl]-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxamide, 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-benzimidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-6-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 4-cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(2,2-difluoroethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(2,2-difluoroethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-6-fluoro-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-6-fluoro-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, N-(4-(difluoromethyl)-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(4-acetamido-3-hydroxyphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-1-(2-methylbenzo[d]oxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-1-(2-methylbenzo[d]oxazol-6-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-fluorophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-fluoro-2-isopropoxypyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-cyanophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(dimethylamino)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-carbamoylphenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(3-(methylthio)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(3-(N-methylsulfamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(3-(methylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorobenzyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(1-amino-1-oxopropan-2-yl)-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(1-amino-1-oxopropan-2-yl)-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, or 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(phenylsulfonyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide It is.

[0139] The present invention includes pharma- ceutically acceptable salts of the compounds defined herein.

[0140] In one embodiment, the invention is a composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharma- ceutically acceptable salt thereof.

[0141] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0142] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of at least one other pharma- ceutical active ingredient (e.g., a chemotherapeutic agent).

[0143] The present invention also provides pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of Formula I, or a pharma- ceutically acceptable salt thereof, and a therapeutically effective amount of at least one other pharma- ceutical active ingredient (e.g., a chemotherapeutic agent), and a pharma- ceutically acceptable carrier.

[0144] In one embodiment, the present invention provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney disease, or cardio-renal disease, such as heart failure, comprising an acceptable carrier and a compound of Formula I or a pharma- ceutically acceptable salt thereof.

[0145] In one embodiment, the present invention provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney disease or cardio-renal disease, such as heart failure, comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof.

[0146] In one embodiment, the present invention provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney disease or heart failure, comprising a compound of Formula I or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

[0147] In one embodiment, the present invention provides a method of treating a cardio-renal disease, such as hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney disease or heart failure in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of formula I, or a pharma- ceutical acceptable salt thereof.

[0148] In one embodiment, the present invention provides a method of treating a cardio-renal disease, such as hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney disease or heart failure in a subject in need thereof, comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharma- ceutical acceptable salt thereof, and a pharma- ceutical acceptable carrier.

[0149] The methods of the present invention include administering a pharmaceutical composition comprising at least one compound of the present invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0150] In another embodiment, the present invention comprises a method of treating NASH and / or fibrosis comprising administering to a patient in need of treatment a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0151] In another embodiment, the invention includes a method of treating NASH and / or fibrosis comprising administering to a patient in need of treatment a compound of formula I, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0152] In another embodiment, the present invention comprises a method of treating NASH and / or fibrosis comprising administering to a patient in need of treatment a composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof.

[0153] In another embodiment, the present invention comprises a method of treating NASH and / or fibrosis comprising administering to a patient in need of treatment a composition comprising a compound of formula I or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0154] In another embodiment, the present invention provides the use of a compound of formula I, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating NASH and / or fibrosis.

[0155] In another embodiment, the invention includes the use of a compound of formula I or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for treating NASH and / or fibrosis.

[0156] "Alkyl" means both branched and straight-chain saturated aliphatic hydrocarbon groups, where specified, having the specified number of carbon atoms. If no number is specified, 1 to 6 carbon atoms are intended for straight-chain alkyl groups, and 3 to 7 carbon atoms for branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, octyl, nonyl, and the like. For example, "C 1-6 The term alkyl is defined as follows: 1-4 In addition to all of the above, "alkyl" includes linear or branched alkyl groups having 5 or 6 carbon atoms, including all possible isomers. 1-6 "Alkyl" means a straight-chain or branched alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, including all the possible isomers, and includes each of the hexyl and pentyl isomers. 1-6 Each of the alkyl groups encompassed by alkyl includes n-, iso-, sec-, and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively "C4 alkyl"; Bu = butyl), n- and i-propyl (propyl, i-propyl, collectively "C3 alkyl"; Pr = propyl), ethyl (Et) and methyl (Me). Commonly used abbreviations for alkyl groups are used throughout the specification, for example, methyl is "Me" or CH3 or for example. [ka]

[0157] where ethyl can be represented by "Et" or CH2CH3, propyl can be represented by "Pr" or CH2CH2CH3, butyl can be represented by "Bu" or CH2CH2CH2CH3, etc. For example, the following structure: [ka]

[0158] have equivalent meanings. 1-6 Alkyl includes n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. If no number is specified, 1 to 6 carbon atoms are intended for straight or branched alkyl groups.

[0159] "Alkoxy" refers to an alkyl group linked to an oxygen. Examples of alkoxy groups include methoxy, ethoxy, propoxy, and the like.

[0160] "Aryl" refers to an aromatic monocyclic or polycyclic ring moiety containing 6 to 14 ring carbon atoms. In one embodiment, an aryl group contains about 6 to 10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl. Polycyclic rings include naphthyl and phenyl. 5-7 Cycloalkyl ring or C 5-7 and bicyclic rings fused to a cycloalkenyl ring, but are not limited to these. Aryl groups may be optionally substituted with one or more substituents as defined herein. Attachment may be via any of the carbon atoms of any ring.

[0161] "Fused aryl" refers to an aryl ring fused to a heterocycle or cycloalkyl.

[0162] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine.

[0163] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing about 3 to 10 ring carbon atoms. If no number of atoms is specified, 3 to 10 carbon atoms are intended. Cycloalkyls can also be fused to form 1 to 3 carbocyclic rings. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl groups are unsubstituted or substituted with one or more ring system substituents, which may be the same or different, and are as defined herein. ... 3-6 The term "cycloalkyl" refers to a cycloalkyl group having 3 to 6 ring carbon atoms. Thus, for example, "C 3-6 "Cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When cycloalkyl is a substituent on an alkyl group, the cycloalkyl substituent can be attached to any available carbon on the alkyl group. The following illustrates a -C on an alkyl group where the substituent is cyclopropyl in bold: 3-6 Cycloalkyl substituents are shown. [ka]

[0164] "Haloalkyl" refers to an alkyl group, as defined herein, in which one or more of the alkyl group's hydrogen atoms are replaced with a halogen. In one embodiment, a haloalkyl group has 1 to 6 carbon atoms. Non-limiting examples of haloalkyl groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2Cl, and CCl3. 1-6 Haloalkyl" or "HaloC 1-6 The term "alkyl" refers to a haloalkyl group having 1 to 6 carbons.

[0165] "Haloalkoxy", "haloalkyl-O" and "halo(C 1-6Derivatives such as "alkoxy" are used interchangeably and refer to halo-substituted alkyl groups linked through an oxygen atom.

[0166] Haloalkoxy includes mono- and multiply halo-substituted alkoxy groups. For example, trifluoromethoxy, chloromethoxy, and bromomethoxy are also included in OCH2CF3, OCH2CHF2, OCF2CF3, and OCF2CHF2.

[0167] "Heterocyclyl," "heterocycle," or "heterocyclic" refers to a monocyclic ring structure in which one or more of the atoms in the ring, the heteroatom, is an element other than carbon.

[0168] Heteroatoms are typically O, S, or N atoms. Heterocycles containing multiple heteroatoms may contain different heteroatoms. Bicyclic ring moieties include fused, spirocyclic, and bridged bicyclic rings, and any of the rings may contain one or more heteroatoms. The ring bonded to the rest of the molecule may or may not contain heteroatoms. Any of the rings of a bicyclic heterocycle may be saturated, partially unsaturated, or unsaturated. The heterocycle may be bonded 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, oxirane, or aziridine.

[0169] "Bicyclic heterocyclyl", "bicyclic heterocycle" or "bicyclic heterocyclic" refers to a heterocycle fused to another ring system. The fused ring may be bridged or unbridged.

[0170] Unless otherwise noted, the term "heteroaryl" as used herein refers to a stable monocyclic, bicyclic, or tricyclic ring of up to 10 atoms in each ring, in which at least one ring is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Heteroaryl groups within this definition include benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyrid ... These include, but are not limited to, nyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetrahydroquinoline.

[0171] A "fused heteroaryl" is a heteroaryl fused with an aryl or heteroaryl.

[0172] "Oxo" means an oxygen that is connected to an atom by a double bond. Examples of oxo groups are the double-bonded oxygen in ketones, sulfoxides, sulfones, and sulfates.

[0173] "Hydroxyalkyl" or "hydroxy(C 1-3 "Alkyl" means an alkyl group having one or more hydrogen atoms replaced by a hydroxyl (-OH) group.

[0174] "Cyanoalkyl" means an alkyl group having one or more hydrogen atoms replaced by a cyano (-CN) group.

[0175] "Hydroxyhaloalkyl" means an alkyl group having one or more hydrogen atoms replaced by a hydroxyl (-OH) group and one or more hydrogen atoms replaced by a halogen.

[0176] "Hydroxycycloalkyl" means a cyclic alkyl group having one or more hydrogen atoms replaced by a hydroxyl (-OH) group.

[0177] The term "composition" is intended to encompass an article of manufacture containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts.

[0178] The term "at least one" means one or more. The meaning of "at least one" with respect to the number of compounds of the invention is independent of its meaning with respect to the number of chemotherapeutic agents.

[0179] The term "chemotherapeutic agent" refers to an agent (drug or active pharmaceutical ingredient) for treating cancer (i.e., an antitumor agent).

[0180] The term "effective amount" means a "therapeutically effective amount." The term "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the physiological or medical response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, physician, or other clinical practitioner.

[0181] The term "treating cancer" or "treatment of cancer" refers to the administration to a mammal afflicted with a cancerous condition, and refers to an effect that alleviates the cancerous condition by killing the cancer cells, and also refers to an effect that results in the inhibition of the growth and / or metastasis of the cancer.

[0182] Except as noted herein, the term "carbocycle" (and variations thereof, such as "carbocycle" or "carbocyclyl") as used herein, unless otherwise specified, refers to a C3 to C6 monocyclic ring, such as C 3-6 refers to a monocyclic carbocycle. The carbocycle can be attached to the rest of the molecule at any carbon atom that results in a stable compound. Saturated carbocycles include, for example, "cycloalkyl" rings, such as cyclopropyl, cyclobutyl, and the like. Unsaturated carbocycles include, for example: [ka]

[0183] Unless otherwise indicated, the term "saturated heterocycle" refers to a stable 4-7 membered monocyclic heteroatom-containing ring system consisting of carbon atoms and 1-4 heteroatoms independently selected from the group consisting of N, O and S, where the nitrogen and sulfur heteroatoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. Particularly useful are rings containing one oxygen or sulfur in combination with one or two nitrogen atoms, one to four nitrogen atoms, or one oxygen or sulfur. The heterocycle may be attached to any heteroatom or carbon atom that results in the creation of a stable structure. Representative examples include azetidine, oxetane, thietane, diazetidine, dioxetane, dithietane, pyrrolidine, tetrahydrofuran, thiolane, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, piperidine, oxane, thiane, piperazine, morpholine, thiomorpholine, dioxane, dithiane, trioxane, trithiane, azepane, oxepane, thiepane and homopiperazine. For example, a "saturated 6-membered heterocycle" is a stable 6-membered monocyclic heteroatom-containing ring system. An example of a saturated 6-membered heterocycle is piperidine. Similarly, without limitation, a "saturated 4-membered heterocycle" is a stable 4-membered monocyclic heteroatom-containing ring system.

[0184] Unless otherwise stated herein, the term "unsaturated heterocycle" refers to a monocyclic unsaturated heterocycle having a specified number of atomic ring members (e.g., 5 members), e.g., a specified number of heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S), e.g., a 5-membered ring containing one nitrogen (pyrrole), one oxygen (furan), or one sulfur (thiophene) atom, a 5-membered ring containing one nitrogen and one sulfur atom (thiazole), a 5-membered ring containing one nitrogen and one oxygen atom (oxazole or isoxazole), a 5-membered ring containing two nitrogen atoms (imidazole or pyrazole), a 5-membered aromatic ring containing three nitrogen atoms (triazole), a 5-membered aromatic ring containing one oxygen, one nitrogen, or one sulfur atom, a 5-membered aromatic ring containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur (e.g., oxazole). Further examples are thiophene, imidazole, isothiazole, oxadiazole, and isoxazole. For example, an "unsaturated 6-membered heterocycle" is a 6-membered ring containing 6 atomic ring members, including at least one heteroatom. Similarly, an "unsaturated 5-membered heterocycle" is a 5-membered ring containing 5 atomic ring members, including at least one heteroatom.

[0185] A "stable" compound is one which can be prepared and isolated and whose structure and properties remain essentially unchanged or unaltered for a period of time sufficient to permit use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0186] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I and embodiments thereof. For example, certain moieties defined in Formula I may be unsubstituted or substituted, the latter being intended to encompass those substitution patterns (i.e., number and type of substituents) that are chemically feasible for that moiety and result in stable compounds.

[0187] The term "substituted" means that one or more hydrogens on the specified atom are replaced with one selected from the specified group, provided that the replacement does not exceed the normal valence of the specified atom in the present environment, and that the replacement results in a stable compound. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently substituted one or more times with 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 permissible only if such combinations result in stable compounds. When a substituent is itself substituted with multiple groups, it is understood that these multiple groups may be on the same or different carbons, so long as a stable structure results. Optionally substituted means compounds that contain any of the specified substituents, as well as compounds that do not contain any of the substituents.

[0188] As used herein, a wavy line: [ka]

[0189] indicates the point of attachment to the remainder of the compound.

[0190] If the ring atom is, for example [ka]

[0191] When represented by a variable such as "X," as in, the variable is defined by showing the atom located at the ring position of the variable without drawing the ring bonds associated with that atom. For example, if X in the above ring is nitrogen, the definition would show "N" and no bonds associated with it would be shown, e.g., no "=N-" would be shown. Similarly, if X is a carbon atom substituted with bromide, the definition would show "C-Br" and no bonds associated with it would be shown, e.g., [ka] is not drawn.

[0192] The present invention also includes derivatives of the compounds of formula I that act as prodrugs and solvates. Pharmaceutically acceptable prodrug modifications of the compounds of the present invention that result in in vivo conversion to compounds within the scope of the present invention are also within the scope of the present invention. Prodrugs are converted to compounds of formula I in the body after administration to a patient by normal metabolic or chemical processes, such as by hydrolysis in the blood. Such prodrugs include those that exhibit high bioavailability, tissue specificity and / or cellular delivery to improve drug absorption of the compounds of formula I. The effect of such prodrugs can be due to modifications of physicochemical properties such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine the permeation characteristics of the drug.

[0193] For example, esters can be made by esterification of an available carboxylic acid group or by forming an ester at an available hydroxyl group in the compound. Similarly, unstable amides can be made. Pharmaceutically acceptable esters or amides of the compounds of the invention are included within the scope of the invention, especially since they can be prepared to act as prodrugs that can be hydrolyzed in vivo back to the acid (or -COO- depending on the pH of the fluid or tissue where the conversion occurs) or hydroxy form. Included are esters and acyl groups known in the art to modify solubility or hydrolysis properties for use as sustained release or prodrug formulations. Examples of pharma-ceutically acceptable prodrug modifications include -C 1-6 -C substituted with alkyl esters and phenyl esters 1-6 Examples include, but are not limited to, alkyl.

[0194] "Celite®" (Fluka) diatomaceous earth is diatomaceous earth and can be referred to as "celite". 1When R, R, etc., occurs more than once in any constituent or in Formula I or other general formulas herein, its definition at each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In selecting compounds of the present invention, the various substituents, i.e., R 1 Those skilled in the art will recognize that the substituents, such as, should be selected consistent with known principles of connectivity and stability of chemical structures. Unless expressly stated to the contrary, substitution with a named substituent is permitted on any atom in the ring (e.g., aryl, heteroaryl ring, or saturated heterocyclic ring), provided that such ring substitutions are chemically permissible and result in a stable compound.

[0195] It should be noted that in the event of a discrepancy between a chemical name and a structure, the structure is understood to control.

[0196] The compounds of formula I may contain one or more asymmetric centers and may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. All asymmetric centers present in the compounds of formula I may have, independently of one another, S or R configurations. When a bond to a chiral carbon is depicted as a straight line in the structural formula of the present invention, it is understood that both the (R) and (S) configurations of that chiral carbon, and therefore both enantiomers and mixtures thereof, are included in the formula. Similarly, when a compound name is described without a chiral designation of a chiral carbon, it is understood that both the (R) and (S) configurations of that chiral carbon, and therefore individual enantiomers and mixtures thereof, are included in the name. The preparation of a particular stereoisomer or mixtures thereof may be specified in the examples in which such stereoisomer or mixture was obtained, but this is in no way a limitation to include all stereoisomers and mixtures thereof within the scope of the present invention.

[0197] The compounds of the present invention include all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers in any ratio, such as mixtures of enantiomers and / or diastereomers.Enantiomers are therefore subject of the present invention in enantiomerically pure form, both as levorotatory and dextrorotatory chemical enantiomers, in the form of racemates and in the form of mixtures of two enantiomers in any ratio.In the case of cis / trans isomerism, the present invention includes both the cis and trans forms, as well as mixtures of these forms in any ratio.The present invention encompasses all such stereoisomeric forms of the compounds of structural formula I.

[0198] The compounds of structural formula I can be separated into their individual diastereomers, for example, by fractional crystallization from a suitable solvent, such as MeOH or EtOAc, or mixtures thereof, or via chiral chromatography using an optically active stationary phase. Optionally, derivatization can be performed before the separation of stereoisomers. Separation of the mixture of stereoisomers can be performed at an intermediate stage during the synthesis of the compounds of formula I, or on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of crystalline products or crystalline intermediates that have been derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer or isomer of the compounds of formula I 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 (such as hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers, and mixtures thereof.

[0199] If desired, racemic mixtures of compounds can be separated so that the individual enantiomers are isolated. Separation can be carried out by methods known in the art, such as coupling a racemic mixture of compounds with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation into the individual diastereomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to the pure enantiomer by cleavage of the added chiral residue. Racemic mixtures of compounds can also be directly separated by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0200] For compounds of Formula I described herein that contain olefinic double bonds, unless otherwise specified, both E and Z geometric isomers are intended to be included.

[0201] Some of the compounds described herein can exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, ketones and their enol forms are keto-enol tautomers. The individual tautomers as well as mixtures thereof are included in the compounds of formula I of the present invention.

[0202] In the compounds of structural formula I, the atoms can exhibit their natural isotopic enrichment, or one or more of the atoms can be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The invention described and claimed herein includes all suitable isotopic variations of the compounds of structural formula I, and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium (also denoted herein as D 2H). Protium is the predominant hydrogen isotope found in nature. Enrichment for deuterium may provide certain therapeutic advantages, such as increased in vivo half-life, or reduced dosage requirements, or may provide compounds useful as standards for characterization of biological samples. Isotopically enriched compounds within structural formula I may be prepared without undue experimentation by conventional techniques familiar to those of skill in the art, or by processes analogous to those described in the Schemes and Examples herein, using appropriate isotopically enriched reagents and / or intermediates.

[0203] It will be understood that the compounds of structural formula I can be prepared as pharma- ceutically acceptable salts, or as salts that are not pharma-ceutically acceptable when used as free compounds or as precursors to their pharma- ceutically acceptable salts, or in other synthetic operations. The compounds of the present invention, such as the compounds of the examples, can also include any salts of the compounds of formula I that are not directly suitable for use in medicines due to poor physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically acceptable salts.

[0204] The compounds of the present invention can be administered in the form of pharma- ceutically acceptable salts. The term "pharma-ceutically acceptable salts" refers to salts prepared from pharma- ceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or organic acids.

[0205] Salts of basic compounds encompassed within the term "pharmaceutical acceptable salts" refer to non-toxic salts of the compounds of the present invention, typically prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isopropyl alcohol, ethyl ... Non-limiting examples include isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, theoclate, thiocyanate, tosylate, triethiodide, and valerate. Additionally, when a compound of the invention contains an acidic moiety, suitable pharma- ceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganous, manganous, potassium, sodium, zinc, etc. In one embodiment, salts of acidic compounds include the following: ammonium, calcium, magnesium, potassium, and sodium salts.

[0206] The compounds of formula I form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia, organic bases or otherwise basic amino acids.

[0207] Salts derived from pharma- ceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Basic nitrogen-containing groups may also be quaternized with agents such as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, such as benzyl and phenethyl bromides, and others.

[0208] The preparation of pharmacologically acceptable salts from the compounds of formula I capable of forming salts, including stereoisomeric forms, can be carried out in a known manner, for example by mixing the compounds of the present invention with a solution containing an equivalent amount and the desired acid, base, etc., and then recovering the desired salt by filtering the salt or evaporating the solvent. The compounds of the present invention and their salts can form solvates with solvents such as water, ethanol, or glycerol. The compounds of the present invention can simultaneously form acid addition salts and salts with bases, depending on the type of substituents on the side chain.

[0209] In the case where the compounds of formula I simultaneously contain acidic and basic groups in the molecule, the present invention includes, in addition to the salt forms mentioned, also inner salts or betaines (zwitterions). Salts can be obtained from the compounds of formula I by common methods known to those skilled in the art, for example by combination with organic or inorganic acids or bases in a solvent or dispersion medium, or by anion or cation exchange from other salts.

[0210] The present invention includes compounds of structural formula I, as well as salts thereof, particularly pharma- ceutically acceptable salts of such compounds, solvates and solvated salt forms thereof, all of which are possible unless otherwise specified.

[0211] Additionally, the compounds of the present invention may exist in amorphous form and / or one or more crystalline forms, and therefore, all amorphous and crystalline forms of the compounds of formula I, as well as mixtures thereof, are intended to be within the scope of the present invention. Additionally, some of the compounds of the present invention may 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 pharma- ceutically acceptable solvates and hydrates, are also intended to be within the scope of the present invention, along with the unsolvated and anhydrous forms.

[0212] Thus, the compounds encompassed by the general structural formulas above, the embodiments described in the examples and the specific compounds claimed herein include salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvates and hydrate forms thereof and any combination of these forms, as well as salts thereof, prodrug forms, and salts of their prodrug forms (such forms are possible unless otherwise indicated).

[0213] The present invention also relates to a medicament comprising at least one compound of formula I and / or a pharma- ceutically acceptable salt of a compound of formula I and / or any stereoisomeric form of a compound of formula I or a pharma- ceutically acceptable salt of a stereoisomeric form of a compound of formula I, together with a pharma- ceutically acceptable vehicle, carrier, excipient and / or other active substances and auxiliaries.

[0214] The medicaments according to the invention can be administered orally, by inhalation, rectally or transdermally, or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred. Coating of stents and other surfaces in contact with blood in the body with the compounds of formula I is possible.

[0215] The present invention also relates to a method for the manufacture of a medicament, which comprises bringing at least one compound of formula I into a suitable administration form using a pharma- ceutically acceptable carrier and, optionally, further suitable active substances, additives or auxiliaries.

[0216] The present invention also relates to processes for the preparation of compounds of formula I, which are described below and from which the compounds of the invention can be obtained.

[0217] The term "therapeutically effective (or effective) amount" and similar descriptions such as "therapeutically effective amount" refer to an amount of a pharmaceutical agent that will alleviate the disorder, condition, or disease being treated in an animal or human (i.e., a disorder, condition, or disease associated with DGAT2 activity). The term "prophylactically effective (or effective) amount" and similar descriptions such as "prophylactically effective amount" refer to an amount of a pharmaceutical agent that prevents or reduces the symptoms or occurrence of the disorder, condition, or disease being treated in an animal or human (i.e., a disorder, condition, or disease associated with DGAT2 activity). By way of example, the dose administered to a patient can be selected to achieve a desired reduction in blood pressure; the dose administered to a patient may be titrated over time to achieve a target blood pressure. Dosage regimens utilizing the compounds of the present invention are selected according to various factors, such as the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition 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 is well within the purview of the ordinarily skilled clinician for purposes of determining the therapeutically or prophylactically effective dose required to prevent, combat, or arrest the progression of a condition. It is clear that a specific daily dose can simultaneously be both a therapeutically effective amount for the treatment of, for example, hepatic steatosis, diabetes, obesity, hyperlipidemia, hypercholesterolemia, and a prophylactically effective amount for the treatment of, for example, NASH.

[0218] Disorders, conditions, and diseases that can be treated or prevented by inhibiting DAGT2 using compounds of Formula I include, for example, nonalcoholic steatohepatitis (NASH), fibrosis, hyperlipidemia, type I diabetes, type II diabetes, cognitive decline, dementia, coronary heart disease, ischemic stroke, restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial dyslipidemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, chronic renal failure, and the like. , diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue disorders, hyperapo B lipoproteinemia, non-alcoholic fatty liver disease, cardio-renal diseases such as chronic kidney disease and heart failure, and related diseases and conditions.

[0219] The compounds of formula I and their pharma- ceutically acceptable salts can be administered to animals, preferably mammals, especially humans, as medicines, either by themselves, in admixture with each other, or in the form of pharmaceutical preparations. The term "patient" includes animals, preferably mammals, especially humans, who use the active agents of the present invention for the prevention or treatment of medical diseases. The administration of a drug to a patient includes both self-administration and administration to the patient by another person. A patient may need or desire treatment of an existing disease or medical condition, or may need or desire prophylactic treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, a patient "in need" of treatment or prophylactic treatment of an existing condition includes both the determination of need by a medical professional, as well as the patient's desire for such treatment.

[0220] A further subject of the present invention is a pharmaceutical formulation (or pharmaceutical composition) comprising, as active ingredient, a therapeutically effective dose of at least one compound of formula I and / or a pharma- ceutically acceptable salt thereof, and a customary pharma- ceutically acceptable carrier, i.e. one or more pharma- ceutically acceptable carrier substances and / or excipients.

[0221] A subject of the present invention is therefore, for example, the above-mentioned compounds and their pharma- ceutically acceptable salts for use as medicaments, pharmaceutical preparations comprising a therapeutically effective dose of said compounds and / or their pharma- ceutically acceptable salts and a customary pharma- ceutically acceptable carrier, and the use of said compounds and / or their pharma- ceutically acceptable salts in the therapy or prophylaxis of the abovementioned syndromes, as well as their use for producing medicaments for these purposes.

[0222] The medicaments according to the invention can be administered orally, for example, in the form of pills, tablets, lacquered tablets, dragees, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be parenterally, for example subcutaneously, intramuscularly or intravenously, in the form of injection or infusion solutions. Other suitable administration forms are, for example, transdermal or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, inhalation administration, for example, in nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and its severity.

[0223] For the preparation of pills, tablets, dragees 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 or hardened oils, etc. Suitable carriers for the preparation of liquids, such as injection solutions, or emulsions or syrups, are, for example, water, physiological sodium chloride solution, ethanol, glycerin, alcohols such as polyhydric alcohols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to freeze-dry the compounds of formula I and their pharma-ceutically acceptable salts and use the resulting lyophilisates, 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.

[0224] Suitable solid or galenical preparations include, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations with extended release of active substances, in the preparation of which common excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, propellants and lubricants, flavorings, sweeteners and solubilizers are used. Frequently used adjuvants that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycols and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerin.

[0225] Besides the active compound and the carrier, the pharmaceutical formulations may also contain conventional additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, fragrances, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing the osmotic pressure, coating agents or antioxidants.

[0226] The dose of the active compound of formula I and / or its pharma- ceutically acceptable salts administered will depend on each individual case and, as is commonly done, will be adapted to the individual circumstances to achieve the optimal effect.It will therefore depend on the nature and severity of the disorder, condition or disease to be treated, and the sex, age, weight and individual response of the human or animal to be treated, the potency and duration of action of the compound used, whether the therapy is acute, chronic or prophylactic, or whether other active compounds are administered in addition to the compound of formula I.

[0227] Concomitant medications The compounds of the present invention can be administered alone or in combination with one or more additional therapeutic agents disclosed herein or other suitable agents depending on the condition to be treated. Thus, in some embodiments, one or more compounds of the present invention are co-administered with the other agents described above. When used in combination therapy, the compounds described herein are administered simultaneously or separately with the second agent. This co-administration can include co-administration of the two agents in the same dosage form, co-administration in separate dosage forms, and separate administration. That is, the compound of formula (I) and any of the agents described above can be formulated together in the same dosage form and administered at the same time. Alternatively, the compound of formula (I) and any of the agents described above can be administered at the same time, but in separate formulations. In another alternative, any of the agents described above can be administered immediately after the compound of formula (I), or vice versa. In some embodiments of the separate administration protocol, the compound of formula (I) and any of the agents described above are administered minutes apart, or hours apart, or days apart.

[0228] Since one aspect of the present invention contemplates the treatment of a disease / condition with a combination of pharma- ceutical active compounds that can be administered separately, the present invention further relates to combining separate pharmaceutical compositions in kit form. The kit includes two separate pharmaceutical compositions, a compound of formula (I) and a second pharmaceutical compound. The kit includes a container for containing the separate compositions, such as a divided bottle or a divided foil packet. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for the 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), administered at different dosing intervals, or when titration of the individual components of the combination is desired by the prescribing medical professional.

[0229] One or more additional pharmacologically active agents may be administered in combination with the compound of formula I. By additional active agent(s) is meant an intracellularly active pharmacologic agent(s) different from the compound of formula I, such as a prodrug that is converted into a pharmacologic active form after administration, including free acid, free base and pharmacologic acceptable salts of said additional active agents. In general, any suitable additional active agent(s) such as, but not limited to, antihypertensive agents, antiobesity agents such as lipid-modifying compounds, anti-inflammatory agents, antifibrotic agents and antiatherosclerotic agents, antidiabetic agents and / or antiobesity agents, may be used in any combination with the compound of formula I in a single formulation (fixed dose drug combination) or may be administered to the patient in one or more separate formulations that allow for simultaneous or sequential administration of the active agents (co-administration of separate agents).

[0230] Examples of additional active agents that can be used include angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, sipirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., losartan, i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan, and hydrochlorothiazides such as HYZAAR®). any of these agents in combination with an azide; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., urea derivatives of di- and tri-peptides, amino acids and derivatives, amino acid chains linked by non-peptide bonds, di- and tri-peptide derivatives, peptidyl aminodiols and peptidyl beta-aminoacyl aminodiol carbamates); and small molecule renin inhibitors such as diol sulfonamides and N-morpholino derivatives, N-heterocyclic alcohols and pyrrolimidazolones;Furthermore, pepstatin derivatives and fluoro- and chloro-derivatives of statin-containing peptides, enalklein, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]-octanamide hemifumarate) SPP600, SPP630 and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g. sildenafil, tadalfil and vardenafil), vasodilators, Calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, gallopamil, niludipine, nimodipine, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprikalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholytics, β-adrenergic blocking agents (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, tartrate, or metoprolol tartrate), alpha-adrenergic blocking agents (e.g., doxazosin, prazosin, or alpha methyldopa), central alpha-adrenergic agonists, peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, for example, HMG-CoA reductase inhibitors such as simvastatin and lovastatin, marketed as ZOCOR® and MEVACOR®, which are in lactone prodrug form and function as inhibitors after administration, and pharma- ceutically acceptable salts of dihydroxy open acid HMG-CoA reductase inhibitors such as atorvastatin (especially the calcium salt sold as LIPITOR®), rosuvastatin (especially the calcium salt sold as CRESTOR®), pravastatin (especially the sodium salt sold as PRAVACHOL®), fluvastatin (especially the sodium salt sold as LESCOL®), cerivastatin, and pitavastatin;Cholesterol absorption inhibitors such as ezetimibe (ZETIA®) and any other lipid lowering agent such as the HMG-CoA reductase inhibitors mentioned above, especially ezetimibe in combination with simvastatin (VYTORIN®) or atorvastatin calcium; niacin in immediate or sustained release form, and / or with HMG-CoA reductase inhibitors; niacin receptor agonists such as acipimox and acifran, and niacin receptor partial agonists; PCSK9 inhibitors (alirocumab, evolocumab) , Nexletol™ (bempedoic acid, an ACL inhibitor), and Vascepa® (ethyl icosapentate); insulin and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, such as (i) β-Klotho / FGFR1 activating monoclonal antibodies (e.g., MK-36 55), pan FGFR1-4 / KLB regulators, FGF19 analogs (e.g., aldafermin); (ii) PPARγ agonists, such as the glitazones (e.g., pioglitazone, AMG131, CHS131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and other PPAR ligands, such as (1) PPARα / γ dual agonists (e.g., ZYH2, ZYH1, GFT505, tiglitazar, muraglitazar, aleglitazar, soderglitazar, and naveglitazar); (2) P PARα agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARγ modulators (SPPARγMs), (e.g., those disclosed in WO02 / 060388, WO02 / 08188, WO2004 / 019869, WO2004 / 020409, WO2004 / 020408, and WO2004 / 066963); (4) PPARγ partial agonists; (5) PPARα / δ dual agonists (e.g., elafibranor);(iii) metformin and its pharma- ceutically acceptable salts, particularly biguanides such as metformin hydrochloride and sustained release formulations thereof such as Grumezza®, Fortamet® and Glucophage XR®; and (iv) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro, and their respective inhaled formulations); and leptin derivatives and agonists; amylin and amylin analogues (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide); alpha-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-2409021 and KT6-971); insulins such as GLP-1, GLP-1 analogues, derivatives and mimetics. Cretinomimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including nasal, transdermal, and once-weekly formulations), bile acid sequestrants (e.g., colestilan, colestimide, colestivalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of cross-linked dextran), acyl-CoA:cholesterol acyltransferase inhibitors (e.g., acetylcholine, acetylsalicylic acid ... inhibitors (e.g. avasimibe); anti-obesity compounds; agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs or NSAIDs, glucocorticoids and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g. AZD6370); 11β-hydroxysteroid dehydrogenase type 1 inhibitors (e.g. those disclosed in U.S. Pat. No. 6,730,690 and LY-2523199); CETP inhibitors (e.g. anacetrapib, torcetrapib and evacetrapib);Fructose 1,6-bisphosphatase inhibitors (e.g., such as those disclosed in U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); acetyl-CoA carboxylase-1 or 2 inhibitors (ACC1 or ACC2); AMP-activated protein kinase (AMPK) activators; other G protein-coupled receptor agonists: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982, and PSN821), and (iii) GPR-40 (e.g., TAK87 5); SSTR3 antagonists (e.g., those disclosed in WO2009 / 001836); Neuromedin U receptor agonists (e.g., those disclosed in WO2009 / 042053, such as, but not limited to, Neuromedin S (MS)); SCD modulators (e.g., aramchol); GPR-105 antagonists (e.g., those disclosed in WO2009 / 000087); SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2, such as empagliflozin, dapagliflozin, canagliflozin and ertugliflozin, BI-107 73, , remogliflozin, TS-071, tofogliflozin, ipragliflozin and LX-4211; acyl-coenzyme A inhibitors (ACC, MK-4074): inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); fatty acid synthase inhibitors; acyl-coenzyme A: monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2) inhibitors; TGR5 receptor (also called GPBAR1, BG37, GPCR19, GPR131 and M-BAR) agonists; ileal bile acid transactivators transporter inhibitors; bile acid regulators, 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 against HSP47 (e.g., BMS-986263); pirfenidone-derived NSAIDs (e.g., hydronidone), A3AR agonists (e.g., namodenoson, FM101);TGFTX4 (e.g., nitazoxanide); 5-lipoxygenase inhibitors (e.g., tipelukast), bifunctional uric acid inhibitors (e.g., ACQT1127), adiponectin receptor agonists (e.g., ALY688), TNF receptor antagonists (e.g., atrocimab), autotaxin inhibitors (e.g., BLD-0409, TJC0265, TJC0316), CCL24 blocking monoclonal antibodies (e.g., CM101), IL-11 inhibitors (e.g., ENx108A), LPA1 receptor antagonists (e.g., EPGN696), dual JAK1 / 2 inhibitors (e.g., EX76545), GPR antagonists (e.g., GPR91 antagonists), integrin av01, av03 and av06 inhibitors (e.g., IDL2965), NLRP3 antagonists (e.g., IFM -514), inflammasome inhibitors (e.g., JT194, JT349), cell membrane permeability inhibitors (e.g., larazotide), CCR5 antagonists (e.g., leronlimab), TNF inhibitors (e.g., LIVNate), integrin avβ6 inhibitors (e.g., MORFβ6), NLRP inflammasome antagonists, siRNA (e.g., OLX701), dual TFGp / hedgehog inhibitors (e.g., Oxy200), GPR40 agonists / GPR84 antagonists (e.g., PBI-4547), neutrophil elastase inhibitors (e.g., PHP-303), integrin inhibitors (e.g., PLN-1474), TGFβ1 modulators (e.g., PRM-151), CCK receptor antagonists (e.g., proglumide), LOXL2 inhibitors (e.g., PXS-5338K; , PXS-5382A), IL-11 inhibitors, MPYS protein inhibitors (e.g., cGAS / STING antagonists), kinase inhibitors RNase, membrane protein mAbs, tumor necrosis factor inhibitors, NRF2 activators (e.g., SCO116), SSAO inhibitors (e.g., TERN201), TRAIL2 agonists (e.g., TLY012), IL-6 receptor antagonists (e.g., TZLS501), AOC3 inhibitors (e.g., UD-014), SSAO / VAP-1 inhibitors, TREM2; antioxidants (e.g., vitamin E); anti-inflammatory agents (e.g., norfloxacin, ciprofloxacin, ceftriaxone); coagulation modifiers (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, DD01, G49, PB-718); dual GLP-1 (e.g., CT868); GLP-1 / GRA / GIP triple agonists ( e.g., HM15211); GRP120 stimulators / inflammasome modulators / PPARγ dual agonists (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW003); selective thyroid hormone receptor-β agonists (e.g., resmetirom); apoptosis modulators (JNK-1 inhibitors (e.g., CC-90001), peroxidase inhibitors (e.g., AZM198), ASK-1 inhibitors ( Erythropoietin stimulators (erythropoietin receptor agonists (e.g., sibinetide)); glucose pathway regulators (SGLT-2 inhibitors (e.g., Fixiga, Farxiga (dapagliflozin)); dual SGLT-1 / 2 inhibitors (e.g., licogliflozin), glucose-6-P dehydrogenase inhibitors (e.g., fluasterone) LAPS glucagon combo (e.g., HM14320), SGLT-1 inhibitors (e.g., SGL5213));Immunomodulators (TLR4 inhibitors (e.g., GBK-233), immunomodulatory polyclonal antibodies (e.g., IMM-124E), TLR4 antagonists (e.g., JKB-122), CD3 monoclonal antibodies (e.g., foralumab), TLR4 antagonists (e.g., JKB133), TLR4 inhibitors (e.g., mocedipimod), macrophage inhibitors via CD206 targeting (e.g., MT2002), TLR2 / 4 antagonists (e.g., VB-201, VB-703), immunomodulatory polyclonal antibodies (e.g., IMM-124E)); incretin-based therapies (GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW003), GLP-1 / glucagon dual receptor agonists (e.g., HM12525A), pre-prandial insulin (e.g., ORMD0801 )); lipid regulators (AMPK activators / glutathione transferase (e.g., oltipraz), THR-β agonists (e.g., resmetirom, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN501), IBAT inhibitors (e.g., eloxibibat, CJ14199), omega-6-fatty acids (e.g., epereuton), FASN inhibitors (e.g., TVB2640, FT4101, FT8225), ANGPTL3 inhibitors (e.g., bupanorsen), PNPLA3 inhibitors (e.g., AZD2693), RAS domain kinase inhibitors (e.g., BioE1115), NTCP inhibitors (e.g., brevirtide), P2Y13 receptor agonists (e.g., CER-209), omega-3 fatty acids, HSD17β13 inhibitors;Metabolic regulators (FXR agonists (e.g., Ocaliva (obeticholic acid), IOT022), recombinant variants of FGF19 (e.g., 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 acid FXR agonists (e.g., cilofexor, EDP-305, EYP001, tropifexor, MET409, AGN-242256, A GN-242266, EDP297, HPG1860, MET642, RDX023, TERN101), ACC inhibitors (e.g., filsocostat, PF-05221304), ketohexokinase inhibitors (e.g., PF-06835919), AMPK activators (e.g., PXL770, MSTM101, 0304), bile acid regulators (e.g., Albiero), FGF21 analogs (e.g., BI089-100), MOTSc analogs (e.g., CB4211), cyclophilin inhibitors (e.g., CRV431), FGF19 (e.g., DEL30), mitochondrial uncouplers (e.g., GEN3026), FXR / GPCR dual agonists (e.g., INT-767), cysteamine derivatives (e.g., KB-GE-001), dual amylin and calcitonin receptor agonists (e.g., KBP-089), temporary FXR agonists (e.g., M1217), anti-β-Klotho (KLB)-FGFR1c receptor complex mAb (e.g., MK3655), GDF15 analogs (e.g., NGM395), cyclophilin inhibitors (e.g., NV556), LXR modulators (e.g., PX329, PX655, PX788), LXR inverse agonists (e.g., PX016), deuterated obeticholic acid (e.g., ZG5216); PPAR modulators (dual PPARα / γ agonists (e.g., elafibranor), PPAR pan agonists (e.g., lanifibranor), PPARα agonists (e.g., palmodia), PPARγ agonists (e.g., CHS131), MPC inhibitors (e.g., PXL065), PPARδ / γ agonists (e.g., T3D959));RAASmIM modulators (mineralocorticoid receptor antagonists (e.g., aparenone, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulators, CB1 receptor antagonists (e.g., CRB-4001, IM-102, nimakimab), TPH1 inhibitors (e.g., CU02), GPR120 agonists (e.g., KBR2001), combinations of cannabinoids and phyto-anti-inflammatory compounds (e.g., SCN002) ); PDE modulators (PDE4 inhibitors (e.g., ART648); CYP2E1 inhibitors (e.g., SNP-610); cell therapy (e.g., HepaStem); and metabolic modifiers including bromocriptine mesylate and rapid release formulations thereof, or, where chemically feasible, combinations with other drugs useful in the prevention or treatment of said conditions, including nitroprusside and diazoxide, including the free acid, free base and pharma- ceutically acceptable salt forms of said active agents;

[0231] The present invention includes pharma- ceutically acceptable salts of the compounds defined herein, including pharma- ceutically acceptable salts of all structural formulas, embodiments, and classes defined herein.

[0232] Dosage of Compounds of Formula (I) After completing the treatment cycle, if the patient is responding or stable, the treatment cycle can be repeated according to the judgment of a skilled clinician.When the treatment cycle is completed, the patient can continue the compound of the present invention at the same dose administered in the treatment protocol.This maintenance dose can be continued until the patient progresses or can no longer tolerate the dose (in which case the dose can be reduced and the patient can continue at the reduced dose).

[0233] Those skilled in the art will recognize that the actual dosage and protocol for administration used in the method of the present invention can be varied according to the judgment 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. The determination of the appropriate dosage for a particular situation is within the skill of the art. A skilled clinician can decide to change the dosage and administration protocol after considering factors such as the age, condition and size of the patient, as well as the severity of the condition being treated and the patient's response to treatment.

[0234] The dosing regimen utilizing the compounds of the present invention is selected according to various factors, such as the type, species, age, weight, sex, and 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. It is within the scope of a physician of ordinary skill to consider these factors in order to determine the therapeutically or prophylactically effective dosage required to prevent, combat, or arrest the progression of a condition. It is understood that a particular daily dose may be both a therapeutically effective amount for the treatment of, for example, a neoplastic condition, and a prophylactically effective amount for the prevention of, for example, a neoplastic condition, at the same time.

[0235] While individual needs vary, determining the optimal range of effective amounts of the compounds of the present invention is within the skill of the art.When administered to humans in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, a representative dosage of the compounds of the present invention can be about 0.05 mg / kg / day to about 50 mg / kg / day, such as at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, which can be, for example, about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dosage of the compound may be 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, The dose may be about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses.

[0236] Pharmaceutical Compositions The compounds of formula I and their pharma- ceutically acceptable salts can be administered to animals, preferably mammals, and especially humans, either as pharmaceuticals per se, mixed with each other, or in the form of pharmaceutical compositions. The term "subject" or "patient" includes animals, preferably mammals, and especially humans, who use the present active agents for the prevention or treatment of a medical condition.

[0237] The administration of the compound of formula I to a subject includes both self-administration and administration to a patient by another person. The subject may need or desire treatment of an existing disease or condition, or may need or desire prophylactic treatment to prevent or reduce the risk of developing said disease or condition. As used herein, a subject "in need" of treatment or prophylactic treatment of an existing condition includes both the determination of need by a medical professional and the patient's desire for such treatment.

[0238] Methods for the safe and effective administration of most of these drugs are known to those of skill in the art, and, in addition, their administration is explained in the standard literature.

[0239] If the patient is responding or stable after a treatment cycle is completed, the treatment cycle can be repeated according to the judgment of a skilled clinician. Once the treatment cycle is completed, the patient can continue treatment with the compounds of the invention at the same dose administered in the treatment protocol. This maintenance dose can be continued until the patient improves or can no longer tolerate the dose (in which case the dose can be reduced and the patient can continue on the reduced dose).

[0240] It will be apparent to those skilled in the art that the actual dosage and administration protocol used in the methods of the present invention can be varied according to the judgment of a skilled clinician. The actual dosage used can vary depending on the requirements of the patient and the severity of the condition being treated. The determination of the appropriate dosage for a particular situation is within the skill of the art. The decision to vary the dosage and administration protocol can be made by those skilled in the art taking into account factors such as the age, condition and size of the patient, as well as the severity of the condition being treated and the patient's response to treatment.

[0241] The amounts and frequency of administration of the compound of formula I and the additional agent will be regulated according to the judgment of the attending clinician (physician), taking into account such factors as the age, condition and size of the patient and the severity of the condition being treated.

[0242] The compounds of the present invention are also useful in the preparation of a medicament useful in the treatment of NASH and fibrosis.

[0243] The compounds are also useful in combination with therapeutic, chemotherapeutic and anti-cancer agents for the treatment of hepatocellular carcinoma. Combinations of the presently disclosed compounds with therapeutic, chemotherapeutic and anti-cancer agents are within the scope of the present invention. Examples of such agents are described in Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 9 th edition (May 16, 2011), Lippincott Williams & Wilkins Publishers. A person skilled in the art would be able to identify which combinations of agents would be useful based on the particular characteristics of the agents and the cancer involved. Such agents include estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, gamma-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.

[0244] The chemotherapeutic agent can be administered according to treatment protocols known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent can vary depending on the cancer being treated and the known effect of the chemotherapeutic agent on the disease. Furthermore, the treatment protocol (e.g., dosage and frequency of administration) can be varied according to the knowledge of a skilled clinician, taking into account the observed effect of the therapeutic agent administered to the patient and the observed response of the cancer to the therapeutic agent administered. The particular choice of chemotherapeutic agent will depend on the attending physician's diagnosis and the attending physician's judgment of the patient's condition and the appropriate treatment protocol.

[0245] Initial administration can be according to established protocols known in the art, and then, based on the effects observed, the dosage form and frequency of administration can be varied by the skilled clinician.

[0246] The determination of the sequence of administration of chemotherapeutic agents and the number of repetitions of administration during a treatment protocol is within the knowledge of a skilled physician after evaluation of the condition being treated and the condition of the patient.

[0247] Thus, according to experience and knowledge, practitioners may vary each protocol of chemotherapy administration as treatment progresses to meet the needs of individual patients, and all such variations are within the scope of the present invention.

[0248] The agents can be administered according to treatment protocols known in the art. It will be apparent to one of skill in the art that administration of anti-cancer agents can vary depending on the cancer being treated and the known effects of that anti-cancer agent on that disease.

[0249] Initial administration can be according to established protocols known in the art, and then, based on the effects observed, the dosage form and frequency of administration can be varied by the skilled clinician.

[0250] The particular choice of agent will depend on the attending physician's diagnosis and judgment of the patient's condition and the appropriate treatment protocol.

[0251] The determination of the order in which drugs are administered and the number of times administration is repeated during a treatment protocol is within the knowledge of a skilled physician after evaluation of the cancer being treated and the condition of the patient.

[0252] Thus, according to experience and knowledge, practitioners may vary each protocol of anticancer drug administration as treatment progresses and according to the needs of individual patients, and all such variations are within the scope of the present invention.

[0253] In determining whether the treatment is effective at the dose administered, the attending physician will consider the patient's general health as well as more definitive signs such as reduction in cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Tumor size can be measured by standard methods such as radiological tests, e.g., CAT or MRI scans. Serial measurement data can be used to determine whether tumor growth is slowing or regressing. Reduction in disease-related symptoms such as pain and improvements in overall condition can also help determine the effectiveness of treatment.

[0254] The compounds, compositions and methods provided herein are useful in the treatment of cancer.Cancers treatable by the compounds, compositions and methods disclosed herein include, but are not limited to, liver: hepatocellular carcinoma (liver cancer), cholangiocarcinoma, hepatoblastoma, hemangiosarcoma, hepatocellular adenoma, hemangioma, etc.

[0255] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL-1 inhibitors include atezolizumab, avelumab, and durvalumab.

[0256] The present invention further relates to a method of treating hepatocellular carcinoma in a human patient, comprising administering to the patient a compound of the present invention (i.e., a compound of Formula I) and a PD-1 antagonist. The compound of the present invention and the PD-1 antagonist can be administered simultaneously or sequentially.

[0257] In a specific embodiment, the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof. In another 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™, Merck & Co., Inc., Kenilworth, NJ, USA), nivolumab (OPDIVO™, Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO™, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab (TECENTRIQ™, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI™, AstraZeneca Pharmaceuticals, LP, Wilmington, DE), and avelumab (BAVENCIO™, Merck KGaA, Darmstadt, Germany).

[0258] In some embodiments, the PD-1 antagonist is pembrolizumab. In certain subembodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every 3 weeks. In other subembodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every 6 weeks.

[0259] In a further subembodiment, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every 3 weeks. In a particular subembodiment, the patient is a pediatric patient.

[0260] In some embodiments, the PD-1 antagonist is nivolumab. In certain subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other subembodiments, the method comprises administering 480 mg of nivolumab to the patient about every four weeks.

[0261] In some embodiments, the PD-1 antagonist is cemiplimab. In certain embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.

[0262] In some embodiments, the PD-1 antagonist is atezolizumab. In certain subembodiments, the method comprises administering to the patient 1200 mg of atezolizumab about every 3 weeks.

[0263] In some embodiments, the PD-1 antagonist is durvalumab. In certain subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every two weeks.

[0264] In some embodiments, the PD-1 antagonist is avelumab. In certain subembodiments, the method comprises administering to the patient 800 mg of avelumab about every two weeks.

[0265] The compounds of the invention, or pharma- ceutically acceptable salts thereof, may be used in the treatment of the following therapeutic agents: pembrolizumab (Keytruda®), abarelix; (Plenaxis Depot®); aldesleukin (Prokine®); aldesleukin (Proleukin®); alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); registered trademark); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calsterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine + Polifeprosan 20 Implant (Gliadel Wafer®); Celecoxib (Celebrex®); Cetuximab (Erbitux®); Chlorambucil (Leukeran®); Cisplatin (Platinol®); Cladribine (Leustatin®, 2-CdA®); Clofarabine (Clolar®); Cyclophosphamide (Cytoxan®, Neosar®); Cyclophosphamide (Cytoxan Injection®); Cyclophosphamide (Cytoxan Tablets®); Cytarabine (Cytosar-U®); Cytarabine liposomal (DepoCyt®);Dacarbazine (DTIC-Dome®); Dactinomycin, Actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); Daunorubicin liposomal (DanuoXome®); Daunorubicin, daunomycin (Daunorubicin®); Daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); Dexrazoxane (Zinecard®); Docetaxel (Taxotere®); Doxorubicin (AdriamycinPFS®); Doxorubicin (Adriamycin®, Rubex®); Doxorubicin (Adriamycin PFS Injection®); Doxorubicin Liposomal (Doxil®); Dromostanolone Propionate (Dromostanolone®); Dromostanolone Propionate (Masterone Injection®); Elliot's B Solution (Elliot's B Solution®); Epirubicin (Ellence®); Epoetin Alfa (Epogen®); Erlotinib (Tarceva®); Estramustine (Emcyt®); Etoposide Phosphate (Etopophos®); Etoposide, VP-16 (Vepesid®); Exemestane (Aromasin®); Filgrastim (Neupog en®);floxuridine (arterial administration) (FUDR®);fludarabine (Fludara®);fluorouracil, 5-FU (Adrucil®);fulvestrant (Faslodex®);gefitinib (Iressa®);gemcitarabine (Gemzar®);gemtuzumab ozogamicin (Mylotarg®);goserelin acetate (Zoladex implant®);goserelin acetate (Zoladex®);histrelin acetate (Histrelin implant®);hydroxyurea (Hydrea®);ibritumomab tiuxetan (Zevalin®);Idarubicin (Idamycin®); Ifosfamide (IFEX®); Imatinib mesylate (Gleevec®); Interferon alpha-2a (RoferonA®); Interferon alpha-2b (IntronA®); Irinotecan (Camptosar®); Lenalidomide (Revlimid®); Letrozole (Femara®); Leucovorin (Wellcovorin®, Leucovorin®); Leuprolide acetate (Eligard®); Levamisole (Ergamisol®); Lomustine, CCNU (CeeBU®); Mechlorethamine, nitrogen mustard nitrogen (Mustargen®); Megestrol acetate (Megace®); Melphalan, L-PAM (Alkeran®); Mercaptopurine, 6-MP (Purinethol®); Meth Mesna (Mesnex®); Mesna (Mesnextabs®); Methotrexate (Methotrexate®); Methoxsalen (Uvadex®); Mitomycin C (Mutamycin®); Mitotane (Lysodren®); Mitoxantrone (Novantrone®); Nandrolone phenpropionate (Durabolin-50®); Nelarabine (Arranon®) ); nofetumomab (Verluma®); oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); pegfilgrastin (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);Pipobroman (Vercyte®); Plicamycin, Mitalamycin (Mithracin®); Porfimer Sodium (Photofrin®); Procarbazine (Matulane®); Quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; Sargramostin (Leukine®); Sargramostin (Prokine®); Sorafenib (Nexavar®); Streptozocin (Zanosar®); Sunitinib Maleate (Sutent®); Talc (Sclerosol®) trademark); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); tositumomab (Bexxar®); tositumomab / I-131 tositumomab (Bexxar®); trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); uracil mustard (Uracil It may also be useful in treating cancer in combination with Mustard capsules®; valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®), or a pharma- ceutically acceptable salt thereof.

[0266] Method for producing the compounds of the present invention The following examples are provided so that the invention might be more fully understood. Unless otherwise specified, starting materials were commercially available. They should not be construed as limiting the invention in any way.

[0267] Some methods for preparing the compounds of the present invention are described in the following schemes and examples. Starting materials and intermediates are either purchased, made by known procedures, or otherwise shown. Some frequently applied routes to compounds of formula I are also illustrated by the following schemes. In some cases, the order of carrying out the steps of the reaction schemes may be changed to facilitate the reaction or to avoid undesired reaction products. In the case of stereoisomers, enantiomer A refers to the enantiomer that elutes faster / faster upon separation, and enantiomer B refers to the enantiomer that elutes slower / slower, and this nomenclature is maintained throughout the remainder of the synthetic procedure for a given enantiomer series, regardless of the possibility that subsequent intermediates and final compounds may have the same or reverse elution order.

[0268] Throughout the synthetic schemes and examples, abbreviations and acronyms may be used with the following meanings, unless otherwise noted.

[0269] ACN = acetonitrile BPO = Benzoyl Peroxide Brett phos Pd G3 CDI = 1,1'-carbonyldiimidazole Cu(OAc)2 = Copper acetate DMF = Dimethylformamide DMS = Dimethyl Sulfide DCM = dichloromethane DIPEA = N,N-diisopropylethylamine DPPA = diphenylphosphoryl azide dppf = 1,1'-bis(diphenylphosphino)ferrocene Et = ethyl Ethyl acetate = ethyl acetate EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride DCE = 1,2-dichloroethane RP HPLC = Reversed Phase High Pressure Liquid Chromatography h or hrs = hours HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide-hexafluorophosphate Hex = Hexane HOBT = Hydroxybenzotriazole IPA = Isopropanol Me = methyl mCPBA = metachloroperbenzoic acid MgSO4 = Magnesium sulfate MP-cyanoborohydride = macroporous polymer supported cyanoborohydride rt or RT = room temperature nBu4LI = Tetra-n-butylammonium iodide NBS = N-bromosuccinimide NCS = N-chlorosuccinimide NIS=N-iodosuccinimide PdCl2(dppf) = Bis(diphenylphosphino)ferrocene]dichloropalladium(II) SFC = Supercritical Fluid Chromatography SM=Departure tBuBrettPhos = 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl THF = tetrahydrofuran TCMS = methyltrichlorosilane TFA = trifluoroacetic acid Xphos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos Pd G2 = chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0270] Also, aq. is aqueous; TLC is thin layer chromatography; Ts is tosyl; UV is ultraviolet; W is watts; wt.% is weight percent; xg is times gravity; [D] is specific rotation of polarized light at 589 nm; °C is Celsius; and %w / v is the weight percent of the former agent relative to the volume of the latter agent.

[0271] LCMS conditions: Column: SUPELCO Ascentis Express C18 3×100 mm, 2.7 μm. Solvent system: A-0.05% TFA / water and B-0.05% TFA / acetonitrile.

[0272] Gradient conditions: 10% to 99% B in 3.5 min.

[0273] General synthesis scheme While the present invention has been described in conjunction with the above specific examples, many alternatives, modifications and variations thereof will be apparent to those skilled in the art. In some cases, the order of carrying out the steps of the reaction schemes can be varied to facilitate the reaction or to avoid unwanted reaction products. All such alternatives, modifications and variations are intended to be within the spirit and scope of the present invention.

[0274] [General diagram 1] [ka]

[0275] The compound of formula I is SN Ar Via R 1 -NH2 from 1-1 followed by reduction of the nitro group to an amino group to give 1-3. Cyclization with carbonyldiimidazole gave 1-4 followed by SN2 with R2-I to give 1-5. Saponification of 1-5 gave the corresponding carboxylic acid (1-5) followed by amide coupling with the appropriate amine according to the method described by the general scheme to give compounds of formula (I). The order of steps for some examples can be altered to facilitate synthesis.

[0276] [General diagram 2] [ka]

[0277] The compound of formula I is SN Ar Via R 2 The cyclization product 2-4 was prepared from 2-1 by reaction with -NH2, followed by reduction of the nitro group to an amino group to give 2-3. The cyclization product 2-4 was formed by reaction with carbodiimidazole (CDI), and the corresponding R 1 -Bromide, R 1 -boronic acid, or R 1 -CC coupling with a boronic ester species gave 2-5. Hydrolysis of the ester in 2-5 to the carboxylic acid gave 2-6, which was then coupled to the required amine to form compounds of formula (I) following the methods described by the general scheme. The order of steps for some examples can be altered for ease of synthesis.

[0278] Intermediates Intermediate-1: Methyl 3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate [ka]

[0279] Step A: Methyl 3-(isopropylamino)-4-nitrobenzoate To a stirred solution of methyl 3-fluoro-4-nitrobenzoate (4 g, 20.09 mmol) in DMSO (50 mL) was added propan-2-amine (1.140 g, 19.28 mmol) and DIPEA (7.02 mL, 40.2 mmol). The reaction mixture was stirred at 100° C. for 12 h and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4 (s), and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography eluting with 5% EtOAc / PE to give the title compound. LC / MS=239.2 [M+1].

[0280] Step B: 4-Amino-3-(isopropylamino)benzoate To a stirred solution of methyl 3-(isopropylamino)-4-nitrobenzoate (4.4 g, 18.47 mmol) in MeOH (60 mL) was added Pd / C (0.983 g, 9.23 mmol). The reaction mixture was stirred at 25° C. under 1 atm of hydrogen for 12 h, filtered, and washed with DCM / MeOH (V / V=10:1). The filtrate was concentrated under reduced pressure to give the title compound. LC / MS=209.3[M+1].

[0281] Step C: Methyl 3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of methyl 4-amino-3-(isopropylamino)benzoate (3.9 g, 18.73 mmol) in THF (50 mL) was added Et3N (7.83 mL, 56.2 mmol) and CDI (21.26 g, 131 mmol). The reaction mixture was stirred at 25° C. under nitrogen atmosphere for 12 h and diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were concentrated under reduced pressure. The residue was diluted with water. The mixture was stirred at room temperature for 30 min, filtered, and the filter cake was concentrated under reduced pressure to give the title compound. 1H NMR (500 MHz, chloroform-d) δ 10.09 (s, 1H), 7.86 - 7.79 (m, 2H), 7.18 - 7.08 (m, 1H), 4.76 (septad, J = 7.0 Hz, 1H), 3.93 (s, 3H), 1.59 (d, J = 7.0 Hz, 6H). LC / MS = 235.2 [M+1]. EXAMPLES

[0282] The following experimental procedures detail the preparation of specific examples 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.

[0283] Example 1: (R)-1,3-bis(4-fluorophenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0284] Step A: Methyl 1,3-bis(4-fluorophenyl)-2-oxo-2.3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirring solution of methyl 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (470 mg, 2.446 mmol) and (4-fluorophenyl)boronic acid (5133 mg, 36.7 mmol) in DMF (20 mL) was added Cu(OAc)2 (533 mg, 2.93 mmol) and pyridine (2 mL, 2.446 mmol) at 15° C. After the addition was complete, the reaction mixture was stirred at 15° C. for 16 h, then poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=381[M+1].

[0285] Step B: 1,3-bis(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid Lithium hydroxide hydrate (10 mg, 0.238 mmol) was added to a stirred solution of methyl 1,3-bis(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (60 mg, 0.158 mmol) in MeOH (1 mL), THF (3 mL) and water (1 mL) at 15° C. After the addition was complete, the reaction mixture was stirred at 50° C. for 2 h and then concentrated under reduced pressure. The residue was dissolved in H2O and 1N HCl was added to adjust the solution to pH=4. The mixture was extracted with DCM and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LC / MS=367[M+1].

[0286] Step C: (A) -1,3-bis(4-fluorophenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 1,3-bis(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (50 mg, 0.136 mmol) and (R)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide (25 mg, 0.168 mmol) in DMF (1.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (53 mg, 0.410 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (78 mg, 0.205 mmol) at 15° C. After the addition was complete, the reaction mixture was stirred at 15° C. for 16 h. The crude material was directly purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% TFA modifier) ​​to give the title compound. LC / MS = 498 [M+1]. 1 H NMR (400 MHz, DMSO-d6, ppm) δ 8.31 (s, 1H), 7.68 (dt, J = 5.0, 8.5 Hz, 5H), 7.51 - 7.41 (m, 5H), 7.11 (d, J = 8.0 Hz, 1H), 3.90 (m, 1H), 3.27 (br d, J = 9.0 Hz, 2H), 3.16 (m, 1H), 2.80 - 2.60 (m, 1H), 2.17 (m, 1H), 1.53 (s, 3H). Human DGAT2 IC 50 = 573 nM Example 2: 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0287] Step A: Methyl 3-((4-fluorophenyl)amino)-4-nitrobenzoate To a stirred solution of methyl 3-fluoro-4-nitrobenzoate (4.8 g, 24.10 mmol) in DMSO (150 mL) was added 4-fluoroaniline (2.68 g, 24.10 mmol) and DIEA (8.42 mL, 48.2 mmol) at 15° C. After the addition was complete, the reaction mixture was stirred at 100° C. for 16 h. The mixture was poured into H2O and filtered. The filter cake was dissolved in ethyl acetate and concentrated under reduced pressure to give the title compound. LC / MS=291[M+1].

[0288] Step B: Methyl 4-amino-3-((4-fluorophenyl)amino)benzoate To a solution of Pd-C (600 mg, 5.64 mmol) in MeOH (150 mL) was added methyl 3-((4-fluorophenyl)amino)-4-nitrobenzoate (5.4 g, 18.60 mmol) at 15° C. The mixture was purged with H2, stirred under 1 atm H2 at 15° C. for 16 h, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=261[M+1].

[0289] Step C: Methyl 3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of methyl 4-amino-3-((4-fluorophenyl)amino)benzoate (2 g, 7.68 mmol) in THF (80 mL) was added CDI (4.98 g, 30.7 mmol) at 15° C. After the addition was complete, the reaction mixture was stirred at 15° C. for 16 h, poured into H2O, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound (1.37 g). LC / MS=287[M+1].

[0290] Step D: Methyl 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred solution of methyl 3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (400 mg, 1.397 mmol) and 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4 g, 14.81 mmol) in DMF (20 mL) was added Cu(OAc)2 (305 mg, 1.677 mmol) and pyridine (3 mL, 37.2 mmol) at 15° C. After the addition was complete, the reaction mixture was stirred at 75° C. for 48 h, then poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound (200 mg). LC / MS=429[M+1].

[0291] Step E: 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid Lithium hydroxide hydrate (78 mg, 1.868 mmol) was added to a stirred solution of methyl 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (200 mg, 0.467 mmol) in THF (6 mL) and water (2 mL) at 15° C. The reaction mixture was stirred at 15° C. for 16 h, then concentrated under reduced pressure and dissolved in H2O. HCl (1N aq.) was added to the mixture until pH=4. The mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LC / MS=415[M+1].

[0292] Step F: 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (35 mg, 0.084 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (64 mg, 0.168 mmol) in DMF (1.5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.070 mL, 0.422 mmol) at 15° C. After the mixture was stirred for 15 minutes, 3-amino-3-methylthietane 1,1-dioxide (14 mg, 0.104 mmol) was added to the mixture. After the addition was complete, the reaction mixture was stirred at 15° C. for 2 hours. The crude mixture was purified by mass-triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) ​​to afford the title compound.

[0293] LC / MS = 532 [M+1]. 1H NMR (400 MHz, DMSO-d6, ppm) δ 7.60-7.53 (m, 4H), 7.51 - 7.45 (m, 2H), 7.40 (t, J = 2.0 Hz, 1H), 7.30 - 7.26 (m, 2H), 7.26 - 7.21 (m, 2H), 7.18 - 7.14 (m, 1H), 6.76 - 6.49 (m, 1H), 4.62 - 4.50 (m, 2H), 4.21 - 4.09 (m, 2H), 1.25 (br d, J = 3.5 Hz, 3H). Human DGAT2 IC 50 = 1.8 nM The following compounds were synthesized by using a procedure similar to that described in Example 2 using the appropriate amine and (hetero)aryl halide reagents and were characterized by LC / MS. [Table 1]

[0294] Example 4: 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxamide [ka]

[0295] Step A: Methyl 6-amino-5-((4-fluorophenyl)amino)nicotinate To a stirred solution of methyl 6-amino-5-bromonicotinate (300 mg, 1.298 mmol) in THF (8 mL) was added 4-fluoroaniline (1443 mg, 12.98 mmol), Cs2CO3 (1269 mg, 3.90 mmol) and Brettphos Pd G3 (118 mg, 0.130 mmol) in a glove box at 25° C. The reaction mixture was stirred at 70° C. for 16 h, then poured into H2O and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=262[M+1].

[0296] Step B: Methyl 1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate To a stirring solution of methyl 6-amino-5-((4-fluorophenyl)amino)nicotinate (822 mg, 3.15 mmol) in THF (30 mL) was added CDI (2041 mg, 12.59 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 16 h, then poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=288[M+1].

[0297] Step C: Methyl 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate To a stirred solution of methyl 1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate (720 mg, 2.507 mmol) and 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5416 mg, 20.05 mmol) in DMF (15 mL) was added Cu(OAc)2 (683 mg, 3.76 mmol) and pyridine (4.04 mL, 50.1 mmol) at 25° C. The reaction mixture was stirred at 80° C. for 16 h (open to air with a drying tube), poured into H2O, and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / Hexanes) to give the title compound. LC / MS=430 [M+1].

[0298] Step D: 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylic acid To a stirred solution of methyl 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate (100 mg, 0.233 mmol) in THF (1 mL) was added lithium hydroxide hydrate (30 mg, 0.715 mmol) at 25° C. The reaction mixture was stirred at 25° C. for 0.5 h, then concentrated under reduced pressure and dissolved in H2O. HCl (1N aq.) was added to the mixture until pH=4. The mixture was then extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LC / MS=416[M+1].

[0299] Step E: 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxamide To a stirred solution of 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (95 mg, 0.229 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (130 mg, 0.343 mmol) in DMF (2 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.114 mL, 0.686 mmol) at 25° C. After the addition was complete, the reaction mixture was stirred at 25° C. for 5 min, and then 3-amino-3-methylthietane 1,1-dioxide (38 mg, 0.281 mmol) was added. The reaction mixture was stirred at 25° C. for 1.5 h. The crude mixture was directly purified by mass-triggered reverse phase HPLC (ACN / water+0.1% TFA modifier) ​​to give the title compound as a TFA salt. LC / MS = 533 [M+1]. 1 H NMR (500MHz, methanol-d4, ppm) δ = 8.64 (d, J=1.8 Hz, 1H), 7.86 (d, J=1.8 Hz, 1H), 7.76 - 7.61 (m, 5H), 7.45 - 7.37 (m, 2H), 7.34 - 7.28 (m, 1H), 7.12 - 6.78 (m, 1H), 4.58 (d, J=14.6 Hz, 2H), 4.27 - 4.19 (m, 2H), 1.83 (s, 3H). Human DGAT2 IC 50 = 8.5 nM Example 5: 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0300] Step A: Methyl 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate A 20 mL vial was charged with 4-bromo-2-(difluoromethoxy)-5-fluoropyridine (279 mg, 1.15 mmol), methyl 3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (150 mg, 0.640 mmol), copper(I) iodide (122 mg, 0.640 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (182 mg, 1.28 mmol), potassium phosphate tripotassium (408 mg, 1.92 mmol), and 1,4-dioxane (6.4 mL) at 20° C. The vial was evacuated and refilled with N2 three times and the mixture was stirred at 100° C. for 7 h. The volatiles were then evaporated and the residue was purified by flash silica gel chromatography (0-80% EtOAc / Hexanes) to give the title compound. LC / MS=396[M+1].

[0301] Step B: 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a stirred mixture of methyl 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (39 mg, 0.099 mmol) in THF (0.4 mL) and MeOH (0.1 mL) at 20° C. was added a solution of lithium hydroxide hydrate (33.1 mg, 0.789 mmol) in water (0.4 mL) and the mixture was stirred at 50° C. for 1 h. Then, HCl (1N aqueous solution) (0.79 mL, 0.79 mmol) was added and the mixture was stirred vigorously. The volatiles were evaporated to give the title compound. LC / MS=382[M+1].

[0302] Step C: 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred mixture of 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (19 mg, 0.050 mmol) and HATU (37.9 mg, 0.100 mmol) in DMF (1.0 mL) was added DIPEA (44 μL, 0.25 mmol) followed by 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (12 mg, 0.075 mmol) at 20° C. The mixture was stirred at 20° C. for 2 h and then directly purified by reverse phase HPLC (55% to 95% MeCN / water) to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.89 (s, 1H), 7.80 (s, 1H), 7.73 (t, J = 72.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 4.8 Hz, 1H), 7.14 (dd, J = 8.3, 2.4 Hz, 1H), 4.71 (septad, J = 6.6 Hz, 1H), 3.21 - 3.11 (m, 2H), 3.10 - 3.03 (m, 2H), 2.85 - 2.76 (m, 2H), 2.08 - 1.96 (m, 2H), 1.55 (d, J = 6.9 Hz, 6H), 1.44 (s, 3H). LC / MS = 527 [M+1]. Human DGAT2 IC 50 = 34 nM. The following compounds were synthesized by using the appropriate aryl bromide and amine reagents using procedures similar to those described in Example 5. These compounds were characterized by LC / MS. [Table 2] TIFF0007604636000059.tif220167TIFF0007604636000060.tif220166TIFF00076046360 00061.tif221168TIFF0007604636000062.tif220165TIFF0007604636000063.tif179168

[0303] Example 25: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0304] Step A: Methyl 4-((3-(difluoromethoxy)phenyl)amino)-3-nitrobenzoate To a stirring solution of methyl 4-fluoro-3-nitrobenzoate (7.0 g, 35.2 mmol) in DMSO (176 mL) at room temperature was added 3-(difluoromethoxy)aniline (4.34 mL, 35.2 mmol) and DIPEA (12.28 mL, 70.3 mmol). The reaction was heated to 100° C. and stirred overnight. The reaction was cooled to room temperature. Water was added and the resulting solid was collected by vacuum filtration and dissolved in ethyl acetate. The aqueous fraction was extracted three times with ethyl acetate. The combined organic fractions were washed with brine, dried over Na2SO4 (s), filtered, and concentrated under reduced pressure to give the title compound. LC / MS=339[M+1].

[0305] Step B: Methyl 3-amino-4-((3-(difluoromethoxy)phenyl)amino)benzoate To a stirred mixture of methyl 4-((3-(difluoromethoxy)phenyl)amino)-3-nitrobenzoate (10.8 g, 31.9 mmol) in methanol (106 mL), THF (53.2 mL), and saturated aqueous ammonium chloride (53.2 mL) at room temperature was added zinc (10.44 g, 160 mmol). The reaction was stirred at room temperature for 2 h and filtered through Celite. The Celite was washed with methanol. The mixture was concentrated, EtOAc was added, and the aqueous layer was separated. The organic layer was dried over Na2SO4 (s), filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=309[M+1].

[0306] Step C: 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate Methyl 3-amino-4-((3-(difluoromethoxy)phenyl)amino)benzoate (5.90 g, 19.14 mmol) was dissolved in THF (191 mL) at room temperature.

[0307] CDI (15.52 g, 96 mmol) was added and the reaction was stirred at room temperature for 16 h. Water and EtOAc were added, the layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 (s), filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=335[M+1].

[0308] Step D: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate Methyl 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (0.93 g, 2.78 mmol) was dissolved in DMF (27.8 mL) at room temperature and cesium carbonate (2.72 g, 8.35 mmol) was added. 2-Iodopropane (0.833 mL, 8.35 mmol) was added and the mixture was stirred under nitrogen atmosphere and heated to 80° C. and stirred at that temperature overnight. Water and ethyl acetate were added, the layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=377[M+1].

[0309] Step E: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of methyl 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (937 mg, 2.490 mmol) in THF (4.15 mL) and methanol (4.15 mL) was added an aqueous solution of lithium hydroxide (298 mg, 12.45 mmol) (water 4.15 mL) at room temperature. The reaction was stirred at room temperature and the reaction mixture was acidified to pH=1 with 1N aqueous HCl. EtOAc was added and the layers were separated. The aqueous layer was extracted 3 times with EtOAc and the combined organic layers were dried over MgSO4 (s), filtered, and concentrated under reduced pressure to give the title compound. LC / MS=363[M+1].

[0310] Step F: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide DIPEA (0.052 mL, 0.298 mmol) was added to a stirred solution of -(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (36 mg, 0.099 mmol), HATU (41.6 mg, 0.109 mmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (17.84 mg, 0.109 mmol) in DMF (0.994 mL) at room temperature. The reaction was stirred at room temperature for 16 hours. The next morning, the reaction was complete as determined by LCMS and the DMF was evaporated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes, then 0% to 30% acetone / DCM) to give the title compound.

[0311] 1H NMR (500 MHz, methanol-d4) δ 7.82 (d, J = 1.4 Hz, 1H), 7.66 - 7.60 (m, 2H), 7.42 (dd, J = 8.0, 1.1 Hz, 1H), 7.36 (t, J = 2.0 Hz, 1H), 7.28 (dd, J = 8.2, 2.0 Hz, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.94 (t, J = 73.6 Hz, 1H), 4.84 - 4.75 (m, 1H), 3.29 - 3.21 (m, 2H), 3.02 (d, J = 13.7 Hz, 2H), 2.91 (d, J = 14.7 Hz, 2H), 2.25 - 2.14 (m, 2H), 1.64 (d, J = 7.0 Hz, 6H), 1.55 (s, 3H). LC / MS = 508 [M+1]. Human DGAT2 IC 50 = 23nM. The following compounds were synthesized using procedures similar to those described in Example 25 with the appropriate reagents and were characterized by LC / MS. [Table 3] TIFF0007604636000066.tif254166TIFF0007604636000067.tif254162TIFF0007604636000068.t if254161TIFF0007604636000069.tif254165TIFF0007604636000070.tif254164TIFF00076046360 00071.tif254164TIFF0007604636000072.tif240169TIFF0007604636000073.tif241169TIFF000 7604636000074.tif255169TIFF0007604636000075.tif253170TIFF0007604636000076.tif219168

[0312] Example 64: 1-(3-(difluoromethoxy)phenyl)-3-(2-hydroxy-2-methylpropyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0313] Step A: 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of methyl 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (211 mg, 0.631 mmol) in THF (2 mL), MeOH (2 mL) and water (2 mL) was added lithium hydroxide hydrate (79 mg, 1.894 mmol) at 25 °C. After the addition was complete, the reaction mixture was stirred at 50° C. for 5 h and concentrated under reduced pressure. The residue was dissolved in H2O and HCl (1N aq.) was added to the mixture until pH=4. The mixture was then extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LC / MS=321[M+1].

[0314] Step B: 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred solution of 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (179 mg, 0.559 mmol) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (319 mg, 0.838 mmol) in DMF (5 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.278 mL, 1.677 mmol) at 25° C. After the addition was complete, the reaction mixture was stirred at 25° C. for 5 min and 3-amino-3-methylthietane 1,1-dioxide (83 mg, 0.615 mmol) was added. After the addition was complete, the reaction mixture was stirred at 50° C. for 2 h. The crude mixture was directly purified by mass-triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) ​​to give the title compound. LC / MS=438 [M+1].

[0315] Step C: 1-(3-(difluoromethoxy)phenyl)-3-(2-hydroxy-2-methylpropyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide A flask was charged with 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (39 mg, 0.089 mmol), 1-chloro-2-methylpropan-2-ol (48.4 mg, 0.446 mmol), and cesium carbonate (87 mg, 0.267 mmol) in DMF (2 mL). The reaction mixture was sparged with a stream of N2 for 2 min and stirred at 90 °C under N2 atmosphere for 16 h. The crude mixture was directly purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% TFA modifier) ​​to give the title compound. LC / MS = 510 [M+1]. 1H NMR (500MHz, methanol-d4, ppm) δ 7.90 (s, 1H), 7.71 - 7.62 (m, 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.41 (s, 1H), 7.32 (br d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.13 - 6.79 (m, 1H), 4.61 (m, 2H), 4.27 (m, 2H), 4.01 (s, 2H), 1.87 (s, 3H), 1.37 (s, 6H). Human DGAT2 IC 50 = 35.6 nM Example 65: 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0316] Step A: Methyl 4-bromo-3-((3-hydroxy-3-methylbutan-2-yl)amino)benzoate To a mixture of methyl 3-amino-4-bromobenzoate (1 g, 4.35 mmol) in DMF (15 mL) was added 3-hydroxy-3-methylbutan-2-one (0.666 g, 6.52 mmol) at 20° C. The resulting mixture was degassed and backfilled with N2 (3 times), then TMCS (1.161 mL, 13.04 mmol) and sodium cyanoborohydride (0.410 g, 6.52 mmol) were added under N2 at 0° C. The resulting mixture was stirred at 20° C. for 1 h under N2, then poured into H2O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=316[M+1].

[0317] Step B: Methyl 4-amino-3-((3-hydroxy-3-methylbutan-2-yl)amino)benzoate In a glove box at 20° C., an 8 mL tube was charged with methyl 4-bromo-3-((3-hydroxy-3-methylbutan-2-yl)amino)benzoate (300 mg, 0.949 mmol), aqueous ammonia (66.5 mg, 1.898 mmol), K3PO4 (242 mg, 1.139 mmol), BPPO (37.2 mg, 0.095 mmol), copper(I) iodide (18.07 mg, 0.095 mmol) and DMSO (4 mL). The reaction was then sealed and stirred at 90° C. for 24 h. The mixture was poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=253[M+1].

[0318] Step C: Methyl 3-(3-hydroxy-3-methylbutan-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate A mixture of methyl 4-amino-3-((3-hydroxy-3-methylbutan-2-yl)amino)benzoate (110 mg, 0.436 mmol) and di(1H-imidazol-1-yl)methanone (353 mg, 2.180 mmol) in THF (3 mL) was stirred at 30° C. for 12 h. The mixture was poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=279[M+1].

[0319] Step D: Methyl 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a mixture of 2-(5-(difluoromethoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (279 mg, 0.970 mmol) in DMF (5 mL) was added pyridine (0.521 mL, 6.47 mmol), methyl 3-(3-hydroxy-3-methylbutan-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (90 mg, 0.323 mmol), and copper(II) acetate (70.5 mg, 0.388 mmol). The mixture was stirred at 80° C. open to air under a drying tube for 16 h. The mixture was poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica (0-100% EtOAc / Hexanes) to give the title compound. LC / MS=439 [M+1].

[0320] Step E: 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a solution of methyl 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (90 mg, 0.205 mmol) in MeOH (3 mL) / water (1.00 mL) was added lithium hydroxide hydrate (17.23 mg, 0.411 mmol). The reaction mixture was stirred at 40° C. for 3 h and concentrated under reduced pressure. The concentrated mixture was dissolved in H2O. HCl (1N aq.) was added to the mixture until pH=4. The mixture was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LC / MS=425[M+1].

[0321] Step F: 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide An 8 mL tube was charged with 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (60 mg, 0.141 mmol), DIEA (0.074 mL, 0.424 mmol), HATU (81 mg, 0.212 mmol), 3-amino-3-methylthietane 1,1-dioxide (28.7 mg, 0.212 mmol) and DMF (1 mL) at 25° C. The mixture was stirred at 25° C. for 0.5 h, poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica (0% to 100% EtOAc / Hexanes) to provide the title compound. LC / MS=542[M+1].

[0322] The mixture of two stereoisomers was purified by chiral SFC (IC-H column, 40% / 60% ethanol / CO2). EX-65a (eluted first): LC / MS = 542 [M+1]. 1H NMR (500 MHz, methanol-d4) δ 7.99 (br s, 1H), 7.53 (br d, J = 7.48 Hz, 1H), 7.21 - 7.45 (m, 3H), 6.58 - 7.03 (m, 2H), 4.43 - 4.56 (m, 3H), 4.13 (br d, J = 14.95 Hz, 2H), 1.73 (s, 3H), 1.58 (br d, J = 7.02 Hz, 3H), 1.25 - 1.35 (m, 3H), 1.00 - 1.21 (m, 3H). Human DGAT2 IC 50 = 53 nM. Human DGAT2 IC50 = 53 nM. E X-65b (later eluted): LC / MS = 542 [M+1]. 1H NMR (500 MHz, methanol-d4) δ 7.96 (br s, 1H), 7.53 (br d, J = 7.48 Hz, 1H), 7.23 - 7.45 (m, 3H), 6.59 - 6.98 (m, 2H), 4.46 - 4.54 (m, 3H), 4.13 (br d, J = 14.80 Hz, 2H), 1.67 - 1.82 (m, 3H), 1.58 (br d, J = 7.17 Hz, 3H), 1.29 (s, 3H), 1.13 (br s, 3H). Human DGAT2 IC 50 = 0.7 nM. The following compounds were synthesized by using a procedure similar to that described in Example 65 with the appropriate amine reagent and were characterized by LC / MS. [Table 4] TIFF0007604636000080.tif221164TIFF0007604636000081.tif221163TIFF00076046360 00082.tif219163TIFF0007604636000083.tif221162TIFF0007604636000084.tif226162 TIFF0007604636000085.tif221163TIFF0007604636000086.tif222164TIFF00076046360 00087.tif220164TIFF0007604636000088.tif221164TIFF0007604636000089.tif221163

[0323] Example 79: 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0324] Step A: Methyl 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred mixture of 2-(5-(difluoromethoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.15 g, 7.47 mmol), methyl 3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (0.700 g, 2.99 mmol), and diacetoxycopper (1.09 g, 5.98 mmol) in DCE (14.9 mL) was added triethylamine (1.67 mL, 12.0 mmol) at 20° C., and the mixture was stirred at 95° C. for 32 h. The volatiles were then evaporated and the residue was purified by flash silica gel chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=395[M+1].

[0325] Step B: 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a stirred mixture of methyl 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (990 mg, 2.51 mmol) in THF (5.71 mL) and MeOH (1.14 mL) at 20° C. was added a solution of lithium hydroxide hydrate (316 mg, 7.53 mmol) in water (5.71 mL water) and the mixture was stirred vigorously at 50° C. for 5 h. The mixture was then neutralized to pH 7 with HCl (aq, 12N) (628 μL, 7.53 mmol), the volatiles were evaporated, and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 (s), and the volatiles were evaporated to give the title compound. LC / MS=381[M+1].

[0326] Step C: 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred mixture of 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (690 mg, 1.81 mmol) and HATU (1.00 g, 2.63 mmol) in DMF (5.00 mL) and ethyl acetate (3.00 mL) at 20° C. was added 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (600 mg, 3.00 mmol) followed by DIPEA (0.951 mL, 5.44 mmol). The mixture was stirred at 20° C. for 1 h and then partitioned between EtOAc and LiOH (aq, 10 wt%). The organic layer was separated, washed with LiOH (aq, 10 wt%), brine, dried over Na2SO4 (s), and the volatiles were evaporated. The residue was purified by flash silica gel chromatography (0 to 100% EtOAc / hexanes) to provide the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 7.85 (s, 1H), 7.79 (s, 1H), 7.66 (d, J = 8.3 Hz, 1H), 7.62 (t, J = 9.4 Hz, 1H), 7.57 (dd, J = 6.0, 3.0 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.30 (t, J = 73.6 Hz, 1H), 6.93 (d, J = 8.3 Hz, 1H), 4.71 (septad, J = 6.9 Hz, 1H), 3.17 (t, J = 13.2 Hz, 2H), 3.06 (d, J = 13.6 Hz, 2H), 2.81 (d, J = 14.5 Hz, 2H), 2.02 (t, J = 12.9 Hz, 2H), 1.55 (d, J = 6.9 Hz, 6H), 1.44 (s, 3H). LC / MS = 526 [M+1]. Human DGAT2 IC 50 = 2.1 nM. The following compounds were synthesized by using a procedure similar to that described in Example 79 with the appropriate amine and (hetero)aryl halide reagents and were characterized by LC / MS. [Table 5] TIFF0007604636000092.tif113166

[0327] Example 85: 3-(1-amino-1-oxopropan-2-yl)-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0328] Step A: 2-(3-(3-(difluoromethoxy)phenyl)-6-((4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)carbamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propanoic acid Sodium hydride (20.62 mg, 0.516 mmol) was added to a mixture of 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (160 mg, 0.344 mmol) in DMF (2 mL) under N2 at 0° C. The mixture was stirred at 0° C. for 0.5 h. Then, ethyl 2-bromopropanoate (93 mg, 0.516 mmol) was added to the mixture. The mixture was stirred at 15° C. for 12 h under N2. LCMS showed that the desired product was formed.

[0329] The mixture was poured into NH4Cl and the mixture was extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LC / MS=538[M+1].

[0330] Step B: 3-(1-amino-1-oxopropan-2-yl)-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a solution of 2-(3-(3-(difluoromethoxy)phenyl)-6-((4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)carbamoyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propanoic acid (200 mg, 0.372 mmol), DIEA (0.195 mL, 1.116 mmol), HATU (212 mg, 0.558 mmol) in DMF (3 mL) was added NH4Cl (25 mg, 0.467 mmol). The mixture was stirred at 15 °C for 1 h. LCMS showed that the desired product was formed. The mixture was poured into H2O and the mixture was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=537 [M+1]. The mixture of two stereoisomers 3-(1-amino-1-oxopropan-2-yl)-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (100 mg) was purified by chiral SFC (IC-H column, 40% / 60% ethanol / CCE). Isomer EX-85a (eluted first): LC / MS = 537 [M+1]. 1 H NMR (400 MHz, methanol-d4) δ 7.70 (d, J=1.43 Hz, 1H), 7.61-7.67 (m, 2H), 7.44-7.48 (m, 1H), 7.41 (t, J=2.03 Hz, 1H), 7.29 (dd, J=2.09, 8.29 Hz, 1H), 6.75-7.18 (m, 2H), 5.28 (q, J=7.27 Hz, 1H), 3.19-3.28 (m, 2H), 2.99-3.02 (m, 2H), 2.84-2.93 (m, 2H), 2.14-2.23 (m, 2H), 1.79 (d, J=7.39 Hz, 3H), 1.53 (s, 3H). Human DGAT2 IC50 = 551 nM. Isomer EX-85b (later eluted): LC / MS = 537 [M+1].1 H NMR (400 MHz, methanol-d4) δ 7.70 (d, J=1.43 Hz, 1H), 7.61-7.67 (m, 2H), 7.46 (d, J=7.99 Hz, 1H), 7.41 (t, J=1.97 Hz, 1H), 7.29 (dd, J=2.09, 8.29 Hz, 1H), 6.75-7.18 (m, 2H), 5.28 (q, J=7.39 Hz, 1H), 3.19-3.28 (m, 2H), 2.99-3.02 (m, 2H), 2.84-2.94 (m, 2H), 2.15-2.24 (m, 2H), 1.79 (d, J=7.39 Hz, 3H), 1.53 (s, 3H). Human DGAT2 IC50 = 1752 nM. Example 86: 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(phenylsulfonyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0331] Step A: Methyl 1-(3-(difluoromethoxy)phenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a solution of methyl 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (500 mg, 1.496 mmol) in THF (10 mL) was added NaH (90 mg, 2.244 mmol) at 0 °C under N2. The mixture was stirred at 0 °C for 0.5 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (374 mg, 2.244 mmol) was added dropwise to the mixture. The mixture was stirred at 15 °C under N2 for 15 h. LCMS showed that the desired product was formed. The mixture was poured into NH4Cl and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=465[M+1].

[0332] Step B: 1-(3-(difluoromethoxy)phenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a solution of methyl 1-(3-(difluoromethoxy)phenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (590 mg, 1.270 mmol) in MeOH (2 mL), THF (2 mL) and H2O (1 mL) was added LiOH·H2O (107 mg, 2.54 mmol). The mixture was stirred at 15 °C for 12 h. LCMS showed that the desired product was formed. The mixture was concentrated under reduced pressure and dissolved in H2O. HCl (1N aq.) was added to the mixture until pH = 4. The mixture was then extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LC / MS = 451 [M+1].

[0333] Step C: 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a solution of 1-(3-(difluoromethoxy)phenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (500 mg, 1.110 mmol) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (430 mg, 3.33 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (633 mg, 1.665 mmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (266 mg, 1.332 mmol). The reaction was stirred at 15° C. for 1 h. LCMS showed that the desired product had formed. The mixture was poured into H2O and extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / Hexanes) to give the title compound. LC / MS=596[M+1].

[0334] Step D: 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a solution of 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (790 mg, 1.326 mmol) in THF (10 mL) was added TBAF (4 mL, 4.00 mmol). The mixture was stirred at 65° C. for 15 h. LCMS showed that the desired product was formed. The mixture was poured into H2O and extracted with DCM (3x). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=466[M+1].

[0335] Step E: 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(phenylsulfonyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a mixture of 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide (70 mg, 0.150 mmol) in DMF (2 mL) at 0 °C under N2 was added sodium hydride (10 mg, 0.250 mmol). The mixture was stirred at 0 °C for 0.5 h. Then benzenesulfonyl chloride (54 mg, 0.306 mmol) was added to the mixture. The mixture was stirred at 15 °C under N2 for 12 h. LCMS showed that the desired product was formed. The mixture was poured into NH4Cl and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% NH4HCO3 modifier) ​​to give the title compound. LC / MS = 606 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 8.44 (d, J=1.53 Hz, 1H), 8.17-8.21 (m, 2H), 7.73-7.79 (m, 2H), 7.58-7.67 (m, 3H), 7.27-7.34 (m, 3H), 6.76-7.09 (m, 2H), 3.23-3.29 (m, 2H), 3.02-3.05 (m, 2H), 2.89-2.92 (m, 2H), 2.18-2.25 (m, 2H), 1.56 (s, 3H). Human DGAT2 IC50 = >9990 nM. Example 87: 1-Isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide [ka]

[0336] Step A: Methyl 5-nitro-6-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)amino)nicotinate At room temperature, methyl 6-chloro-5-nitronicotinate (0.206 g, 0.95 mmol) was dissolved in dioxane (4.75 mL) and 3-(1,1,2,2-tetrafluoroethoxy)aniline (0.209 g, 1.00 mmol) and DIPEA (0.199 mL, 1.140 mmol) were added. The reaction was heated to 100° C. for 1 h. The reaction was cooled to room temperature and the dioxane was removed under reduced pressure to give the title compound: LC / MS=390[M+1].

[0337] Step B: Methyl 5-amino-6-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)amino)nicotinate Methyl 5-nitro-6-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)amino)nicotinate (370 mg, 0.951 mmol) was dissolved in THF (3.80 mL), methanol (1.901 mL), and saturated aqueous ammonium chloride (3.80 mL) at room temperature. Zinc (311 mg, 4.75 mmol) was added and the reaction was stirred at room temperature for 20 minutes. The reaction was filtered through Celite and the THF and methanol were removed under reduced pressure. EtOAc and water were added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered, and concentrated under reduced pressure to provide the title compound. LC / MS=360[M+1].

[0338] Step C: Methyl 2-oxo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-imidazo[4.5-b]pyridine-6-carboxylate Methyl 5-amino-6-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)amino)nicotinate (341 mg, 0.95 mmol) was dissolved in THF (9.50 mL) at room temperature and di(1H-imidazol-1-yl)methanone (462 mg, 2.85 mmol) was added. The reaction was stirred at room temperature for 16 h. The next morning, water was added and the THF was removed under reduced pressure. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate and the combined organic layers were washed with brine. The organic fraction was dried over MgSO4 (s), filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) and the combined fractions were taken up in EtOAc and washed with 1N HCl and brine, then dried over MgSO4 (s), filtered and concentrated to give the title compound. LC / MS=386[M+1].

[0339] Step D: Methyl 1-isopropyl-2-oxo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate Methyl 2-oxo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate (187.5 mg, 0.487 mmol) and cesium carbonate (634 mg, 1.947 mmol) were suspended in DMF (2.433 mL) at room temperature. 2-Iodopropane (0.097 mL, 0.973 mmol) was added and the reaction was heated to 80° C. and stirred for 1 h. The reaction was then cooled to room temperature and water was added followed by EtOAc. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 10% EtOAc / DCM) to provide the title compound. LC / MS=428[M+1].

[0340] Step E: 1-isopropyl-2-oxo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylic acid Methyl 1-isopropyl-2-oxo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylate (144 mg, 0.337 mmol) was dissolved in THF (1.444 mL) and methanol (0.481 mL) at room temperature. A solution of lithium hydroxide (40.3 mg, 1.685 mmol) in water (1.444 mL water) was added. The reaction was stirred at room temperature overnight. The next morning, 1N aqueous HCl was added to pH 0. Ethyl acetate and water were added, the layers were separated, and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered, and concentrated under reduced pressure to give the title compound. LC / MS=414 [M+1].

[0341] Step F: 1-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxamide 1-Isopropyl-2-oxo-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (31.1 mg, 0.075 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (13.5 mg, 0.083 mmol), and HATU (31.5 mg, 0.083 mmol) were dissolved in DMF (0.75 mL) at room temperature. DIPEA (0.04 mL, 0.226 mmol) was added and the reaction was stirred at room temperature for 16 h. The crude residue was purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% formic acid modifier) ​​to give the title compound. 1H NMR (500 MHz, methanol-d4) δ 8.52 (d, J = 1.5 Hz, 1H), 8.04 (d, J = 1.5 Hz, 1H), 7.75 - 7.71 (m, 1H), 7.68 (s, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.35 (d, J = 7.7 Hz, 1H), 6.36 (t, J = 52.6 Hz, 2H), 4.84 - 4.75 (m, 1H), 3.30 - 3.25 (m, 2H), 3.08 - 2.99 (m, 2H), 2.94 - 2.86 (m, 2H), 2.27 - 2.17 (m, 2H), 1.63 (d, J = 6.9 Hz, 6H), 1.55 (s, 3H). LC / MS = 559 [M+1]. Human DGAT2 IC 50 = 20 nM. The following compounds were synthesized using procedures similar to those described in Example 87 with the appropriate reagents and were characterized by LC / MS. [Table 6] TIFF0007604636000097.tif219162TIFF0007604636000098.tif222162TIFF0007604636000099.tif209163TIFF0007604636000100.tif114163

[0342] Example 105: 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxamide [ka]

[0343] Step A: 2-Chloro-N-isopropyl-5-nitropyridin-4-amine To a solution of 2,4-dichloro-5-nitropyridine (300 mg, 1.555 mmol) in THF (6 mL) was added propan-2-amine (110 mg, 1.865 mmol) and Et3N (0.433 mL, 3.11 mmol). The reaction mixture was stirred at 25° C. for 3 h, poured into saturated NH4Cl, and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=216[M+1].

[0344] Step B: 6-Chloro-N-isopropylpyridine-3,4-diamine To a solution of 2-chloro-N-isopropyl-5-nitropyridin-4-amine (300 mg, 1.391 mmol) in MeOH (4 mL) was added iron (194 mg, 3.48 mmol) and ammonium chloride (0.186 mL, 3.48 mmol). The reaction mixture was stirred at 65° C. for 13 h, poured into saturated NH4Cl, and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=186[M+1].

[0345] Step C: 6-Chloro-1-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one To a solution of 6-chloro-N4-isopropylpyridine-3,4-diamine (200 mg, 1.077 mmol) in THF (5 mL) was added Et3N (0.450 mL, 3.23 mmol) and CDI (873 mg, 5.39 mmol). The reaction mixture was stirred at 25° C. under a N2 balloon for 12 h, poured into saturated NH4Cl, and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=212[M+1].

[0346] Step D: 6-Chloro-3-(3-(difluoromethoxy)phenyl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one To a solution of 6-chloro-1-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (190 mg, 0.898 mmol) in DMF (3 mL) was added 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1212 mg, 4.49 mmol), pyridine (1.452 mL, 17.95 mmol), 4 Å molecular sieves (200 mg) and Cu(OAc)2 (326 mg, 1.795 mmol). The mixture was stirred at 80° C. for 13 h, opened to air with a drying tube, poured into saturated NH4Cl and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / Hexanes) to give the title compound. LC / MS=354 [M+1].

[0347] Step E: Ethyl 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylate A solution of 6-chloro-3-(3-(difluoromethoxy)phenyl)-1-isopropyl-1H-imidazo[4,5-c]pyridin-2(3H)-one (300 mg, 0.848 mmol) in EtOH (20 mL) was treated with potassium acetate (0.159 mL, 2.54 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium ( II) (124 mg, 0.170 mmol) was added. The mixture was stirred at 100° C. under a CO balloon for 16 h, poured into saturated NH4Cl, and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=392[M+1].

[0348] Step F: 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid To a solution of ethyl 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylate (217 mg, 0.554 mmol) in MeOH (4 mL) and water (0.4 mL) was added lithium hydroxide monohydrate (46.5 mg, 1.109 mmol). The mixture was stirred at 25° C. for 8 h, concentrated under reduced pressure, and dissolved in H2O. HCl (1N aq.) was added to the mixture until pH=4. The mixture was extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LC / MS=364[M+1].

[0349] Step G: 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxamide To a solution of 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid (30 mg, 0.083 mmol) in DMF (2 mL) was added DIEA (0.072 mL, 0.413 mmol) and HATU (47.1 mg, 0.124 mmol). The mixture was stirred at 25° C. for 0.5 h. Then, 3-amino-3-methylthietane 1,1-dioxide (14.51 mg, 0.107 mmol) was added to the mixture, which was then stirred at 25° C. for 1 h. The crude mixture was directly purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% TFA modifier) ​​to give the title compound as the TFA salt. LC / MS = 481 [M+1]. 1H NMR (400 MHz, methanol-d4, ppm) δ 8.33 (s, 1H), 8.12 (s, 1H), 7.58-7.71 (m, 1H), 7.42-7.54 (m, 2H), 7.31 (dd, J = 1.6, 8.4 Hz, 1H), 6.71-7.14 (m, 1H), 4.76-4.84 (m, 1H), 4.65 (br d, J = 14.8 Hz, 2H), 4.18-4.29 (m, 2H), 1.84 (s, 3H), 1.63 (d, J = 7.2 Hz, 6H). Human DGAT2 IC 50 = 1804 nM. The following compounds were synthesized using procedures similar to those described in Example 72 with the appropriate reagents and were characterized by LC / MS. [Table 7]

[0350] Example 107: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxamide [ka]

[0351] Step A: 6-Chloro-N-isopropyl-3-nitropyridin-2-amine To a solution of 2,6-dichloro-3-nitropyridine (3 g, 15.55 mmol) in pure EtOH (30 mL) was added propan-2-amine (2.66 mL, 31.1 mmol). The resulting mixture was stirred at 15° C. for 20 min and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS = 217 [M+1]. 1H NMR (400 MHz, methanol-d4, ppm) δ 8.41 (d, J = 8.61 Hz, 1H), 6.68 (d, J = 8.61 Hz, 1H), 4.35 - 4.51 (m, 1H), 1.31 (d, J = 6.26 Hz, 6H). Step B: 6-Chloro-N2-isopropylpyridine-2,3-diamine NH4Cl (2.98 g, 55.6 mmol) in H2O (10 mL) was added to a solution of 6-chloro-N-isopropyl-3-nitropyridin-2-amine (2 g, 9.27 mmol) in MeOH (20 mL), and then iron (2.59 g, 46.4 mmol) was added to the above mixture. The resulting mixture was stirred at 75 °C for 13 h, poured into saturated NaHCO3, and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS = 186 [M+1]. 1 H NMR (400 MHz, methanol-d4, ppm) δ 6.75 (d, J = 7.83 Hz, 1H), 6.32 (d, J = 7.58 Hz, 1H), 4.11 - 4.27 (m, 1H), 1.20 (d, J = 6.36 Hz, 6H). Step C: 5-Chloro-3-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one A mixture of 6-chloro-N2-isopropylpyridine-2,3-diamine (400 mg, 2.155 mmol) and CDI (1747 mg, 10.77 mmol) in THF (5 mL) was stirred at 20° C. for 2 h. The mixture was poured into saturated NaHCO3 and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=213[M+1].

[0352] Step D: 5-Chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one To a solution of 5-chloro-3-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (280 mg, 1.323 mmol) and 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1787 mg, 6.61 mmol) in DMF (4 mL) at 80° C. was added diacetoxycopper (288 mg, 1.588 mmol) and pyridine (2.131 mL, 26.5 mmol). The mixture was stirred for 5 h, poured into saturated NaHCO3, and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=355[M+1].

[0353] Step E: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid A 50 mL flask was charged with 5-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-imidazo[4,5-b]pyridin-2(3H)-one (100 mg, 0.283 mmol), K2CO3 (78 mg, 0.565 mmol), diacetoxypalladium (19.04 mg, 0.085 mmol), propane-1,3-diylbis(dicyclohexylphosphonium) (69.2 mg, 0.113 mmol), DMSO (2 mL) and HO (0.2 mL) at 20° C. The mixture was degassed and backfilled with CO (3 times) and stirred under CO (pressure: 15 psi) at 110° C. for 5 h. The mixture was poured into water and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. LC / MS=364[M+1].

[0354] Step F: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxamide An 8 mL tube was charged with 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxylic acid (30 mg, 0.083 mmol), DIEA (0.043 mL, 0.248 mmol), 3-amino-3-methylthietane 1,1-dioxide (16.74 mg, 0.124 mmol), HATU (47.1 mg, 0.124 mmol) and DMF (0.5 mL) at 20° C. and stirred for 0.5 h. The crude mixture was purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% TFA modifier) ​​to give the title compound as the TFA salt. LC / MS = 481 [M+1]. 1 H NMR (500 MHz, methanol-d4, ppm) δ 8.99 (s, 1H), 7.91 (d, J = 8.24 Hz, 1H), 7.61 - 7.70 (m, 1H), 7.55 (d, J = 8.09 Hz, 1H), 7.47 (dd, J = 0.99, 8.01 Hz, 1H), 7.43 (s, 1H), 7.30 (dd, J = 1.75, 8.32 Hz, 1H), 6.80 - 7.15 (m, 1H), 5.14 (d, J = 6.89 Hz, 1H), 4.69 (br d, J = 14.50 Hz, 2H), 4.29 (d, J = 14.80 Hz, 2H), 1.89 (s, 3H), 1.69 (d, J = 6.87 Hz, 6H). Human DGAT2 IC50 = 1083 nM Example 108: 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide [ka]

[0355] Step A: Methyl 4-((3-(difluoromethoxy)phenyl)amino)-3-fluoro-5-nitrobenzoate Methyl 3,4-difluoro-5-nitrobenzoate (761 mg, 3.50 mmol), 3-(difluoromethoxy)aniline (0.432 mL, 3.50 mmol), and DIPEA (1.224 mL, 7.01 mmol) were dissolved in DMSO (17.5 mL) at room temperature. The mixture was heated to 100° C. and stirred overnight. The reaction was cooled to room temperature and water was added. EtOAc was added and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica gel chromatography (0% to 100% EtOAc) to give the title compound. LC / MS=357[M+1].

[0356] Step B: Methyl 3-amino-4-((3-(difluoromethoxy)phenyl)amino)-5-fluorobenzoate Methyl 4-((3-(difluoromethoxy)phenyl)amino)-3-fluoro-5-nitrobenzoate (911 mg, 2.56 mmol) was dissolved in THF (5.11 mL), methanol (2.56 mL) and saturated aqueous ammonium chloride (5.11 mL) at room temperature. Zinc (836 mg, 12.8 mmol) was added. The reaction was stirred at room temperature for 30 min, filtered through Celite, and the Celite was washed with EtOAc. The mixture was concentrated under reduced pressure. Water and EtOAc were added and the layers were separated. The aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered, and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=327[M+1].

[0357] Step C: Methyl 1-(3-(difluoromethoxy)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate Methyl 3-amino-4-((3-(difluoromethoxy)phenyl)amino)-5-fluorobenzoate (777 mg, 2.381 mmol) was dissolved in THF (23.81 mL) at room temperature. Di(1H-imidazol-1-yl)methanone (1545 mg, 9.53 mmol) was added and the reaction was stirred overnight. The next day, water was added and THF was removed under reduced pressure. EtOAc was added, the layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 50% EtOAc / DCM) to give the title compound. LC / MS=353[M+1].

[0358] Step D: Methyl 1-(3-(difluoromethoxy)phenyl)-7-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate Methyl 1-(3-(difluoromethoxy)phenyl)-7-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (176 mg, 0.500 mmol) and cesium carbonate (651 mg, 1.998 mmol) were suspended in DMF (2.5 mL) at room temperature. 2-Iodopropane (100 μL, 0.999 mmol) was added and the reaction was heated to 80° C. for 2 days. The reaction was cooled to room temperature and water and EtOAc were added. The layers were separated and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered and concentrated under reduced pressure. The crude residue was purified by flash silica gel column chromatography (0% to 15% EtOAc / DCM) to give the title compound. LC / MS=395[M+1].

[0359] Step E: 1-(3-(difluoromethoxy)phenyl)-7-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a stirred solution of methyl 1-(3-(difluoromethoxy)phenyl)-7-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (0.198 g, 0.500 mmol) in THF (0.714 mL) and methanol (2.143 mL) was added a solution of lithium hydroxide (0.060 g, 2.500 mmol) in water (2.143 mL). The reaction was stirred at room temperature for 16 hours. Aqueous hydrochloric acid (1N, 10 mL, 10.00 mmol) was added until pH=1 and EtOAc was added. The layers were separated and the aqueous layer was extracted 3 times with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 (s), filtered and concentrated under reduced pressure to give the title compound. LC / MS=381[M+1].

[0360] Step F: 1-(3-(difluoromethoxy)phenyl)-7-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide DIPEA (0.262 mL, 1.499 mmol) was added to a stirring solution of 1-(3-(difluoromethoxy)phenyl)-7-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (190 mg, 0.500 mmol), 3-amino-3-methylthietane 1,1-dioxide hydrochloride (94 mg, 0.550 mmol), and HATU (209 mg, 0.550 mmol) in DMF (5.00 mL) at room temperature. DIPEA (0.262 mL, 1.499 mmol) was added and the reaction was stirred at room temperature. DMF was then removed under reduced pressure. The crude residue was purified twice by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes then 0% to 30% acetone / DCM) to give the title compound. 1H NMR (500 MHz, methanol-d4) δ 7.74 (d, J = 1.3 Hz, 1H), 7.58 (t, J = 8.2 Hz, 1H), 7.49 (dd, J = 12.0, 1.3 Hz, 1H), 7.38 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.29 (dd, J = 8.3, 2.1 Hz, 1H), 6.93 (t, J = 73.7 Hz, 1H), 4.79 (septad, J = 6.9 Hz, 1H), 4.65 - 4.58 (m, 2H), 4.30 - 4.22 (m, 2H), 1.86 (s, 3H), 1.65 (d, J = 7.0 Hz, 6H). LC / MS = 498 [M+1]. Human DGAT2 IC50 = 12 nM The following compounds were synthesized by using a procedure similar to that described in Example 108 with the appropriate amine reagent and were characterized by LC / MS. [Table 8]

[0361] Example 112: 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0362] Step A: Ethyl 2-fluoro-5-(isopropylamino)-4-nitrobenzoate To a stirred mixture of ethyl 2,5-difluoro-4-nitrobenzoate (1.00 g, 4.33 mmol) in acetonitrile (8.65 mL) at 20° C. was added propan-2-amine (1.11 mL, 13.0 mmol), and the mixture was stirred at 40° C. for 12 hours. The volatiles were then evaporated to give the title compound. LC / MS=271[M+1].

[0363] Step B: Ethyl 4-amino-2-fluoro-5-(isopropylamino)benzoate To a stirred mixture of ethyl 2-fluoro-5-(isopropylamino)-4-nitrobenzoate (1.17 g, 4.33 mmol) in THF (8.66 mL) and MeOH (4.33 mL) saturated aqueous ammonia hydrochloride solution (8.66 mL) was added zinc (1.13 g, 17.3 mmol) at 0° C. The mixture was stirred at 20° C. for 1 h, filtered through sand, and the filtrate was concentrated. The residue was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 (s), and the volatiles were evaporated to give the title compound. LC / MS=241[M+1].

[0364] Step C: Ethyl 6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred mixture of ethyl 4-amino-2-fluoro-5-(isopropylamino)benzoate (1040 mg, 4.33 mmol) in THF (8.66 mL) was added 1,1′-carbonyldiimidazole (2.81 g, 17.3 mmol) at 20° C. The mixture was stirred at 20° C. for 16 h, filtered, and the volatiles removed. The residue was purified by flash silica gel chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=267[M+1].

[0365] Step D: Ethyl 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred mixture of ethyl 6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (100 mg, 0.376 mmol) and (3-(difluoromethoxy)phenyl)boronic acid (85 mg, 0.451 mmol) was added DCE (1.25 mL) and copper(II) acetate (82 mg, 0.451 mmol) at 20° C. The mixture was stirred at 50° C. for 3 days. The volatiles were then evaporated and the residue was purified by flash silica gel chromatography (0% to 70% EtOAc / Hexanes) to give the title compound. LC / MS=409[M+1].

[0366] Step E: 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a stirred mixture of ethyl 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (58 mg, 0.142 mmol) in THF (1.22 mL) and MeOH (0.40 mL) was added a solution of lithium hydroxide hydrate (23.8 mg, 0.568 mmol) in water (1.22 mL water) at 20° C. The mixture was stirred for 1 h at 20° C., then 1N HCl (1 mL, aq) was added and the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 (s), filtered and the volatiles were evaporated to give the title compound. LC / MS=381[M+1].

[0367] Step F: 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred mixture of 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (50 mg, 0.13 mmol) and HATU (65 mg, 0.17 mmol) in DMF (0.9 mL) was added 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (53 mg, 0.26 mmol) followed by DIPEA (92 μL, 0.53 mmol) at 20° C. The mixture was stirred for 1 h at 20° C. and partitioned between LiCl (10 wt%, aq, 10 mL) and EtOAc (10 mL). The organic layer was separated, washed with brine, dried over Na2SO4 (s), and the volatiles were evaporated. The residue was purified by flash silica gel chromatography (0 to 100% EtOAc / hexanes) and then lyophilized to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.08 (s, 1H), 7.64 (t, J = 8.2 Hz, 1H), 7.50 (d, J = 5.7 Hz, 1H), 7.43 (dd, J = 8.0, 1.1 Hz, 1H), 7.38 (t, J = 2.1 Hz, 1H), 7.34 (t, J = 73.8 Hz, 1H), 7.29 (dd, J = 8.3, 2.3 Hz, 1H), 7.06 (d, J = 10.0 Hz, 1H), 4.70 (septad, J = 7.1 Hz, 1H), 3.18 - 3.09 (m, 2H), 3.09 - 3.01 (m, 2H), 2.72 - 2.65 (m, 2H), 2.03 - 1.94 (m, 2H), 1.51 (d, J = 6.9 Hz, 6H), 1.44 (s, 3H). LC / MS = 526 [M+1]. Human DGAT2 IC 50 = 73.8 nM. The following compounds were synthesized using procedures similar to those described in Example 112 with the appropriate reagents and were characterized by LC / MS. [Table 9]

[0368] Example 115: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0369] Step A: Methyl 2-fluoro-5-(isopropylamino)-4-nitrobenzoate A mixture of methyl 2,5-difluoro-4-nitrobenzoate (20 g, 92 mmol), propan-2-amine (7.08 g, 120 mmol), and potassium carbonate (12.73 g, 92 mmol) in THF (200 mL) was stirred at 40° C. for 15 h. The mixture was poured into H2O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=257[M+1].

[0370] Step B: Methyl 4-amino-2-fluoro-5-(isopropylamino)benzoate A mixture of methyl 2-fluoro-5-(isopropylamino)-4-nitrobenzoate (13.8 g, 53.9 mmol) and Pd / C (2.5 g, 2.349 mmol) in THF (20 mL) was stirred under 15 psi H2 at 50° C. for 2 h. The suspension was filtered through a pad of Celite and the filter cake was washed with EtOAc (30 mL). The combined filtrates were concentrated. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=227[M+1].

[0371] Step C: Methyl 4-((2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)amino)-2-fluoro-5-(isopropylamino)benzoate To a mixture of methyl 4-amino-2-fluoro-5-(isopropylamino)benzoate (4.5 g, 19.89 mmol), 2-(2,2-difluoroethoxy)-5-fluoro-4-iodopyridine (7.23 g, 23.87 mmol) in THF (50 mL) at 20° C. was added Cs2CO3 (19.44 g, 59.7 mmol), Brettphos Pd G3 (1.5 g, 1.655 mmol). The mixture was then heated to 80° C. under N2 for 15 h, poured into H2O, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=402[M+1].

[0372] Step D: Methyl 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate A mixture of methyl 4-((2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)amino)-2-fluoro-5-(isopropylamino)benzoate (6.42 g, 16.00 mmol) and CDI (12.97 g, 80 mmol), DIEA (8.38 mL, 48.0 mmol) in THF (70 mL) was stirred at 70° C. for 40 h, then poured into H2O and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=428[M+1].

[0373] Step E: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid A mixture of lithium hydroxide hydrate (1.304 g, 31.1 mmol) and methyl 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (6.64 g, 15.54 mmol) in THF (15 mL) and water (15 mL) was stirred at 35° C. for 2 h. The mixture was concentrated under reduced pressure, the resulting concentrate was dissolved in H2O, and the pH was adjusted to 4 by adding HCl (1N aq.). The mixture was then extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure to give the title compound. LC / MS=414[M+1].

[0374] Step F: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide In a 100 mL eggplant bottle was placed 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (6.62 g, 16.02 mmol), DIEA (8.39 mL, 48.0 mmol), HATU (9.13 g, 24.02 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3.92 g, 24.02 mmol) and DMF (40 mL) at 20° C., and the mixture was stirred at 20° C. for 0.5 h. The mixture was poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / Hexanes) to provide the title compound. LC / MS = 559 [M+1]. 1H NMR (400 MHz, methanol-d4) δ 8.32 (d, J = 1.96 Hz, 1H), 8.05 (br s, 1H), 7.58 (d, J = 5.48 Hz, 1H), 7.17 (d, J = 4.70 Hz, 1H), 6.95 (dd, J = 2.35, 10.17 Hz, 1H), 5.98 - 6.45 (m, 1H), 4.73 (s, 1H), 4.58 (m, 2H), 3.13 - 3.27 (m, 2H), 2.99 (m, 2H), 2.81 (m, 2H), 2.11 - 2.25 (m, 2H), 1.59 (m, 6H), 1.54 (s, 3H). Human DGAT2 IC 50 = 4.1 nM. The following compounds were synthesized using procedures similar to those described in Example 115 with the appropriate reagents and were characterized by LC / MS. [Table 10] TIFF0007604636000110.tif178170

[0375] Example 122: 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0376] Step A: 5-Fluoro-4-iodopyridin-2-ol 2,5-Difluoro-4-iodopyridine (25 g, 104 mmol) was added to concentrated HCl (12N aq.) (100 mL), dioxane (100 mL) and H2O (100 mL). The mixture was heated to 110° C. and stirred at 110° C. for 16 h. The reaction was concentrated to dryness to give the title compound which was used directly in the next step. LC / MS=240 [M+1].

[0377] Step B: 2-(difluoromethoxy)-5-fluoro-4-iodopyridine Chlorodifluoromethane (43.4 g, 502 mmol) was added over 25 min to a mixture of 5-fluoro-4-iodopyridin-2-ol (24 g, 100 mmol) and Cs2CO3 (110 g, 338 mmol) in DMF (300 mL) at 25° C., and the mixture was stirred at 50° C. for 1 h. The mixture was poured into saturated NH4Cl and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 3% EtOAc / Hexanes) to give the title compound. LC / MS=290[M+1].

[0378] Step C: Methyl 4-((2-(difluoromethoxy)-5-fluoropyridin-4-yl)amino)-2-fluoro-5-(isopropylamino)benzoate To a mixture of methyl 4-amino-2-fluoro-5-(isopropylamino)benzoate (4.5 g, 19.89 mmol), 2-(difluoromethoxy)-5-fluoro-4-iodopyridine (6.9 g, 23.87 mmol) in THF (50 mL) at 20° C. was added Cs2CO3 (19.4 g, 59.7 mmol), BRETTPHOS PD G3 (1.5 g, 1.655 mmol). The resulting mixture was heated to 80° C. under N2 for 15 h, then poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=388[M+1].

[0379] Step D: Methyl 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate A mixture of methyl 4-((2-(difluoromethoxy)-5-fluoropyridin-4-yl)amino)-2-fluoro-5-(isopropylamino)benzoate (6.35 g, 16.39 mmol) and CDI (13.29 g, 82 mmol), DIEA (8.6 mL, 49.2 mmol) in THF (80 mL) was stirred at 70° C. for 40 h, then poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=414[M+1].

[0380] Step E: 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a solution of methyl 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (6.4 g, 15.48 mmol) in THF (50 mL) / water (50 mL) was added lithium hydroxide monohydrate (1.95 g, 46.5 mmol). The reaction mixture was stirred at 40° C. for 2 h and concentrated under reduced pressure. The residue was dissolved in H2O and the pH was adjusted to 4 by adding HCl (1N aq.). The mixture was then extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LC / MS=400[M+1].

[0381] Step F: 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide The tube was charged with 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (6.15 g, 15.4 mmol), DIEA (13.5 mL, 77 mmol), HATU (8.78 g, 23.10 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3.02 g, 18.48 mmol) and DMF (80 mL) at 20° C. After stirring for 1 h at 20° C., the mixture was poured into H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) and mass-triggered reverse phase HPLC (ACN / water) to give the title compound. LC / MS = 545 [M+1]. 1H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J=1.47 Hz, 1H), 8.08 (s, 1H), 7.68-7.88 (m, 1H), 7.50 (dd, J=2.32, 5.26 Hz, 2H), 7.17 (dd, J=2.08, 9.90 Hz, 1H), 4.67-4.71 (m, 1H), 3.07-3.16 (m, 2H), 2.99-3.07 (m, 2H), 2.64-2.75 (m, 2H), 1.96-2.12 (m, 2H), 1.48 (d, J=6.85 Hz, 6H), 1.41 (s, 3H). Human DGAT2 IC 50 = 56 nM. The following compounds were synthesized using a procedure similar to that described in Example 122 with the appropriate amine reagent and were characterized by LC / MS. [Table 11]

[0382] Example 124: (S)-1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0383] Step A: Methyl 2,3-difluoro-4-nitrobenzoate To a stirred mixture of 2,3-difluoro-4-nitrobenzoic acid (490 mg, 2.41 mmol) in MeOH (2.41 mL) was added sulfuric acid (51.4 μL, 0.965 mmol) at 20° C. The mixture was stirred at 80° C. for 24 h, cooled to 20° C., concentrated, and partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over Na2SO4 (s), filtered, and the volatiles were evaporated to give the title compound. LC / MS=218[M+1].

[0384] Step B: Methyl 2-fluoro-3-(isopropylamino)-4-nitrobenzoate To a stirred mixture of methyl 2,3-difluoro-4-nitrobenzoate (0.521 g, 2.40 mmol) in acetonitrile (4.80 mL) at 20° C. was added propan-2-amine (0.452 mL, 5.28 mmol), and the mixture was stirred at 40° C. for 12 hours. The volatiles were evaporated to give the title compound. LC / MS=257[M+1].

[0385] Step C: Methyl 4-amino-2-fluoro-3-(isopropylamino)benzoate To a stirred mixture of methyl 2-fluoro-3-(isopropylamino)-4-nitrobenzoate (0.615 g, 2.40 mmol) in THF (4.80 mL) and MeOH (2.40 mL) and saturated aqueous ammonia hydrochloride (4.80 mL) was added zinc (0.471 g, 7.20 mmol) at 0° C. The mixture was stirred at 20° C. for 1 h, filtered through sand and the filtrate was concentrated. The residue was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 (s) and the volatiles were evaporated to give the title compound. LC / MS=227[M+1].

[0386] Step D: Methyl 4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred mixture of methyl 4-amino-2-fluoro-3-(isopropylamino)benzoate (543 mg, 2.40 mmol) in THF (4.80 mL) at 20° C. was added 1,1′-carbonyldiimidazole (1.17 g, 7.20 mmol), and the mixture was stirred at 20° C. for 16 h. The volatiles were evaporated. The residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=253[M+1].

[0387] Step E: Methyl 1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred mixture of methyl 4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (100 mg, 0.396 mmol), (3-(difluoromethoxy)phenyl)boronic acid (112 mg, 0.595 mmol) was added DCE (1.32 mL) and copper(II) acetate (108 mg, 0.595 mmol) at 20° C. The mixture was stirred at 50° C. for 3 days, the volatiles were evaporated, and the residue was purified by flash silica gel column chromatography (0% to 50% EtOAc / Hexane) to give the title compound. LC / MS=395[M+1].

[0388] Step F: 1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid To a stirred mixture of methyl 1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (74 mg, 0.188 mmol) in THF (0.80 mL) and MeOH (0.27 mL) was added a solution of lithium hydroxide hydrate (31.5 mg, 0.751 mmol) in water (0.80 mL water) at 20° C. The mixture was stirred for 1 h at 20° C., then 1N HCl (1 mL, aq) was added and the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 (s), filtered and the volatiles were evaporated to give the title compound. LC / MS=381[M+1].

[0389] Step G: (S)-1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred mixture of 1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (20 mg, 0.053 mmol) and HATU (30.0 mg, 0.079 mmol) in DMF (0.53 mL) was added DIPEA (36.7 μL, 0.210 mmol) followed by (S)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (14.7 mg, 0.079 mmol) at 20° C. The mixture was stirred at 20° C. for 1 h and then purified by mass-triggered reverse phase HPLC (C18, 40% to 80% ACN / water, 0.1% FA modifier) ​​to give the title compound. 1 H NMR (500 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.31 (d, J = 8.9 Hz, 1H), 7.31 (t, J = 73.7 Hz, 1H), 7.26 - 7.22 (m, 1H), 6.94 (d, J = 8.2 Hz, 1H), 4.85 (septad, J = 6.9 Hz, 1H), 3.94 (d, J = 13.6 Hz, 1H), 3.32 (dd, J = 8.9, 5.3 Hz, 1H), 3.20 (d, J = 13.7 Hz, 1H), 2.65 (dd, J = 12.8, 6.0 Hz, 1H), 2.20 (dt, J = 13.7, 9.3 Hz, 1H), 1.57 (s, 3H), 1.50 (d, J = 6.8 Hz, 6H). The position of one proton could not be determined due to overlap with the solvent or water peaks. No. LC / MS = 512 [M+1]. Human DGAT2 IC 50 = 191 nM. The following compounds were synthesized using a procedure similar to that described in Example 124 with the appropriate amine reagent and were characterized by LC / MS. [Table 12]

[0390] Example 127: (S)-6-Chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0391] Step A: Methyl 2-chloro-4-fluoro-5-nitrobenzoate To a stirred mixture of 2-chloro-4-fluoro-5-nitrobenzoic acid (1.00 g, 4.55 mmol) in MeOH (4.55 mL) was added sulfuric acid (0.097 mL, 1.82 mmol) at 20° C. The mixture was stirred at 80° C. for 24 h, concentrated, and partitioned between EtOAc and water. The organic layer was separated, washed with water and brine, dried over Na2SO4 (s), and filtered. The volatiles were evaporated to give the title compound. LC / MS=234[M+1].

[0392] Step B: Methyl 2-chloro-4-((3-(difluoromethoxy)phenyl)amino)-5-nitrobenzoate To a stirred mixture of methyl 2-chloro-4-fluoro-5-nitrobenzoate (1.06 g, 4.55 mmol) in acetonitrile (9.10 mL) was added 3-(difluoromethoxy)aniline (0.668 mL, 5.46 mmol) and DIPEA (0.874 mL, 5.01 mmol) at 20° C. The mixture was stirred at 80° C. for 16 h. The volatiles were then evaporated to give the title compound. LC / MS=373[M+1].

[0393] Step C: Methyl 5-amino-2-chloro-4-((3-(difluoromethoxy)phenyl)amino)benzoate To a stirred mixture of methyl 2-chloro-4-((3-(difluoromethoxy)phenyl)amino)-5-nitrobenzoate (1.696 g, 4.55 mmol) in THF (9.10 mL), MeOH (4.55 mL) and saturated aqueous ammonia hydrochloride (9.10 mL) was added zinc (0.892 g, 13.65 mmol) at 0° C. The mixture was stirred at 20° C. for 1 h, filtered and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 (s) and the volatiles were evaporated to give the title compound. LC / MS=343[M+1].

[0394] Step D: Methyl 6-chloro-1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred mixture of methyl 5-amino-2-chloro-4-((3-(difluoromethoxy)phenyl)amino)benzoate (1.56 g, 4.55 mmol) in THF (15.0 mL) was added 1,1'-carbonyldiimidazole (2.21 g, 13.7 mmol) at 20°C. The mixture was stirred at 20°C for 16 h. The volatiles were then removed and the residue was purified by flash silica gel chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=369[M+1].

[0395] Step E: Methyl 6-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a stirred mixture of methyl 6-chloro-1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (93.0 mg, 0.252 mmol) in DMF (2.52 mL) was added 2-iodopropane (49.0 μL, 0.504 mmol) and Cs2CO3 (247 mg, 0.757 mmol) at 20° C. The mixture was stirred at 80° C. for 2 h and partitioned between EtOAc and water. The organic layer was separated, washed with brine and the solvent was evaporated to give the title compound. LC / MS=411[M+1].

[0396] Step F: 6-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acidTo a stirred mixture of methyl 6-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (104 mg, 0.253 mmol) in THF (1.09 mL) and MeOH (0.36 mL) was added a solution of lithium hydroxide hydrate (42.5 mg, 1.01 mmol) in water (1.09 mL water) at 20° C. The mixture was stirred at 20° C. for 1 h. Then, 1N HCl (1 mL, aq) was added and the mixture was partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over Na2SO4 (s), filtered and the volatiles were evaporated to give the title compound. LC / MS=397[M+1].

[0397] Step G: 6-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide To a stirred mixture of 6-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (30 mg, 0.076 mmol) and HATU (43.1 mg, 0.113 mmol) in DMF (0.76 mL) was added DIPEA (52.8 μL, 0.302 mmol) followed by (4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (18.5 mg, 0.113 mmol) at 20° C. The mixture was stirred at 20° C. for 1 h and directly purified by mass-triggered reverse phase HPLC (C18, 40% to 70% ACN / water, 0.1% FA modifier) ​​to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.65 (t, J = 8.1 Hz, 1H), 7.49 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.36 (s, 1H), 7.31 (t, J = 73.7 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.10 (s, 1H), 4.69 (septad, J = 6.7 Hz, 1H), 3.24 (t, J = 12.8 Hz, 2H), 3.04 (d, J = 13.5 Hz, 2H), 2.68 (d, J = 13.7 Hz, 2H), 1.98 (t, J = 13.5 Hz, 2H), 1.51 (d, J = 6.8 Hz, 6H), 1.46 (s, 3H). LC / MS = 542 [M+1]. Human DGAT2 IC 50 = 112 nM Example 128: 4-Chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0398] Step A: 1-Bromo-2-chloro-3-fluoro-4-nitrobenzene To a solution of 4-bromo-3-chloro-2-fluoroaniline (5 g, 22.28 mmol) in toluene (70 mL) was added mCPBA (19.22 g, 89 mmol). The mixture was stirred at 50° C. for 12 h, poured into saturated Na2SO3 (80 mL) and stirred at 25° C. for 10 min. The pH value of the solution was adjusted to pH=10 by adding HCl (1N) and the mixture was extracted with DCM (50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound. 1 H NMR (400 MHz, chloroform-d) δ 7.23-7.29 (m, 1H), 7.09-7.20 (m, 1H).

[0399] Step B: 3-Bromo-2-chloro-N-isopropyl-6-nitroaniline Solid K2CO3 (6.52 g, 47.2 mmol) was added to a mixture of 1-bromo-2-chloro-3-fluoro-4-nitrobenzene (6 g, 23.58 mmol) and propan-2-amine (1.951 g, 33.0 mmol) in DMF (40 mL) at 25°C. The mixture was heated at 60°C for 3 h, then poured into saturated NaHCO3 and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS = 293 and 295 [M+1].

[0400] Step C: 5-Bromo-6-chloro-N-isopropylbenzene-1,2-diamine Iron powder (1.5 g, 26.9 mmol) was added to a mixture of ammonium chloride (1.676 g, 31.3 mmol) and 3-bromo-2-chloro-N-isopropyl-6-nitroaniline (2.3 g, 7.84 mmol) in THF (10 mL), water (10 mL) and EtOH (10 mL). The mixture was stirred at 60° C. for 2 h, poured into saturated NaHCO3 and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=263 and 265 [M+1].

[0401] Step D: 6-Bromo-7-chloro-1-isopropyl-1H-benzo[d]imidazol-2(3H)-one A mixture of 5-bromo-6-chloro-N1-isopropylbenzene-1,2-diamine (1.2 g, 4.55 mmol) and CDI (4.43 g, 27.3 mmol) in THF (15 mL) was stirred at 60° C. for 12 h. TLC showed complete consumption of starting material and appearance of two new spots. The mixture was poured into H2O and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=289 and 291 [M+1].

[0402] Step E: 5-Bromo-4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-benzo[d]imidazol-2(3H)-one To a solution of 6-bromo-7-chloro-1-isopropyl-1H-benzo[d]imidazol-2(3H)-one (300 mg, 1.036 mmol) in DMF (4 mL) was added 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1 g, 3.70 mmol), pyridine (1.676 mL, 20.72 mmol), 4 Å molecular sieves (200 mg) and diacetoxycopper (376 mg, 2.072 mmol). The mixture was stirred at 80° C. for 13 h and opened to air with a drying tube. LCMS showed complete consumption of starting material. The mixture was poured into H2O and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0-100% EtOAc / Hexanes) to give the title compound (300 mg).

[0403] LC / MS=431 and 433[M+1].

[0404] Step F: Ethyl 4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate To a mixture of 5-bromo-4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-benzo[d]imidazol-2(3H)-one (300 mg, 0.695 mmol) and potassium acetate (205 mg, 2.085 mmol) in dry EtOH (10 mL) was added Pd(dppf)Cl2 (50.9 mg, 0.069 mmol) under CO (15 psi) at 25° C. The mixture was stirred at 80° C. under CO (15 psi) for 15 h, concentrated, and the residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=425[M+1].

[0405] Step G: Lithium 4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate Lithium hydroxide monohydrate (12 mg, 0.286 mmol) was added to a mixture of ethyl 4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (40 mg, 0.094 mmol) in MeOH (3 mL) and water (0.4 mL). The mixture was stirred at 25° C. for 12 h and lyophilized to give the title compound. LC / MS=397[M+1].

[0406] Step H: 4-Chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide 4-Amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (10 mg, 0.061 mmol) was added to a mixture of lithium 4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (30 mg, 0.074 mmol), HATU (56.7 mg, 0.149 mmol) and DIEA (0.052 mL, 0.298 mmol) in DMF (1 mL). The mixture was stirred at 25° C. for 15 min and purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% TFA modifier) ​​to give the title compound. LC / MS=542[M+1]. Human DGAT2 IC 50 =1381nM.

[0407] Example 129: 4-Cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide [ka]

[0408] Step A: 6-Chloro-2-(isopropylamino)-3-nitrobenzonitrile Isopropylamine (1.421 mL, 16.59 mmol) was added to a mixture of 2,6-dichloro-3-nitrobenzonitrile (3 g, 13.82 mmol) in THF (20 mL). The mixture was stirred at 0° C. for 2 h, poured into saturated NH4Cl, and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=240[M+1].

[0409] Step B: 3-Amino-6-chloro-2-(isopropylamino)benzonitrile Iron powder (0.932 g, 16.69 mmol) was added to a mixture of 6-chloro-2-(isopropylamino)-3-nitrobenzonitrile (1 g, 4.17 mmol) and ammonium chloride (0.339 mL, 6.34 mmol) in THF (5 mL). The mixture was stirred at 60° C. for 5 h, then poured into saturated NH4Cl and extracted with DCM (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=210[M+1].

[0410] Step C: 5-Chloro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile Triethylamine (0.598 mL, 4.29 mmol) was added to a mixture of 3-amino-6-chloro-2-(isopropylamino)benzonitrile (300 mg, 1.431 mmol) and CDI (1160 mg, 7.15 mmol) in THF (3 mL). The mixture was stirred at 25° C. for 24 h and concentrated under reduced pressure. The crude product was poured into saturated NH4Cl and extracted with EtOAc (3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was then poured into H2O and stirred at 25° C. for 3 min (a white solid formed). The mixture was filtered to give the title compound. LC / MS=236[M+1].

[0411] Step D: 5-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile Pyridine (0.820 mL, 10.18 mmol) was added to a mixture of 5-chloro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile (120 mg, 0.509 mmol), (3-(difluoromethoxy)phenyl)boronic acid (478 mg, 2.55 mmol) and diacetoxycopper (111 mg, 0.611 mmol) in DMF (15 mL). The mixture was stirred at 50° C. for 12 h, poured into saturated NH4Cl and extracted with DCM (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=378[M+1].

[0412] Step E: Ethyl 4-cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate Pd(dppf)Cl2 (58.1 mg, 0.079 mmol) was added to a mixture of potassium acetate (0.149 mL, 2.382 mmol) and 5-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-4-carbonitrile (300 mg, 0.794 mmol) in EtOH (20 mL) and the solution was stirred under CO (15 psi balloon) at 100 °C for 18 h. The mixture was poured into saturated NH4Cl and extracted with DCM (3 times).

[0413] The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0% to 100% EtOAc / Hexanes) to give the title compound. LC / MS=416[M+1].

[0414] Step F: Lithium 4-cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate Ethyl 4-cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate (70 mg, 0.169 mmol) was added to a mixture of lithium hydroxide hydrate (14.14 mg, 0.337 mmol) in MeOH (1 mL) and water (0.1 mL). The mixture was stirred at 25° C. for 1 h and lyophilized to give the title compound. LC / MS=388[M+1].

[0415] Step G: 4-cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide 4-Cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylic acid (17.08 mg, 0.044 mmol) was added to a mixture of 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (6 mg, 0.037 mmol), HATU (28.0 mg, 0.074 mmol) and DIEA (0.026 mL, 0.147 mmol) in DMF (5 mL) and the mixture was stirred at 25° C. for 1 h. The crude mixture was directly purified by mass-triggered reverse phase HPLC (ACN / water + 0.1% TFA modifier) ​​to give the title compound. LC / MS = 533 [M+1]. 1H NMR (400 MHz, methanol-d4, ppm) δ 8.41 (s, 1H), 7.55-7.71 (m, 1H), 7.34-7.40 (m, 2H), 7.31 (t, J = 7.58 Hz, 3H), 6.73-7.14 (m, 1H), 5.39 (td, J = 6.82, 13.51 Hz, 1H), 3.33-3.42 (m, 2H), 2.98 (br d, J = 12.96 Hz, 2H), 2.83 (br d, J = 14.67 Hz, 2H), 2.18 (br t, J = 13.45 Hz, 2H), 1.69 (d, J = 6.85 Hz, 6H), 1.54 (s, 3H). Human DGAT2 IC 50 = 248 nM Assay Insect cell expression and membrane preparation Sf-9 insect cells were maintained in Grace's insect cell medium containing 10% heat-inactivated fetal bovine serum, 1% Pluronic F-68, and 0.14 μg / mL kanamycin sulfate at 27°C in a shaker incubator. Cells were harvested after infection with untagged baculovirus expressing human DGAT2 (hDGAT2) at a multiplicity of infection (MOI) of 3 for 48 h. Cell pellets were suspended in a buffer containing 10 mM Tris-HCl pH 7.5, 1 mM EDTA, 250 mM sucrose, and complete protease inhibitor cocktail (Sigma Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2000×g for 15 min. Membrane fractions were isolated by ultracentrifugation (100,000×g), resuspended in the same buffer, and frozen (−80°C) for later use. Protein concentrations were determined using the Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific). Protein level expression was analyzed by immunoblotting with rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa Fluor® 647 (Abcam, ab150075) and detected using a Typhoon FLA9000 (GE Healthcare).

[0416] LC / MS / MS analysis method LC / MS / MS analysis was performed using a Thermal Fisher LX4-TSQ Vantage system, consisting of an Agilent binary high performance liquid chromatography (HPLC) pump and a TSQ Vantage triple quadrupole MS / MS instrument. For each sample, 2 μL of sample from the upper organic layer of the in-plate liquid-liquid extraction was injected onto a Thermo Betabasic C4 column (2.1 mm × 20 mm, 5 μm particle size). The sample was then eluted using the following conditions; mobile phase: isopropanol:acetonitrile / 10 mM ammonium formate = 50 / 35 / 15 (volume ratio), flow rate: 0.8 mL / min, temperature: 25 °C. Data were acquired in positive mode using a heated electrospray ionization (HESI) interface. Operating parameters for 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. 13 C 18 -Triolein (Q1:920.8>Q3:621.3) and internal standard 13 C 21 - Standard Reference Material (SRM) chromatograms of triolein (Q1: 923.8>Q3: 617.3) were collected for 33 seconds. Peak areas were integrated by Xcalibur Quan software. 13 C 18 Triolein and internal standard 13 C 21 - Using the ratio between that spiked with triolein, percent inhibition and IC 50 The IC values ​​were obtained. Percent compound inhibition was calculated by the following formula: % Inhibition = 1 - [(compound response - low control) / (high control - low control)] x 100%. Potent compounds were titrated and IC 50 was calculated by a four-parameter sigmoidal curve fitting equation.

[0417] DGAT2 enzyme activity assay Using the membrane preparation described above, the enzyme product 13 C 18 -Triolein ( 13 DGAT2 activity was determined by measuring the amount of 1,2,3-tri(cis-9-octadecenoyl)glycerol (C-1,2,3-tri(cis-9-octadecenoyl)glycerol) in ABgene 384-well assay plates in a final volume of 25 μL at room temperature. The assay mixture consisted of 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 membranes.

Claims

1. A compound of formula I: or a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 [In the formula, X, Y, and Z are independently N and C(R ５ ) selected from; R １ teeth, (1) unsubstituted or 1, 2 or 3 R ６ phenyl substituted with (2) a 5- or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or has 1, 2, or 3 R ６ is replaced by (3) 8-10 membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or has 1, 2, or 3 R ６ has been replaced by.] and R ２ teeth, (1) unsubstituted or 1, 2 or 3 R ７ phenyl substituted with (2) a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or has 1, 2 or 3 R ７ is replaced by (3) Unsubstituted or halogen, OH, CF ３ or C which may be mono- or di-substituted by CN; １－６ Alkyl, (4) Is it unsubstituted? １－３ Alkyl, halogen, OH, CF ３ or may be mono- or di-substituted with -CN (C ３－６ ) cycloalkyl, (5)-(C ３－６ ) alkylC(O)NH ２ , (6) A 4- to 6-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O and S, wherein the heterocycle is unsubstituted or contains 1, 2 or 3 R ７ is replaced by . (7) unsubstituted or 1, 2 or 3 R ７ is substituted by -CH ２ -aryl, (8) unsubstituted or 1, 2 or 3 R ７ -SO ２ (C １－６ ) alkyl, or (9) unsubstituted or 1, 2 or 3 R ７ -SO ２ -Aryl and R ３ teeth, (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, O, and S; (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, O, and S; (4)-(C １－６ ) alkyl-aryl, (5)-(C １－６ ) alkyl-heterocycle [the heterocycle is a 3-6 membered ring containing 1 or 2 heteroatoms independently selected from N, O and S; (6)-(C １－６ ) alkyl, (7)-(C ３－６ ) cycloalkyl, (8)-(C １－６ ) hydroxyalkyl, (9)-(C １－６ ) alkyl-S(O) ２ -NR ８ａ R ８ｂ or (10)-(C １－６ ) alkyl-S(O) ２ - (C １－３ ) Alkyl and Each aryl, fused aryl, heteroaryl, cycloalkyl, or heterocycle is unsubstituted or has 1, 2, or 3 R ９ each alkyl is unsubstituted or substituted with 1, 2 or 3 R １０ is substituted with; R ４ teeth, (1) Hydrogen, or (2) (C １－３ ) Alkyl and Or R ３ and R ４ together with the nitrogen atom to which they are attached form a monocyclic or bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from N, O and S, said heterocycle being unsubstituted or containing 1, 2 or 3 R １１ is replaced by If present, each R ５ teeth, (1) hydrogen, (2) (C １－６ ) alkyl, (3) (C ３－６ ) cycloalkyl, (4) (C １－６ ) haloalkyl, (5) cyano, and (6) Halogen is selected from If present, each R ６ is independently (1) Cyano, (2) halogen, (3) -OC １－６ Alkyl, (4) Halogen, C １－３ Alkyl, C １－６ Optionally substituted with haloalkyl or OH (C ３－６ ) cycloalkyl, (5) - (6) ２ 、 (6) -O(C ３－６ ) cycloalkyl [wherein the cycloalkyl is halogen, C １－３ may be substituted with alkyl or OH. (7) hydroxy, (8)N(R １１ ) ２ 、 (9) (C １－６ ) haloalkyl-, (10) -O(C １－６ ) haloalkyl-, (11) -SO ２ (C １－６ ) alkyl, (12) -SO ２ NH (C １－６ ) alkyl, (14)-SC １－６ Alkyl, (15)N(R １１ )C(O)R １１ 、 (16)-SC １－６ Haloalkyl, and (17) (C １－６ ) Alkyl Selected from: If present, each R ７ is independently (1) (C １－３ ) alkyl, (2) halogen, (3) (C １－６ ) alkoxy-, (4) (C １－６ ) haloalkyl-, and (5) Hydroxy Selected from: If present, R ８ａ and R ８ｂ is independently (1) hydrogen, (2) (C １－３ ) alkyl, and (3) (C ３－７ ) Cycloalkyl Selected from: If present, each R ９ is independently (1) (C １－３ ) alkyl, (2) (C １－３ ) haloalkyl-, (3) oxo, (4) (C ３－６ ) cycloalkyl, (5)N(R １１ ) ２ 、 (6) hydroxy, (7) (C １－３ ) alkoxyl-, (8) cyano, and (9) Halogen Selected from: If present, R １０ is independently (1) (C １－３ ) alkoxy-, (2) hydroxy, (3) halogens, (4) (C １－３ ) haloalkyl-, and (5)N(R １１ ) ２ Selected from: R １１ If present, (1) Hydrogen, or (2) (C １－３ ) Alkyl It is.]

2. R １ but, (a) independently halogen, hydroxy, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ Cycloalkyl, O.C. １－３ Alkyl, O.C. １－３ Haloalkyl, O.C. ３－６ Cycloalkyl, -SC １－３ Alkyl, -SC １－３ Haloalkyl, S(O) ２ C １－３ Alkyl and C １－６ phenyl optionally substituted with 1 to 3 substituents selected from alkyl-CN, wherein the cycloalkyl is optionally substituted with halogen or OH; (b) independently selected from halogen, hydroxy, C １－６ Alkyl, C １－６ Haloalkyl, C ３－６ Cycloalkyl, O.C. １－３ Alkyl, O.C. １－３ Haloalkyl, O-C ３－６ 6-membered heteroaryl containing 1 or 2 nitrogen atoms, optionally substituted with 1 to 3 substituents selected from cycloalkyl and CN, wherein if said cycloalkyl is cyclopropyl, said cyclopropyl may be substituted with halogen or OH; (c) independently a halogen, (C １－３ ) alkyl, (C ３－６ ) cycloalkyl, (C １－３ ) haloalkyl-, OH and OC １－３ a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents selected from alkyl; or (d) 8-10 membered fused heteroaryl containing 1, 2, 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with halogen, (C １－３ ) alkyl, (C ３－６ ) cycloalkyl, (C １－３ ) haloalkyl-, OH or OC １－３ is substituted with alkyl.

2. The compound of claim 1, wherein:

3. R １ but, (a) halogen, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ Cycloalkyl, O-C ３－６ Cycloalkyl, CN, NHC(O)C １－３ Alkyl, NC １－３ Alkyl, C(O)NH ２ , S.C. １－３ Alkyl, S(O) ２ N.H.C. １－３ Alkyl, S(O) ２ C １－３ Alkyl, O.C. １－３ Alkyl or O １－３ phenyl optionally substituted with haloalkyl, said cycloalkyl being optionally further substituted with 1 to 3 halogens; (b) independently halogen, C １－３ Alkyl, C ３－６ Cycloalkyl, O.C. １－３ Alkyl and O １－３ pyridyl optionally substituted by 1 to 3 substituents selected from haloalkyl; (c) independently a halogen, (C １－３ ) alkyl, (C ３－６ ) cycloalkyl, (C １－３ ) haloalkyl-, OH and OC １－３ a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents selected from alkyl; or (d) 8-10 membered fused heteroaryl containing 1, 2, 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with halogen, (C １－３ ) alkyl, (C ３－６ ) cycloalkyl, (C １－３ ) haloalkyl-, OH or OC １－３ is substituted with alkyl.

3. The compound according to claim 1, wherein:

4. R １ but, (a) independently, F, CF ３ , C.N., N(CH ３ ) ２ , C(O)NH ２ , S.C.H. ３ , S(O) ２ N.H.C.H. ３ , S(O) ２ CH ３ , O.C.H. ２ CH ３ , OCH(CH ３ ) ２ , O.C.H.F. ２ , O.C.H. ２ CHF ２ , O.C.F. ３ , O.C.F. ２ CHF ２ , NHC(O)CH ３ phenyl optionally substituted with 1 to 3 substituents selected from cyclopropyl and O-cyclopropyl, wherein the cyclopropyl is optionally further substituted with 1 to 3 F; (b) independently, OC(F) ２ (CH ３ ), O.C.H. ２ CH ３ , OCH(CH ３ ) ２ , O.C.H.F. ２ , O.C.H. ２ CHF ２ , O.C.F. ３ , O.C.F. ２ CHF ２ , O.C.F. ２ CHF ２ pyridyl optionally substituted by 1 to 3 substituents selected from cyclopropyl and cyclopropyl; (c) independently a halogen, (C １－３ ) alkyl, (C ３－６ ) cycloalkyl, (C １－３ ) haloalkyl-, OH and OC １－３ a 5-membered heteroaryl containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, optionally substituted with 1 to 2 substituents selected from alkyl; or (d) CH ３ 8-10 membered fused heteroaryl containing 1 to 3 heteroatoms selected from N, O and S atoms, optionally substituted with 4. The compound according to claim 1, wherein:

5. R １ is based on the following formula: 【Chemistry 2】 5. The compound according to any one of claims 1 to 4, wherein:

6. R １ is unsubstituted or independently F, CF ３ , C.N., N(CH ３ ) ２ , C(O)NH ２ , S.C.H. ３ , S(O) ２ N.H.C.H. ３ , S(O) ２ CH ３ , O.C.H.F. ２ , O.C.F. ３ , OCH(CH ３ ) (CH ３ ), O.C.F. ２ CHF ２ , O.C.H. ２ CHF ２ , O.C.H. ２ CH ３ , NHC(O)CH ３ 6. The compound according to claim 1, wherein the phenyl is substituted with 1, 2 or 3 substituents selected from cyclopropyl, cyclopropyl and O-cyclopropyl, and the cyclopropyl is optionally further substituted with 1 to 3 halogen atoms, or a pharma- ceutically acceptable salt of the compound.

7. R １ is a 5- or 6-membered heteroaryl containing one N, said heteroaryl being unsubstituted or independently selected from OCHF ２ , O.C.H. ２ CH ３ , O.C.F. ２ CHF ２ , OCH(CH ３ ) ２ , O.C.H. ２ CHF ２ , O.C.F. ２ CH ３ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, which is substituted with 1, 2 or 3 substituents selected from , F and cyclopropyl.

8. R １ is based on the following formula: 【Chemistry 3】 6. The compound according to any one of claims 1 to 5, wherein:

9. R ２ but, (a) halogen, C １－３ Haloalkyl, C １－３ 4-6 membered heteroaryl containing 0-1 oxygen atom and / or 0-2 nitrogen atom, optionally mono- or di-substituted with alkyl or OH; (b) unsubstituted or halogen, OH, CF ３ , (C ３－６ ) cycloalkyl, phenyl or C(O)NH ２ may be mono-, di- or trisubstituted with １－６ Alkyl, (c) C １－６ Alkyl, halogen, OH or CF ３ may be mono-, di- or trisubstituted with ３－６ Cycloalkyl, (d) halogen, C １－３ Haloalkyl, C １－３ a 4-6 membered heterocycle containing 0-1 oxygen atom and / or 0-2 nitrogen atom, optionally mono- or di-substituted by alkyl or OH; (e) C １－６ phenyl optionally substituted with alkyl or halogen, or (f) S(O) ２ C １－６ Alkyl or S(O) ２ -Phenyl 9. The compound according to any one of claims 1 to 8, wherein:

10. R ２ but, (a) C １－３ a 5- or 6-membered heteroaryl containing two N atoms, optionally substituted with alkyl or halogen; (b) phenyl substituted with halogen; (c) C １－６ Alkyl or C ３－６ Cycloalkyl [each alkyl or cycloalkyl is C １－６ Alkyl, halogen, C(O)NH ２ , O.H., C.F. ３ or may be mono-, di- or tri-substituted by CN. (d) a 5-membered saturated heterocycle containing one oxygen atom, which may be substituted with OH; (e) halogen, C １－３ Haloalkyl or C １－３ a 6-membered saturated heterocycle containing 0 or 1 oxygen atom and 0 or 1 nitrogen atom, optionally mono- or di-substituted with alkyl; or (f) S(O) ２ C １－６ Alkyl or S(O) ２ -Phenyl 10. The compound according to any one of claims 1 to 9, wherein:

11. R ２ teeth, (a) phenyl substituted with halogen; (b) C １－６ Alkyl or C ３－６ Cycloalkyl [each alkyl or cycloalkyl is C １－６ Alkyl, halogen, OH or CF ３ may be mono-, di- or tri-substituted with; or (c) halogen, C １－３ Haloalkyl or C １－３ The compound according to any one of claims 1 to 10, which is a 6-membered saturated heterocycle containing 0 or 1 oxygen atom and 0 or 1 nitrogen atom, which may be mono- or di-substituted with alkyl, or a pharma- ceutically acceptable salt of said compound.

12. R ２ But, C １－６ Alkyl, C ３－６ Cycloalkyl, C １－６ AlkylOH, C １－６ Haloalkyl, Phenyl, C ３－６ Heterocycle, C ３－６ AlkylC(O)NH ２ , S(O) ２ -phenyl or C １－６ alkyl-phenyl, wherein the alkyl is 1 to 3 halogens or CF ３ and said phenyl is optionally substituted with halogen; or a pharma- ceutically acceptable salt thereof.

13. R ２ phenyl substituted with halogen; C optionally substituted with 1 to 3 halogens or OH １－６ Alkyl, C １－３ Haloalkyl, C １－６ Alkyl-OH or C ３－６ 12. The compound of any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, which is cycloalkyl.

14. R ２ is based on the following formula: 【Chemistry 4】 12. The compound according to any one of claims 1 to 11, wherein:

15. R ２ is based on the following formula: 【Chemistry 5】 12. The compound according to any one of claims 1 to 11, wherein:

16. R ３ but, (a) a 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (b) a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (c)-(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; (d)-(C １－６ ) alkyl-aryl, (e)-(C １－６ ) alkyl-heterocycle [the heterocycle is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S; (f)-(C １－６ ) alkyl, (g)-(C ３－６ ) cycloalkyl, or (h) (C １－６ ) Hydroxyalkyl and Each aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or has 1, 2 or 3 R ９ each alkyl is unsubstituted or substituted with 1, 2 or 3 R １０ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, substituted with:

17. R ３ but, (a) a 4- to 6-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (b)-(C ３－６ ) cycloalkyl, or (c) (C １－６ ) Hydroxyalkyl and Each aryl, heteroaryl, cycloalkyl or heterocycle is unsubstituted or has 1, 2 or 3 R ９ each alkyl is unsubstituted or substituted with 1, 2 or 3 R １０ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, substituted with:

18. R ３ but, (a) halogen, OH, C １－６ Alkyl or C ０－６ 4- to 6-membered cycloalkyl optionally mono-, di- or tri-substituted by alkyl(OH); (b) halogen, C １－３ Alkyl, C １－３ a 4- to 6-membered heterocycle containing one sulfur atom or one oxygen atom, which may be mono-, di- or tri-substituted with alkyl (OH) or oxo; (c) C １－６ Alkyl, wherein the alkyl may be mono-, di- or tri-substituted with halogen or OH.

16. The compound according to any one of claims 1 to 15, wherein:

19. R ３ but, (1) 4- to 6-membered cycloalkyl optionally mono-, di- or tri-substituted with F or OH; (2) oxo, CHF ２ or CH ３ a 4- to 6-membered heterocycle containing one sulfur atom, which may be mono-, di- or trisubstituted by (3) CH ３ or a 5- or 6-membered heterocycle containing one oxygen atom, which may be mono-, di- or tri-substituted by OH; (4) C １－６ alkyl-heterocycle, wherein the heterocycle is a 5-membered heterocycle containing one oxygen atom, which may be mono-, di- or tri-substituted with OH; (5) C １－６ Alkyl-heteroaryl, wherein the heteroaryl is CH ３ or CH ２ CH ３ and contains two nitrogen atoms. (6) CH ３ a 5-membered heteroaryl containing two nitrogen atoms and one sulfur atom, which may be mono-, di- or trisubstituted with (7) C １－６ Alkyl, wherein the alkyl may be mono-, di- or tri-substituted with halogen or OH.

16. The compound according to any one of claims 1 to 15, wherein:

20. R ３ is based on the following formula: 【Chemistry 6】 16. The compound according to any one of claims 1 to 15, wherein:

21. R ３ is based on the following formula: 【Chemistry 7】 16. The compound according to any one of claims 1 to 15, wherein:

22. R ４ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 21, wherein

23. R ５ The compound according to any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, wherein is H, halogen or CN.

24. R ５ The compound according to any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, wherein is H, F, Cl or CN.

25. R ６ is halogen, hydroxy, CN, C １－３ Alkyl, C １－３ Haloalkyl, C ３－６ Cycloalkyl, O.C. １－３ Alkyl, O.C. １－３ Haloalkyl, O.C. ３－６ Cycloalkyl, S(O) ２ C １－３ Alkyl, NHC(O)C １－３ Alkyl, NC １－６ Alkyl, C(O)NH ２ , S.C. １－６ Alkyl or S(O) ２ N.H.C. １－６ 25. The compound according to any one of claims 1, 9 to 24, wherein cycloalkyl is optionally substituted with halogen, or a pharma- ceutically acceptable salt thereof.

26. R ６ C １－３ Alkyl, C ３－６ Cycloalkyl, O-C ３－６ Cycloalkyl, O.C. １－３ Alkyl, O.C. １－３ Haloalkyl, or S(O) ２ C １－３ 25. The compound according to any one of claims 1, 9 to 24, wherein said cycloalkyl is optionally further substituted with 1 to 3 F, or a pharma- ceutically acceptable salt thereof.

27. R ６ F, CF ３ , O.C.H.F. ２ , O.C.F. ３ , O.C.H. ２ CH ３ , OCH(CH ３ ) ２ , O.C.F. ２ CHF ２ , O.C.H. ２ CHF ２ , cyclopropyl, O-cyclopropyl, CN, N(CH ３ ) ２ , C(O)NH ２ , S.C.H. ３ , S(O) ２ N.H.C.H. ３ , NHC(O)CH ３ , O.H., O.C.F. ２ CHF ２ Or S(O) ２ CH ３ and the cyclopropyl is optionally further substituted with 1 to 3 halogen atoms, or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 and 9 to 24.

28. R ７ F, CF ３ or OH, or a pharma- ceutically acceptable salt of said compound according to any one of claims 1 to 8, 16 to 27.

29. R ９ GA ２ , =O, OH, C １－６ Alkyl, C １－６ Haloalkyl, halogen, or C １－６ 29. The compound according to any one of claims 1 to 17, 22 to 28, or a pharma- ceutically acceptable salt of said compound, wherein said compound is alkylOH.

30. R ９ But, O ２ , =O, OH, CH ３ , C.H. ２ CH ３ , F., C.F. ３ , C.H.F. ２ or CH ２ 30. The compound according to any one of claims 1 to 17, 22 to 29, or a pharma- ceutically acceptable salt thereof, wherein R is 0 or 1;

31. R １０ Ga = O, OH, C １－６ Alkyl, C １－６ Haloalkyl or C １－６ The compound according to any one of claims 1 to 17, and 22 to 30, which is alkylOH, or a pharma- ceutically acceptable salt of said compound.

32. R １０ =O, OH, CH ３ , C.H. ２ CH ３ , F., C.F. ３ , or C.H. ２ 32. The compound according to any one of claims 1 to 17, 22 to 31, or a pharma- ceutically acceptable salt thereof, wherein R is 0 or 1;

33. X is N and Y is C(R ５ ) and Z is C(R ５ 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein:

34. X is C(R ５ ), Y is N, and Z is C(R ５ 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein:

35. X is C(R ５ ) and Y is C(R ５ 33. The compound of any one of claims 1 to 32, wherein:

36. X, Y and Z are C(R ５ 33. The compound according to any one of claims 1 to 32, or a pharma- ceutically acceptable salt thereof, wherein:

37. The compound: 【Chemistry 8】 【change】 37. The compound according to any one of claims 1 to 36, wherein:

38. The compound: 【Chemistry 9】 37. The compound according to any one of claims 1 to 36, wherein:

39. The compound: 【Chemistry 10】 【change】 【change】 【change】 【change】 【change】 or a pharma- ceutically acceptable salt of said compound.

40. (R)-1,3-bis(4-fluorophenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-(3-(difluoromethoxy)phenyl)-1-(4-fluorophenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-6-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]benzimidazole-5-carboxamide, 1-(3-isopropoxyphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-1-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]benzimidazole-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-(3-ethoxyphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]benzimidazole-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[4-(difluoromethoxy)-2-pyridyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-(3-cyclopropylphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(cyclopropoxy)phenyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(2,2-difluorocyclopropyl)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-(2-hydroxy-1,2-dimethyl-propyl)-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1S,2S)-2-hydroxycyclopentyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(3R,4S)-3-hydroxytetrahydropyran-4-yl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-1-[3-(difluoromethoxy)phenyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1R,2R)-2-hydroxycyclohexyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-N-[(1S,2S)-2-hydroxycyclohexyl]-3-isopropyl-2-oxo-benzimidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-cyclobutyl-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-cyclopentyl-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-ethyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-cyclopropyl-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-(1,1-difluoropropan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-3-(1,1-difluoropropan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-(sec-butyl)-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(sec-butyl)-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(sec-butyl)-1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-(2-hydroxy-2-methylpropyl)-N-(3-methyl-1,1-dioxidothiethan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-(difluoromethoxy)pyridin-3-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-cyclopropylpyridin-3-yl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-3-[3-(trifluoromethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-3-[3-(trifluoromethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 1-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-ethoxyphenyl)-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-isopropoxyphenyl)-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-isopropoxyphenyl)-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[5-(difluoromethoxy)-2-fluoro-phenyl]-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[5-(difluoromethoxy)-2-fluoro-phenyl]-1-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-[3-(difluoromethoxy)phenyl]-1-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-imidazo[4,5-b]pyridine-6-carboxamide, 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxamide, 3-(3-(difluoromethoxy)phenyl)-1-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-benzimidazole-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-benzimidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-4-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-6-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidetetrahydrothiophen-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 4-chloro-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 4-cyano-1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(difluoromethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(difluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(difluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(3-(2,2-difluoroethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(3-(2,2-difluoroethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-6-fluoro-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-6-fluoro-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(5-(2,2-difluoroethoxy)-2-fluorophenyl)-6-fluoro-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-1-(2-ethoxy-5-fluoropyridin-4-yl)-3-(3-hydroxy-3-methylbutan-2-yl)-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, N-(4-(difluoromethyl)-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(4-acetamido-3-hydroxyphenyl)-3-isopropyl-N-(3-methyl-1,1-dioxidothiethan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-1-(2-methylbenzo[d]oxazol-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-1-(2-methylbenzo[d]oxazol-6-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-fluorophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(5-fluoro-2-isopropoxypyridin-4-yl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-cyanophenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(3-(trifluoromethyl)phenyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(dimethylamino)phenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-carbamoylphenyl)-3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(3-(methylthio)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(3-(N-methylsulfamoyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 3-isopropyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-1-(3-(methylsulfonyl)phenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-(4-fluorobenzyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-N-((1-ethyl-1H-pyrazol-4-yl)methyl)-3-isopropyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (R)-3-(1-amino-1-oxopropan-2-yl)-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, (S)-3-(1-amino-1-oxopropan-2-yl)-1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, or The compound according to any one of claims 1 to 39, which is 1-(3-(difluoromethoxy)phenyl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-2-oxo-3-(phenylsulfonyl)-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, or a pharma- ceutically acceptable salt thereof.

41. 40. A composition for treating a condition selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, chronic kidney disease and heart failure comprising a compound of any one of claims 1 to 39 or a pharma- ceutically acceptable salt of said compound and a pharmaceutical carrier.

42. 40. A composition comprising a pharma- ceutically acceptable carrier and a compound according to any one of claims 1 to 39, or a pharma- ceutically acceptable salt of said compound.

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

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