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

Abstract

Disclosed are compounds of Formula I as well as pharmaceutically acceptable salts, esters, and prodrugs thereof, which are DGAT2 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases and heart failure and related diseases and conditions, comprising administering a compound of Formula I to a patient in need thereof.

Description

PREPARATION OF OXALAMIDE DERIVATIVES AS NOVEL DIACYLGLYCERIDE O-ACYLTRANSFERASE 2 INHIBITORSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Application No. 63 / 735,548, filed December 18, 2024, the entirety of which is incorporated herein by reference.FIELD

[0002] The present disclosure is directed to novel pharmaceutical compounds which inhibit diacylglyceride O-acyltransferase 2 (“DGAT2”), and may be useful for preventing, treating or acting as a reversing agent for hepatic steatosis, nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases and heart failure, and related diseases and conditions, as well as methods of making such compounds and pharmaceutical compositions comprising such a compound and a pharmaceutical carrier.BACKGROUND

[0003] Triacylglycerols (“TGs”) serve several functions in living organisms. One such function of TGs is in the storage of energy. TGs also play a role in the synthesis of membrane lipids. TG synthesis in cells may protect them from the potentially toxic effects of excess fatty' acid (“FA”). In enterocytes and hepatocytes, TGs are synthesized for the assembly and secretion of lipoproteins which transport FA between tissues. TGs play a role in the skin’s surface water barrier, and TGs in adipose tissue provide insulation for organisms.

[0004] The glycerol phosphate and the monoacylglycerol pathways are the major pathways for the biosynthesis of TG. However, the last step in the synthesis of TG involves the reaction of a fatty acyl-CoA and diacylglycerol (“DAG”) to form TG. The reaction is catalyzed by acyl-CoA:diacylglycerol acyltransferase (“DGAT”) enzy mes. There have been identified two DGAT enzymes, DGAT1 and DGAT2. Although DGAT1 and DGAT2 catalyze the same reaction, they differ significantly at the level of DNA and protein sequences. DGAT2 can utilize endogenous fatty acid to synthesize TG in in vitro assays, whereas DGAT1 appears to be more dependent on exogenous fatty acid (Y en et al., J. Lipid Research, 2008, 49, 2283). Inactivation of DGAT2 impaired cytosolic lipid droplet growth, whereas inactivation of DGAT1 exerts opposite effect. (Li et al., Arter ioscler. Thromb. Vase. Biol. 2015, 35, 1080).

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

[0006] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been mostly comprehended from effort exploiting anti-sense oligonucleotides (ASO) in rodents. In this setting, DGAT2 knockdown in ob / ob mice with a DGAT2 gene-specific ASO resulted in a dose dependent decrease in very’ low density lipoprotein i 'VLDL") and a reduction 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 a decrease in weight gain, adipose weight and hepatic TG content. Id. In another study, antisense treatment of ob / ob mice improved hepatic steatosis and hyperlipidemia (Y u, et al., Hepatology, 2005, 42, 362). Another study showed that diet-induced hepatic steatosis and insulin resistance was improved by¬ knocking down DGAT2 in rats. These effects seem to be unique to inhibition of DGAT2, as ASO against DGAT1 did not lead to similar beneficial effects. Although the molecular mechanism behind these observations remains uncertain, the collective data suggest that suppression of DGAT2 is associated with reduced expression of lipogenic genes (SREBPlc, ACC1. SCD1, and mtGPAT) and increased expression of oxidative / thermogenic genes (CPT1, UCP2) (Choi etal., J. Bio. Chem., 2007, 282, 22678).

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

[0008] DGAT2 inhibitor compounds are described in WO2022140169, WO2022076495, WO2022076496, W02022050749, WO2021236401, WO2021236405. WO2021133035, W02021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, W02013150416, US20150259323, WO2015077299, W02017011276, WO2018033832, US201801628, W02003053363, WO2024118858, WO2024097576, WO2024097575, and WO2024097573.SUMMARY

[0009] The present disclosure is directed to compounds having structural Formula I:as well as pharmaceutically acceptable salts, esters, and prodrugs thereof, which are DGAT2 inhibitors. Also provided are methods of making compounds of Formula I, pharmaceutical compositions comprising compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases and heart failure and related diseases and conditions, comprising administering a compound of Formula I to a patient in need thereof.DET AILED DESCRIPTION

[0010] The present disclosure is directed to compounds of structural Formula I:or pharmaceutically acceptable salts thereof wherein:W, X, Y and Z are each independently selected from -C(H)-, -C(Ci-6alkyl)-, -C(C3-6cycloalkyl)-, -C(halo)-, -C(Ci-6haloalkyl)-, -C(OH)-, and -N-;R1is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with 1-3 R3;R2is(1) 4-7 membered heterocyclyl containing 1-3 ring heteroatoms independently selected from N, O and S, or(2) -(C3-6)cycloalkylwherein each heterocyclyl or cycloalkyl is unsubstituted or substituted with 1 -3 R4;when present, each R3is independently selected from:(1) halogen,(2) -(Ci-3)alkyl,(3) -(Ci-3)haloalkyl,(4) -O-(Ci-3) alkyl, and(5) -O-(Ci-3)haloalkyl;when present, each R4is independently selected from:(1) hydroxy,(2) halogen,(3) (Ci-3)alkyl,(4) (Ci-3)haloalkyl, and(5) =0.

[0011] In Embodiment 2 of this disclosure are compounds of Formula I, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from, halogen, -(Ci-3)alkyl, -(Ci- 3)haloalkyl and -O-(Ci-3)haloalkyl.

[0012] In Embodiment 3 of this disclosure are compounds of Formula I, or Embodiment 2 or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is a 6 membered heteroaryl having 1-2 nitrogen ring atom, substituted with 1-2 substituents independently selected from halogen, -(Ci-3)alkyl, -(Ci-3)haloalkyl. and -O-(Ci-3)haloalkyl.

[0013] In Embodiment 4 of this disclosure are compounds of Formula I, or any one of Embodiments 2-3 or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is pyridinyl substituted with 1-2 substituents independently selected from -F, -Cl, -O-CH2CF3, -O- CH2CHF2, -CHF2, or -O-CF2CHF2.

[0014] In Embodiment 5 of this disclosure are compounds of Formula I, or any one of Embodiments 2-3 or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is pyrazinyl substituted with 1-2 substituents independently selected from -O-CH2CF3, -O- CH2CHF2, or -CHF2.

[0015] In Embodiment 6 of this disclosure are compounds of Formula I. or any one of Embodiments 2-5 or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is‘O ‘o. N, NN, or

[0016] In Embodiment 7 of this disclosure are compounds of Formula I, or any one of Embodiments 2-6 or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is26118(1) 4-7 membered heterocyclyl having 1, 2 or 3 ring heteroatoms independently selected from N, O and S, or(2) -(C3-6)cycloalkyl,wherein each, heterocyclyl or cycloalkyl is unsubstituted or substituted with 1, 2. or 3 substituents independently selected from-OH. halogen, -(Ci-3)alkyl, -(Ci-3)haloalkyl. and =0.

[0017] In Embodiment 8 of this disclosure are compounds of Formula I, or any one of Embodiments 2-7 or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is (1) 4-6 membered heterocyclyl having 1 ring heteroatom selected from O and S, wherein the heterocyclyl is unsubstituted or substituted with 1 or 2 substituents independently selected from =0 and methyl, or(2) -(C5-6)cycloalkyl, wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from -OH and -F.

[0018] In Embodiment 9 of this disclosure are compounds of Formula I, or any one of Embodiments 2-8 or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is tetrahydro-2H-thiopyran, substituted with one methyl substituent and two =0 substituents; thietanyl, substituted with one methyl substituent and two =0 substituents; cyclohexyl, substituted with one -OH substituent and 2 -F substituents; tetrahydrothiophenyl, substituted with one methyl substituent and two =0 substituents; and tetrahydrofuranyl, substituted with one methyl substituent.

[0019] In Embodiment 10 of this disclosure are compounds of Formula I, or any one of Embodiments 2-9 or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is

[0020] In Embodiment 11 of this disclosure are compounds of Formula I, or any one of Embodiments 2-10 or a pharmaceutically acceptable salt of any of the foregoing, wherein X is -C(H)-, -C(Ci-6alkyl)-, -C(C3-6cycloalkyl)-, -C(halo)-, -C(Ci-6haloalkyl)-, -C(OH)-, or -N-.

[0021] In Embodiment 12 of this disclosure are compounds of Formula I, or any one of Embodiments 1-11 or a pharmaceutically acceptable salt of any of the foregoing, w herein X is -C(H)-, -C(CH3)-. -C(CH2CH3)-, -C(cyclopropyl)-, -C(F)-. -C(C1)-, -C(CHF2)-, -C(OH)-, or -N-.

[0022] In Embodiment 13 of this disclosure are compounds of Formula I, or any one of Embodiments 1 -12 or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is -C(H)-, -C(Ci-6alkyl)-, -C(halo), or -N-.

[0023] In Embodiment 14 of this disclosure are compounds of Formula I, or any one of Embodiments 1-13 or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is -C(H)-, -C(CHs)-, -C(F)-, or -N-.

[0024] In Embodiment 15 of this disclosure are compounds of Formula I, or any one of Embodiments 1-14 or a pharmaceutically acceptable salt of any of the foregoing, wherein Z is -C(H)-, -C(Ci-6alkyl)-, -C(halo)-, or -N-.

[0025] In Embodiment 16 of this disclosure are compounds of Formula I, or any one of Embodiments 1-15 or a pharmaceutically acceptable salt of any of the foregoing, wherein Z is -C(H)- or -N-.

[0026] In Embodiment 17 of this disclosure are compounds of Formula I, or any one of Embodiments 1-16 or a pharmaceutically acceptable salt of any of the foregoing, wherein W is -C(H)-, -C(Ci-6alkyl)-, -C(halo)-, or -N-.

[0027] In Embodiment 18 of this disclosure are compounds of Formula I, or any one of Embodiments 1-17 or a pharmaceutically acceptable salt of any of the foregoing, wherein W is -C(H)-, -C(CH3)-, -C(F)-, or -N-.

[0028] In Embodiment 19 of this disclosure are compounds of structural Formula (II):IIor pharmaceutically acceptable salts thereof wherein:X is selected from -C(H)-, -C(Ci-6alkyl)-, -C(C3-6Cycloalkyl)-, -C(halo)-, -C(Ci-6haloalkyl)-, -C(OH)-, and -N-;Y is selected from -C(H)-, -C(Ci-6alkyl)-, -C(halo)- and -N-;Z is selected from -C(H)-, -C(Ci-6alkyl)-, -C(halo)-, and -N-;W is selected from -C(H)-, -C(Ci-6alkyl)-, -C(halo)-, and -N-;X1is selected from -C(H)- and -N-;R3ais selected from:(1) -O-(Ci-3)alkyl, and(2) -O-(Ci-3)haloalkyl;each R3bis independently selected from:(1) halogen,(2) -(Ci-3)alkyl, and(3) -(Ci-3)haloalkyl;R2is(1) 4-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, or(2) -(C3-6)cycloalkylwherein each heterocyclyl or cycloalkyl is unsubstituted or substituted with 1 -3 R4;when present, each R4is independently selected from:(1) halogen,(2) (Ci-3)alkyl,(3) (Ci-3)haloalkyl,(4) hydroxy, and(5) =0.

[0029] In Embodiment 20 of this disclosure are compounds of Formula I or II, or Embodiment 19, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3bis halogen or haloalkyl.

[0030] In Embodiment 21 of this disclosure are compounds of Formula I or II, or Embodiments 19-20. or a pharmaceutically acceptable salt of any of the foregoing, wherein R3bis F, Cl, or CHF2.

[0031] In Embodiment 22 of this disclosure are compounds of Formula I or II, or Embodiment 19, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3ais -O(Ci-6)haloalkyl.

[0032] In Embodiment 23 of this disclosure are compounds of Formula 1 or II, or Embodiments 19-20, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3ais -OCH2CF3, -OCH2CHF2, -OCF2CHF2.

[0033] In Embodiment 24 of this disclosure, the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is:jV1-(5-((5-Fluoro-3-(2, 2, 2-tri fluoroethoxy )pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-jV2-(4-methyl- 1, 1 -dioxi dotetrahydro-27 / -thi opy ran-4-y I )o\al amide,jV1-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)pyridine-3-yl)-7V2-(4-methyl-l, 1-dioxidolelrahydro-27 / -thiopyran-4-yl)oxal amide,A^1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)pyridine-2-yl)-7V2-(4-methyl-l,l-dio\idotetrahydro-2 / / -thiopyran-4-yl)o\al amide,A^1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-6-methylpyri din-2 -yl)-V2-(4-methyl- 1, 1 -dioxi dotetrahy dro-27 / -lhiopy ran-4-y I Joxal amide,JV1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-6-methylpyridin-2-yl)-jV2-(3-methyl- 1,1 -di oxidothietan-3-yl)oxal amide,JV1-(5-((5-Chloro-3-(2.2.2-trifluoroethoxy)pyridine-2-yl)oxy)-6-methylpyri din-2 -yl)-jV2-((15,2?)- 3,3-difluoro-2-hydroxycyclohexyl)oxalamide,jV1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-V2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I Joxal amide.7V1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-A^2-(3-methyl- 1, 1 -dioxidothietan-3-yl)oxal amide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-((1S,2R)- 3,3-difluoro-2-hydroxycyclohexyl)oxalamide,JV1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-3-methylpyridin-2-yl)-V2-(4-methyl- 1, 1 -dioxidotetrahy dro-27 / -thiopyran-4-yl)oxal amide,jV1-(5-((5-Chloro-3-(2,2-difluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-7V2-(4-methyl- 1, 1 -dioxi dotetrahydro-27 / -thi opy ran-4-y I Joxal amide,jV1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-jV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2H-thi opy ran-4-y I Joxal amide.jV1-(5-((5-Fluoro-3-(2,2-difluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-JV2-(4-methyl- 1, 1 -dioxi dotetrahydro-2 / / -thi opy ran-4-y I Joxal amide,JV1-(5-((3-(2,2-Difluoroethoxy )pyrazin-2-y l)oxy)-4-methy Ipyri din-2 -yl)-V2-(4-methyl- 1,1-dioxidoletrahydro-2 / / -thiopyran-4-yl Joxal amide,Ad-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-5-methylpyridin-3-yl)-V2-(4-methyl- 1, 1 -dioxidotetrahy dro-27 / -thiopy ran -4-yl Joxal amide,JV1-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-2-methylpyridin-3-yl)-jV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I Joxal amide.(7?)-jV1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-A^2-(3-methyl- 1, 1 -dioxidotetrahy drothiophen-3-yl)oxal amide,jV1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-JV2-(3-methyl- 1, 1 -di oxidothietan-3-yl)oxal amide,(<S’)-7V1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-jV2-(3-methyl- 1, 1 -dioxidotetrahy drothiophen-3-yl)oxalamide,(R)-N1-(5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyltetrahydrofuran-3-yl)oxalamide,(< S’)-A^1-(5-((5-fluoro-3-(2, 2, 2-trifluoroethoxy)pyri din-2 -yl)oxy)-4-methylpyri din-2 -yl)-A^2-(3-methyltetr ahydrofuran-3-yl)oxal amide,(iS)-jV1-(5-((3-(2,2-Difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-4-methylpyridin-2-yl)-jV2-(3-methyl- 1, 1 -dioxidotetrahy drothiophen-3-yl)oxalamide,JV1-(5-((3-(2,2-Difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-4-methylpyridin-2-yl)-A^2-(3-methyl- 1, 1 -dioxidothietan-3-yl)oxal amide,jV1-(5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazin-2-yl)-V2-(4-methyl-l,l-dioxidotetrahy dro-2 / / -thiopyran-4- l)oxal amide.7V1-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridazin-3-yl)-JV2-(4-methyl-l,l-dioxidotetrahy dro-27 / -thiopyran-4-yl)oxal amide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,JV1-(5-((5-(Difluoromethyl)-3-(2,2-difluoroethoxy)pyri din-2 -yl)oxy)-4-methylpyri din-2 -yl)-JV2-(4-methyl- 1, 1 -dioxidotetrahy dro-27 / -thiopyran-4-yl)oxal amide,N1-(5-((5-(Difluoromethyl)-3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-(Difluoromethyl)-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide.N1-(4-Cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,V1-(4-Ethyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-V2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I Joxal amide,Ad-(4-Difluoromethyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-JV2-(4-methyl- 1, 1 -dioxidotetrahy dro-27 / -thiopy ran -4-yl Joxal amide,JV1-(4-Chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-jV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I Joxal amide,JV1-(4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-7V2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thiopy ran-4-y l)oxal amide,jV1-(4-hydroxy-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-jV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I Joxal ami de.7V / -(5-Fluoro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)-7V2-(4-methyl- 1, 1 -dioxi dotetrahydro-2-thiopyran-4-yl)oxal amide,Ar7-(3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A^-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I Joxal amide,A^1-(3-Fluoro-5-((5-fluoro-3-(2, 2, 2-trifluoroethoxy)pyri din-2 -yl)oxy)-4-methylpyri din-2 -yl)-A^2-(4-methyl- 1, 1 -dioxidotetrahy dro-2H-thi opy ran -4- l )oxalamide.JV / -(5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-6-methylpyrazin-2-yl)-JV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / 7-thi opy ran-4-y I )oxal amide,JV1-(5-((5-Fluoro-3-( 1,1, 2, 2-tetrafluoroethoxy)pyri din-2 -yl)oxy)-4-methylpyri din-2 -yl)-JV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thiopyran-4-yl)oxal amide, orjV1-(4-methyl-l,l-dioxidotetrahydro-2 / / -thiopyran-4-yl)-JV2-(4-methyl-5-((3-(l,l,2,2-tetrafluoroethoxy)pyri din-2 -yl)oxy)pyri din-2 -yl)oxal ami de.

[0034] In Embodiment 25 of this disclosure, the compound of Formula I or II. or a pharmaceutically acceptable salt thereof, is:

[0035] The term “compound(s) of Formula (I)”, includes compounds of Embodiments 1-25 as well as compounds of Formula (II).

[0036] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined therein.

[0037] In one embodiment, the present disclosure is a composition comprising an effective amount of at least one compound of Formula I and II, or a pharmaceutically acceptable salt thereof.

[0038] The disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula I and II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0039] The disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula I and II. or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent).

[0040] The disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula I and II. or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

[0041] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases or heart failure comprising an acceptable carrier and a compound of Formula I and II, or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases or heart failure, comprising a compound of Formula I and II, or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases or heart failure, comprising a compound of Formula I and II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0044] In one embodiment, the present disclosure provides a method of treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases or heart failure in a subject in need of such treatment, comprisingadministering to said subject a therapeutically effective amount of at least one compound of Formula I and II, or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, the present disclosure provides a method of treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney diseases or heart failure in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of at least one compound of Formula I and II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0046] The methods of the disclosure include the administration of a pharmaceutical composition comprising at least one compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0047] In another embodiment, the present disclosure includes a method of treating NASH / MASH and / or fibrosis, comprising administering to a patient in need thereof a compound of Formula I and II, or a pharmaceutically acceptable salt thereof.

[0048] In another embodiment, the present disclosure includes a method of treating NASH / MASH and / or fibrosis, comprising administering to a patient in need thereof a compound of Formula I and II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0049] In another embodiment, the present disclosure includes a method of treating NASH / MASH and / or fibrosis, comprising administering to a patient in need thereof a composition comprising a compound of Formula I and II, or a pharmaceutically acceptable salt thereof.

[0050] In another embodiment, the present disclosure includes a method of treating NASH / MASH and / or fibrosis, comprising administering to a patient in need thereof a composition comprising a compound of Formula I and II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0051] In another embodiment, the present disclosure provides for the use of a compound of Formula I and II, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating NASH / MASH and / or fibrosis.

[0052] In another embodiment, the present disclosure includes the use of a compound of Formula I and II, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of NASH / MASH and / or fibrosis.26118

[0053] " Alkyl" means branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms when noted. If no number is specified, 1-6 carbon atoms are intended for linear and 3-7 carbon atoms for branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec- and tert-butyl, and the like. For example, the term “Ci-ealkyl” includes all of 'iC1-4alkyl” defined as follows, plus the linear or branched chain alkyl groups, including all possible isomers, having 5 or 6 carbon atoms. “Ci-ealkyl” means linear or branched chain alkyl groups, including all possible isomers, having 1, 2, 3, 4, 5 or 6 carbon atoms, and includes each of the alkyl groups within Ci-ealkyl including each of the hexyl and pentyl isomers as well as n-, iso-, sec- and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively “C4alkyl”; Bu = butyl), n- and i-propyl (propyl, i-propyl, collectively “Csalkyl”; Pr = propyl), ethyl (Et) and methyl (Me). Commonly used abbreviations for alkyl groups are used throughout the specification, e.g.. methyl may be represented by conventional abbreviations including “Me” or CH3 or a symbol that is an extended bond as the terminal group, " _ "e.g., ethyl may be represented by '‘Et” or CH2CH3, propyl may be represented by ‘'Pr” or CH2CH2CH3, butyl may be represented by “Bu” or CH2CH2CH2CH3, etc. For example, the HN^"^3structuresand have equivalent meanings. If no number is specified, 1- 6 carbon atoms are intended for linear or branched alkyl groups.

[0054] “Alkoxy” refers to an alkyl group linked to oxygen. Examples of alkoxy groups include methoxy, ethoxy, propoxy and the like.

[0055] “Aryl” refers to an aromatic monocyclic or multi cyclic ring moiety comprising 6 to 14 ring carbon atoms. In one embodiment, an aryl group contains from about 6 to 10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl. Multi cyclic rings include, but are not limited to, naphthyl and bicyclic rings wherein phenyl is fused to a C5-7cycloalkyl or C5-7cycloalkenyl ring. Aryl groups may be optionally substituted with one or more substituents as defined herein. Bonding can be through any of the carbon atoms of any ring.

[0056] “Halogen” or “Halo” includes fluorine, chlorine, bromine and iodine.

[0057] “Cycloalkyl” refers to a non-aromatic mono-or multi cyclic ring system comprising about 3 to 10 ring carbon atoms. If no number of atoms is specified, 3-10 carbon atoms are intended. Cycloalkyl may also be fused, forming 1-3 carbocyclic rings. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term Ci-ecycloalkyl” refers to a cycloalkyl group having 1 to 6 ring carbon atoms. The term Cs-ecycloalkyl” refers to a cycloalkyl group having 3 to 6 ring carbon atoms.26118Thus, for example, “C3-6 cycloalkyl” includes each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group is unsubstituted or substituted with one or more ring system substituents which may be the same or different, and are as defined within. When cycloalkyl is a substituent on an alkyl group, the cycloalkyl substituent can be bonded to any available carbon in the alkyl group. The following are illustrations of -C3-6cycloalkyl substituents on an alkyl groupwherein the substituent is cyclopropyl in bold:

[0058] “Haloalkyl” refers to an alkyl group as defined within, wherein one or more of the alkyl group’s hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has from 1 to 6 carbon atoms. Non-limiting examples of haloalkyl groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2CI, CH2CF2CH3, and CCI3. The term “Ci-ehaloalkyl” or “haloCi-ealkyl” refers to a haloalkyl group having from 1 to 6 carbons, either straight or branched chain.

[0059] " Haloalkoxy,” “haloalkyl-O" and expressions such as “halo(Ci-6)alkoxy” or “-O(Ci-6)haloalkyl” or likewise “-O(Ci-3)haloalkyl, refer to halo substituted alkyl groups linked through the oxygen atom. Haloalkoxy include mono- substituted as well as multiple halo substituted alkoxy groups. For example, trifluoromethoxy, chloromethoxy, and bromomethoxy are included as well as OCH2CF3, OCH2CHF2, OCF2CF3, and OCF2CHF2.

[0060] " Heterocyclyl," "heterocycle" or "heterocyclic" refers to monocyclic ring structures in which one or more atoms in the ring, the heteroatom(s), is an element other than carbon.Heteroatoms are typically O, S or N atoms. A heterocycle containing more than one ring heteroatom may contain different heteroatoms. Bicyclic ring moieties include fused, spirocyclic and bridged bicyclic rings and may comprise one or more heteroatoms in either of the rings. The ring attached to the remainder of the molecule may or may not contain a heteroatom. Either ring of a bicyclic heterocycle may be saturated, partially unsaturated or unsaturated. The heterocycle may be attached to the rest of the molecule via a ring carbon atom, a ring oxygen atom or a ring nitrogen atom. Examples of heterocyclyl groups include: piperidine, piperazine, morpholine. pyrrolidine, tetrahydrofuran. azetidine, oxirane, tetrahydro-2-thiopyran. tetrahydrothiophenyl, tetrahydrofuranyl, thietanyl, aziridine, and the like.

[0061] “Bicyclic heterocyclyl,” “bicyclic heterocycle” or “bicyclic heterocyclic” refers to a heterocyclic ring fused to another ring system. The fusion may be bridged or unbridged.

[0062] Except where noted, the term “heteroaryl”, as used herein, represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is26118aromatic and contains from 1 to 4 ring heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl. isoindolyl. isoquinolyl, isothiazolyl, isoxazolyl. naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, pyridinyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline.

[0063] ‘‘Oxo'’ means an oxygen linked to an atom by a double bond. An example of an oxo group is a double bonded oxygen in a ketone, sulfoxide, sulfone, sulfate, or double bonded oxygen fused to nonaromatic cycloalkyl or heteroalkyl.

[0064] “Hydroxy alkyl” or “hydroxy(Ci-3)alkyl” means an alkyl group having one or more hydrogen atoms replaced by hydroxyl (-OH) groups. An example includes -CH(OH)CHs, -CHC(OH)(CH3)2and -CH2OH.

[0065] “Hydroxyhaloalkyl” means an alkyl group having one or more hydrogen atoms replaced by hydroxyl (-OH) groups, and one or more hydrogen atoms replaced by a halogen substituent. An example includes -CH(CF3)OH.

[0066] The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0067] The term “at least one” means one or more than one. The meaning of “at least one” with reference to the number of compounds of the disclosure is independent of the meaning with reference to the number of chemotherapeutic agents.

[0068] The term “effective amount” means a “therapeutically effective amount”. The term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0069] Except where noted herein, the term "carbocycle" (and variations thereof such as "carbocyclic" or "carbocyclyl") as used herein, unless otherwise indicated, refers to a C3to Ce monocyclic ring, e.g., C3-6 monocyclic carbocycle. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. Saturated carbocyclic rings26118include, for example, "cycloalkyl" rings, e.g., cyclopropyl, cyclobutyl, etc. Unsaturatedcarbocyclic rings include, for example o o.

[0070] A "stable" compound is a compound which can be prepared and isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0071] The compounds of the present disclosure are limited to stable compounds embraced by Formula I, and its embodiments. For example, certain moieties as defined in Formula I, may be unsubstituted or substituted, and the latter is intended to encompass substitution patterns (i.e., number and kind of substituents) that are chemically possible for the moiety and that result in a stable compound.

[0072] The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selected from the indicated group, provided that the designated atom’s normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Where multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted by one or more of the disclosed or claimed substituent moieties. singly or plurally. By independently substituted, it is meant that the (two or more) substituents can be the same or different. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure result. By optionally substituted, it is meant that compounds containing the specified optional substituent(s) as well as compounds that do not contain the optional substituent(s).

[0073] The wavy line , as used herein, indicates a point of attachment to the rest of the compound.

[0074] Where ring atoms are represented by variables such as X, e.g., , the variables are defined by indicating the atom located at the variable ring position without depicting the ring bonds associated with the atom. For example, when X in the above ring is nitrogen, the definition will show “N” and will not depict the bonds associated with it, e.g., will not show “=N-“ Likewise, when X is a carbon atom that is substituted with bromide, the definition will show “C-Br” and will not depict the bonds associated with it, e.g., will not show— C-BrII

[0075] The disclosure also includes derivatives of the compound of Formula I, acting as prodrugs and solvates. Any pharmaceutically acceptable pro-drug modification of a compound of the disclosure which results in conversion in vivo to a compound within the scope of the disclosure is also within the scope of the disclosure. Prodrugs, following administration to the patient, are converted in the body by normal metabolic or chemical processes, such as through hydrolysis in the blood, to the compound of Formula I. Such prodrugs include those that demonstrate enhanced bioavailability, tissue specificity, and / or cellular delivery, to improve drug absorption of the compound of I. The effect of such prodrugs may result from modification of physicochemical properties such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine the permeation properties of the drug.

[0076] For example, esters can optionally be made by esterification of an available carboxylic acid group or by formation of an ester on an available hydroxy group in a compound. Similarly, labile amides can be made. Pharmaceutically acceptable esters or amides of the compounds of the disclosure may be prepared to act as pro-drugs which can be hydrolyzed back to an acid (or -COO-depending on the pH of the fluid or tissue where conversion takes place) or hydroxy form particularly in vivo and as such are encompassed within the scope of the disclosure. Included are those esters and acyl groups known in the art for modifying the solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Examples of pharmaceutically acceptable pro-drug modifications include, but are not limited to, -Ci-ealkyl esters and -Ci ealkyl substituted with phenyl esters.

[0077] " Celite K" (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite".

[0078] When any variable (e.g., R1etc.) occurs more than one time in any constituent or in Formula I, or other generic Formula herein, its definition on 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 choosing compounds of the present disclosure, one of ordinary skill in the art will recognize that the various substituents, i.e., R1etc., are to be chosen in conformity with well-known principles of chemical structure connectivity and stability. Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., aryl, a heteroaryl ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.

[0079] It should be noted that, if a discrepancy between the chemical name and structure exists, the structure is understood to dominate.

[0080] Compounds of structural Formula I, may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereoisomeric mixtures and individual diastereoisomers. Centers of asymmetry that are present in the compounds of Formula I can all independently of one another have S configuration or R configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the disclosure, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formulas. Similarly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name. The production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of the disclosure.

[0081] The compounds of this disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and / or diastereomers, in all ratios. Thus, enantiomers are a subject of the disclosure in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis / trans isomerism the disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The present disclosure is meant to comprehend all such stereo-isomeric forms of the compounds of structural Formula I.

[0082] Compounds of structural Formula I may be separated into their individual diastereoisomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof, or via chiral chromatography using an optically active stationary phase. Optionally a derivatization can be carried out before a separation of stereoisomers. The separation of a mixture of stereoisomers can be earned out at an intermediate step during the synthesis of a compound of Formula I, or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary’, with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer or isomers of a compound of Formula I may’ be obtained by’ stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. The presentdisclosure includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0083] If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereoisomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art.

[0084] For compounds of Formula I described herein which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.

[0085] Some of the compounds described herein may exist as tautomers which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I of the present disclosure.

[0086] In the compounds of structural Formula I the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of structural Formula I and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (1H) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples. Isotopically-enriched compounds within structural Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0087] It will be understood that the compounds of structural Formula I may be prepared as pharmaceutically acceptable salts or as salts that are not pharmaceutically acceptable when they26118are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations. The compounds of the present disclosure, including the compounds of the Examples, may also include all salts of the compounds of Formula I which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of physiologically acceptable salts.

[0088] The compounds of the present disclosure may be administered in the form of a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.

[0089] Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this disclosure which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present disclosure include, but are not limited to, 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, gly colly larsanilate. hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,hydroxy naphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, 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, teoclate, thiocyanate, tosylate, triethiodide, valerate and the like. Furthermore, where the compounds of the disclosure carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous. potassium, sodium, zinc, and the like. In one embodiment, the salts of acidic compounds are as follows, the ammonium, calcium, magnesium, potassium, and sodium salts.

[0090] With basic reagents such as hydroxides, carbonates, hydrogencarbonates, alkoxides and ammonia, organic bases or alternatively basic amino acids the compounds of the Formula I, form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts.

[0091] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-26118exchange 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. Also, included are the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

[0092] The preparation of pharmacologically acceptable salts from compounds of the Formula I capable of salt formation, including their stereoisomeric forms is carried out known methods, for example, by mixing a compound of the present disclosure with an equivalent amount and a solution containing a desired acid, base, or the like, and then collecting the desired salt by filtering the salt or distilling off the solvent. The compounds of the present disclosure and salts thereof may form solvates with a solvent such as water, ethanol, or glycerol. The compounds of the present disclosure may form an acid addition salt and a salt with a base at the same time according to the type of substituent of the side chain.

[0093] If the compounds of Formula I simultaneously contain acidic and basic groups in the molecule the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I by customary methods which are known to the person skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from other salts.

[0094] The present disclosure includes compounds of structural Formula I as well as salts thereof, particularly pharmaceutically acceptable salts, solvates of such compounds and solvated salt forms thereof, where such forms are possible unless specified otherwise.

[0095] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and cry stalline forms and mixtures thereof of the compounds of Formula I including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant disclosure may form solvates with water (i.e., a hydrate) or common organic solvents such as but not limited to EtOAc. Such solvates and hydrates, particularly the pharmaceutically acceptable26118solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this disclosure, along with un-solvated and anhydrous forms.

[0096] Accordingly, the compounds within the generic structural formulas, embodiments and specific compounds described in the Examples and claimed herein encompass salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvate and hydrate forms thereof and any combination of these forms, as well as the salts, pro-drug forms thereof, and salts of pro-drug forms thereof, where such forms are possible unless specified otherwise,

[0097] The disclosure also relates to medicaments containing at least one compound of the Formula I and / or of a pharmaceutically acceptable salt of the compound of the Formula I and / or an optionally stereoisomeric form of the compound of the Formula I, or a pharmaceutically acceptable salt of the stereoisomeric form of the compound of Formula I together with a pharmaceutically acceptable vehicle, carrier, additive and / or other active substances and auxiliaries.

[0098] The medicaments according to the disclosure can be administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred.

[0099] The disclosure also relates to a process for the production of a medicament, which comprises bringing at least one compound of the Formula I into a suitable administration form using a pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0100] The present disclosure also relates to processes for the preparation of the compounds of Formula I which are described in the following and by which the compounds of the disclosure are obtainable.

[0101] The terms "therapeutically effective (or efficacious) amount" and similar descriptions such as "an amount efficacious for treatment" are intended to mean that amount of a pharmaceutical drug that will alleviate the symptoms of the disorder, condition or disease being treated (i.e., disorder, condition or disease associated with DGAT2 activity) in an animal or human. The terms "prophylactically effective (or efficacious) amount" and similar descriptions such as "an amount efficacious for prevention" are intended to mean that amount of a pharmaceutical drug that will prevent or reduce the symptoms or occurrence of the disorder, condition or disease being treated (i.e., disorder, condition or disease associated with DGAT2 activity) in an animal or human. The dosage regimen utilizing a compound of the instant disclosure is selected in accordance with a variety of factors including type, species, age, weight,26118sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of hepatic steatosis, diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, and a prophylactically effective amount, e.g., for treatment of NASH.

[0102] Disorders, conditions and diseases which can be treated or prevented by inhibiting DGAT2 by using the compounds of Formula I are, for example, diseases such as non-alcoholic steatohepatitis (NASH), hepatic fibrosis, hyperlipidemia, type I diabetes, type II diabetes mellitus, cognitive decline, dementia, coronary heart disease, ischemic stroke, restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attacks, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue disorders, hyper-apo B lipoproteinemia, non-alcoholic fatty liver disease, cardiorenal diseases such as chronic kidney diseases and heart failure, and related diseases and conditions.

[0103] The compounds of Formula I and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical preparations. The term "mammaf’ includes humans, and companion animals such as dogs and cats. The compounds of Formula I and their pharmaceutically acceptable salts can be administered to animals, including dogs and cats, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical preparations. The term “patient’' includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition. Administering of the drug to the patient includes both self-administration and administration to the patient by another person. The patient may need, or desire, treatment for an existing disease or medical condition, or may be in need of or desire26118prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a patient "in need" of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0104] Furthermore, a subject of the present disclosure is pharmaceutical preparations (or pharmaceutical compositions) which comprise as active component a therapeutically effective dose of at least one compound of Formula I and / or a pharmaceutically acceptable salt thereof and a customary' pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0105] Thus, a subject of the disclosure is, for example, said compound and its pharmaceutically acceptable salts for use as a pharmaceutical, pharmaceutical preparations which comprise as active component a therapeutically effective dose of said compound and / or a pharmaceutically acceptable salt thereof and a customary pharmaceutically acceptable carrier, and the uses of said compound and / or a pharmaceutically acceptable salt thereof in the therapy or prophylaxis of the above mentioned syndromes as well as their use for preparing medicaments for these purposes.

[0106] The pharmaceuticals according to the disclosure can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration can also be carried out parenterally, for example subcutaneously, intramuscularly or intravenously in the form of solutions for injection or infusion. Other suitable administration forms are, for example, percutaneous or topical administration, for example in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or the inhalative administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and on its severity.

[0107] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules it is possible to use, for example, lactose, starch, for example maize starch, or starch derivatives, talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions, for example of solutions for injection, or of emulsions or syrups are, for example, water, physiologically sodium chloride solution, alcohols such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to lyophilize the compounds of Formula I and their pharmaceutically acceptable salts and to use theresulting lyophilisates, for example, for preparing preparations for injection or infusion. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0108] Suitable solid or galenical preparation forms are. for example, granules, powders, coated tablets, tablets, (micro)capsules. suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions and preparations having prolonged release of active substance, in whose preparation customary excipients such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners and solubilizers are used.Frequently used auxiliaries which may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and plant oils such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol and solvents such as, for example, sterile water and mono- or polyhydric alcohols such as glycerol.

[0109] Besides the active compounds and carriers, the pharmaceutical preparations can also contain customary additives, for example fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.

[0110] The dosage of the active compound of Formula I and / or of a pharmaceutically acceptable salt thereof to be administered depends on the individual case and is, as is customary, to be adapted to the individual circumstances to achieve an optimum effect. Thus, it depends on the nature and the severity of the disorder, condition or disease to be treated, and also on the sex, age, weight and individual responsiveness of the human or animal to be treated, on the efficacy and duration of action of the compounds used, on whether the therapy is acute or chronic or prophylactic, or on whether other active compounds are administered in addition to compounds of Formula I.Combination Agents

[0111] The compounds of the present disclosure can be administered alone or in combination with one or more additional therapeutic agents disclosed herein or other suitable agents, depending on the condition being treated. Hence, in some embodiments the one or more compounds of the invention will be co-administered with other agents as described herein. When used in combination therapy, the compounds described herein are administered with the second agent simultaneously or separately. This administration in combination can include simultaneousadministration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, a compound of Formula I, la, lb, Ic, Id, and i.e., and any of the agents described herein can be formulated together in the same dosage form and administered simultaneously. Alternatively, a compound of Formula I, la, lb, Ic, Id, and i.e., and any of the agents described herein can be simultaneously administered, wherein both the agents are present in separate formulations. In another alternative, a compound of Formula I, la, lb, Ic, Id, and i.e., can be administered just followed by any of the agents described herein, or vice versa. In some embodiments of the separate administration protocol, a compound of Formula I, la, lb. Ic, Id, and i.e., and any of the agents described herein are administered a few minutes apart, or a few hours apart, or a few days apart.

[0112] As one aspect of the present disclosure contemplates the treatment of the disease / conditions with a combination of pharmaceutically active compounds that may be administered separately, the invention further relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I, la, lb, Ic, Id, and i.e., and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit comprises directions 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), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing health care professional.

[0113] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I, la, lb, Ic, Id, and i.e.. An additional active agent (or agents) is intended to mean a pharmaceutically active agent (or agents) that is active in the body, including pro-drugs that convert to pharmaceutically active form after administration, which are different from the compound of Formula I, la. Ib, Ic, Id. and i.e., and also includes free-acid, free-base and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable additional active agent or agents, including but not limited to anti-hypertensive agents, anti-obetic, anti-inflammatory, anti-fibrotic, and anti-atherosclerotic agents such as a lipid modifying compound, anti-diabetic agents and / or anti-obesity agents may be used in any combination with the compound of Formula I, la, Ib, Ic, Id, and i.e., in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one ormore separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents).

[0114] Examples of additional active agents which may be employed include but are not limited to angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat. fosinopril, imidapril. lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., losartan i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan and any of these drugs used in combination with hydrochlorothiazide such as HYZAAR®); 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-peptidic bonds, di- and tri-peptide derivatives, peptidyl amino diols and peptidyl beta-aminoacyl aminodiol carbamates; also, and small molecule renin inhibitors including diol sulfonamides and, N-morpholino derivatives, N-heterocyclic alcohols and pyrolimidazolones; also, pepstatin derivatives and fluoro- and chloroderivatives of statone-containing peptides, enalkrein, remikiren, A 65317, terlakiren, ES 1005, ES 8891, SQ 34017, SPP600, SPP630 and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalfil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem. gallopamil. niludipine. nimodipins, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholitics, beta-adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartate), alpha adrenergic blocking drugs (e.g.. doxazosin, prazosin or alpha methyldopa) central alpha adrenergic agonists, peripheral vasodilators (e.g., hydralazine); lipid lowering agents e g., HMG-CoA reductase inhibitors such as simvastatin and lovastatin which are marketed as ZOCOR® and MEV AC OR® in lactone pro-drug form and function as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open ring acid HMG-CoA reductase inhibitors such as atorvastatin (particularly the calcium salt sold in LIPITOR®), rosuvastatin (particularly the calcium salt sold in CRESTOR®), pravastatin (particularly the sodium salt sold in PRAVACHOL®), fluvastatin (particularly the sodium salt sold in LESCOL®), cerivastatin, and pitavastatin; a cholesterol absorption inhibitor such as ezetimibe (ZETIA®) and ezetimibe in combination with any other lipid lowering agents such as the HMG-CoA reductase inhibitors noted above and particularly with simvastatin (VYTORIN®) or with atorvastatin calcium; niacin in immediate-release or controlled release forms, and / or with an HMG-CoA reductase inhibitor; niacin receptor agonists such as acipimox and acifran, as well as26118niacin receptor partial agonists; anti-cholesterol agents such as PCSK.9 inhibitors (alirocumab. evolocumab), Nexletol™ (bempedoic acid, ACL inhibitor), and Vascepa® (Icosapent ethyl); metabolic altering agents including 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, including (i) [3-klotho / FGFRl activating monoclonal antibody (e.g., MK-3655), pan FGFR1-4 / KLB modulators, FGF19 analogue (e.g., Aldafermin) (ii) PPARy agonists, such as the glitazones (e.g., pioglitazone, AMG 131, mitoglitazone, lobeglitazone, rosiglitazone, and balaglitazone), and other PPAR ligands, including (1) PPARa / y dual agonists (e.g. ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelghtazar, and naveglitazar); (2) PPARa agonists such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARy modulators (SPPARyM’s), (e.g., such as those disclosed in WO 02 / 060388, WO 02 / 08188, WO 2004 / 019869, WO 2004 / 020409, WO 2004 / 020408, and WO 2004 / 066963); (4) PPARy partial agonists, (5) PPAR a / 5 dual agonists (e.g., Elafibranor); (iii) biguanides, such as metformin and its pharmaceutically acceptable salts, in particular, metformin hydrochloride, and extended-release formulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™; and (iv) protein tyrosine phosphatase- IB (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro and inhalable formulations of each); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, meglitinides, nateglinide and repaglinide); a-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol); glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-2409021 and KT6-971); incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including intranasal, transdermal, and once-weekly formulations thereof), bile acid sequestering agents (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of a cross-linked dextran), acyl Co A: cholesterol acyltransferase inhibitors, (e.g., avasimibe); antiobesity compounds; agents intended for use in inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs orNSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g., AZD6370); inhibitors of lip-hydroxy steroid dehydrogenase type 1, (e.g., such as those disclosed in U. S. Patent No. 6,730,690, and LY- 2523199); CETP inhibitors (e.g., anacetrapib, torcetrapib, and evacetrapib); inhibitors of fructose261181,6-bisphosphatase, (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); inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated Protein Kinase (AMPK) activators; other agonists of the G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g.. TAK875); SSTR3 antagonists (e.g., such as those disclosed in WO 2009 / 001836); neuromedin U receptor agonists (e.g., such as those disclosed in WO 2009 / 042053, including, but not limited to, neuromedin S (NMS)); SCD modulators (e.g., Aramchol); GPR-105 antagonists (e.g., such as those disclosed in WO 2009 / 000087); glucose pathway modulators such as SGLT inhibitors (e.g.. ASP1941, SGLT-3, SGLT-2 such as empagliflozin, dapagliflozin, canagliflozin. and ertugliflozin, BI-10773, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); dual SGLT-1 / 2 inhibitor (e.g., licogliflozin), Glucose-6-P dehydrogenase inhibitor (e.g., fluasterone) LAPS glucagon combo (e.g., HM14320), SGLT-1 inhibitor (e.g., SGL5213)); inhibitors of acyl coenzyme A carboxylase (ACC. MK-4074); inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid synthase; inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; IL-lb antibodies, (e.g., XOMA052 and canakinumab); anti-fibrotic and / or anti-inflammatory agents (CCR2 / CCR5 dual receptor antagonist (e.g., cenicriviroc); galectin 3 inhibitor (e.g., belapectin, GB-1107, GB-1211), siRNA against HSP 47 (e.g., BMS-986263); NSAID derived from pirfenidone (e.g., hydronidone), A3 AR agonist (e.g., namodenoson, FM101); TGFTX4 (e.g., nitazoxanide); 5-lipoxygenase inhibitor (e.g., tipelukast), Bifunctional urate inhibitor (e.g., ACQT1127), adiponectin receptor agonist (e.g., ALY688), TNF receptor antagonist (e.g., atrosimab), Autotaxin inhibitor (e g., BLD-0409, TJC 0265, TJC 0316), CCL24 blocking monoclonal antibody (e.g., CM101), IL-11 inhibitor (e.g., ENx 108A), LPA1 receptor antagonist (e g., EPGN 696), Dual JAK1 / 2 inhibitor (e.g., EX 76545), GPR antagonist (e.g., GPR91 antagonist), Integrin avbl. avb3 and avb6 inhibitor (e.g., IDL 2965), NLRP3 antagonist (e g., IFM-514), inflammasome inhibitors (e.g., JT194, JT349), Cell membrane permeability inhibitor (e.g., Larazotide), CCR5 antagonist (e.g., leronlimab), TNF inhibitor (e.g., LIVNate), integrin avP6 inhibitor (e.g., MORF beta6), NLRP inflammasome antagonists, siRNA (e g., OLX 701), dual TFGp / Hedgehog inhibitor (e.g., Oxy 200), GPR40 agonist / GPR84 antagonist (e.g., PBI-4547), neutrophil elastase inhibitor (e.g., PHP-303), integrin inhibitor (e.g., PLN-1474), TGFpi modulator (e.g. PRM-151), CCK receptor antagonist (e.g., proglumide), LOXL2 inhibitor (e.g., PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitor (e.g., cGAS / STING26118antagonists), kinase inhibiting RNase, membrane protein mAbs, tumor necrosis factor inhibitor, NRF2 activator (e.g., SCO 116), SSAO inhibitor (e.g., TERN 201), TRAIL2 agonist (e.g., TLY012), IL-6 receptor antagonist (e.g., TZLS 501), AOC3 inhibitor (e.g., UD-014), SSAO / VAP-1 inhibitor, TREM2); anti-oxidant (e g., vitamin E); anti-inflammatory agents (e.g., norfloxacin, ciprofloxacin, ceftriaxone); coagulation modifiers (e.g., anti-coagulants, anti-platelet agents, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonist (e.g., tirzepetide); dual GLP-l / GRA (e.g., cotadutide, ALT-801, DD 01, G49, PB-718); dual GLP-1 (e.g., CT 868); GLP-l / GRA / GIP triple agonist (e.g., HM15211); GRP120 stimulant / inflammasome modulator / PPARg dual agonist (e.g., KDT501); GLP-1 / FGF21 (e.g.. YH25724); GLP-1 agonist (e.g., Ozempic (semaglutide sc), XW 003); selective thyroid hormone receptor-P agonist (e.g., resmetirom); apoptosis modulators (JNK-1 inhibitor (e.g., CC-90001), Peroxidase inhibitor (e.g., AZM198), ASK-1 inhibitor (e.g., CS-17919, SRT 015)); erythropoietin-stimulating agents (erythropoietin receptor agonist (e.g., cibinetide)); immune modulators (TLR4 inhibitor (e.g., GBK-233), immunomodulatory polyclonal antibody (e.g., IMM-124E), TLR4 antagonist (e.g., JKB-122), CD3 monoclonal antibody (e g., foralumab), TLR4 antagonist (e.g., JKB 133), TLR4 inhibitor (e.g., mosedipimod), Macrophage inhibitor via CD206 targeting (e.g., MT2002), TLR2 / 4 antagonist (e.g., VB-201, VB-703), immunomodulatory polyclonal antibody (e.g.. IMM-124E)); incretin-based therapies (GLP-1 agonist (e.g., Ozempic (semaglutide sc), XW 003), GLP-l / glucagon dual receptor agonist (e.g., HM12525A), prandial insulin (e.g., ORMD 0801)); lipid modulators (AMPK Activator / Glutathione transferase (e.g., oltipraz), THR-beta agonist (e.g., resmetirom, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN 501), IBAT inhibitor (e.g., elobixibat. CJ 14199), omega-6- fatty acid (e.g., epeleuton), FASN inhibitor (e.g., TVB2640, FT 4101, FT 8225), ANGPTL3 inhibitor (e.g., vupanorsen), PNPLA3 inhibitor (e.g., AZD2693), RAS domain kinase inhibitor (e.g., BioE1115), NTCP inhibitor (e.g., bulevirtide), P2Y13 receptor agonist (e.g., CER-209), omega-3 fatty acid. HSD17 13 inhibitor; metabolism modulators (FXR agonist (e.g.. Ocaliva (obeticholic acid). IOT022). recombinant variant of FGF19 (e.g.. aldafermin), bispecific FGFR1 / KLB antibody (e.g., BFKB8488A), mTOT modulator (e g., MSDC-0602K), pegylated analog of FGF21 (e.g., pegbelfermin, BMS-986171), non-bile FXR agonist (e.g., cilofexor, EDP-305, EYP 001, tropifexor, MET409, AGN-242256, AGN-242266, EDP 297, HPG 1860. MET642, RDX023, TERN 101), ACC inhibitor (e.g.. firsocostat. PF-05221304), ketohexokinase inhibitor (e.g., PF-06835919), AMPK activator (e.g., PXL770, MSTM 101, 0304), bile acid modulator (e.g., Albiero), FGF21 analog (e.g., BI089-100), MOTSc analog (e.g., CB4211), cyclophilin inhibitor (e.g., CRV 431), FGF19 (e.g., DEL 30), mitochondrial26118uncoupler (e.g., GEN 3026), FXR / GPCR dual agonist (e.g., 1NT-767), Cysteamine derivative (e.g., KB-GE-001), dual amylin and calcitonin receptor agonist (e.g., KBP-089), transient FXR agonist (e.g., M 1217), anti-beta-klotho (KLB)-FGFRlc receptor complex mAb (e.g., MK3655), GDF15 analog (e.g., NGM395), cyclophilin inhibitor (e.g., NV556), LXR modulator (e.g., PX 329, PX 655. PX 788). LXR inverse agonist (e.g.. PX016), deuterated obeticholic acid (e.g., ZG 5216)); PPAR modulators (dual PPARo / y agonist (e.g., elafibranor), PPAR pan agonist (e.g., lanifibranor), PPARa agonists (e.g., Parmodia), PPARy agonist (e.g., CHS 131), MPC inhibitor (e.g., PXL065), PPAR 5 / y agonist (e.g. T3D 959)); RAAS mIMModulators (mineralocorticoid receptor antagonist (e.g.. apararenone. eplerenone, spironolactone), angiotensin receptor blocker (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulator, CB1 receptor antagonist (e.g., CRB-4001, IM-102, nimacimab), TPH1 inhibitor (e.g., CU 02), GPR120 agonist (e.g., KBR2001), combination of cannabinoid and botanical anti-inflammatory compound (e.g., SCN 002)); PDE Modulator (PDE4 inhibitor (e.g.. ART 648)); CYP2E1 inhibitor (e.g., SNP-610); cell therapies (e.g., HepaStem)and bromocriptine mesylate and rapid release formulations thereof; or with other drugs beneficial for the prevention or the treatment of the above-mentioned diseases including nitroprusside and diazoxide the free-acid, free-base, and pharmaceutically acceptable salt forms of the above active agents where chemically possible.

[0115] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined herein, including the pharmaceutically acceptable salts of all structural formulas, embodiments and classes defined herein. Reference to the compounds of structural Formula I, la, lb, Ic, Id, and i.e., includes the compounds of other generic structural Formulas, such as Formulas and embodiments that fall within the scope of Formula I, la, lb. Ic, Id, and le.Dosages of the Compounds of Formula I

[0116] If the patient is responding, or is stable, after completion of the therapy cycle, the therapy cycle can be repeated according to the judgment of the skilled clinician. Upon completion of the therapy cycles, the patient can be continued on the compounds of the disclosure at the same dose that was 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 be continued on the reduced dose).

[0117] Those skilled in the art will recognize that the actual dosages and protocols for administration employed in the methods of the disclosure may be varied according to the judgment of the skilled clinician. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the26118proper dosage for a particular situation is within the skill of the art. A determination to vary the dosages and protocols for administration may be made after the skilled clinician considers such factors as the patient’s age, condition and size, as well as the severity of the condition being treated and the response of the patient to the treatment.

[0118] The dosage regimen utilizing a compound of the instant disclosure is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound chosen to be administered; the route of administration; and the renal and hepatic function of the patient. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the purpose of determining the therapeutically effective or prophylactically effective dosage amount needed to prevent, counter, or arrest the progress of the condition. It is understood that a specific daily dosage amount can simultaneously be both a therapeutically effective amount, e.g., for treatment of an oncological condition, and a prophylactically effective amount, e.g., for prevention of an oncological condition.

[0119] While individual needs vary, determination of optimal ranges of effective amounts of the compound of the disclosure is within the skill of the art. For administration to a human in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, typical dosages of the compounds of the present disclosure can be about 0.05 mg / kg / day to about 50 mg / kg / day, for example 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 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. For example, dosages of the compounds can be about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.05 mg / kg / day to about 10 mg / kg / day, about 0.05 mg / kg / day to about 5 mg / kg / day, about 0.05 mg / kg / day to about 3 mg / kg / day, about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / kg / day, about 0.05 mg / kg / day to about 0.1 mg / kg / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses.26118Pharmaceutical Compositions

[0120] The compounds of Formula I and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and in particular to humans, as pharmaceuticals by themselves, in mixtures with one another or in the form of pharmaceutical compositions. The term “subject” or “patient” includes animals, preferably mammals and especially humans, who use the instant active agents for the prevention or treatment of a medical condition.

[0121] Administering of the compound of Formula I to the subject includes both self-administration and administration to the patient by another person. The subject may need, or desire, treatment for an existing disease or medical condition, or may be in need of or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a subject "in need" of treatment of an existing condition or of prophylactic treatment encompasses both a determination of need by a medical professional as well as the desire of a patient for such treatment.

[0122] Those skilled in the art will recognize that the actual dosages and protocols for administration employed in the methods of the disclosure may be varied according to the judgment of the skilled clinician. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage for a particular situation is within the skill of the art. A determination to vary the dosages and protocols for administration may be made after the skilled clinician takes into account such factors as the patient’s age, condition and size, as well as the severity of the condition being treated and the response of the patient to the treatment.

[0123] The amount and frequency of administration of the compound of Formula I and any additional agents will be regulated according to the judgment of the attending clinician (physician) considering such factors as age, condition and size of the patient as well as severity of the condition being treated.

[0124] The compounds of the disclosure are also useful in preparing a medicament that is useful in treating NASH and fibrosis.

[0125] The instant compounds may also be useful in combination with therapeutic, chemotherapeutic and anti-cancer agents for the treatment of hepatic cellular carcinoma.Combinations of the presently disclosed compounds with therapeutic, chemotherapeutic and anticancer agents are within the scope of the disclosure. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellman (editors), 9thedition (May 16, 2011), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular26118characteristics of the drugs and the cancer involved. Such agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed deathligand 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, y-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and agents that interfere with cell cycle checkpoints.

[0126] The chemotherapeutic agent can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent can be varied depending on the cancer being treated and the known effects of the chemotherapeutic agent on that disease. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the cancer to the administered therapeutic agents. The particular choice of chemotherapeutic agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.

[0127] The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0128] The determination of the order of administration, and the number of repetitions of administration of the chemotherapeutic agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the condition being treated and the condition of the patient.

[0129] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of a chemotherapeutic agent according to the individual patient’s needs, as the treatment proceeds. All such modifications are within the scope of the present disclosure.

[0130] The agent can be administered according to therapeutic protocols well known in the art. It will be apparent to those skilled in the art that the administration of the anti-cancer agent can be varied depending on the cancer being treated and the known effects of the anti-cancer agent on that disease.26118

[0131] The initial administration can be made according to established protocols known in the art, and then, based upon the observed effects, the dosage, modes of administration and times of administration can be modified by the skilled clinician.

[0132] The particular choice of agent will depend upon the diagnosis of the attending physicians and their judgment of the condition of the patient and the appropriate treatment protocol.

[0133] The determination of the order of administration, and the number of repetitions of administration of the agent during a treatment protocol, is well within the knowledge of the skilled physician after evaluation of the cancer being treated and the condition of the patient.

[0134] Thus, in accordance with experience and knowledge, the practicing physician can modify each protocol for the administration of an anti-cancer agent according to the individual patient's needs, as the treatment proceeds. All such modifications are within the scope of the present disclosure.

[0135] The attending clinician, in judging whether treatment is effective at the dosage administered, will consider the general well-being of the patient as well as more definite signs such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Size of the tumor can be measured by standard methods such as radiological studies, e.g., CAT or MRI scan, and successive measurements can be used to judge whether or not growth of the tumor has been retarded or even reversed. Relief of disease-related symptoms such as pain, and improvement in overall condition can also be used to help j udge effectiveness of treatment.

[0136] The compounds, compositions and methods provided herein are useful for the treatment of cancer. Cancers that may be treated by the compounds, compositions and methods disclosed herein include, but are not limited to: Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

[0137] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab and MPDL3280A. PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab.

[0138] The disclosure further relates to a method of treating hepatic cellular carcinoma in a human patient comprising administration of a compound of the disclosure (i.e., a compound of Formula I) and a PD-1 antagonist to the patient. The compound of the disclosure and the PD-1 antagonist may be administered concurrently or sequentially.

[0139] In particular embodiments, the PD-1 antagonist is an anti-PD-1 antibody, or antigen binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-Ll antibody, or antigen binding fragment thereof. In some embodiments, the PD-1 antagonist is26118pembrolizumab (KEYTRUDA™, Merck & Co., Inc., Rahway, 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), or avelumab (BAVENCIO™, Merck KGaA, Darmstadt, Germany).

[0140] In some embodiments, the PD-1 antagonist is pembrolizumab. In particular subembodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.

[0141] In further sub-embodiments, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every three weeks. In particular sub-embodiments, the patient is a pediatric patient.

[0142] In some embodiments, the PD-1 antagonist is nivolumab. In particular subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to the patient about every’ four weeks.

[0143] In some embodiments, the PD-1 antagonist is cemiplimab. In particular embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.

[0144] In some embodiments, the PD-1 antagonist is atezolizumab. In particular subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every three weeks.

[0145] In some embodiments, the PD-1 antagonist is durvalumab. In particular subembodiments, the method comprises administering 10 mg / kg of durvalumab to the patient about every two weeks.

[0146] In some embodiments, the PD-1 antagonist is avelumab. In particular sub-embodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks.

[0147] A compound of the instant disclosure, or a pharmaceutically acceptable salt thereof, may also be useful for treating cancer in combination with the following therapeutic agents: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®);26118bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with 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 Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DaunoXome®); daunorubicin. daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone injection®); Elliott's B Solution (Elliot's B Solution®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP- 16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (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 alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan. L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); 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 (Adagen26118(Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); Rasburicase (Elitek®); Rituximab (Rituxan®); Ridaforolimus; sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide. VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®);Tositumomab (Bexxar®); Tositumomab / I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®), or a pharmaceutically acceptable salt thereof.Methods for Making the Compounds of Present Disclosure

[0148] The following examples are provided so that the disclosure might be more fully understood. Unless otherwise indicated, the starting materials are commercially available. They should not be construed as limiting the disclosure in any way.

[0149] Several methods for preparing the compounds of this disclosure are described in the following Schemes and Examples. Starting materials and intermediates are purchased, made from known procedures, or as otherwise illustrated. Some frequently applied routes to the compounds of Formula I are also described by the Schemes as follows. In some cases, the order of carrying out the steps of reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. For stereoisomers, enantiomer A refers to the faster / earlier eluting enantiomer and enantiomer B refers to the slower / later eluting enantiomer at the point of separation and this nomenclature is maintained through the remainder of a synthetic sequence for a given enantiomeric series regardless of the possibility that subsequent intermediates and final compounds may have the same or opposite orders of elution.List of Abbreviations:ACN= acetonitrileAcOH= acetic acid26118BAST= (bis(2-methoxyethyl)amino)sulfur trifluorideBHMPO= N 1, N2-Bis(4-hydroxy-2,6-dimethylphenyl)oxalamideBn = BenzylmCPBA = meta-Chloroperoxybenzoic acidDAST = Diethylaminosulfur trifluorideDME= Dimethyl etherDMF = N,N-dimethylformamideDMA = N,N-dimethylacetamideDMSO = Dimethyl sulfoxideDCM = DichloromethaneDIBAL-H= Diisobutylaluminum hydrideDIPEA = N,N-diisopropylethylamineEt = EthylEtOAc = Ethyl acetateFA= 4-FluoroamphetamineHPLC = High Pressure Liquid Chromatographyh = hour or hoursHATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphateHex = HexanesIPA = Iso-PropanolLC / MS = Liquid chromatography - mass spectrometryMe = MethylMeCN= methyl cyanideMeOD= Methanol-dMeOH= MethanolNBS= N-BromosuccinimidePdCl2(dppf)= [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pet. Ether= Petroleum etherPMB = p-MethoxybenzylpyBOP = benzotriazol- 1-yloxy tri pyrrolidino phosphonium hexafluoro phosphate RT = Room temperatureSFC = Supercritical fluid chromatographyTBAF = Tetrabutyl ammonium fluoride26118TBS = tert-butyldimethylsilylTBDPS = tert-butyldiphenylsilylTHF = TetrahydrofuranTFA = Trifluoroacetic acidTLC= Thin-layer chromatographyXPhos Pd G2= Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l, T-biphenyl)[2-(2'-amino-1, 1 '-biphenyl)] pall adium(II)LC / MS conditions: column: Acquity UPLC-QDa BEH C18, 1.7mm, 2.1 x 50mm. Solvent system: A: Water 0.1% FA, B: ACN 0.1% FAGradient condition: 10-90% B, in 1.7 min, total run time 2.4 minGENERAL SYNTHETIC SCHEMES

[0150] While the present disclosure has been described in conjunction with the specific examples set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. In some cases, the order of carrying out the steps of the reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present disclosure.[General Scheme 1]1-1 1-2 1-31-4 1-5

[0151] Compounds of the formula 1-5 were prepared from 1-1 with Rj-X via SxAr or copper-mediated C-0 coupling. Amidation with ethyl oxalyl chloride afforded 1-3. Saponification of 1-3 provided the corresponding carboxylic acid (1-4) and subsequent amide coupling with the appropriate amines provided compounds of formula (1-5) as described by the general scheme. The order of steps for some examples may be varied to facilitate the syntheses.INTERMEDIATES26118Intermediate 15-Chloro-3-(2,2-difluoroethoxy)-2-fluoropyridineSTEP A: 5-Chloro-3-(2.2-difluoroethoxy)-2-fluoropyridine

[0152] To a mixture of 5-chloro-2-fluoropyridin-3-ol (5.40 g. 36.6 mmol) and K2CO3 (6.58 g, 47.6 mmol) in DMF (25 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (5.49 mL, 38.4 mmol) at RT. After 1 h, the mixture was fdtered over Celite, and the fdtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 212 [M+l], By using procedures similar to those described in Intermediate 1 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.Intermediate Structure Name LC / MS [M+l]3-(2,2-difluoroethoxy)-2,5- 2 196difluoropyridine2,5-difluoro-3-(2,2,2- 3 214Fv trifluoroethoxy)pyridineF^o 3-(2,2-difluoroethoxy)-2-fluoro,5- 4 212c, Xr chloropyridine2-(2,2-difluoroethoxy)-3- 5 179fluoropyrazine3-(2,2,2-trifluoroethoxy)-2-iodo,5- 6 321FXX fluoropyridineEXAMPLES

[0153] The following experimental procedures detail the preparation of specific examples of the instant disclosure. The examples are for illustrative purposes only and are not intended to limit the scope of the instant disclosure in any way.Example 1V1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)- / V2-(4-methyl- 1, 1 -dioxidotctrahy dro-2 / 7-thiopy ran-4-y I )o\al amide26118STEP A: 5-((5-Fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine

[0154] To a stirred solution of 6-amino-4-methylpyridin-3-ol (11.0 g, 89 mmol) and 2,5-difluoro-3-(2,2,2-trifluoroethoxy)pyridine (28.3 g, 133 mmol) in DMF (89 mL, 1.0 M) was added CS2CO3 (37.5 g, 115 mmol) and the mixture was heated to 55 °C. After 16 hours the reaction mixture was fdtered, concentrated in vacuo, and the crude residue was subjected to flash silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford the title compound. MS (ESI) m / z 318.1 (M + H)+.STEP B: Ethyl 2-((5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)amino)-2-oxoacetate

[0155] To a stirred solution of 5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine (15.9 g, 50.1 mmol) in 4:1 DCM / pyridine (500 mL, 0.1 M) was added ethyl oxalyl chloride (5.89 mL, 52.6 mmol) dropwise at 0 °C. After 2 hours the solvent was removed in vacuo. The crude residue was subjected to flash silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford the title compound. MS (ESI) m / z 418.2 (M + H)+.STEP C: 2-((5-((5-Fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)amino)-2-oxoacetic acid

[0156] To a stirred solution of ethyl 2-((5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)amino)-2-oxoacetate (1.10 g, 2.64 mmol) in THF (7.5 mL), EtOH (3.8 mL), and H2O (1.9 mL) was added LiOH (69.5 mg, 2.90 mmol) at RT. After 2 hours the reaction mixture was acidified with HC1 (IM aq. soln.) and extracted with DCM. The combined organic fractions were washed with NaCl (sat. aq. soln ), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound which was used without further purification. MS (ESI) m / z 390.2 (M + H)+.STEP D: jV1-(5-((5-Fluoro-3-(2.2.2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-A2-(4-methyl- 1, 1 -dioxidotetrahvdro-2 / 7-thiopyran-4-yl joxal amide

[0157] To a stirred solution of 2-((5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)amino)-2-oxoacetic acid (1.01 g, 2.61 mmol), 4-amino-4-methyltetrahydro-261182 / 7-thiopyran 1,1-dioxide hydrochloride (573 mg, 2.87 mmol), DIPEA (1.4 mL, 7.83 mmol) in DMF (26 mL) was added HATU (1.10 g, 2.87 mmol) at RT. After 16 hours the solvent was removed in vacuo and the crude material was subjected to flash silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford the title compound. Further purification was performed using mass-triggered reverse phase HPLC (40-98% MeCN / water with 0.1% FA modifier) to afford the title compound as a white solid. MS (ESI) nvz 535.0 (M + H)+. 'H NMR (500 MHz. DMSO) 5 10.18 (s, 1H), 8.59 (s, 1H), 8.17 (s, 1H), 8.02 (s, 1H), 7.86 (dd, J = 9.6, 2.5 Hz, 1H), 7.77 (d, J= 2.5 Hz, 1H), 5.00 (q, J= 8.8 Hz, 2H), 3.21 (t, J = 13.2 Hz, 2H), 3.00 (d, J= 13.7 Hz, 2H), 2.78 (d, J= 14.3 Hz, 2H), 2.14 (s. 3H), 1.99 (t, J= 12.3 Hz, 2H).1.38 (s, 3H). Hu DGAT2 IC50 = 6.3 nM.

[0158] By using procedures similar to those described in Example 1 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.Human LC / MS DGAT2 Example Structure Name[M+l] IC50(nM) A1-(6-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)pyridine-3-yl)-jV2-(4- 2C1£r -uB537 5.9 methy 1-1,1 - '0dioxidotetrahydro-277- thiopyran-4-yl)oxalamideM-(5-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)pyridine-2-yl)- / V2-(4- 3 c> A" 537 7.2 methy 1-1.1 - 'bdioxidotetrahydro-2 / 7- thiopyran-4-yl)oxal amideA1-(5-((5-Chloro-3-(2,2,2- r>r^0trifluoroethoxy)pyridine-2- 4CIA^N 551 95 yl)oxy)-6-methylpyridin-2- '0yl)-A2-(4-methyl-l, 1 -26118dioxidotetrahydro-277- thiopyran-4-yl)oxal amideAd-(5-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)-6-methylpyridin-2- 5 523 717 yl)-jV2-(3 -methyl- 1, 1- 8"°dioxidothietan-3- yl)oxal amideAd-(5-((5-Chloro-3-(2.2.2- trifluoroethoxy)pyridine-2- yl)oxy)-6-methylpyridin-2- F^06 yl)-7V2-((15',27?)-3,3- 539 4039 difluoro-2- hydroxycyclohexyl)oxalamidejV1-(5-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)-4-methylpyridin-2- 7 ^ 551 5.0 yl)-jV2-(4-methyl-l, 1 - dioxidotetrahydro-2 / 7- thiopyran-4-yl)oxal amideA^1-(5-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)-4-methylpyridin-2- 8 SnW 553 14 yl)-JV2-(3 -methyl- 1, 1 - dioxidothietan-3- yl)oxal amide2V1-(5-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- 9 yl)oxy)-4-methylpyridin-2- 539 362A X^N\K'-|^ yl)-^2-((lS,27?)-3,3- difluoro-2-26118hydroxy cyclohexyl)oxalamide? / 1-(5-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- ^0yl)oxy)-3-methylpyridin-2- 10 551 >9990 yl)-2V2-(4-methyl-l, 1 - 'bdi ox idotet rahy dro-27 / - lhiopyran-4-yl)oxal amidejV1-(5-((5-Chloro-3-(2,2- difluoroethoxy)pyridine-2- yl)oxy)-4-methylpyridin-2- 11 533 2.2 yl)-JV2-(4-methy 1- 1, 1 - 'bdioxidotetrahydro-27 / - thiopyran-4-yl)oxalamideJV1-(5-((5-Fluoro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)-4-methylpyridin-2- 12 F Xif X^N 535 6.H\ oK'K 3 k^s=o y 1 )-Ar2-( 4-methy 1- 1, 1 - 'odioxidotetrahydro-2 / / - thiopyran-4-yl)oxal amidejV1-(5-((5-Fluoro-3-(2,2- difluoroethoxy)pyridine-2-Fv° 1 yl)oxy)-4-methylpyridin-2- 13Fjf^r°V i 8hi 517 2.4Ho \z^r° yl)-jV2-(4-methy 1- 1, 1 - 'odioxidotetrahydro-27 / - thiopyran-4-yl)oxalamide2V1-(5-((3-(2,2- Difluoroethoxy)pyrazin-2- ^0 INX^°'T<^1 o yl)oxy)-4-methylpyridin-2- 14 500 3.7 y l)-jV2-(4-methy 1- 1,1- 'odioxidotetrahydro-27 / - thiopyran-4-yl)oxal amide26118A^1-(6-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)-5-methylpyridin-3- 15 551 242 yl)-7V2-(4-methy 1- 1, 1 - 'bdioxidolelrahydro-27 / - thiopyran-4-yl)oxal amideJV1-(6-((5-Chloro-3-(2,2,2- trilluoroethoxy)pyridine-2- >|^°yl)oxy)-2-methylpyridin-3- 16 551 413 y l)-A'2-(4-melhy 1- 1, 1 - 'odioxidotetrahydro-277- thiopyran-4-yl)oxal amide(7?)-Ad-(5-((5-Fluoro-3- (2,2,2- trifluoroethoxy)pyridine-2- 17 yl)oxy)-4-methylpyridin-2- 521 40VXJ'°yl)-jV2-(3 -methyl- 1,1- dioxidotetrahydrothiophen- 3-yl)oxal amideJV1-(5-((5-Fluoro-3-(2,2,2- trifluoroethoxy)pyridine-2- yl)oxy)-4-methylpyridin-2- 18FA 506 41 yl)-2V2-(3 -methyl- 1, 1- 8''°dioxidothietan-3- yl)oxal amide(5)-^-(5-((5-Fluoro-3- (2,2,2- trifluoroethoxy)pyridine-2- FY^° I19 if^T Y ] UHz^'°n yl)oxy)-4-methylpyridin-2- 521 16H nyl)-jV2-(3-methyl-l,l- dioxidotetrahydrothiophen- 3-yl)oxalamide26118(^-^-(S-CCS-fluoro-S- (2,2,2- trifluoroethoxy)pyridin-2- 20 Ihyl)oxy)-4-methylpyridin-2- 473 503 yl)-7V2-(3- methyltetrahy drofuran-3 - yl)oxal amide(< S’)-JV1-(5-((5-lluoro-3- (2,2,2- trifluoroethoxy)pyridin-2- 21 yl)oxy)-4-methylpyridin-2- 473 109 yl)-7V2-(3- zz 2 »^0 methyltetrahy drofuran-3 - yl)oxalamideCS)-2V1-(5-((3-(2,2- Difluoroethoxy)-5- sfluoropyridin-2-yl)oxy)-4- 22 methylpyridin-2-yl)-JV2-(3- 503 4.6~AAw ’ methyl-1,1- dioxidotetrahydrothiophen- 3-yl)oxal amide7V1-(5-((3-(2,2- Difluoroethoxy)-5- fluoropyridin-2-yl)oxy)-4- 23 A Avt, 489 4.4 methylpyridin-2-yl)-jV2-(3- o °methyl- 1.1 -dioxidothietan- 3-yl)oxal amideExample 24jV1-(5-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)pyrazin-2-yl)-JV2-(4-methy 1-1,1- dioxidotelrahydro-2H-thiopyran-4-yl)oxal amide26118STEP A: 5-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)pyrazin-2-amine

[0159] To a stirred solution of tert-butyl (5-hydroxypyrazin-2-yl)carbamate (250 mg, 1.18 mmol) and 5-chloro-3-(2,2-difluoroethoxy)-2-fluoropyridine (501 mg, 2.37 mmol) in DMF (2.4 mL) was added CS2CO3 (501 mg, 1.54 mmol) at 20 °C. After 10 minutes the reaction mixture was heated to 80 °C. After 2 hours the reaction mixture was quenched with MeOH, diluted with water, and extracted with EtOAc. The combined organic fractions were washed with LiCl (IM aq. soln.), dried over MgSOq. filtered, and concentrated in vacuo. The crude residue was subjected to flash silica gel column chromatography using a 0-10% MeOH in DCM gradient to afford the title compound. LC / MS = 303 [M+l],STEP B: A1-(5-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)pyrazin-2-yl)-2-(4-methyl-1, 1 -dioxi dotetrahvdro-2 / / -thi opyran-4-v I )oxalamide

[0160] To a stirred solution of 2-((4-methyl- 1, 1 -dioxidotetrahydro-2-thiopyran-4-yl)amino)-2-oxoacetic acid (27.4 mg. 0.12 mmol) in pyridine (1.1 mL) was added HATU (46.2 mg, 0.12 mmol) and the reaction mixture was allowed to stir at 50 °C for 30 min. Subsequently 5-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)pyrazin-2-amine (32 mg, 0.11 mmol) was added. After 16 hours the solvent was removed in vacuo. The residue was taken up in toluene and the solvent was removed in vacuo. The crude material was dry absorbed on SiCh and subjected to flash silica gel column chromatography using a 0-40% EtOAc / hexanes gradient. Further purification using mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier) afforded the title compound. LC / MS = 520 [M+l], ’H NMR (500 MHz, MeOD) 59.03 (s, 1H), 8.36 (d, J= 1.1 Hz, 1H), 7.90 (d, J= 2.1 Hz, 1H), 7.76 (d, J= 2.1 Hz, 1H), 6.08 (tt, J= 54.5, 3.6 Hz. 1H), 4.36 (td, J= 13.7, 3.7 Hz, 2H). 3.26 (t. J= 15.1 Hz, 2H), 3.00 (d, J= 13.7 Hz, 2H). 2.87 (d, J= 14.7 Hz, 2H), 2.19 (t, J= 13.5 Hz, 2H), 1.50 (s, 3H). Human DGAT2 IC50 = 9.5 nM. By using procedures similar to those described in Example 24 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.LC / MS Human Example Structure Name[M+l] DGAT226118IC50 (nM) A1-(6-((5-Chloro-3-(2,2,2- trifluoroethoxy)pyridin-2- yl)oxy)pyridazin-3-yl)-A2- 25 538 2525 (4-methy 1-1,1 - di oxi dotet rahy dro-27 / - thiopyran-4-yl)oxal amideA1-(5-((5-Chloro-3-(2.2.2- trifluoroethoxy)pyridin-2- yl)oxy)pyrimidin-2-yl)-A2- 26 538 9.1 (4-methyl- 1,1- dioxidolelrahydro-27 / - thiopyran-4-yl)oxalamideExample 27A1-(5-((5-(Difluoromethyl)-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-4-methylpyri din-2 -yl)-A2-(4- methyl-1, 1 -dioxidotetrahydro-2 / / -lhiopyran-4-y l)oxal amideSTEP A: 3-(Difluoromethyl)-5-fluoropyridine

[0161] A mixture of 3-fluoro-5-formylpyridine (3.0 g. 24.0 mmol) in DCM (30 mL) was cooled to -78 °C. Then BAST (10.2 mL, 55.2 mmol) was added at -78 °C under N2. The reaction mixture was warmed to 25 °C. After 2 hours the solution was quenched with saturated NaHCOs aq (150 mL) and extracted with DCM (100 mL x3). The combined organic layers were dried26118over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash silica gel column chromatography using a 0-10% DCM in pet. ether gradient to afford the title compound. LC / MS = 148 [M+l],STEP B; 3-(2.2-Difluoroethoxy)-5-(difluoromethyl)pyridine

[0162] To a solution of 2,2-difluoroethan-l-ol (1.55 mL, 24.5 mmol) in DMF (30 mL) was added sodium hydride (0.98 g, 24.5 mmol) at 0 °C under N2. The mixture was stirred at 25 °C for 0.5 h. Then 3-(difluoromethyl)-5-fluoropyridine (2.4 g, 16.3 mmol) was added in the mixture and the mixture was stirred at 25 °C. After 16 hours the reaction mixture was diluted with MTBE (100 mL). The organic layer was washed with H2O (50 mL x3), NaCl aq. (50 mL). dried with Na2SO4, filtered and concentrated in vacuo (caution volatile). The crude material was purified by flash silica gel column chromatography using DCM to afford the title compound. LC / MS = 210 [M+l],STEP C: 3-(2.2-Difluoroethoxy)-5-(difluoromethyl)pyridine-l-oxide

[0163] To an 100 mL flask was added the 3-(2,2-difluoroethoxy)-5-(difluoromethyl)pyridine (2.5 g, 12.0 mmol) and DCM (30 mL). Then m-CPBA (2.7 g, 15.54 mmol) was added. After 16 hours the reaction was quenched with Na2S2O3 (20 mL sat. aq. soln.) and stirred for 1 h. The solution was diluted with aqueous NaHCOs (50 mL) and extracted with DCM (50 mL x3). The combined organic fractions were dried over Na2SO4 and concentrated in vacuo to afford the title compound which was used in the next step without further purification. LC / MS = 226 [M+l], STEP D: 3-(2.2-Difluoroethoxy)-5-(difluoromethyl)-2-((6-(2.5-dimethyl-177-pyrrol-l-yl)-4-methylpyridin-3-yl)oxy)pyridine

[0164] To a stirred solution of 6-(2,5-dimethyl- 1 / / -pyrrol- l-yl)-4-methylpyri din-3 -ol (99 mg, 0.49 mmol), 3-(2,2-difluoroethoxy)-5-(difluoromethyl)pyridine 1 -oxide (100 mg, 0.444 mmol), and DIEPA (0.23 mL, 1.33 mmol) in DCM (6 mL) was added PyBrop (311 mg, 0.666 mmol). The reaction was stirred at 40 °C. After 16 hours the reaction mixture was diluted with water (15 mL) and extracted with DCM (15 mL x3). The combined organic layers were washed with NaCl (10 mL sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was subjected to Prep-TLC (Pet.ether: EtOAc=5:l) to afford the title compound. LC / MS = 410 [M+l],STEP E; 5-((3-(2.2-Difluoroethoxy)-5-(difluoromethyl)pyridin-2-yl)oxy)-4-methylpyridin-2-amine

[0165] Hydroxylamine hydrochloride (50.9 mg, 0.73 mmol) was added to a stirred mixture of 3-(2,2-difluoroethoxy)-5-(difluoromethyl)-2-((6-(2,5-dimethyl-17f-pyrrol-l-yl)-4-methylpyridin-3-yl)oxy)pyridine (15 mg, 37 pmol) in EtOH (1 mL) and water (0.2 mL), and the mixture was26118heated to 80 °C. After 18 h the reaction mixture was cooled, the pH was adjusted to >8 using NH3·MeOH. and the remaining solvent was removed in vacuo. The residue was purified by prep-TLC (pet. ether) to afford the title compound. LC / MS = 331 [M+l],STEP F; Afl-(5-((3-(2.2-Dinuoroethox\ )-5-(dinuorometh\ l)D\ ridin-2-\'l)ox\ )-4-meth\ lp\ ridin-2-yl)-N2-(4-methyl- 1, 1 -dioxidotetrahvdro-2 / / -thiopyran-4-yl joxalamide

[0166] To a solution of 5-((3-(2,2-difluoroethoxy)-5-(difluoromethyl)pyridin-2-yl)oxy)-4-methylpyridin-2-amine (12 mg, 36 pmol) in pyridine (1.0 mL) was added 2-((4-methyl-l,l-dioxidotetrahydro-2 / / -thiopyran-4-yl)amino)-2-oxoacetic acid (12.8 mg, 54 pmol) and POCl3(10.13 pl, 109 pmol). The reaction was stirred at RT. After 16 h the reaction mixture was diluted with H2O (3 mL) and extracted with EtOAc (3 mL x3). The combined organic fractions were dried over Na2SC>4, filtered, and concentrated in vacuo. The crude material was purified by prep-TLC (pet. ether: EtOAc=l: 1) to afford the title compound. LC / MS = 549 [M+l], 'H NMR (400 MHz, MeOH-74) 5 ppm 8.19 (s, 1 H), 8.11 (s. 1 H). 7.84 (d, 7=1.43 Hz, 1 H), 7.69 (s, 1 H), 6.82 (t, J =55.55 Hz, 1 H), 6.28 (ft, 7=54.60. 3.81 Hz, 1 H), 4.47 (td, 7=13.59, 3.81 Hz, 2 H). 3.23 (br d, 7=15.26 Hz, 2 H), 2.99 (br d, 7=14.78 Hz, 2 H), 2.86 (br d, 7=15.74 Hz, 2 H), 2.21 (s, 3 H), 2.14 - 2.19 (m, 2 H), 1.49 (s, 3 H). Human DGAT2 ICso = 4.1 nM.Example 28A1-(5-((5-(Diliuoromethyl)-3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-4-methylpyridin-2-yl)-A2-(4- methyl- 1, 1 -di oxi dotetrahydro-2 / / -thiopy ran-4-y I )oxal amideSTEP A: 5-Bromo-3-(2.2-difluoroethoxy)pyrazin-2-amine

[0167] To a stirred mixture of 5-bromo-3-chloropyrazin-2-amine (7.0 g, 33.6 mmol) in THF (30 mL) at 0 °C was added NaH (4.03 g, 101 mmol). After 30 min 5-bromo-3-chloropyrazin-2-26118amine (7.0 g, 33.6 mmol) was added and the reaction mixture was warmed to 50 °C. After 18 h the mixture was cooled, diluted with water, and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. soln), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash silica gel column chromatography using pet. ether / EtOAc = 10: 1 to afford the title compound. LC / MS = 254 and 256 [M+l],STEP B: Ethyl 5-amino-6-(2.2-difluoroethoxy)pyrazine-2-carboxylate

[0168] To a stirred mixture of 5-bromo-3-(2,2-difluoroethoxy)pyrazin-2-amine (4.0 g, 15.8 mmol) and potassium acetate (4.64 g, 47.2 mmol) in EtOH (40 mL) was added PdC12(dppf) (1.152 g, 1.58 mmol), and the mixture was heated to 95 °C under and atmosphere of CO. After 12 h the mixture was filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using 5:1 pet. ether EtOAc to afford the title compound. LC / MS = 248 [M+l],STEP C: Ethyl 6-(2.2-difluoroethoxy)-5-iodopyrazine-2-carboxylate

[0169] To a stirred mixture of ethyl 5-amino-6-(2,2-difluoroethoxy)pyrazine-2-carboxylate (2.0 g, 8.1 mmol), Cui (0.46 g, 2.43 mmol) and h (1.44 g, 5.66 mmol) in DME (20 mL) was added tert-butyl nitrite (4.17 g, 40.5 mmol) at RT. After 10 min the mixture was heated to 60 °C. After 2 h the reaction mixture was concentrated in vacuo. Na2SOs (20 mL, 10% aq. soln.) was added, and the reaction mixture was extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The residue w as purified by flash silica gel column chromatography using 10:1 pet. ether / ethyl acetate to afford the title compound. LC / MS = 359 [M+l],STEP D: (6-(2.2-Difluoroethoxy)-5-iodopyrazin-2-yl)methanol

[0170] To a stirred solution of ethyl 6-(2,2-difluoroethoxy)-5-iodopyrazine-2-carboxylate (1.0 g, 2.79 mmol) in DCM (10 mL) was added DIBAL-H (3.07 mL, 3.07 mmol) at -78 °C After 3 hours the reaction mixture was quenched with w ater. The mixture w as filtered, concentrated in vacuo, and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by prep-TLC (pet. ether / EtOAc =3 / 1) to afford the title compound. LC / MS = 317 [M+l], STEP E: 6-(2.2-Difluoroethoxy)-5-iodopyrazine-2-carbaldehvde

[0171] To a stirred solution of (6-(2,2-difluoroethoxy)-5-iodopyrazin-2-yl)methanol (800 mg, 2.53 mmol) in CH2CI2 (8 mL) was added manganese(IV) oxide (2201 mg, 25.3 mmol) at RT. After 3 h. the mixture was filtered, and the solution was concentrated in vacuo to afford the title compound. LC / MS = 315 [M+l],STEP F: 3-(2.2-Difluoroethoxy)-5-(difluoromethyl)-2-iodopyrazine26118

[0172] To a stirred solution of 6-(2,2-difluoroethoxy)-5-iodopyrazine-2-carbaldehyde (700 mg, 2.23 mmol) in DCM (10 mL) was added DAST (1.18 mL, 8.92 mmol) at RT. After 2 h. the reaction mixture was poured into water and extracted with DCM. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over NazSO-i. filtered, and concentrated in vacuo to afford the title compound. LC / MS = 337 [M+l]STEP G: 3-(2,2-Difluoroethoxy)-5-(difluoromethyl)-2-((6-(2.5-dimethyl-17 / -pyrrol-l-yl)-4-methylpyridin-3-yl)oxy)pyrazine

[0173] To a stirred solution of 1,10-phenanthroline (118 mg, 0.66 mmol), K3PO4 (1.04 g, 4.91 mmol). 6-(2.5-dimelhyl-l / / -pyrrol-l-yl)-4-methylpyridin-3-ol (331 mg, 1.64 mmol) and 3-(2,2-difluoroethoxy)-5-(difluoromethyl)-2-iodopyrazine (550 mg, 1.64 mmol) in DMSO (10 mL) was added Cui (62.3 mg, 0.33 mmol) and the reaction mixture was heated to 100 °C After 18 hours the reaction mixture was cooled, diluted with water, and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried overNa2SO4, filtered, and concentrated in vacuo. The crude residue was purified by prep-TLC (pet. ether / EtOAc =3 / 1) to afford the title compound. LC / MS = 411 [M+l],STEP H: 5-((3-(2.2-Difluoroethoxy)-5-(difluoromethyl)pyrazin-2-yl)oxy)-4-methylpyridin-2-amine

[0174] To a stirred mixture of 3-(2,2-difluoroethoxy)-5-(difluoromethyl)-2-((6-(2,5-dimethyl-l / 7-pyrrol-l-yl)-4-methylpyridin-3-yl)oxy)pyrazine (70 mg, 0.17 mmol) in EtOH (3 mL) and water (1 mL) was added hydroxylamine hydrochloride (119 mg, 1.71 mmol) and the reaction mixture was heated to 85 °C. After 12 h. the reaction mixture was extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. soln ), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified using prep-TLC (pet. ether / EtOAc = 1: 1 ) to afford the title compound. LC / MS = 333 [M+l],STEP I: A / -(5-((3-(2.2-Difluoroethoxy)-5-(difluoromethyl)pyrazin-2-yl)oxy)-4-methylpyridin-2-yl)-A2-(4-methyl-l.l-dioxidotetrahydro-27 -thiopyran-4-yl)oxal amide

[0175] To a stirred mixture of 5-((3-(2,2-difluoroethoxy)-5-(difluoromethyl)pyrazin-2-yl)oxy)-4-methylpyridin-2-amine (20 mg, 60 pmol), 2-((4-methyl-l,l-dioxidotetrahydro-2 / 7-thiopyran-4-yl)amino)-2-oxoacetic acid (14.16 mg, 60 pmol) and pyridine (24 pL, 0.30 mmol) in DCM (1 mL) was added POCl3(17 pL, 0.18 mmol) at RT. After 2 h. the solution was directly purified by Prep-HPLC (Prep-HPLC (Column: YMC-Actus Triart C18 150*30mm*5um. 40-60% ACN-water(0.1%TFA); Gradient time: 11.5 min; Flow Rate: 40 mL / min) to afford the title compound. LC / MS = 550 [M+l],NMR (400 MHz, methanol-d4) 5 8.39 (s, 1H), 8.22 (s, 2H), 7.93 (s, 1H), 6.61-6.90 (m, 1H), 6.19-6.50 (m, 1H), 4.73-4.81 (m, 2H), 3.22-3.30 (m, 2H), 3.01 (br d,26118J=13.83 Hz, 2H), 2.88 (br d. J=14.42 Hz, 2H), 2.26 (s, 3H). 2.20 (br t, J=12.22 Hz, 2H). 1.51 (s.3H). Human DGAT2 ICso =18 nM.

[0176] By using procedures similar to those described in Example 28 with appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.Human LC / MS DGAT2 Example Structure Name[M+l] IC50 (nM) A^5-((5-(Difluoromethyl)- 3-(2,2,2- trifluoroethoxy)pyrazin-2- 29 yl)oxy)-4-methylpyridin-2- 568 14.2 '0 y 1 )-Ar2-( 4-methy 1- 1, 1 - dioxidotetrahydro-277- thiopyran-4-yl)oxal amideExample 30A1-(4-Cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)- / V2-(4- methyl-1, 1 -di oxidotetrahydro-2 / 7-thi opy ran-4-y 1 )oxalamideSTEP A: 4-Cvclopropyl-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-JV. / V-bis(4-methoxybenzyl)pyridin-2-amine

[0177] To a stirred mixture of 4-chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-A, A-bis(4-methoxybenzyl)pyridin-2-amine (150 mg, 0.26 mmol), cyclopropylboronic acid (123 mg, 1.43 mmol) and K3PO4 (165 mg, 0.78 mmol) in THF (3 mL) and water (1 mL) was added XPhos Pd G2 (20.42 mg, 26 pmol), and the reaction mixture was heated to 110 °C. After 12 hours the reaction mixture was poured into water and extracted with DCM. The combined organic fractions were washed withNaCl (sat. aq. soln.), dried overNa2SO4, filtered, and26118concentrated in vacuo. The crude residue was purified by flash silica gel column chromatography using using 10% EtOAc in hexanes to afford the title compound. LC / MS = 584 [M+l], STEP B: 4-Cyclopropyl-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0178] To a stirred solution of 4-cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-jV,jV-bis(4-methoxybenzyl)pyridin-2-amine (110 mg, 0.19 mmol) in DCM (1 mL) was added TFA (1 mL) at RT. After 12 h the reaction mixture was concentrated under reduced pressure and extracted with EtOAc. The combined organic fractions were washed with NaHCOs (sat. aq. soln.) andNaCl (sat. aq. soln.), dried overNa2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash silica gel column chromatography using 10% EtOAc in hexanes to afford the title compound. LC / MS = 344 [M+l],STEP C; A1-(4-Cvclopropyl-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A2-(4-methyl-l.l-dioxidotetrahvdro-2 7-thiopyran-4-yl)oxal amide

[0179] To a stirred solution of 4-cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (65 mg, 0.19 mmol), 2-((4-methyl-l,l-dioxidotetrahydro-2 / 7-thiopyran-4-yl)amino)-2-oxoacetic acid (134 mg, 0.57 mmol) and pyridine (77 pL, 0.95 mmol) in DCM (1.5 mL) was added POCl3(0.018 mL, 0.19 mmol) at RT. After 2h the reaction mixture was poured into water and extracted with DCM. The combined organic layers were washed with NaCl (sat. aq. soln.), dried overNa2SO4, filtered, and concentrated in vacuo. The crude residue was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the title compound. LC / MS = 561 [M+l], *HNMR (MeOH-d4, 400 MHz) 8 8.13 (s, 1H), 7.75 (s, 1H), 7.65 (d, 1H, 7=2.0 Hz), 7.59 (br d, 1H, 7=9.1 Hz), 4.77 (q, 2H, 7=8.4 Hz), 3.2-3.3 (m. 2H), 2.99 (br d, 2H, 7=13.9 Hz). 2.85 (br d, 2H, 7=14.2 Hz), 2.18 (br t, 2H.7=13.3 Hz), 2.04 (br dd. 1H.7=5.2, 7.3 Hz). 1.48 (s, 3H). 1.06 (br d, 2H, 7=6.3 Hz), 0.85 (br d, 2H, 7=3.5 Hz). Human DGAT2 ICso= 2.5 nM.Example 317V1-(4-Ethyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-7V2-(4-methyl- 1.1 -dioxidotetrahy dro-27f-thiopyran-4-yl)oxal amide26118STEP A: 4-Ethyl-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)Dyridin-2-yl)oxy)-jV,jV-bis(4-methoxybenzyl)pyridin-2-amine

[0180] To a stirred solution of 4-chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)- / V / V-bis(4-methoxybenzyl)pyridin-2-amine (150 mg, 0.26 mmol), tri ethylborane (0.52 mL, 0.52 mmol). CS2CO3 (254 mg, 0.78 mmol) in THF (1 mL) was added X-Phos Pd G2 (21 mg, 27 pmol) at RT. The mixture was spared with nitrogen for 1 min and heated to 80 °C. After 12 h the reaction mixture was poured into water and extracted with DCM. The combined organic fractions were washed withNaCl (sat. aq. soln.), dried over NazSCL. filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using a 0-100% EtOAc in hexanes gradient to afford the title compound. LC / MS = 572 [M+l],STEP B; 4-Ethyl-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0181] To a stirred solution of 4-ethyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-A. A-bis(4-melhoxybenzyl)pyridin-2-amine (150 mg, 0.26 mmol) in DCM (1 mL) was added TFA (0.5 mL) at RT. After 5 h the reaction mixture was concentrated under reduced pressure and extracted with EtOAc. The combined organic fractions were washed with NaHCO3(sat. aq. soln.) and NaCl (sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using a 0-100% EtOAc in hexanes gradient to afford the title compound. LC / MS = 332 [M+l],STEP C: jVj-(4-Ethyl-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy')pyridin-2-yl)-2-(4-methyl- 1.1 -dioxi dotetrahvdro-2H-thiopyran-4-yl)oxal ami de

[0182] To a stirred solution of 4-ethyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (68 mg, 0.21 mmol), 2-((4-methy 1-1,1 -di oxidotetrahydro-2H-thiopyran-4-yl)amino)-2-oxoacetic acid (145 mg, 0.62 mmol) and pyridine (83 pL, 1.03 mmol) in DCM (1 mL) was added POCI3 (38 pL, 0.41 mmol) at RT. After 2h the mixture was poured into water and extracted with DCM. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over NazSCh, filtered, and concentrated in vacuo. The residue was purified by mass triggered reverse phase HPLC (MeCN / water lOmM-NFLHCO? modifier) to afford the title compound. LC / MS = 549 [M+l], ‘H NMR (400 MHz, METHANOL-d4) 5 8.17 (br s, 2H), 7.57-7.68 (m, 2H), 4.76 (q, J=8.23 Hz, 2H), 3.19-3.27 (m, 2H), 2.97-3.01 (m, 2H), 2.84-2.88 (m, 2H), 2.66 (br d,.7=7.27 Hz, 2H), 2.15-2.22 (m, 2H), 1.49 (s, 3H), 1.23 (br t,.7=7.21 Hz, 3H). Human DGAT2 IC50 = 3.7 nM.Example 32A1-(4-Difluoromethyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-7V2-(4- methyl- 1.1 -dioxidotctrahydro-2 / 7-thiopy ran -4-yl)oxal amide26118STEP A: 2-Bromo-4-(difluoromethyl)-5-fluoropyridine

[0183] To a stirred solution of 2-bromo-5-fluoroisonicotinaldehyde (3.0 g, 14.7 mmol) in DCM (200 mL) was added DAST (5.93 g, 36.8 mmol) drop- wise over 15 minutes keeping the reaction temperature below 5 °C. The reaction mixture was allowed to warm to RT overnight. The reaction mixture was quenched with NH4CI (sat. aq. soln.), poured into H2O, and extracted with DCM. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using 10% EtOAc in hexanes to afford the title compound. LC / MS = 226 [M+l],STEP B; Ethyl 4-(difluoromethyl)-5-fluoropicolinate

[0184] To a stirred solution of 2-bromo-4-(difluoromethyl)-5-fluoropyridine (1.8 g, 7.96 mmol) and KO Ac (2.34 g. 23.9 mmol) in EtOH (20 mL) was added PdCh(dppf) (0.58 g, 0.80 mmol) under an atmosphere of CO. The reaction mixture was heated to 80 °C. After 6 hours the reaction mixture was poured into water and extracted with DCM. The combined organic fractions were washed wi th NaCl (sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using 10% EtOAc in hexanes to afford the title compound LC / MS = 220 [M+l],STEP C: Ethyl 4-(difluoromethyl)-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)picolinate

[0185] To a stirred solution of CS2CO3 (463 mg, 1.42 mmol), ethyl 4-(difluoromethyl)-5-fluoropicolinate (187 mg, 0.85 mmol) in DMA (2 mL) was added 5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-ol (150 mg, 0.711 mmol) and the mixture was heated to 60 °C. After 12 h the mixture was poured into water and extracted with DCM. The combined organic layers were washed with NaCl (sat. aq. soln.), dried overNa2SO4, filtered, and concentrated in vacuo.26118The crude residue was purified by flash silica gel column chromatography using 10% EtOAc in hexanes to afford the title compound. LC / MS = 411 [M+l],STEP D; 4-(Difluoromethyl)-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)picolinic acid

[0186] To a stirred solution of ethyl 4-(difluoromethyl)-5-((5-fluoro-3-(2,2.2-trifluoroethoxy)pyridin-2-yl)oxy)picolinate (140 mg, 0.34 mmol) in THF (1.5 mL) and water (0.5 mL) was added LiOH lEO (43.0 mg, 1.02 mmol) at RT. After 12 h. the mixture was poured into water and extracted with DCM. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound.LC / MS = 383 [M+l],STEP E; 4-(Difluoromethyl)-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0187] To a stirred solution of 4-(difluoromethyl)-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)picolinic acid (100 mg, 0.26 mmol) and triethylamine (53.0 mg, 0.52 mmol) in toluene (2 mL) was added water (23.57 mg, 1.308 mmol) followed by diphenylphosphinyl azide (127 mg, 0.52 mmol), and the reaction mixture was heated at 90 °C. After 2 h the reaction mixture was poured into water and extracted with DCM. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried overNa2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using 10% EtOAc in hexanes to afford the title compound. LC / MS = 354 [M+l],STEP F; / V / -(4-(Difluoromethyl)-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A?-(4-methyl-l.l-dioxidotetrahvdro-2H-thiopyran-4-yl)oxal amide

[0188] POCls (0.016 mL, 0.170 mmol) was added to a stirred mixture of 4-(difluoromethyl)-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (60 mg, 0.170 mmol), 2-((4-methyl-l. l-dio\idotetrahydro-2 / / -thiopyran-4-yl)amino)-2-o\oacetic acid (120 mg, 0.510 mmol) and pyridine (0.069 mL, 0.849 mmol) in DCM (1.5 mL) at 25 °C and the mixture was stirred at 25 °C for 2 h. LCMS showed that desired target was formed. The mixture was poured into H2O, then the mixture was extracted with DCM (x 3), the combined organic layers were washed wi th NaCl (sat. aq. soln.), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the title compound as the TFA salt. LC / MS = 571 [M+l], 'H NMR (methanol-d4, 400 MHz) 5 8.50 (s, 1H), 8.39 (s, 1H), 8.33 (s, 1H), 7.69 (d, 1H, J=2.5 Hz), 7.60 (dd, 1H, J=2.5, 8.9 Hz), 6.95 (t, 1H,.7=54.3 Hz), 4.75 (q, 2H, J=8.3 Hz), 3.2-3.3 (m, 2H), 2.98 (m, 2H), 2.86 (m, 2H), 2.1-2.2 (m, 2H), 1.48 (s, 3H). Human DGAT2 IC50 = 0.89 nM.26118Example 33A1-(4-Chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / 7-thiopy ran-4-y I JoxalamideSTEP A: 4-Chloro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyri din-2 -yl)oxy)pyridin-2-amine

[0189] To a mixture of 4-chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7V, / V-bis(4-methoxybenzyl)pyridin-2-amine (100 mg. 0.17 mmol) in DCM (1 mL) was added TFA (1 mL), then the mixture was stirred at 25 °C for 12 h. LCMS showed that desired target was formed. The reaction mixture was diluted with aqueous NaHCO3. The residue was purified by flash silica gel column chromatography (10% EtOAc / hexanes) to afford the title compound. LC / MS = 338 [M+l], 'H NMR (methanol-d4,(or CDsOD) 400 MHz) 57.79 (s. 1H), 7.62 (d, 1H,.7=2,5 Hz), 7.52 (dd, 1H. J=2.5, 9.1 Hz). 6.72 (s, 1H), 4.74 (q. 2H, J=8.4 Hz).STEP B: A1-(4-Chloro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A2-(4-methyl- 1, 1 -di oxidotetrahvdro-27 / -thiopyran-4-yl)oxal amide

[0190] POCl3(0.646 mL, 6.93 mmol) was added to a stirred mixture of 4-chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (36 mg, 0.107 mmol).2-((4-methyl-1,1 -dioxidotetrahy dro-2H-thiopyran-4-yl)amino)-2-oxoacetic acid (75 mg, 0.320 mmol) and pyridine (0.467 mL, 5.77 mmol) in DCM (1.5 mL) at 25 °C. The mixture was stirred at 25 °C for 12 h. LCMS showed that desired target was formed. The mixture was poured into H2O, then the mixture was extracted with DCM (x 3). The combined organic layers were washed with brine, dried overNa2SO4, then filtered and concentrated under reduced pressure. The residue was purified by mass triggered reverse phase HPLC (ACN / water with 0.1% TFA modifier) to afford the title compound as the TFA salt. LC / MS = 555 [M+l], 'H NMR (methanol-d4, 400 MHz) 3 8.43 (s, 1H), 8.28 (s, 1H), 7.63 (d,.7=2,5 Hz, 1H), 7.59 (dd, J=2.4, 8.9 Hz, 1H), 4.77 (q, J=8.3 Hz. 2H), 3.2-3.3 (m, 2H), 2.99 (br d, J=13.6 Hz, 2H), 2.86 (m, 2H,), 2.1-2.2 (m, 2H), 1.48 (s, 3H). Human DGAT2 IC50 = 3.4 nM.Example 34 and 357V1-(4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A2-(4-methyl- 1.1 -dioxidotetrahy dro-2 / 7-thiopyran-4-yl)oxalamide and A'-(4-hydroxy-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A2-(4-methyl-l,l-dioxidotetrahydro-2 / / - thiopyran-4-yl)oxal amideSTEP A: 5-Bromo-4-fluoropyridin-2-amine

[0191] To a stirred solution of 4-fluoropyridin-2-amine (5 g, 44.6 mmol) in MeCN (50 mL) was added NBS (8.73 g, 49.1 mmol) portion wise at 0 °C followed by warming to RT. After 2 h the reaction mixture was concentrated in vacuo. NaHCOs (100 mL, sat. aq. soln.) was added and the reaction mixture was stirred at RT for 1 h. The precipitate was collected via filtration. The solid was suspended in water (100 mL) and stirred at for 1 hour at RT. The mixture was filtered to afford the title compound. LC / MS = 191 [M+l J.STEP B; A. A-Dibenzyl-5-bromo-4-fluoropyridin-2-amine

[0192] To a stirred solution of 5-bromo-4-fluoropyridin-2-amine (2 g, 10.47 mmol) in DMF (30 mL) at 0 °C was added NaH (0.96 g, 24.1 mmol). After 30 min (bromomethyl)benzene (2.74 mL, 23.04 mmol) was added. After 2 hours the reaction mixture was quenched with water and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq. soln.), dried over Na2SC>4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography using 20: 1 EtOAc in pet. ether to afford the title compound. LC / MS = 371, 373 [M+l],STEP C: (6-(Dibenzylamino)-4-fl uoropyri din-3 -vDboronic acid

[0193] To a stirred solution of KOAc (0.48 g, 4.85 mmol), bis(pinacolato)diboron (0.616 g, 2.424 mmol), and / V,jV-dibenzjd-5-bromo-4-fluoropyridin-2-amine (0.60 g, 1.62 mmol) in 1,4-dioxane (20 mL) was added Pd(dppf)Ch (0.12 g, 0.16 mmol) and the reaction was heated to 110 °C After 16 h the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with NaCl (sat. aq. soln.), dried overNa2SO4, filtered, and concentrated in vacuo to afford the crude title compound which was used in next step without further purification. LC / MS = 337 [M+l],STEP D: 6-(Dibenzylamino)-4-fluoropyridin-3-ol

[0194] To a stirred mixture of (6-(dibenzylamino)-4-fluoropyridin-3-yl)boronic acid (0.54 g, 1.62 mmol) in THF (10 mL) and water (10 mL) was added sodium l,2,3-dioxaboriran-3-olate tetrahydrate (1.0 g, 6.5 mmol) at 15 °C. After 2 hours the reaction mixture was diluted with water, and the pH was adjusted to ~6, and the mixture was extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by flash silica gel column chromatography using a 10-25% EtOAc in pet. ether gradient to afford the title compound. LC / MS = 309 [M+l],STEP E; A, A-Dibenzyl-4-fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0195] To a stirred mixture of 1, 10-Phenanthroline (18.7 mg, 104 pmol), K3PO4 (165 mg, 0.78 mmol), 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (100 mg, 0.31 mmol), 6-(dibenzylamino)-4-fluoropyridin-3-ol (80 mg, 0.26 mmol), Cui (9.88 mg, 52 pmol) under N2 was added DMSO (2 mL) and the reaction mixture was heated to 110 °C. After 3 h the reaction mixture was diluted with water and extracted with EtOAc. The combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo The crude residue was purified by Prep-TLC (pet. ether: EtOAc = 10:1) to the title compound. LC / MS = 502 [M+l],STEP F; 4-Fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0196] To a solution of A. / V-dibenzyl-4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (25 mg, 0.050 mmol) in MeCN (1.8 mL) and water (0.2 mL) was added ammonium cerium(IV) nitrate (109 mg, 0.199 mmol). The mixture was stirred at 20 °C for 0.5 h. LCMS showed that major desired product was formed. The reaction solution was diluted with NaHCOs (5 mL) and extracted with EtOAc (5 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by Prep-TLC (Pet. ether: EtOAc=l:2) to give 4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine. LC / MS = 322 [M+l],STEP G: A / -(4-Fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A-7-(4-methyl-Ll-dioxidotetrahvdro-2H-thiopyran-4-yl)oxalamide & Aj-(5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-4-hvdroxypyridin-2-yl)- / V2-(4-methyl- 1, 1 -dioxidotetrahvdro-2 / / -thiopyran-4-yl)oxal amide

[0197] To a solution of 2-((4-methyl-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-2-oxoacetic acid (9.67 mg, 0.041 mmol) in DCM (1.0 mL) was added 4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (11 mg, 0.034 mmol), pyridine (0.014 mL, 0.171 mmol) and POCl3(9.58 pl, 0.103 mmol) successively. The reaction was stirred at 20°C for 8 hours. LCMS showed major desired product was formed. The reaction solution was diluted with NaHCO3(5 mL), extracted with EtOAc (5 mL x3). The combined organic layers were dried over Na2SC, filtered and concentrated in vacuo to give the crude product.

[0198] The crude product was purified by Prep-HPLC (Column YMC-Actus Triart C18 150*30mm*5um Condition water(0.1%TFA)-ACN Begin B 46 End B 66 Gradient Time(min) 11.5 100%B Hold Time 1 Flow Rate(mL / min) 40 Injected 1) to give EX-34: A;-(4-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)- / V2-(4-methyl-l,l-dioxidotetrahydro-2 / / -thiopyran-4-yl)oxalamide. LC / MS = 539 [M+l],1H NMR (400 MHz, CDCh) 5 ppm 9.85 - 10.09 (m, 1 H), 8.32 (d,.7=9.54 Hz, 1 H), 8.18 (d,.7=11.44 Hz, 1 H), 7.67 (d, 7=2.50 Hz, 1 H), 7.39 (s, 1 H), 7.20 (dd, 7=8.17, 2.44 Hz, 1 H), 4.54 (q, 7=7.99 Hz, 2 H), 3.08 - 3.18 (m, 2 H), 2.97 - 3.06 (m, 2 H), 2.76 (br d,.7=15.50 Hz, 5 H), 2.28 - 2.39 (m, 2 H), 1.54 (s, 3 H). Human DGAT2 ICso = 11.6 nM And EX-35: A7-(5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy )-4-hydroxypyridin-2-yl)-A2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / 7-thiopyran-4-yl)oxalamide. LC / MS = 537 [M+l], 'H NMR (400 MHz, CDCh) 6 ppm 8.17 (br s, 1 H), 7.69 (d, 7=2.15 Hz, 1 H), 7.55 (s, 1 H), 7.22 (dd, 7=8.11, 2.15 Hz, 1 H), 4.55 (q, 7=7.99 Hz, 2 H), 3.17 - 3.28 (m, 2 H), 2.94 - 3.03 (m, 2 H), 2.80 - 2.87 (m, 2 H), 2.61 - 2.64 (m, 3 H), 2.44 (br d, 7=13.23 Hz, 2 H), 1.62 - 1.69 (m, 3 H). Human DGAT2 IC50 = 157 nM Example 36V7-(5-Fluoro-6-((5-fluoro-3-(2, 2, 2-tri fluoroethoxy )pyridin-2-yl)oxy)pyridin-3-yl)-A2-(4-methyl- 1, 1 -dioxidotetrahy dro-277-thiopyran-4-yl)oxal amideSTEP A: 5-Chloro-3-fluoro-2-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridine

[0199] An 8 mL tube was charged with 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (783 mg, 2.440 mmol), 5-chloro-3-fluoropyridin-2-ol (300 mg, 2.033 mmol), Potassium phosphate tribasic (1295 mg, 6.10 mmol), A / . V-dimethylglycine (84 mg, 0.813 mmol) and copper(I) iodide (77 mg, 0.407 mmol) in DMSO (3 mL) under N2 atmosphere. Then the tube was sealed and heated to 100 °C for 12 h. LCMS was showed that the desired target was formed. Water was added in the mixture, then the mixture was extracted with EtOAc (x 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 (pet. ether / ethyl acetate =5 / 1) to afford the title compoundLC / MS = 341 [M+l], 'H NMR (400 MHz. CDCh) 67.98 (d,26118J=2.15 Hz. 1H), 7.85 (d. J=2.50 Hz. 1H), 7.59 (dd, J=2.21. 8.76 Hz, 1H), 7.20 (dd. J=2.56, 8.17 Hz, 1H), 4.44 (q, J=7.91 Hz, 2H).STEP B: 5-Fluoro-6-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-3-amine

[0200] To a solution of 5-chloro-3-fluoro-2-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridine (90 mg, 0.264 mmol), ammonia hydrate (309 mg, 2.64 mmol), potassium phosphate (168 mg, 0.793 mmol), jV2-di([l, T-biphenyl]-2-yl)oxalamide (41.5 mg, 0.106 mmol) in DMSO (3 mL) was added copper(I) iodide (10.06 mg, 0.053 mmol) under N2 atmosphere. The mixture was stirred at 90 °C for 15 h. LCMS was showed that the desired target was formed. The mixture was poured into H2O (30 mL), then the mixture was extracted with EtOAc (x 3). The combined organic layers were washed with brine, dried overNa2SO4, then filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (pet. ether / ethyl acetate =2 / 1) to afford the title compound. LC / MS = 322 [M+l],STEP C: A / -(5-Fluoro-6-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)-A2-(4-methyl- 1.1 -di oxidotetrahy dro-27 / -thiopyran-4-yl)oxal amide

[0201] An 8 mL tube was charged with 5-fluoro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-3-amine (15 mg, 0.047 mmol), 2-((4-methy 1-1,1 -di oxi dotetrahydro-2 / 7-thiopyran-4-yl)amino)-2-oxoacetic acid (12.08 mg, 0.051 mmol). DIEA (0.024 mL, 0.140 mmol) in DMF (1 mL) at 20 °C, HATU (26.6 mg, 0.070 mmol) was added in the mixture. The mixture was stirred at 20 °C for 0.5 h. LCMS showed that the desired target was formed. The resulting solution was purified by pre-HPLC to afford the title compound. LC / MS = 539 [M+l], 'H NMR (400 MHz, CD3OD) 58.27-8.33 (m. 2H), 7.80 (d. J=2.50 Hz. 1H), 7.63 (dd,.7=2,44. 9.00 Hz, 1H), 4.67 (q. J=8.34 Hz. 2H), 3.18-3.29 (m. 2H), 2.98 (br d, J=13.59 Hz. 2H), 2.84 (br d, J=14.78 Hz, 2H), 2.10-2.22 (m, 2H), 1.47 (s, 3H). Human DGAT2 IC50 = 805 nM.Example 37V / -(3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A2-(4-methyl- 1.1 -dioxidotetrahy dro-2 / f-thiopyran-4-yl)oxal amide26118STEP A: A, / V-Dibenzyl-5-bromo-3-fluoropyridin-2-amine

[0202] A solution of 5-bromo-3-fluoropyridin-2-amine (5 g, 26.2 mmol) in DMF (80 mL), the solution was stirred at 0 °C. NaH (2.408 g, 60.2 mmol) was added in the mixture at 0 °C. The mixture was stirred at 0 °C for 30 min. (Bromomethyl)benzene (6.84 mL, 57.6 mmol) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 2 h. Water (500 mL) was added in the mixture, then the mixture was extracted with EtOAc (100 mLx 3). The combined organic layers were washed with brine (500 mL x2), dried over NaiSOr. then filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (Pet. ether: EtOAc=10:l) to afford the title compound. LC / MS = 371, 373 [M+H+], 'H NMR (400 MHz, CDCh) 58.03-8.06 (m, 1H), 7.29-7.40 (m, 6H), 7.24-7.28 (m, 5H), 4.73 (s, 4H)STEP B; 6-(Dibenzylamino)-5-fluoropyridin-3-ol

[0203] Lithium hydroxide monohydrate (0.339 g, 8.08 mmol) was added to a stirred mixture of A / ,7V2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (0.354 g, 1.077 mmol), Copper(II) acetylacetonate (0.141 g, 0.539 mmol) and MA'-dibenzyl-5-bromo-3-fluoropyndin-2-amine (1.0 g, 2.69 mmol) in DMSO (15 mL) and water (5 mL). Then the mixture was stirred at 80 °C for 16 h. The crude product was diluted with water (50 mL), and pH was adjusted to ~6. The complex was extracted with EtOAc (50 mL x3). The combined organic layers were dried over NazSO-i. filtered, and concentrated in vacuo to give the crude product. The filtrate was concentrated to give a residue which was purified by flash silica gel column chromatography (eluent of 20% EtOAc / Pet.ether gradient) to afford the title compound. LC / MS = 309 [M+H+], 'H NMR (400 MHz, CDCh) 5 ppm 7.91 - 8.02 (m, 1 H), 7.29 - 7.35 (m, 8 H), 7.27 (br d, J=1.19 Hz, 2 H), 7.16 (br s, 1 H), 4.65 (s. 4 H).STEP C: A. A-Dibenzyl-3-fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0204] A 40 mL of tube was charged with 1,10-phenanthroline (46.8 mg, 0.259 mmol), K3PO4 (413 mg, 1.946 mmol), 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (250 mg, 0.778 mmol), 6-(dibenzylamino)-5-fluoropyridin-3-ol (200 mg, 0.649 mmol). Copper(I) Iodide (24.71 mg. 0.130 mmol) and DMSO (5 mL) under N2. Then the tube stirred at 110 °C for 2 h. The reaction solution was diluted with water (15 mL), extracted with EtOAc (15 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel column chromatography (eluent of 5% EtOAc / Pet.ether gradient) to afford the title compound. LC / MS = 502 [M+H+],26118STEP D: 3-Fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0205] To a solution of jV,7V-dibenzyl-3-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (155 mg, 0.309 mmol) in t-BuOH (5 mL) and 1 drop of cone HC1 was added Pd-C (99 mg, 0.093 mmol) and Pd(OH)2 (65.1 mg, 0.093 mmol). The mixture was stirred at 20 °C under H2 for 1.5 h. LCMS showed that major desired product was formed. The solution was filtered and concentrated in vacuo to afford the title compound, which was used in next step without further purification. LC / MS = 322 [M+H+],STEP E; A,-(3-Fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A2-(4-methy 1- 1, 1 -di oxidotetrahvdro-2 -thiopyran-4-yl)oxal amide

[0206] To a solution of 2-((4-methyl-l,l-dioxidotetrahydro-2ff-thiopyran-4-yl)amino)-2-oxoacetic acid (80 mg, 0.340 mmol) in DCM (5.0 mL) was added 3-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine (95 mg, 0.283 mmol), pyridine (0.229 mL, 2.83 mmol) and POCI3 (0.132 mL, 1.417 mmol) successively. The reaction was stirred at 20 °C for 1 hours. The reaction solution was diluted with NaHCO3(15 mL), extracted with EtOAc (15 mL x3). The combined organic layers were dried over Na2SC>4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by Prep-HPLC (Column YMC- Actus Triart C18 150*30mm*5um Condition water(0.1%TFA)-ACN Begin B 35 End B 55 Gradient Time(min) 11.5 100%B Hold Time 1 Flow Rate(mL / min) 40 Injected 2) to give jV7-(3-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A -(4-methyl- l,l-dioxidotetrahydro-2-thiopyran-4-yl)oxalamide. LC / MS = 539 [M+H+], 'H NMR (400 MHz, CDCh) 5 ppm 9.54 (br s, 1 H), 8.24 (d,.7=2.26 Hz, 1 H), 7.75 (d, J=2.38 Hz, 1 H), 7.40 - 7.56 (m, 2 H), 7.20 (dd, J=8.23. 2.38 Hz, 1 H), 4.51 (q. J=7.87 Hz. 2 H). 3.09 - 3.20 (m. 2 H), 2.98 (br d, J=14.19 Hz, 2 H), 2.77 (br d. J=14.90 Hz, 2 H), 2.24 - 2.38 (m, 2 H), 1.53 (s. 3 H). Human DGAT2 IC50 = 641 nM.Example 38rl-(3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-2- (4-methyl- 1, 1 -dioxidotetrahy dro-2 / 7-thiopy ran-4-y I joxalamide26118STEP A: 5-Bromo-3-fluoro-4-methylpyridin-2-amine

[0207] To a solution of 2-amino-3-fluoro-4-methylpyridine (4.128 g, 32.7 mmol) in MeCN (100 mL), N-bromosuccinimide (6.12 g, 34.4 mmol) was added portion wise upon stirring and cooling at 0 °C. The reaction mixture was stirred at 20 °C for 1 h. LCMS showed major desired product was formed. After evaporation under reduced pressure, the residue was diluted with K2CO3 aq. (50 mL) and extracted with EtOAc (50 mL x3). The combined organic layers were washed with NaCl aq. (50 mL), dried over Na2SO-i. filtered and concentrated in vacuo to afford the title compound, which was used in next step without further purification. LC / MS = 205, 207 [M+H+], 'H NMR (400 MHz, CD3OD) 6 ppm 7.81 (s, 1 H), 2.29 (d, J=2.38 Hz, 3 H) STEP B: -Dibenzyl-5-bromo-3-fluoro-4-methylpyridin-2-amine

[0208] To a solution of 5-bromo-3-fluoro-4-methylpyridin-2-amine (3 g, 14.63 mmol) in DMF (30 mL) was added NaH (1.346 g, 33.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then (bromomethyl)benzene (3.82 mL, 32.2 mmol) was added in the mixture at 0 °C. The mixture was stirred at 0 °C for another 2 h. LCMS showed that the desired target was formed. Water (300 mL) was added slowly to quench the excess NaH, then the mixture w as extracted with EtOAc (50 mLx 3), the combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The residue w as purified by flash silica gel column chromatography (Pet. ether: EtOAc=20: 1) to afford the title compound. LC / MS = 385, 387 [M+H+], ‘HNMR (400 MHz, Chloroform-d) 58.06 (s, 1H), 7.24-7.31 (m, 11H), 4.70 (s, 4H), 2.32 (d, J=2.62 Hz, 3H)STEP C: 6-(Dibenzylarnino)-5-fluoro-4-methylpyridin-3-ol

[0209] Lithium hydroxide monohydrate (0.327 g, 7.79 mmol) was added to a stirred mixture of N1, A--bis(4-Hydroxy-2.6-dimethylphenyl)o.\al amide (0.341 g, 1.038 mmol), Copper(ll) acetylacetonate (0.136 g, 0.519 mmol) and A / V-dibenzyl-5-bromo-3-fluoro-4-methylpyridin-2-amine (1.0 g, 2.60 mmol) in DMSO (15 mL) and water (5 mL). Then the mixture was stirred at 80 °C for 16 h. The crude product was diluted with water (50 mL) and pH was adjusted to ~6. The complex was extracted with EtOAc (50 mL x3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The filtrate was concentrated to give a residue which w as purified by flash silica gel column chromatography (eluent of 20% EA / Pet. ether gradient) to afford the title compound. LC / MS = 323 [M+H+],1H NMR (400 MHz, Chloroform-d) 5 ppm 7.86 - 7.93 (m, 1 H), 7.27 - 7.33 (m, 8 H), 7.25 (br d, J=3.10 Hz, 2 H), 4.60 (s, 3 H), 2.22 - 2.28 (m, 3 H)26118STEP D: A, / V-Dibenzyl-3-fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine

[0210] A 40 mL of tube was charged with 1,10-Phenanthroline (44.7 mg, 0.248 mmol), K3PO4 (395 mg, 1.861 mmol), 5-fluoro-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine (239 mg, 0.744 mmol), 6-(dibenzylamino)-5-fluoro-4-methylpyridin-3-ol (200 mg. 0.620 mmol), Copper(I) Iodide (23.63 mg, 0.124 mmol) and DMSO (5 mL) under N2. Then the tube stirred at 110 °C for 3 h. The reaction solution was diluted with water (15 mL), extracted with EtOAc (15 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel column chromatography (eluent of 5% EtOAc / Pet. ether gradient) to afford the title compound. LC / MS = 516 [M+H+], STEP E; 3-Fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine

[0211] To a solution of A, A-dibenzyl-3-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine (120 mg, 0.233 mmol) in LBuOH (5 mL) was added Pd-C (74.3 mg, 0.070 mmol) and Pd(OH)2 (49.0 mg, 0.070 mmol). The mixture was stirred at 15 °C under H2 for 6 h. The solution was filtered and concentrated in vacuo to afford the title compound, which was used in next step without further purification. LC / MS = 336 [M+H+], STEP F; AL(3-Fluoro-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-A -(4-methyl-l.l-dioxidotetrahydro-2H-thiopyran-4-yl)oxal amide

[0212] To a solution of 2-((4-methyl- 1, 1 -dio\idotetrahydro-2 / 7-thiopyran-4-yl)amino)-2-oxoacetic acid (65.7 mg, 0.279 mmol) in DCM (5.0 mL) was added 3-fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine (78 mg, 0.233 mmol), pyridine (0.188 mL, 2.327 mmol) and POCI3 (0.108 mL, 1.163 mmol) successively. The reaction was stirred at 20 °C for 1 hours. The reaction solution was diluted with NaHCO3(15 mL), extracted with EtOAc (15 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by Prep-HPLC (Column YMC-Actus Triart C18 150*30mm*5um Condition water (0.1%TFA)-ACN Begin B 40 End B 60 Gradient Time(min) 11.5 100%B Hold Time 1 Flow Rate(mLZmin) 40 Injected 3) to afford the title compound. LC / MS = 553 [ M+H |. 'H NMR (400 MHz, Methanol-d4) 5 ppm 8.06 (s, 1 H), 7.67 (d,.7=2.38 Hz, 1 H), 7.61 (dd,.7=8.94, 2.38 Hz, 1 H), 4.77 (q,.7=8.34 Hz, 2 H), 3.19 - 3.29 (m, 2 H), 2.98 (br d..7=13.71 Hz, 2 H), 2.85 (br d,.7=14.31 Hz. 2 H). 2.12 - 2.27 (m. 5 H).1.49 (s, 3 H). Human DGAT2 IC50= 2416 nM.26118Example 39TV7-(5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-6-methylpyrazin-2-yl)-A2-(4-methyl- 1, 1 -dioxidotetrahy dro-2H-thiopy ran-4-y I oxalamideSTEP A: 5-Chloro-2-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylpyrazine

[0213] To a solution of 5-chloro-3-methylpyrazin-2-ol (900 mg, 6.23 mmol), 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (2188 mg. 6.85 mmol), K3PO4 (3304 mg, 15.56 mmol), BHMPO (409 mg, 1.245 mmol) in DMSO (25 mL) was added copper(I) iodide (119 mg, 0.623 mmol) under N2 atmosphere. The mixture was stirred at 100 °C for 15 h. LCMS showed that desired target was formed. The mixture was cooled, w ater w as added, and the mixture was extracted with EtOAc(x 3). The combined organic fractions were washed with brine, dried by Na2SO4, and filtered. The organic layer was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (pet. ether / ethyl acetate =1 / 1) to afford the title compound. LC / MS = 337 [M+l], 'H NMR (400 MHz, CDCh) 8 7.81-7.92 (m, 2H), 7.27 (d, J=2.03 Hz, 1H), 5.72-6.04 (m, 1H), 4.14 (dt, J=3.99, 12.79 Hz, 2H), 2.54 (s, 3H).STEP B; 5-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-6-methylpyrazin-2-amine

[0214] To a solution of 5-chloro-2-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylpyrazine (200 mg, 0.595 mmol), ammonia hydrate (209 mg, 5.95 mmol), potassium phosphate (379 mg, 1.785 mmol), N1, N2-di([l,l'-biphenyl]-2-yl)oxalamide (93 mg, 0.238 mmol) in DMSO (3 mL) was added copper(I) iodide (11.33 mg, 0.060 mmol) under N2 atmosphere. The mixture was stirred at 75 °C for 20 h. LCMS showed the desired product w as formed. The mixture w as extracted with EtOAc (x 3), washed with H2O. The combined organic layers were washed with brine, dried over Na2SO4 and filtered. The residue was purified by Prep-TLC (silica gel, pet. ether / ethyl acetate = 2 / 1) to afford the title compound. LC / MS = 317 [M+l], 'H NMR (400 MHz, Methanol-d4) 37.71 (d, J=2.15 Hz, 1H), 7.63 (d,.7=2.15 Hz, 1H), 7.41-7.48 (m, 1H), 6.00-6.33 (m, 1H), 4.37 (dt,.7=3.70, 13.65 Hz, 2H), 2.26 (s, 3H).26118STEP C: A / -(5-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-6-methylpyrazin-2-yl)-A -(4-methyl- 1, 1 -dioxidotetrahy dro-277-thiopyran-4-yl)oxalamide

[0215] A 8 mL tube was charged with 2-((4-methyl-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-2-oxoacetic acid (10 mg, 0.043 mmol), DIEA (0.022 mL, 0.128 mmol), HATU (24.24 mg, 0.064 mmol) and 5-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-6-methylpyrazin-2-amine (16.15 mg, 0.051 mmol) in DMF (1 mL) at 20 °C. The mixture was stirred at 20 °C for 0.5 h. LCMS showed that the desired target was formed. The mixture was cooled, water was added, and the mixture was extracted with EtOAc (x3). The combined organic fractions were washed with brine, dried by Na2SO4. filtered and the organic layer was evaporated under reduced pressure. The residue was purified by Prep-HPLC (reverse phase C-18 column), eluting with Acetonitrile / Water + 0.1% TFA, to afford the title compound. LC / MS = 534 [M+l],NMR (400 MHz, Methanol-d-i) 5 8.80 (s, 1H), 7.89 (d,.7=2.15 Hz, 1H), 7.73 (d,.7=2,03 Hz, 1H), 5.87-6.20 (m, 1H), 4.32 (dt,,7=3.58. 13.77 Hz, 2H), 3.18-3.29 (m, 2H), 2.98 (br d,.7=13.71 Hz, 2H), 2.85 (br d,,7=14.78 Hz, 2H). 2.52-2.55 (m, 3H). 2.10-2.23 (m, 2H). 1.47 (s. 3H). Human DGAT2 IC50 = 1184 nM.Example 40 and 41A1-(5-((5-Fluoro-3-(l,l,2,2-tetrafluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-A2-(4- methyl-l,l-dioxidotetrahydro-2 / / -thiopyran-4-yl)oxalamide & / V'-(4-methyl-l. l- dioxidotetrahydro-2 / 7-thiopyran-4-yl)-A2-(4-methyl-5-((3-(l,l,2,2-tetrafluoroethoxy)pyri din-2- yl)oxy)pyridin-2-yl)oxal amide26118STEP A: 3-(2-Bromo- 1, 1.2.2-tetrafluoroethoxy)-5-fluoro-2-iodopyridine

[0216] A 40 mL tube was added 5-fluoro-2-iodopyridin-3-ol (4.0 g, 16.74 mmol), NaH (1.674 g, 41.8 mmol) and DMF (50 mL). Then the mixture was stirred at room temperature for 30 min. Next, 1,2-dibromotetrafluoroethane (6.0 mL, 50.2 mmol) was added into above reaction system. The mixture was stirred at 47 °C for 16 h. The mixture was quenched with H2O (200 mL) and extracted with EtOAc (100 mL x3). The combined organic layers were washed with NaCl aq. (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel chromatography (eluent of 5% EtOAc / Pet. ether gradient) to afford the title compound. LC / MS = 418, 420 [M+H+],STEP B: 3-(2-Bromo-1,1,2,2-tetrafluoroethoxy)-2-((6-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-3-yl)oxy)-5-fluoropyridine

[0217] A40 mL oftube was charged with 1,10-phenanthroline (0.285 g, 1.582 mmol), K3PO4 (0.840 g, 3.96 mmol), 3-(2-bromo-l,l,2,2-tetrafluoroethoxy)-5-fluoro-2-iodopyridine (1.984 g, 4.75 mmol), 6-(2,5-dimethyl-7 / 7-pyrrol-l-yl)-4-methylpyridin-3-ol (0.800 g. 3.96 mmol), Copper(I) Iodide (0.151 g, 0.791 mmol) and DMSO (20 mL) under N2. Then the tube stirred at 110 °C for 2 h. The crude product was diluted with water (30 mL), extracted with EtOAc (40 mL x3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give a residue which was purified by flash silica gel26118chromatography (eluent of 6% EtOAc / Pet. ether gradient) to afford the title compound. LC / MS = 492, 494 [M+H+],STEP C: 2-((6-(2,5-Dimethyl-1H-pyrrol-1-yl)-4-methylpyridin-3-yl)oxy)-5-fluoro-3-(1,1,2,2-tetrafluoroethoxy)pyridine and 2-(2,5-dimethyl-1H-pyrrol-1-yl)-4-methyl-5-((3-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)oxy)pyridine

[0218] 3-(2-bromo-l,l,2,2-tetrafluoroethoxy)-2-((6-(2,5-dimethyl-177-pyrrol-l-yl)-4-methylpyridin-3-yl)oxy)-5-fluoropyridine (80 mg, 0.101 mmol) and AcOH (0.029 mL, 0.504 mmol) were dissolved in MeOH (3 mL). Then Zinc (39.5 mg, 0.605 mmol) was added to the above solution in batches. Then the reaction was stirred at 50 °C for 2 h. The reaction was filtered, and the filtrate was added NH3·MeOH to adjust pH>7. The filtrate then was concentrated in vacuo to give the crude product. The crude product was purified by prep-TLC (Pet. ether: EtOAc=5: 1) to give Int-7A: LC / MS = 414 [M+H+] and Int-7B: LC / MS = 396 [M+H+], STEP D: 5-((5-Fluoro-3-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-amine and 4-methyl-5-((3-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine

[0219] Hydroxylamine hydrochloride (286 mg, 4.11 mmol) was added to a stirred mixture of 2-((6-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methylpyridin-3-yl)oxy)-5-fluoro-3-(l, 1,2,2-tetrafluoroethoxy)pyridine (85 mg, 0.206 mmol) in ethanol (2 mL) and water (0.4 mL) at 25°C, and the mixture was stirred at 85 °C for 18 h. The mixture was cooled, NH3·MeOH was added to adjust pH >8, and the solvent was evaporated under reduced pressure. The residue was purified by prep-TLC (Pet. ether: EtOAc=l:2) to afford the title compound (Int-8A). LC / MS = 336 [M+H+],

[0220] Hydroxylamine hydrochloride (35.2 mg, 0.506 mmol) was added to a stirred mixture of 2-(2,5-dimethy l-77 / -pyrrol-l -yl)-4-methyl-5-((3-( 1, 1,2,2-tetrafluoroethoxy)pyridin-2-yl)oxy)pyridine (10 mg, 0.025 mmol) in ethanol (1 mL) and water (0.2 mL), and the mixture was stirred at 85 °C for 18 h. LCMS (ESI) showed starting material was consumed and new product formed. The mixture was cooled, NH3·MeOH was added to adjust pH >8, and the solvent was evaporated under reduced pressure. The residue was purified by prep-TLC (Pet. ether:EtOAc=l:2) to afford the title compound (Int-8B). LC / MS = 318 [M+H+],STEP E; A1-(5-((5-fluoro-3-(1.1.2.2-tetrafluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-A2-(4-methyl-l.1 -di oxidotetrahvdro-2 / / -thiopyran-4-yl)oxal amide fe d-H-methyl-Ll-dioxidotetrahydro-2-thiopyran-4-yl)-A2-(4-methyl-5-((3-(1.1.2.2-tetrafluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)oxal amide

[0221] To a solution of 2-((4-methyl- 1, 1 -dioxidotetrahydro-2 / 7-thiopyran-4-yl)amino)-2-oxoacetic acid (48.0 mg, 0.204 mmol) in DCM (1.0 mL) was added 5-((5-fluoro-3-(l, 1,2,2-26118tetrafluoroethoxy )pyri din-2 -yl)oxy)-4-methylpyri din-2 -amine (57 mg, 0.170 mmol), pyridine (0.069 mL, 0.850 mmol) and POCl3(0.048 mL, 0.510 mmol) successively. The reaction was stirred at 20 °C for 16 hours. LCMS showed major desired product was formed. The reaction solution was diluted with NaHCO3(5 mL), extracted with EtOAc (5 mL x3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude product. The crude product was purified by Prep-HPLC (Column YMC-Actus Triart C18 150*30mm*5um Condition water(0.1%TFA)-ACN Begin B 43 End B 63 Gradient Time(min) 11.5 100%B Hold Time 1 Flow Rate(mL / min) 40 Injected 3) to afford the title compound (Ex-40). LC / MS = 553 [M+H+],1H NMR (400 MHz, CDCl3) δ ppm 8.22 (s, 1 H), 8.14 (s, 1 H), 7.91 (d, J=2.62 Hz, 1 H), 7.55 (dd, J=7.45, 2.56 Hz, 1 H), 7.39 (s, 1 H), 5.89 - 6.19 (m, 1 H), 3.08 - 3.18 (m, 2 H), 2.96 - 3.05 (m, 2 H), 2.76 (br d, J=15.14 Hz, 2 H), 2.28 - 2.37 (m, 5 H), 1.54 (s, 3 H). Human DGAT2 IC50: 40 nM

[0222] To a solution of 2-((4-methyl-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)amino)-2-oxoacetic acid (4.98 mg, 0.021 mmol) in DCM (1.0 mL) was added 4-methyl-5-((3-(l, 1,2,2-tetrafluoroethoxy)pyridin-2-yl)oxy)pyridin-2-amine (5.6 mg, 0.018 mmol), pyridine (7.14 pl, 0.088 mmol) and POCl3(4.94 pl, 0.053 mmol) successively. The reaction was stirred at 20 °C for 16 hours. The reaction solution was diluted with NaHCO3(5 mL), extracted with EtOAc (5 mL x3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product. The crude product was purified by Prep-HPLC (Column Boston Green ODS 150*30mm*5um Condition water(0.1%TFA)-ACN Begin B 45 End B 65 Gradient Time(min) 11 100%B Hold Time 2 Flow Rate(mL / min) 25 Injected 1) to afford the title compound (Ex-41). LC / MS = 535 [M+H+],1H NMR (400 MHz, CDCl3) δ ppm 9.70 (br s, 1 H), 8.33 (br s, 1 H), 8.25 - 8.31 (m, 1 H), 8.17 (br s, 1 H), 8.08 (br s, 1 H), 7.38 - 7.46 (m, 1 H), 7.08 (br s, 1 H), 5.78 - 6.10 (m, 1 H), 3.09 - 3.18 (m, 2 H), 2.96 - 3.06 (m, 2 H), 2.76 (br d, J=14.66 Hz, 2 H), 2.28 - 2.39 (m, 5 H), 1.55 (br s, 3 H). Human DGAT2 IC50: >9990 nM.ASSAYSInsect cell expression and membrane preparation

[0223] Sf-9 insect cells were maintained in Grace's insect cell culture medium with 10 % heated-inactivated fetal bovine serum, 1 % Pluronic F-68 and 0.14 μg / ml Kanamycine sulfate at 27 °C in a shaker incubator. After infection with untagged baculovirus expressing human DGAT2 (hDGAT2) at multiplicity of infection (MOI) 3 for 48 hours, cells were harvested. Cell pellets were suspended in 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. Cell26118debris were removed by centrifugation at 2000 x g for 15 minutes. Membrane fractions were isolated by ultracentrifugation (100,000 x g), resuspended in the same buffer, and frozen (- 80 °C) for later use. The protein concentration was determined with the Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific). Expression of protein levels was analyzed by immunoblotting with rabbit anti-DGAT2 antibody (Abeam, ab 102831) and donkey anti-rabbit IgGH& L Alexa Fluor® 647 (Abeam, abl50075) followed by detection using Typhoon FLA9000 (GE Healthcare).LC / MS / MS analysis method

[0224] LC / MS / MS analyses were performed using Thermo Fisher's LX4-TSQ Vantage system. This system consists of an Agilent binary high-performance liquid chromatography (HPLC) pump and a TSQ Vantage triple quadrupole MS / MS instrument. For each sample, 2 pL samples from the top organic layer of in-plate liquid-liquid extraction were injected onto a Thermo Betabasic C4 column (2.1 mm x 20 mm, 5 pm particle size). The samples were then eluted using the following conditions; mobile phase: Isopropanol: acetonitrile / lOmM ammonium formate = 50 / 35 / 15 (v / v / v), flow rate: 0.8 mL / min, temperature: 25 °C. Data were acquired in positive mode using a heated electrospray ionization (HESI) interface. The operational parameters for the TSQ Vantage MS / MS instrument were a spray voltage of 3000 V, capillary’ temperature of 280°C, vaporizer temperature 400 °C, sheath gas 45 arbitrary unit. Aux gas 10 arbitrary units, S-lens 165 and collision gas 1.0 mTorr. Standard reference material (SRM) chromatograms of13C18-triolein (Q1: 920.8 > Q3: 621.3) and internal standard13C21-triolein (Q1: 923.8 > Q3: 617.3) were collected for 33 sec. The peak area was integrated by Xcalibur Quan software. The ratio between the13C18-triolein generated in the reaction and spiked in internal standard13C21-triolein was used to generate percentage inhibition and ICso values. Compound percentage inhibition was calculated by the following formula: Inhibition %=1- [(compound response - low control) / (high control - low control)] x 100%. Potent compounds were titrated and IC50were calculated by 4 parameter sigmoidal curve fitting formula.DGAT2 enzymatic activity assay

[0225] DGAT2 activity’ was determined by measuring the amount of enzy matic product13C18-triolein (13C-1,2,3-Tri(cis-9-octadecenoyl)glycerol) using the membrane prep mentioned above. The assay was carried out in ABgene 384-well assay plates in a final volume of 25 pL at rt. The assay’ mixture contained the following: assay buffer (100 mM Tris*Cl, pH 7.0, 20 mM MgCl2, 5% ethanol), 25 pM of diolein, 5 pM of13C18-oleoyl-CoA and 8 ng / pL of DGAT2 membrane.

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I:Ior pharmaceutically acceptable salts thereof wherein:W, X, Y and Z are each independently selected from -C(H)-, -C(Ci-6alkyl)-, -C(C3-6cycloalkyl)-, -C(halo)-, -C(Ci-6haloalkyl)-, -C(OH)-, and -N-;R1is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with 1-3 R3;R2is(1 ) 4-7 membered heterocyclyl containing 1 -3 ring heteroatoms independently selected from N, O and S, or(2) -(C3-6)cycloalkyl,wherein each heterocyclyl or cycloalkyl is unsubstituted or substituted with 1-3 R4;when present, each R3is independently selected from:(1) halogen,(2) -(Ci-3)alkyl,(3) -(Ci-3)haloalkyl,(4) -O-(Ci-3)alkyl, and(5) -O-(Ci-3)haloalkyl;when present, each R4is independently selected from:(1) halogen,(2) (Ci-3)alkyl,(3) (Ci-3)haloalkyl,(4) hydroxy, and(5) =0.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or substituted with 1-3 substituents independently selected from halogen, -(Ci-3)alkyl, -(Ci-3)haloalkyl and -O-(Ci-3)haloalkyl.

3. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R1is a 6 membered heteroaryl having 1-2 ring nitrogen atoms, substituted with 1-2 substituents independently selected from halogen, -(Ci-3)alkyl, -(Ci-3)haloalkyl, and -O-(Ci-3)haloalkyl.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is pyridinyl substituted with 1-2 substituents independently selected from -F, -Cl. -O-CH2CF3, -O-CH2CHF2, -CHF2, and -O-CF2CHF2.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R1is pyrazinyl substituted with 1 -2 substituents independently selected from -O-CH2CF3, -O-CH2CHF2. and -CHF2.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R1is7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2is(1) 4-7 membered heterocyclyl having 1, 2 or 3 ring heteroatoms independently selected from N, O and S, or(2) -(C3-6)cycloalkyl,wherein each, heterocyclyl or cycloalkyl is unsubstituted or substituted with 1, 2. or 3 substituents independently selected from, halogen, -(Ci-3)alkyl, -(Ci-3)haloalkyl, -OH, and =0.

8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R2is(1) 4-6 membered heterocyclyl having 1 ring heteroatom selected from O and S, wherein the heterocyclyl is unsubstituted or substituted with 1-3 substituents independently selected from =0 and methyl, or(2) -(C5-6)cycloalkyL wherein the cycloalkyl is unsubstituted or substituted with 1-3 substituents independently selected from -OH and -F.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R2is(1) a 4-6 membered heterocyclyl having one sulfur heteroatom selected from: tetrahydro-2-thiopyran, thietanyl, and tetrahydrothiophenyl, wherein the ring sulfur atom is substituted with two oxo substitutents, and wherein a ring carbon atom is substituted with methyl;(2) tetrahydrofuranyl, substituted on a ring carbon atom with one methyl substituent; or(3) where cyclohexyl, substituted with one -OH substituent and 2 -F substituents.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptablesalt thereof, wherein R2is11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein X is -C(H)-, -C(Ci-6alkyl)-, -C(C3-6cycloalkyl)-, -C(halo)-, -C(Ci-6haloalkyl)-, -C(OH)-, and -N-;.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein X is -C(H)-, -C(CH3)-, -C(CH3)-, -C(cyclopropyl)-, -C(F)-, -C(C1)-, -C(CHF2)-. -C(OH)-, or -N-.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein Y is -C(H)-, -C(Ci-5alkyl)-, -C(halo)-, or -N-.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein Y is -C(H)-, -C(CH3)-, -C(F)-, or -N-.2611815. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein Z is -C(H)-, -C(Ci-6alkyl)-, -C(halo), or -N-.

16. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein Z is -C(H)- or -N-.

17. The compound of any one of claims 1-16, or a pharmaceutically acceptable salt thereof, wherein W is -C(H)-, -C(Ci-6alkyl)-, -C(halo)-, or -N-.

18. The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein W is -C(H)-, -C(CH3)-, -C(F)-, or -N-.

19. A compound of Formula II:or pharmaceutically acceptable salts thereof wherein:X is selected from -C(H)-, -C(Ci-6alkyl)-, -C(C3-6cycloalkyl)-. -C(halo)-, -C(Ci-6haloalkyl)-, -C(OH)-, and -N-;Y is selected from -C(H)-, -C(Ci-6alkyl)-, -C(halo)- and -N-;Z is selected from -C(H)-, -C(Ci-6alkyl)-, -C(halo)-, and -N-;W is selected from -C(H)-_ -C(Ci-6alkyl)-, -C(halo)-, and -N-;X1is selected from -C(H)- and -N-;R3ais selected from:(1) -O-(Ci-3)alkyl, and(2) -O-(Ci-3)haloalkyl;each R3bis independently selected from:(1) halogen,(2) -(Ci-3)alkyl, and(3) -(Ci-3)haloalkyl;R2is26118(1) 4-7 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O and S, or(2) -(C3-6)cycloalkylwherein each heterocyclyl or cycloalkyl is unsubstituted or substituted with 1-3 R4;when present, each R4is independently selected from:(1) halogen,(2) (Ci-3)alkyl,(3) (C i-3)haloalkyl,(4) hydroxy, and(5) =0.

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is:N1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)pyridine-3-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)pyridine-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-6-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-6-methylpyridin-2-yl)-N2-(3-methyl-1,1-dioxidothietan-3-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-6-methylpyridin-2-yl)-N2-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyl-1,1-dioxidothietan-3-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-3-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2-difluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Fluoro-3-(2,2-difluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((3-(2,2-Difluoroethoxy)pyrazin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-5-methylpyridin-3-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-2-methylpyridin-3-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,(R)-N1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)oxalamide,N1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyl-1,1-dioxidothietan-3-yl)oxalamide,(S)-N1-(5-((5-Fluoro-3-(2,2,2-trifluoroethoxy)pyridine-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyl-1,1-dioxidotetrahydrothiophen-3-yl)oxalamide,(R)-N1-(5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyltetrahydrofuran-3-yl)oxalamide,(S)-N1-(5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyltetrahydrofuran-3-yl)oxalamide,(< S’)-A^1-(5-((3-(2,2-Difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-4-methylpyridin-2-yl)-A^2-(3-methyl- 1, 1 -dioxidotetrahy drothiophen-3-yl)oxal amide,N1-(5-((3-(2,2-Difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(3-methyl-1,1-dioxidothietan-3-yl)oxalamide,JV1-(5-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)pyrazin-2-yl)-jV2-(4-methyl-l,l-dioxidotetrahydro-2-thiopyran-4-yl)oxal amide,N1-(6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridazin-3-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,N1-(5-((5-(Difluoromethyl)-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-4-methylpyridin-2-yl)-N2-(4-methyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)oxalamide,A^1-(5-((5-(Difluoromethyl)-3-(2,2-difluoroethoxy)pyrazin-2-yl)oxy)-4-methylpyri din-2 -yl)-JV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2H-thi opy ran -4- l )oxalamide.JV1-(5-((5-(Difluoromethyl)-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)-4-methylpyridin-2-yl)-7V2-(4-methyl- 1, 1 -dioxidotetrahy dro-277-thiopy ran-4-yl)oxal amide.JV1-(4-Cyclopropyl-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-7V2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thiopy ran-4-y l)oxal amide,rV1-(4-Ethyl-5-((5-fluoro-3-(2, 2, 2-tri fluoroethoxy )pyridin-2-yl)oxy)pyridin-2-yl)-Ar2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I )oxal amide,7V1-(4-Difluoromethyl-5-((5-fluoro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-jV2-(4-methyl- 1, 1 -dioxidotetrahy dro-27 / -thiopyran-4-yl)oxal amide,Arl-(4-Chloro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-A^2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I )oxal amide,JV1-(4-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-7V2-(4-methyl- 1, 1 -dioxi dotetrahydro-2-thiopyran-4-yl)oxal amide,jV1-(4-hydroxy-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyri din-2 -yl)oxy)pyridin-2-yl)-jV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thiopy ran-4-y I )oxal ami de,jV / -(5-Fluoro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-3-yl)-7V2-(4-methyl- 1, 1 -dioxidotetrahy dro-27 / -thiopyran-4-yl)oxal amide,jV / -(3-Fluoro-5-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyridin-2-yl)-7V2-(4-methyl- 1, 1 -dioxi dotetrahydro-2 / / -thi opy ran-4-y I )oxal amide,V1-(3-Fluoro-5-((5-fluoro-3-(2, 2, 2-trifluoroethoxy)pyri din-2 -yl)oxy)-4-methylpyri din-2 -yl)-2-(4-methyl- 1, 1 -dioxidotetrahy dro-277-thi opy ran-4-yl)oxal amide.A^7-(5-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-6-methylpyrazin-2-yl)-JV2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / / -thi opy ran-4-y I )oxal amide,JV1-(5-((5-Fluoro-3-(l,l, 2, 2-tetrafluoroethoxy)pyri din-2 -yl)oxy)-4-methylpyri din-2 -yl)-V2-(4-methyl- 1, 1 -dioxidotetrahy dro-2 / 7-thi opy ran-4-y I foxalamide. or^-(d-methyl- 1, 1 -dioxi dotetrahy dro-217-thi opyran-4-y l)-JV2-(4-methyl-5-((3-( 1, 1,2,2-tetrafluoroethoxy)pyri din-2 -yl)oxy)pyri din-2 -yl)oxalami de.

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is:

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof,23. A composition for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus. obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure comprising a compound of any of the claims 1-22, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

24. A composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof.2611825. A method for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure comprising administering to a patient in need thereof a compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof.

26. Use of a compound of any of claims 1-22, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition selected from hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type-2 diabetes mellitus, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure.

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