Cyclobutyl derivatives as novel diacylglyceride o-acyltransferase 2 inhibitors

Abstract

Provided are compounds of Formula (I) and the 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), 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, comprising administering a compound of Formula I and the pharmaceutically acceptable salts, esters, and prodrugs thereof, to a patient in need thereof.

Description

CYCLOBUTYL DERIVATIVES AS NOVEL DIACYLGLYCERIDE O-ACYLTRANSFERASE 2 INHIBITORSCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 724,449, filed November 25, 2024; which is incorporated by reference herein in its entirety.FIELD OF THE INVENTION

[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 OF THE INVENTION

[0003] Triacylglycerols (“TGs”) serve several functions in living organisms. One such function of TGs is energy storage. 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”) enzymes. 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 (Yen et al., J. Lipid Research, 2008, 49, 2283). Inactivation of DGAT2impaired cytosolic lipid droplet growth, whereas inactivation of DGAT1 exerts opposite effect. (Li et al., Arterioscler. 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 phenoty pe, 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 (“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 (Yu, 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 et al., J. Bio. Chem., 2007, 282, 22678).

[0007] Inhibitors of DGAT2 may be useful for treating disease related to the spectrum of metabolic syndrome such as hepatic steatosis, non-alcoholic 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.

[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, and W02003053363.SUMMARY OF THE INVENTION

[0009] The present disclosure is directed to compounds having structural Formula I:Tor pharmaceutically acceptable salts thereof, wherein:m is 0 or 1, indicating the absence or presence of a C-H in the ring;n2 is 0 or 1, indicating the absence or presence of a CH2 between theL‘A” ring and Xm is 0 or 1, indicating the absence or presence of a CH2 between the£'A” ring and the oxygen; is 0, 1, 2 or 3;X is independently selected from C and N;Y independently selected from C-H, C-CH3, N, and N-CH3;V is independently selected from C-H, C-CH3, N, N-CH3, O and S;U is independently selected from C-H, C-CH3, N, N-CH3, O and S;ring “A” is 4 to 8-membered mono-, bridged- or multicyclic cycloalkyl group,R1is(1) 6-membered heteroaryl containing 1, or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R6,(2) -(Ci-6)alkyl-O-(Ci-6)alkyl, or(3) -(Ci-3)haloalkyl;R2is(1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(2) phenyl,(3) 5- or 6-membered heteroaiyl containing 1, 2 or 3 heteroatoms independently- selected from N, O, and S,(4) -(Ci-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected fromN, O and S, (5) -(Ci-e)alkyl-aryl,(6) -(Ci-6)heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S, (7) -(Ci-6)alkyl,(8) -(C3-6)cycloalkyl,(9) -(Ci-6)hydroxyalkyl,(10) -(C3-6)cyclic amine, or(11) -SO2(Ci-6)alkyl;wherein each alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl moiety is unsubstituted or substituted with 1, 2. or 3 R5;R3is unsubstituted or substituted with 1 or 2 substituents independently selected from:(1) hydrogen,(2) halogen,(3) (Ci-3)alkyl, and(4) (Ci-3)haloalkyl;when present, each R3is independently selected from(1) -OCi-ealkyl,(2) -O(Ci-6)haloalkyl,(3) halogen,(4) (Ci-3)alkyl,(5) hydroxy, and(6) oxo;when present, each R6is independently selected from:(1) -OCi-salkyl,(2) -O(Ci-6)haloalkyl,(3) halogen, and(4) (Ci-3)alkyl.

[0010] In Embodiment 2 of this disclosure are compounds of Formula I is the compound of Formula la:Xlaor pharmaceutically acceptable salts thereof, wherein:X is independently selected from C and N;Y independently selected from C-H, N, and N-CH3;V is independently selected from C-H, N, and O;U is independently selected from C-H, C-CH3, N, O and S;R1is(1) 6-membered heteroaryl containing 1, or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R6,(2) -(Ci-6)alkyl-O-(Ci-6)alkyl, or(3) -(Ci-3)haloalkyl;R2is(1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(2) phenyl,(3) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S,(4) -(Ci-e)alkyl,(5) -(C3-6)cycloalkyl, or(6) -(Ci-6)hydroxy alkyl,wherein each alkyl, cycloalkyl, aryl and heterocyclyl moiety is unsubstituted or substituted with 1, 2, or 3 R5;R3is unsubstituted or substituted with 1 or 2 substituents selected from the following:(1) hydrogen,(2) halogen,(3) (Ci-3)alkyl, and(4) (Ci-3)haloalkyl;when present, each R5is independently selected from(1) -OCi-ealkyl,(2) -O(Ci-6)haloalkyl,(3) halogen,(4) (Ci-3)alkyl,(5) hydroxy, and(6) oxo;when present, each R6is independently selected from:(1) -OCi-salkyl,(2) -O(Ci-e)haloalkyl,(3) halogen, and(4) (Ci-3)alkyl.

[0011] In Embodiment 3 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-2, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is (1) 6-membered heteroaryl containing 1, or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1, 2, or 3 substituents independently selected from - OCH2CHF2, -OCH2CF3, OCH2CH3, -OCH2CF2CH3. Cl, F, and -CH2CH3;(2) -(Ci-6)alkyl-O-(Ci-6)alkyl; or(3) -(Ci-3)haloalkyl.

[0012] In Embodiment 4 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1 or 2 substituents independently selected from -OCH2CHF2, -OCH2CF3, -OCH2CH3, OCH2CF2CH3, Cl, F, and -CH2CH3.

[0013] In Embodiment 5 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -(Ci-6)alkyl-O-(Ci-6)alkyl.

[0014] In Embodiment 6 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-3 and 5, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is CH2C(CH3)2OCH2CH3.

[0015] In Embodiment 7 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is -(Ci-3)haloalkyl.

[0016] In Embodiment 8 of this disclosure are compounds of Formula 1 or la, or any one of Embodiments 1-3 and 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is CH2CHF2.

[0017] In Embodiment 9 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-3, or a pharmaceutically acceptable salt of any of the foregoing, wherein R1is K K, F FJLFF\b-F. F-,. FF\ixFN LNor F

[0018] In Embodiment 10 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-9, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is (1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(2) phenyl,(3) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S,(4) -(Ci-6)alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2. or 3 heteroatoms independently selected fromN, O and S, (5) -(Ci-6)alkyl-aryl,(6) -(Ci-6)heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,(7) -(Ci-6)alkyl,(8) -(C3-6)cycloalkyl.(9) -(Ci-6)hydroxyalkyl,(10) -(C3-6)cyclic amine, or(11) -SO2(Ci-6)alkyl,wherein each alkyl, and. cycloalky 1. heteroaryl and heterocyclyl moiety’ is unsubstituted or substituted with 1, 2, or 3 R5.

[0019] In Embodiment Ila of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-10, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is (1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(2) phenyl,(3) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S,(4) -(Ci-6)alkyl,(5) -(C3-6)cycloalkyl. or(6) -(Ci-6)hydroxyalkyl,wherein each alkyl, cycloalkyl, aryl and heterocyclyl moiety is unsubstituted or substituted with 1, 2, or 3 R5.

[0020] In Embodiment 11b of this disclosure are compounds of Formula I or la. or any one of Embodiments 1-1 la, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is (1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently- selected from N, O, and S,(3) -(Ci-6)alkyl,(4) -(C3-6)cycloalkyl, or(5) -(Ci-6)hydroxyalkyl,wherein each alkyl, and. cycloalky 1. heteroaryl and heterocyclyl moiety- is unsubstituted or substituted with 1, 2, or 3 R5.

[0021] In Embodiment 12a of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-11, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is (1) 4- to 7-membered heterocyclyl containing 1. 2 or 3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with one, two, or three substituents independently selected from (Ci-3)alkyl or oxo;(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected fromN, O. and S, unsubstituted or substituted with (Ci-3)alkyl;(3) -(C3-6)cycloalkyl. unsubstituted or substituted with one, two, or three substituents independently selected OH, halogen, or (Ci-3)alkyl; or(4) -(Ci-6) alkyd, unsubstituted or substituted with one, two or three halogen substituents.

[0022] In Embodiment 12b of this disclosure are compounds of Formula I or la. or any one of Embodiments l-12a, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is(1) 4- to 7-membered heterocyclyl containing one sulfur atom, unsubstituted or substituted with one, two, or three substituents independently selected from (Ci- 3)alkyl or oxo;(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently- selected from N, O. and S, unsubstituted or substituted with (Ci-3)alkyl;(3) -(C3-6)cycloalkyl unsubstituted or substituted with one, two, or three substituents independently selected OH, halogen, or (Ci-s)alkyl; or(4) -(Ci-6) alkyl, unsubstituted or substituted with one, two or three halogen substituents.

[0023] In Embodiment 13a of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-12, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is (1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with one, two, or three substituents independently selected from CH3 or oxo;(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, unsubstituted or substituted with CH3;(3) -(C3-e)cycloalkyl, unsubstituted or substituted with one, two, or three substituents independently selected OH, F, or CH3; or(4) -(C1-6) alkyl, unsubstituted or substituted with one two or three fluoro substituents.

[0024] In Embodiment 13b of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-12, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is (1) 4- to 7-membered heterocyclyl containing one sulfur atom, unsubstituted or substituted with one, two, or three substituents independently selected from CH3 or oxo;(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected fromN, O. and S, unsubstituted or substituted with CH3;(3) -(C -6)cycloalkyl. unsubstituted or substituted with one, two, or three substituents independently selected OH, F, or CH3; or(4) -(C1-6) alkyl, unsubstituted or substituted with one two or three halogen substituents.

[0025] In Embodiment 14 of this disclosure are compounds of Formula I or la, or any one of Embodiments l-12a and 13a, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independentlyselected from N, O and S, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from (Ci-3)alkyland oxo.

[0026] In Embodiment 15 of this disclosure are compounds of Formula I or la, or any one of Embodiments l-12a, 13a, and 14, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from CFEand oxo.

[0027] In Embodiment 16 of this disclosure are compounds of Formula I or la, or any one of Embodiments l-12a. 13a, 14 and 15, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from (Ci-3)alkyland oxo.

[0028] In Embodiment 17 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-16, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 4- to 6-membered heterocyclyl containing one sulfur atom, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from (Ci-3)alkyland oxo.

[0029] In Embodiment 18 of this disclosure are compounds of Formula I or la, or any one of Embodiments l-l-12a. 13a, and 14-16, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 4- to 6-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from CHsand oxo.

[0030] In Embodiment 19 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-18, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is 4- to 6-membered heterocyclyl containing one sulfur atom, wherein the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from CEEand oxo.

[0031] In Embodiment 20 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, unsubstituted or substituted with (Ci-3)alkyl.

[0032] In Embodiment 21 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13 and 20, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a 5- or 6-membered heteroaryl containing two nitrogen atoms, unsubstituted or substituted with (Ci-3)alkyl.25870

[0033] In Embodiment 22 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13 and 20, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, unsubstituted or substituted with CH.

[0034] In Embodiment 23 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13 and 20-22, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a 5- or 6-membered heteroaryl containing two nitrogen atoms, unsubstituted or substituted with CEE.

[0035] In Embodiment 24 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -(Cs-6)cycloalkyl, unsubstituted or substituted with one, two, or three substituents independently selected OH, halogen, and (Ci-3)alkyl.

[0036] In Embodiment 25 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13 and 24, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is -(C3-6)cycloalkyl unsubstituted or substituted with one, two, or three substituents independently selected OH, F, and CH3.

[0037] In Embodiment 26 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is a -(C1-6) alkyl, unsubstituted or substituted with one, two or three halogen substituents.

[0038] In Embodiment 27 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13 and 26, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is CH2CH2CF3.

[0039] In Embodiment 28 of this disclosure are compounds of Formula 1 or la, or any one of Embodiments 1-13, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is

[0040] In Embodiment 29 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-13, or a pharmaceutically acceptable salt of any of the foregoing, wherein R2is25870

[0041] In Embodiment 30 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-29, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3is H, (Ci-3)alkyl, halogen, or (Ci-3)haloalkyl.

[0042] In Embodiment 31 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-30, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3H. CH3, F, CH2CH3, CF3, or (CH3)2.

[0043] In Embodiment 32 of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-31, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5is oxo, (Ci-3)alkyl, OH. or halogen

[0044] In Embodiment 33a of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-32, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3isoxo, CH3, OH, F, or F2.

[0045] In Embodiment 33b of this disclosure are compounds of Formula I or la, or any one of Embodiments 1-32, or a pharmaceutically acceptable salt of any of the foregoing, wherein R5isoxo, CH3, OH, or F

[0046] In Embodiment 34 of this disclosure are compounds of Formula I, or any one of Embodiments 1-33, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C orN.

[0047] In Embodiment 35 of this disclosure are compounds of Formula I, or any one of Embodiments 1-34, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is C-H, C-CH3, N, or N-CH

[0048] In Embodiment 36 of this disclosure are compounds of Formula I, or any one of Embodiments 1-35, or a pharmaceutically acceptable salt of any of the foregoing, wherein V is C-H, C-CH3, N, N-CH3, O, or S.

[0049] In Embodiment 37 of this disclosure are compounds of Formula I, or any one of Embodiments 1-36, or a pharmaceutically acceptable salt of any of the foregoing, wherein U is C-H, C-CH3. N, N-CH3, O, or S.

[0050] In Embodiment 38 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C.

[0051] In Embodiment 39 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N.25870

[0052] In Embodiment 40 of this disclosure are compounds of Formula I, or any one of Embodiments 1-39, or a pharmaceutically acceptable salt of any of the foregoing, wherein Y is C-H, N, or N-CHs.

[0053] In Embodiment 41 of this disclosure are compounds of Formula I, or any one of Embodiments 1-40, or a pharmaceutically acceptable salt of any of the foregoing, wherein V is C-H, N, or O.

[0054] In Embodiment 42 of this disclosure are compounds of Formula I, or any one of Embodiments 1-41, or a pharmaceutically acceptable salt of any of the foregoing, wherein U is C-H, C-CH3, N, O. or S.

[0055] In Embodiment 43 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C, Y is N, V is O, U is N.

[0056] In Embodiment 44 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C, Y is N, V is N, and U is O.

[0057] In Embodiment 45 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is N, V is N, and U is C-H.

[0058] In Embodiment 46 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C, Y is N-CH3, V is N, and U is C-H.

[0059] In Embodiment 47 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C, Y is N, V is O, and U is C-CH3.

[0060] In Embodiment 48 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C, Y is N, V is N, and U is S.

[0061] In Embodiment 49 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C, Y is N, V is O, and U is N.

[0062] In Embodiment 50 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C, Y is N, V is N, and U is N-CHs.25870

[0063] In Embodiment 51 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is N, V is C-H, and U is C-H.

[0064] In Embodiment 52 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is C-H, V is C-H, and U is N.

[0065] In Embodiment 53 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is N, V is C-H, and U is N.

[0066] In Embodiment 54 of this disclosure are compounds of Formula I, or any one of Embodiments 1-37, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is N, V is N, and U is C-CH3.

[0067] In Embodiment 55 of this disclosure are compounds of Formula lb,Zor any one of Embodiments 1-33, or a pharmaceutically acceptable salt ofany of the foregoing, wherein Z is selected from one of the following,

[0068] In Embodiment 56 of this disclosure are compounds of Formula Ic,25870, or a pharmaceutically acceptable salt thereof whereinR1is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1, 2. or 3 substituents independently selected from -OCH2CHF2. -OCH2CF3, -OCH2CH3, -OCH2CF2CH3, Cl, F, and -CH2CH3;R2is 4- to 7-membered heterocyclyl containing 1 sulfur atom, substituted with one, two, or three substituents independently selected from CH3 and oxo; andR3is H, (Ci-3)alkyl, halogen, or (Ci-3)haloalkyl.

[0069] In Embodiment 57 of this disclosure are compounds of Formula Id,, or a pharmaceutically acceptable salt thereof, whereinR1is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1, 2. or 3 substituents independently selected from -OCH2CHF2, -OCH2CF3, - OCH2CH3, -OCH2CF2CH3, Cl, F, and -CH2CH3;R2is 4- to 7-membered heterocyclyl containing 1 sulfur atom, substituted with one, two, or three substituents independently selected from CH3 and oxo; andR3is H, (Ci-3)alkyl, halogen, or (Ci-3)haloalkyl.

[0070] In Embodiment 58 of this disclosure are compounds of Formula le.25870X, or pharmaceutically acceptable salts thereof, wherein:X is independently selected from C and N;Y independently selected from C-H, N, and N-CH3;V is independently selected from C-H, N, and O;U is independently selected from C-H. C-CH3, N, O and S;R1is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1, 2, or 3 substituents independently selected from -OCH2CHF2, -OCH2CF3, -OCH2CH3, -OCH2CF2CH3, Cl, F, and -CH2CH3;R2is a 4- to 7-membered heterocyclyl containing 1 sulfur atom, substituted with one. two, or three substituents independently selected from CH and oxo; andR3H, (Ci-3)alkyl, halogen, or (Ci-3)haloalkyl.

[0071] In Embodiment 59 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1 -2, or pharmaceutically acceptable salt of any of the foregoing, where when present, each R6is independently selected from:(1) -OCuealkyl,(2) -O(Ci-6)haloalkyl,(3) halogen, and(4) (Ci-3)alkyl.

[0072] In Embodiment 60 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1-2, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, A is selected from:(1) cyclobutyl,(2) cyclopentyl,(3) bicyclo[l.l.l]pentyl, and(4) cubanyl.25870

[0073] In Embodiment 61 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1-2 or 60, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, A is cyclobutyl.

[0074] In Embodiment 62 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1-2. or 60, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, A is cyclopentyl.

[0075] In Embodiment 63 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1-2, or 60, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, A is selected from one of the following:

[0076] In Embodiment 64 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1-60, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, cyclobutyl is selected from one of the following,

[0077] In Embodiment 65 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein the m is 0, indicating the absence of a C-H in the ring.

[0078] In Embodiment 66 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein the m is 0.25870

[0079] In Embodiment 67 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein the m is 0, indicating the absence of a CEE between the “A” ring and X.

[0080] In Embodiment 68 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1. or a pharmaceutically acceptable salt of any of the foregoing, wherein the m is 0.

[0081] In Embodiment 69 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein the ns is 0, indicating the absence of a CH2 between the “A” ring and the oxygen.

[0082] In Embodiment 70 of this disclosure are compounds of Formula I, la, lb, Ic, Id, and le, or any one of Embodiments 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein the ns is 0.

[0083] In Embodiment 71 of the invention, the compound of Formula I, la, lb. Ic, Id, and le, or a pharmaceutically acceptable salt thereof, is:258702587025870

[0084] In Embodiment 61 of the invention, the compound of Formula I, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof, is:Czs-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-JV-(4-methyl- l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,7ra -5-|3-||5-chloro-3-(2.2-dil'luoroethoxy)-2-pyridyl|oxy ]-3-methyl-cyclobutyl]-JV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,Cz3-5-[3-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl-l.l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Cz3-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-(4-methyl- l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Z’ran.s'-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-V-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,5-[3-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-I,2,4-oxadiazole-3-carboxamide,25870Czs-5-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy |-3-methyl-cyclobutyl|-A'-(4-meth\l-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Zra«s-5-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,5-[3-ff5-chloro-3-(2.2-difluoroethoxy)-2-pyridylloxy]-3-methyl-cyclobutyl]-jV-[(l> S’,2R)-3.3-difluoro-2-hydroxy-cyclohexyl]-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-[(lJ?,2S)-3,3-difluoro-2-hydroxy-cyclohexyl]-l,2,4-oxadiazole-3-carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-zV-[(3 )-3-methyl-l,l-dioxo-thiolan-3-yl]-l,2,4-oxadiazole-3-carboxamide,Cz3’-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-zV-[(35)-3-methyl-l,l-dioxo-thiolan-3-yl]-l,2,4-oxadiazole-3-carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-[(3S)-tetrahydrofuran- 3-yl]-l,2,4-oxadiazole-3-carboxarmde,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-7V-(4,4-difluoro-l -methyl-cyclohexyl)-!, 2, 4-oxadiazole-3-carboxamide,5-[3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-N-(3,3-difluoro-l-methyl-cyclobutyl)-!, 2, 4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-7V-(2-methylpyrazol-3-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-N-(3,3,3-trifluoropropyl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[(5-chloro-3-ethoxy-2-pyridyl)oxy]cyclobutyl]-N-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]cyclobutyl]-JV-(4-methyl-l,l-dioxo-thian- 4-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[3-(2,2-Difluoroethoxy)pyrazin-2-yl]oxycyclobutyl]-zV-(4-methyl-l.l-dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-zV-(4-methyl-l,l-dioxo-thian- 4-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Fluoro-3-(2.2.2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian- 4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-7V-(4-methyl-l,l-dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,25870Cz5-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-fluoro-cyclobutyl]-A^-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Zra«s-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-fluoro-cyclobutyl]-jV-(4-methyl-1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,Czis'-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-methyl-cyclobutyl]-jV-(4-methyl- 1.1-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,71raw.s-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-methyl-cyclobutyl]-2 -(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,7ra / 7s-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-l,3-dimethyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-l,3-dimethyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-l-ethyl-3-methyl-cyclobutyl]-7V-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-ethyl-l-methyl-cyclobutyl]-N-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(trifluoromethyl)cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-1.2.4-oxadiazole-3-carboxamide,7zw7s-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(trifluoromethyl)cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3-carboxamide,5-[(lS,3 )-3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-2,2-dimethyl-cyclobutyl]-JV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,5-[(lA,35)-3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-2,2-dimethyl-cyclobutyl]-JV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,Czs-3-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl-1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-5-carboxamide,7zw7s-3-[3-f[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-(4-methyl- 1.1-dioxo-thian-4-yl)-l,2,4-oxadiazole-5-carboxamide,Czs-2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-3-methyl-jV-(4-methyl- 1.1-dioxo-thian-4-yl)imidazole-4-carboxamide and 7,ra / ?5-2-[3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy] cyclobutyl] -3-methy l-. -(4-methy I- 1, 1 -dioxo-thian-4-yl)imidazole-4-carboxamide,Czs-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-5-methyl-jV-(4-methyl- 1, 1 -dioxo-thian-4-y l)oxazole-4-carboxamide, / ra / 7.s-2-|3-||5-Chloro-3-(2.2.2-trinuoroethoxy)-2-pyridyl|oxy|-l-melhyl-cyclobutyl|-5-methyl- / V-(4-methy 1- 1, 1 -dioxo-thian-4-y l)oxazole-4-carboxamide,(7.s-2-|3-||5-Chloro-3-(2.2.2-trinuoroethoxy)-2-pyridyl|oxy|-l-methyl-cyclobutyl|-5-methyl- / V- (4-methy l-l,l-dioxo-thian-4-yl)oxazole-4-carboxamide,Czs'-2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)oxazole-4-carboxamide,71raw.s-2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)oxazole-4-carboxamide,Cz\s-3-(3-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)cy clobuty l)- / V-(4-methyl- 1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-l,2,4-thiadiazole-5-carboxamide,Czs-5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]methyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Tra«x-5-[[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy ]cyclobutyl]methyl]-JV-(4-methyl- 1.1-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Czs-5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]methyl]-jV-(3-methyl-l,l-dioxo-thietan-3-yl)-l,2,4-oxadiazole-3-carboxamide,7zYZZ7s-5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]rnethyl]-JV-(3-methyl- 1.1 -di oxo-thi etan-3 -yl)-l, 2, 4-oxadiazole-3 -carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]cyclobutyl]-zV-(4-methyl-l,l -dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxymethyl]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]cyclobutyl]-JV-(3-methyl- 1.1 -dioxo-thietan-3-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]-l-bicyclo[l.l.l]pentanyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,5-[4-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]cuban-l-yl]-zV-(4-methyl- 1,1 -dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclopentyl]-7V-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Cz\s-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl-JV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,7zY / w.s-5-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl-jV- (4-methy 1- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-triazole-3-carboxamide,(7.s-5-|3-||5-Chloro-3-(2.2.2-trifluoroethoxy)-2-pyndyl|oxy|-l-methyl-cyclobutyl|-2-methyl-A'-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,Cw-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-2-methyl-Ar-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-triazole-3-carboxamide,5-[3-ff5-chloro-3-(2.2-difluoroethoxy)-2-pyridylloxy]-3-methyl-cyclobutyl]-2-methyl-N-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-triazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]-l-bicyclo[l.l.l]pentanyl]-2-methyl-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,Fra / 7s-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-7V-(4-methyl-l.l-dioxo-thian-4-yl)triazole-4-carboxamide,l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-JV-(4-methyl-l,l-dioxo-thian-4-yl)pyrazole-3 -carboxamide,l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian- 4-yl)imidazole-4-carboxamide,l-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)pyrazole-3-carboxamide,l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-zV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,Czs-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-(4-methyl- 1, 1 -dioxo-thian-4-yl)triazole-4-carboxamide,C / s-2-[3-[[5-Fluoro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)triazole-4-carboxamide,Czs-2-[3-[[5-chloro-3-(2.2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-5-methyl-7V-(4-methyl- 1, 1 -dioxo-thian-4-yl)triazole-4-carboxamide,7ra / ?.s-2-|3-||5-chloro-3-(2.2-dil'luoroethoxy)-2-pyndyl|oxy |-3-methyl-cyclobutyl|-5-methyl-; V-(4-methy 1- 1, 1 -dioxo-thian-4-y l)triazole-4-carboxamide,l-[3-ff5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-(4-methyl-l.l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,7,raw.s-l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)pyrazole-3-carboxamide,Cz\s-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-(4-methyl- 1, 1 -dioxo-thian-4-yl)pyrimidine-5 -carboxamide,Czs-6-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)pyridine-3-carboxamide,5-[3-(2-Ethoxy-2-methyl-propoxy)cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Czs-5-[3-(2,2-Difluoroethoxy)-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -di oxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide, or7ra / 7s-5-[3-(2,2-difluoroethoxy)-3-methyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide.

[0085] Embodiment 62 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0086] Embodiment 63 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0087] Embodiment 64 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0088] Embodiment 65 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0089] Embodiment 66 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0090] Embodiment 67 is a compound, or a pharmaceutically acceptable salt thereof, which is

[0091] The present disclosure includes the pharmaceutically acceptable salts of the compounds defined therein.25870

[0092] In one embodiment, the present disclosure is a composition comprising an effective amount of at least one compound of Formula I, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof.

[0093] The disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula I, la, lb. Ic, Id, and le, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0094] The disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula I, la, lb, Ic, Id, and le, 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).

[0095] The disclosure also provides a pharmaceutical composition comprising an effective amount of at least one compound of Formula I, la, lb, Ic, Id, and le, 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.

[0096] 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, or a pharmaceutically acceptable salt thereof.

[0097] 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, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof.

[0098] 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, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.25870

[0099] 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, comprising administering to said subject a therapeutically effective amount of at least one compound of Formula I, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof.

[0100] 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, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0101] 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.

[0102] 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, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof.

[0103] 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, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0104] 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, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof.

[0105] 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, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.25870

[0106] In another embodiment, the present disclosure provides for the use of a compound of Formula I, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating NASH / MASH and / or fibrosis.

[0107] In another embodiment, the present disclosure includes the use of a compound of Formula I, la, lb. Ic, Id, and le, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of NASH / MASH and / or fibrosis.

[0108] " 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, cyclopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, octyl, nonyl, and the like. For example, the term “Ci-ealkyl” includes all ol'" Cj.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 tertbutyl (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” orHN^CH3CH2CH2CH2CH3, etc. For example, the structures ” and l have equivalent meanings. If no number is specified, 1-6 carbon atoms are intended for linear or branched alkyl groups.

[0109] “Alkoxy” refers to an alkyl group linked to oxygen. Examples of alkoxy groups include methoxy, ethoxy, propoxy and the like.

[0110] “Aryl” refers to an aromatic monocyclic or multicyclic 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. Multicyclic rings include, but are not limited to, naphthyl and bicyclic rings wherein phenyl is fused to a Cs-rcycloalkyl or Cs-vcycloalkenyl ring. Aryl groups may be unsubstituted or substituted with one or more substituents as defined herein. Bonding can be through any of the carbon atoms of any ring.25870

[0111] Halogen or “Halo” includes fluorine, chlorine, bromine and iodine.

[0112] “Cycloalkyl” refers to anon-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 Cnecycloalkyl” refers to a cycloalkyl group having 1 to 6 ring carbon atoms. The term C.i-ecycloalkyl” refers to a cycloalkyl group having 3 to 6 ring carbon atoms. Thus, 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 alky l group. The following are illustrations of -Cs-ecycloalkyl substituents on an alkyl groupwherein the substituent is cyclopropyl in bold:

[0113] 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 haloalky l groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2CI, CH2CF2CH3and CCI3. The term “Ci-ehaloalkyl” or “haloCi-ealkyf’refers to a haloalkyl group having from 1 to 6 carbons.

[0114] " Haloalkoxy,” “haloalkyl-O" and derivatives such as “halo(Ci-6)alkoxy” or “O(Ci-6)haloalkyl” or likewise “O(Ci-3)haloalkyl, are used interchangeably and 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.

[0115] " 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 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 nitrogen25870atom. Examples of heterocyclyl groups include: piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, oxirane, or aziridine, and the like.

[0116] “Bicyclic heterocyclyl,” “bicyclic heterocycle” or “bicyclic heterocyclic” refers to a heterocyclic ring fused to another ring system. The fusion may be bridged or unbridged.

[0117] 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 is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroar l 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, indohnyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl. quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline.

[0118] “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.

[0119] “Hydroxyalkyl” or “hydroxy(Ci-3)alkyl” means an alky l group having one or more hydrogen atoms replaced by hydroxyl (-OH) groups. An example includes CH(OH)CH3.CHC(OH)(CH3)2or CH2OH.

[0120] “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.

[0121] 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.

[0122] 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 invention is independent of the meaning with reference to the number of chemotherapeutic agents.

[0123] The term “chemotherapeutic agent” means a drug (medicament or pharmaceutically' active ingredient) for treating cancer (i.e., an antineoplastic agent).25870

[0124] 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.

[0125] The term “treating cancer” or “treatment of cancer” refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, and also refers to an effect that results in the inhibition of growth and / or metastasis of the cancer.

[0126] Except where noted herein, the term "carbocycle" (and variations thereof such as "carbocyclic" or "carbocyclyl") as used herein, unless otherwise indicated, refers to a C3 to 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 rings include, for example, "cycloalkyl" rings, e.g., cyclopropyl, cyclobutyl, etc. Unsaturatedcarbocyclic rings include, for example o o.

[0127] 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).

[0128] The compounds of the present disclosure are limited to stable compounds embraced by Formula I, la, lb, Ic, Id, and le, and its embodiments. For example, certain moieties as defined in Formula I, la, lb. Ic, Id, and le, 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.

[0129] 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 the25870same 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).

[0130] The wavy line °-r'-r'-r,as usej herein, indicates a point of attachment to the rest of the compound.

[0131] 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

[0132] The disclosure also includes denvatives of the compound of Formula I, la, lb, Ic, Id, and le, acting as prodrugs and solvates. Any pharmaceutically acceptable pro-drug modification of a compound of the invention which results in conversion in vivo to a compound within the scope of the invention is also within the scope of the invention. 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, la, lb, Ic, Id, and le. Such prodrugs include those that demonstrate enhanced bioavailability, tissue specificity', and / or cellular delivery, to improve drug absorption of the compound of Formula I, la, lb, Ic, Id, and le. 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.

[0133] 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 invention 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 invention. 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 of25870pharmaceutically acceptable pro-drug modifications include, but are not limited to, -Ci-ealkyl esters and -Ci-ealkyl substituted with phenyl esters.

[0134] " Celite K" (Fluka) diatomite is diatomaceous earth, and can be referred to as "celite".

[0135] When any variable (e.g., R1etc.) occurs more than one time in any constituent or in Formula I, la, lb. Ic, Id, and le 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 heteroaiyl ring, or a saturated heterocyclic ring) provided such ring substitution is chemically allowed and results in a stable compound.

[0136] It should be noted that, if a discrepancy between the chemical name and structure exists, the structure is understood to dominate.

[0137] Compounds of structural Formula I, la, lb, Ic, Id, and le, 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, la, lb, Ic, Id, and le 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 invention, 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 invention.

[0138] 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 invention 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 invention includes both the cis form and the trans form as well as mixtures of these forms in all25870ratios. The present disclosure is meant to comprehend all such stereo-isomeric forms of the compounds of structural Formula I, la, lb, Ic, Id, and le.

[0139] Compounds of structural Formula I, la, lb, Ic, Id, and le 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 carried out at an intermediate step during the synthesis of a compound of Formula I, la, lb, Ic, Id, and le, 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, la, lb, Ic, Id, and le may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. The present disclosure includes all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0140] 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.

[0141] For compounds of Formula I, la, lb, Ic, Id. and le described herein which contain olefinic double bonds, unless specified otherwise, they are meant to include both E and Z geometric isomers.

[0142] 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, la, lb, Ic, Id, and le of the present disclosure.25870

[0143] In the compounds of structural Formula 1, la, lb, Ic, Id, and le 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, la, lb, Ic, Id, and le 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, la, lb, Ic, Id, and le 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.

[0144] It w ill be understood that the compounds of structural Formula I, la, lb, Ic, Id, and le may be prepared as pharmaceutically acceptable salts or as salts that are not pharmaceutically acceptable when they are 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, la, lb, Ic, Id, and le 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.

[0145] 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.

[0146] Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention 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,25870glycollylarsamlate. 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 invention 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.

[0147] With basic reagents such as hydroxides, carbonates, hydrogencarbonates, alkoxides and ammonia, organic bases or alternatively basic amino acids the compounds of the Formula I, la, lb, Ic, Id, and le form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts.

[0148] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary’, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ionexchange resins, such as arginine, betaine, caffeine, choline, N, N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hy drabamine, 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 alkyd 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.

[0149] The preparation of pharmacologically acceptable salts from compounds of the Formula I, la, lb, Ic, Id, and le 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.25870The 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.

[0150] If the compounds of Formula I, la, lb, Ic, Id, and le simultaneously contain acidic and basic groups in the molecule the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from the compounds of Formula I, la, lb, Ic, Id, and le by customary methods which are know n 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.

[0151] The present disclosure includes compounds of structural Formula I, la, lb. Ic, Id, and le 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.

[0152] Furthermore, compounds of the present disclosure may exist in amorphous form and / or one or more crystalline forms, and as such all amorphous and crystalline forms and mixtures thereof of the compounds of Formula I, la, lb, Ic, Id, and le including the Examples, are intended to be included within the scope of the present disclosure. In addition, some of the compounds of the instant invention 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 acceptable solvates and hydrates, of the instant compounds are likewise encompassed within the scope of this invention, along with un-solvated and anhydrous forms.

[0153] 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,

[0154] The invention also relates to medicaments containing at least one compound of the Formula I, la, lb, Ic, Id, and le and / or of a pharmaceutically acceptable salt of the compound of the Formula I, la, lb, Ic, Id, and le and / or an optionally stereoisomeric form of the compound of the Formula I, la, lb, Ic, Id, and le, or a pharmaceutically acceptable salt of the stereoisomeric form of the compound of Formula I. la, lb, Ic. Id, and le together with a pharmaceutically acceptable vehicle, earner, additive and / or other active substances and auxiliaries.25870

[0155] The medicaments according to the invention can be administered by oral, inhalative, rectal or transdermal administration or by subcutaneous, intraarticular, intraperitoneal or intravenous injection. Oral administration is preferred.

[0156] The invention also relates to a process for the production of a medicament, which comprises bringing at least one compound of the Formula I, la, lb, Ic, Id. and le into a suitable administration form using a pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0157] The present disclosure also relates to processes for the preparation of the compounds of Formula I, la, lb. Ic, Id, and le which are described in the following and by which the compounds of the invention are obtainable.

[0158] 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 invention is selected in accordance with a variety of factors including type, species, age, w eight, sex and medical condition of the patient; the severity7of 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 w ell 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 / MASH.

[0159] Disorders, conditions and diseases which can be treated or prevented by inhibiting DGAT2 by using the compounds of Formula I, la, lb, Ic, Id, and le are. for example, diseases such as non-alcoholic steatohepatitis (NASH), metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, hyperlipidemia, type I diabetes, type II diabetes mellitus, cognitive decline, dementia, coronary7heart disease, ischemic stroke, restenosis, peripheral vascular25870disease, intermitent claudication, myocardial infarction, dyslipidemia, post-prandial 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.

[0160] The compounds of Formula I, la, lb, Ic, Id, and le 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 compounds of Formula I, la, lb. Ic, Id, and le 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 desire prophylactic 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.

[0161] Furthermore, a subject of the present disclosure are pharmaceutical preparations (or pharmaceutical compositions) which comprise as active component a therapeutically effective dose of at least one compound of Formula I, la, lb, Ic. Id, and le 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.

[0162] Thus, a subject of the invention 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.25870

[0163] The pharmaceuticals according to the invention can be administered orally, for example in the form of pills, tablets, lacquered tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration can also be carried out parenterally, 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.

[0164] 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, la, lb. Ic, Id, and le and their pharmaceutically acceptable salts and to use the resulting 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.

[0165] 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.

[0166] 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,25870aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.

[0167] The dosage of the active compound of Formula I, la, lb, Ic, Id, and le 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, la, lb, Ic, Id, and le.Combination Agents

[0168] 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 simultaneous administration 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, ld, and le 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 le, 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 le 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 le and any of the agents described herein are administered a few minutes apart, or a few hours apart, or a few days apart.

[0169] 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 le, and a second pharmaceutical compound. The kit comprises a container for containing the separate compositions such as a divided bottle or a25870divided 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.

[0170] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I, la, lb, Ic, Id, and le. 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, lb, Ic, Id, and le 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, lb, Ic, Id, and le in a single dosage formulation (a fixed dose drug combination), or may be administered to the patient in one or more separate dosage formulations which allows for concurrent or sequential administration of the active agents (co-administration of the separate active agents).

[0171] 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, perindopnl, quinapril, ramipnl, spirapnl, 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 phosphorami don), 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, calcium25870channel blockers (e.g., amlodipine, nifedipine, veraparrml, 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 as niacin receptor partial agonists; anti-cholesterol agents such as PCSK9 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) p-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. sodelglitazar, 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);25870insulin 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 CoA: 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 110-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 fructose 1,6-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 PACAP25870receptor 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., PBL4547), 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 / STING antagonists), 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, antiplatelet 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),25870immunomodulatory polyclonal antibody (e.g., 1MM-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. HSD17P13 inhibitor; metabolism modulators (FXR agonist (e.g., Ocaliva (obeticholic acid), 1OT022), recombinant variant of FGF19 (e.g., aldafermin), bi-specific 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), mitochondrial uncoupler (e.g., GEN 3026), FXR / GPCR dual agonist (e.g., INT-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), PPAR5 / y agonist (e.g., T3D 959)); RAAS mlMModulators (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 rapidrelease 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.25870

[0172] 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 le 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. la. Ib, Ic. Id. and le

[0173] 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 invention 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).

[0174] Those skilled in the art will recognize that the actual dosages and protocols for administration employed in the methods of the invention 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 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.

[0175] The dosage regimen utilizing a compound of the instant invention 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.

[0176] While individual needs vary, determination of optimal ranges of effective amounts of the compound of the invention 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,25870typical 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.Pharmaceutical Compositions

[0177] The compounds of Formula I, la, lb, Ic, Id, and le 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.

[0178] Administering of the compound of Formula I, la, lb, 1c, Id, and le 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.

[0179] 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 invention at the same dose that was administered in the treatment protocol. This maintenance dose can be25870continued 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).

[0180] Those skilled in the art will recognize that the actual dosages and protocols for administration employed in the methods of the invention 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.

[0181] The amount and frequency of administration of the compound of Formula I, la, lb, Ic, Id, and le 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.

[0182] The compounds of the invention are also useful in preparing a medicament that is useful in treating NASH / MASH and fibrosis.

[0183] The instant compounds are also 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 invention. 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 particular characteristics 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.

[0184] 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 known25870effects 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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 individual25870patient’s needs, as the treatment proceeds. All such modifications are within the scope of the present disclosure.

[0193] 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 grow th 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 judge effectiveness of treatment.

[0194] 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.

[0195] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab and MPDL3280A. PDL- inhibitors include atezolizumab, avelumab, and durvalumab.

[0196] The invention further relates to a method of treating hepatic cellular carcinoma in a human patient comprising administration of a compound of the invention (i.e., a compound of Formula I, la, lb, Ic, Id, and le) and a PD-1 antagonist to the patient. The compound of the invention and the PD-1 antagonist may be administered concurrently or sequentially.

[0197] 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 is pembrolizumab (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).

[0198] In some embodiments, the PD-1 antagonist is pembrolizumab. In particular subembodiments, the method comprises administering 200 mg of pembrolizumab to the patient about even’ three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.25870

[0199] 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] A compound of the instant invention, 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®); bortezomib (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®);25870daunorubicin 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 (Elliott's B Solution®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (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 (Adagen (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®);25870Tositumomab (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

[0206] The following examples are provided so that the invention might be more fully understood. Unless otherwise indicated, the starting materials are commercially available. They should not be construed as limiting the invention in any way.

[0207] Several methods for preparing the compounds of this invention 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, la, lb, Ic, Id, and le 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:Bn = BenzylDMF = N,N-dimethylformamideDMA = N,N-dimethylacetamideDMSO = Dimethyl sulfoxideDCM = DichloromethaneDIPEA = N,N-diisopropylethylamineEt = EthylEtOAc = Ethyl acetateHPLC = High Pressure Liquid Chromatographyh = hour or hoursHATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate25870Hex = HexanesIPA = Iso-PropanolLC / MS = Liquid chromatography - mass spectrometryMe = MethylRT = Room temperatureSFC = Supercritical fluid chromatographyTBAF = Tetrabutylammonium fluorideTBS = Tert-butyldimethylsilylTBDPS = Tert-butyldiphenylsilylTHF = TetrahydrofuranTFA = Trifluoroacetic acidLC / 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

[0208] While the present invention 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 invention.[General Scheme 1]

[0209] Compounds of the formula 1-5 were prepared from 1-1 with RJ-X via SN2, SNAr or copper-mediated C-0 coupling. Subsequent condensation reactions or decarboxylative couplings of 1-2 provided the corresponding heterocycle derivatives 1-3. After saponification to give 1-4, amide coupling with the appropriate amines provided compounds of formula 1-5 as described by -n -the general scheme. The order of steps for some examples may be varied to facilitate the syntheses.INTERMEDIATESIntermediate 15-Chloro-3-(2,2-difluoroethoxy)-2-fluoropyridineSTEP A: 5-Chloro-3-(2.2-difluoroethoxy)-2-fluoropyridine

[0210] 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 filtered over Celite. and the filtrate 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],

[0211] 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]F'VF% 3-(2,2-difluoroethoxy)-2,5- 2 196difluoropyridineFXLF2,5-difluoro-3-(2,2,2- 3 X) 214trifluoroethoxy)pyridineFAF5 -chloro-2-fluoro-3 -(2,2,2- 4 229trifluoroethoxy)pyridine5 5-chloro-3-ethoxy-2-fluoropyridine 1765-chloro-3-(2,2-difluoropropoxy)-2- 6 226fluoropyridine2-(2,2-difluoroethoxy)-3- 7 179N^YFfluoropyrazineFXF5-ethyl-2-fluoro-3-(2,2,2- 8 224trifluoroethoxy)pyridineEXAMPLES

[0212] 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.EXAMPLES 1A and IBC7s-5-[3-[[5-Chloro-3-(2, 2-di fluoroethoxy )-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2V-(4-methyl- l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide and Tra«.s-5-[3-[[5-chloro-3-(2,2- difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-7V-(4-methyl-l,l-dioxo-thian-4-yl)-L2,4- oxadiazole-3 -carboxamideEX-1 A EX-1BSTEP A: 3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxylic acid

[0213] To a mixture of 3-hydroxy-3-methylcyclobutane-l-carboxylic acid (1.59 g, 12.2 mmol) in DMF (14.0 mL) was added sodium hydride (60 wt. %, 0.980 g, 24.4 mmol) at RT. After 5 min, 5-chloro-3-(2,2-difluoroethoxy)-2-fluoropyridine (2.35 g, 11.1 mmol) was added, and the resulting mixture was heated to 80 °C. After 30 min, the mixture was cooled to RT, poured into aqueous 1 M HC1 solution, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, fdtered, and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 322 [M+l],STEP B; Ethyl 5-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutyl)-1.2.4-oxadiazole-3-carboxylate

[0214] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxylic acid (300 mg, 0.930 mmol) in DCM (3.00 mL) was added 1, T-carbonyldiimidazole (151 mg, 0.930 mmol) at RT. After 5 min, ethyl ( V-hydroxycarbamimidoyl)formate (123 mg, 0.930 mmol) was added. After 1 h, the mixture was concentrated in vacuo, and toluene (10.0 mL) was added, and the resulting mixture was heated to 111 °C. After 16 h, the mixture was cooled to RT and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 418 [M+l],STEP C: 5-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-L2.4-oxadiazole-3 -carboxylic acid

[0215] To a mixture of ethyl 5-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-1.2,4-oxadiazole-3-carboxylate (130 mg, 0.310 mmol) in MeCN (1.50 mL) and water (1.50 mL) was added lithium hydroxide monohydrate (19.6 mg, 0.470 mmol) at RT. After 2 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 390 [M+l],STEP D; CA-5-[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridylloxy1-3-methyl-cvclobutyl]- / V-(4-methyl-Ll-dioxo-thian-4-yl)-1.2.4-oxadiazole-3-carboxamide and 7>p / ?5,-5-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl1oxy] -3 -methyl -cvcl obutv 11 - / V-(4-methyl- 1.1 -dioxo-thian-4-yl)- 1.2.4-oxadiazole-3 -carboxamide

[0216] To a mixture of 5-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-l,2,4-oxadiazole-3-carboxylic acid (120 mg, 0.310 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (67.6 mg, 0.340 mmol) and DIPEA (188 pL. 1.08 mmol) in DMF (1.10 mL) was added HATU (129 mg, 0.340 mmol) at RT. After 125870h, the reaction mixture was directly purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) and then further purified by chiral SFC (IG column, 35% / 65% MeOH / CCh) to afford the title compounds. 5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]- / V-(4-methyl-l, l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide (EX-1A, cisisomer): LC / MS = 535 [M+l], 'H NMR (500 MHz, Methanol-d4) 57.72 (d, J = 2.1 Hz, 1H), 7.41 (d, J= 2.1 Hz, 1H), 6.33 - 6.08 (m, 1H), 4.29 (td, J= 13.7, 3.8 Hz, 2H), 3.77 - 3.69 (m, 1H), 3.28 - 3.18 (m, 2H), 3.06 - 2.97 (m, 2H), 2.92 - 2.81 (m, 6H), 2.26 - 2.14 (m, 2H), 1.80 (s, 3H), 1.53 (s, 3H). Human DGAT2 ICso = 2.1 nM. 5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]- / V-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide (EX-1B, trans-isomer): LC / MS = 535 [M+l], 'H NMR (500 MHz, Methanol-d4) 5 7.75 (d, J= 2.1 Hz, 1H), 7.43 (d, J= 2.1 Hz, 1H), 6.23 (tt, J= 54.8, 3.8 Hz, 1H), 4.32 (td, J = 13.7, 3.8 Hz, 2H), 3.97 (ddd, J= 16.2, 10.1, 6.2 Hz, 1H), 3.29 - 3.20 (m, 2H), 3.14 (s, 2H), 3.09 - 2.99 (m, 2H), 2.91 - 2.83 (m, 2H). 2.78 (dd, J= 13.7, 6.2 Hz, 2H), 2.29 - 2.18 (m, 2H), 1.75 (s, 3H), 1.56 (s, 3H). Human DGAT2 ICso = 1.1 nM.X °

[0217] 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.OExample Structure Name Human LC / MS DGAT2 [M+l] IC50 (nM) 2 CA-5-[3-[[3-(2.2- F Difluoroethoxy)-5-fluoro-2- AFO-N, HN-V V° pyridyl]oxy]-3-methyl- 519 1.0 Y i "■■FTNo cy clobutyl] - / V-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4- oxadiazole-3-carboxamide5-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- pyridyl] oxy] cyclobutyl] -N- 3 (4-methyl- 1, 1 -dioxo-thian- 521 4.84-yl)-1.2.4-oxadiazole-3- carboxamide (2.4:1 cis:trans diastereomer mixture)CA-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- ^. F pyridyl]oxy]-3-methyl- \FO-N4a cy clobutyl] - / V-(4-methy 1- 553 1.71, 1 -dioxo-thian-4-yl)- 1,2,4- oxadiazole-3-carboxamide(faster eluting on SFC IG25870Example Structure Name Human LC / MS DGAT2 LM+1] IC50(nM) column, 30% MeOH / 70%CO2)T’ra«5-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- pyridyl]oxy]-3-methyl- cy clobutyl] -JV-(4-methy 1- 4b O-N. HN-V V°Cl1, 1 -dioxo-thian-4-yl)- 1,2,4- 553 9.5 ^v°Il TNo oxadiazole-3-carboxamide(slower eluting on SFC IGcolumn, 30% MeOH / 70%CO2)5-[3-[[3-(2,2- F Difluoroethoxy)-5-fluoro-2- py ridy 1] oxy] cy cl obuty 1] -N- I 'F O-N HN-V VO5 (4-methyl- 1, 1 -dioxo-thian- 505 6.5 T 1 PTNo 4-y 1)- 1,2,4-oxadiazole-3 - carboxamide (2.4: 1 cis:trans diastereomer mixture)o Czs-5-[3-[[5-Fluoro-3- (2,2,2-trifluoroethoxy)-2- 0 pyridyl]oxy]-3-methyl- cy clobutyl | -JV-(4-methy 1- 6a 1, 1 -dioxo-thian-4-yl)- 1,2,4- 537 14 oxadiazole-3-carboxamide(faster eluting on SFC OD- H column, 20% MeOH / 80% CO2)7raws-5-[3-[[5-Fluoro-3- (2,2,2-trifluoroethoxy)-2- pyridyl]oxy]-3-methyl- J. F cy clobutyl] -JV-(4-methyl- 6b 1FO'N. HN-V V°Fv^<° A'NH ^-A> 1, 1 -dioxo-thian-4-yl)- 1,2,4- 537 84 I T " V7 ° oxadiazole-3-carboxamide(slower eluting on SFC OD- H column, 20% MeOH / 80% CO2)5-[3-[[5-chloro-3-(2,2- difluoroethoxy)-2- F pyridyl]oxy]-3-methyl- cyclobutyl]-jV-[(ES’,27?)-3,3- O-N HN— / \7a V. / ditluoro-2-hydroxy- 523 7.8I N X 'i£jN 0OH TFcyclohexyl] - 1,2,4- oxadiazole-3 -carboxamide(5: 1 cis: trans diastereomermixture)25870Example Structure Name Human LC / MS DGAT2 [M+l] IC50(nM) 5-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- F pyndyl]oxyJ-3-methyl- cyclobutyl]-jV-[(17?,2S)-3,3- O'N HN<* / \7b Ck T k >— Z \ _ / difluoro-2-hydroxy- 523 41 cyclohexyl]- 1,2,4- NX^O y*^jN 0oxadiazole-3 -carboxamide(5:1 cis: trans diastereomermixture)CN-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- py ridy 1] oxy] cy cl obuty 1] -N- 8 |FO'N. HN<'Y ^)O- " o 525 894[(37?)-3-methyl- 1.1 -dioxo- W4^ x°vk thi olan-3-yl]- 1,2,4- oxadiazole-3-carboxamideV / - CN-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- py ridy 1] oxy] cy cl obuty 1] -N- 9 525 5140 [(3S)-3 -methyl- 1.1 -dioxo- thi olan-3-yl]- 1,2,4- oxadiazole-3-carboxamideo 0 CN-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- |FO"\ HN— py ridy 1] oxy] cy cl obuty 1] -N- 10 Ck i ^T^X.077 / XN7 — <( ° 0 463 445[(3S)-tetrahydrofuran-3-yl] - l,2,4-oxadiazole-3- carboxamide5-[3-[[5-Chloro-3-(2,2,2- trifluoroethoxy)-2- LF py ridy 1] oxy] cy cl obuty 1] -N- (4,4-difluoro-l-methyl- 11 [FO-N HN-V VF 525 873 cy cl ohexyl)- 1,2,4- oxadiazole-3-carboxamide(4:1 cis: trans diastereomermixture)5-[3-[[5-chloro-3-(2,2,2- trifluoroethoxy)-2- pyridy 1] oxy] cy clobutj 1] -N- AF(3,3-dilluoro-l-methyl- 12 | 'FO'N. HN-\— 1 497 1171 cy clobutyl)- 1,2,4- oxadiazole-3-carboxamide(4:1 cis: trans diastereomermixture)25870Example Structure Name Human LC / MS DGAT2 [M+l] IC50(nM) 5-[3-[[5-Chloro-3-(2,2,2- trifluoroethoxy)-2- pyridyl] oxy |cy clobuty 11 -N- 13 |Fo-N. HN— z N (2-methylpyrazol-3-yl)- 473 >9990 l,2,4-oxadiazole-3- W ' ■carboxamide (4:1 cis: transdiastereomer mixture)5-[3-[[5-Chloro-3-(2,2,2- tri fluoroethoxy )-2- V F pyridy 1] oxy] cy clobutyl] -N- 14 O'\ HN-^~~yCk / VA L > — / F(3.3.3-trifluoropropyl)- 489 4230 Y 1 [ 7N0 1,2,4-oxadiazole-3- carboxamide (4:1 cis: transdiastereomer mixture)5-[3-[(5-chloro-3-ethoxy-2- pyridy l)oxy] cyclobutyl] -N- f O-N. HN-V \«O (4-methyl- 1, 1 -dioxo-thian- 15 Vv%Il T A / ^N° 485 164-y 1)- 1,2,4-oxadiazole-3 - carboxamide (2.4:1 cis:trans diastereomer mixture)5-[3-[[5-Chloro-3-(2,2- difluoropropoxy)-2- I F O-N HN-V \-FI pyridyl] oxy] cyclobutyl] -N- 16 (4-methyl- 1, 1 -dioxo-thian- 535 12004-yl)-1.2.4-oxadiazole-3- carboxamide (2:1 cis: transdiastereomer mixture)5-[3-[3-(2,2- F Difluoroethoxy)pyrazin-2- y 1] oxy cy cl obutyl] -2V-(4- O-N. HN-V17 I W VVty methyl-1, l-dioxo-thian-4- 488 790( X JJN 0yl)- 1,2,4-oxadiazole-3- carboxamide (3:1 cis: transdiastereomer mixture)5-[3-[[5-Ethyl-3-(2,2,2- tri fluoroethoxy )-2- pyridyl] oxy] cyclobutyl] -N- [ ■FO-N HNV V°18 (4-methyl-l,l-dioxo-thian- 533 89I X ° 4-y 1)- 1,2,4-oxadiazole-3 - carboxamide (1.5: 1 cis:trans diastereomer mixture)5-[3-[[5-Fluoro-3-(2,2,2- XFtrifluoroethoxy)-2- 19 [FO-N. HN-V Vo pyridyl] oxy] cyclobutyl] -N- 523 155 W ” (4-methyl- 1.1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-25870Example Structure Name Human LC / MS DGAT2 [M+l] IC50(nM) carboxamide (9:1 cis: transdiastereomer mixture)5-[3-[[5-Chloro-3-(2,2,2- trifluoroethoxy)-2- pyridyl] oxy |cy clobuty 11 -N- |FO'N. HN-V V°20 (4-methyl- 1, 1 -dioxo-thian- 539 424-yl)- 1,2,4-oxadiazole-3- carboxamide (4:1 cis: transdiastereomer mixture)5-[3-[[5-Chloro-3-(2,2,2- tri fluoroethoxy )-2- py ridy 1] oxy] - 1 -fluoro- X cy clobuty 1] -A'-(4-methy 1- 21a o'N. HN-V V°CI^^O F I V_ / "o 1, 1 -dioxo-thian-4-yl)- 1,2,4- 557 >9990 Y 1 FTN0 oxadiazole-3-carboxamide(faster eluting on SFC AS-Hcolumn. 15% EtOH / 85%CO2)5-[3-[[5-Chloro-3-(2.2.2- trifluoroethoxy)-2- py ridy 1] oxy] - 1 -fluoro- ^. F cy clobuty 1] -A-(4-methy 1- rFO-N HN-V V°21b CI^^O F L X VA> 1, 1 -dioxo-thian-4-yl)- 1,2,4- 557 11Y i / ~rNo oxadiazole-3-carboxamide(slower eluting on SFC AS- H column, 15% EtOH / 85%CO2)CA-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- py ridy 1] oxy] - 1 -methyl - V cyclobutyl] -A-(4-methy 1- [FO-N HN-V V°22a 1, 1 -dioxo-thian-4-yl)- 1,2,4- 553 12 oxadiazole-3-carboxamide(faster eluting on SFC IGcolumn. 20% MeOH with0.1% NH4OH / 80% CO2)rra / 75-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- py ridy 1] oxy] - 1 -methy 1- cy clobuty 1] -A-(4-methy 1 - l ^FO'N HN-V VO22b 1, 1 -dioxo-thian-4-yl)- 1,2,4- 553 540W X oxadiazole-3-carboxamide(slower eluting on SFC IGcolumn, 20% MeOH with0.1% NH4OH / 80% CO2)25870Example Structure Name Human LC / MS DGAT2 [M+l] IC50(nM) Trans -5 - [3 - [ [5 -Chi oro-3 - (2, 2-di fluoroethoxy )-2- A pyridy 1] oxy ]- 1,3 -dimethy 1- 23 549 14 cy clobutyl] -JV-(4-methy 1- 1, 1 -dioxo-thian-4-yl)- 1,2,4- oxadiazole-3-carboxamideCzs-5-|3-[|5-Chloro-3-(2,2- difluoroethoxy)-2- ^ pyndy 1] oxy ]- 1,3 -dimethy 1- 24 549 24 cy clobutyl] -7V-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4- oxadiazole-3 -carboxamide5-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- pyridyl]oxy]-l-ethyl-3- V° methyl-cy clobutyl] -7V-(4- 25 CI^^O ' % 563 104X methyl- 1, 1 -dioxo-thian-4- y 1)- 1,2,4-oxadiazole-3- carboxamide (3:2 cis', transdiastereomer mixture)Czs-5-[3-[[5-Chloro-3-(2,2- F difluoroethoxy)-2- pyridyl]oxy]-3-ethyl-l- 26 f^FO'N. HN-V V° methyl-cy clobutyl] -N-(4- 563 119 methyl-1, 1 -dioxo-thian-4- y 1)- 1,2,4-oxadiazole-3- carboxamide5-[3-[[5-Chloro-3-(2,2,2- trifluoroethoxy)-2- pyridyl]oxy]-3- ^ (trifluoromethy l)cy cl obuty 1]HN-Y '~V° -jV-(4-methyl- 1, 1 -dioxo- 27a 607 86 thian-4-yl)- 1.2.4- xxx1oxadiazole-3-carboxamide(faster eluting on SFC OJ-Hcolumn, 15% IPrOH / 85%CO2)5-[3-[[5-Chloro-3-(2,2,2- trifluoroethoxy)-2- pyridyl]oxy]-3- (trifluoromethyl)cy clobutyl]27b 607 134-jV-(4-methyl- 1, 1 -dioxo- CF3thian-4-yl)-l,2,4- oxadi azol e-3 -carboxami de(slower eluting on SFC OJ-25870Example Structure Name Human LC / MS DGAT2 [M+l] IC50 (nM) H column, 15% zPrOH / 85% CO2)5-[(lS,37?)-3-[[5-chloro-3- (2,2,2-trifluoroethoxy)-2- 1Fo-N, HN-¥ V«O pyridyl]oxy]-2,2-dimethyl- 28 567 >9990 cy clobutyl] -AL(4-methy 1- •w - • 1, 1 -dioxo-thian-4-yl)- 1,2,4- oxadiazole-3-carboxamide5-[(17?,35)-3-[[5-chloro-3- Lr (2,2,2-trifluoroethoxy)-2- \FO-N. HN-Y V° pyndyl]oxy]-2,2-dimethyl- 29 X W Vy % 567 1919 cy clobutyl] -7V-(4-methyl- Y NT O'' O R"N 01, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamideEXAMPLES 30A and 30B(7,s-3-|3-||5-Chloro-3-(2.2-di fluoroethoxy )-2-pyridyl |oxy |-3-methyl-cyclobutyl |-A'-(4-methyl- l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-5-carboxamide and rra / 7s-3-[3-[[5-chloro-3-(2,2- difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-A-(4-methyl-l,l-dioxo-thian-4-yl)-1.2.4- oxadiazole-5 -carboxamideSTEP A: 3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carbonitrile

[0218] To amixture of 3-hydroxy-3-methylcyclobutane-l-carbonitrile (1.56 g, 14.0 mmol) in DMF (6.00 ml) was added sodium hydride (60 wt. %, 561 mg, 14.0 mmol) at RT. After 5 min, 5-chloro-3-(2,2-difluoroethoxy)-2-fluoropyridine (2.97 g, 14.0 mmol) was added, and the resulting mixture was heated to 70 °C. After 1 h, the mixture was cooled to RT, filtered, and the25870filtrate was purified by flash silica gel column chromatography (0-50% EtOAc in hexanes) to afford the title compound. LC / MS = 303 [M+l],STEP B; 3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-A-hvdroxy-3-methylcy clobutane- 1 -carboximidamide

[0219] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcy clobutane- 1 -carbonitrile (500 mg, 1.65 mmol) and K2CO3 (320 mg, 2.31 mmol) in EtOH (33.0 mL) was added hydroxylamine hydrochloride (287 mg, 4.13 mmol), and the resulting mixture was heated to 85 °C. After 3 h, the mixture was cooled to RT, filtered, and the filtrate was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 336 [M+l],STEP C: Methyl 3-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-1.2,4-oxadiazole-5-carboxylate

[0220] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-A-hydroxy-3-methylcy clobutane- 1 -carboximidamide (550 mg, 1.64 mmol) in DCM (7.00 mL) and pyridine (0.700 mL) was added methyl 2-chloro-2-oxoacetate (201 pL, 2.13 mmol) at RT. After 18 h, the mixture was filtered, and the filtrate was purified by flash silica gel column chromatography (0-60% EtOAc in hexanes) to afford the title compound. LC / MS = 404 [M+l],STEP D; 3-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutyl)-L2.4-oxadiazole-5 -carboxylic acid

[0221] To a mixture of methyl 3-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-l,2,4-oxadiazole-5-carboxylate (286 mg, 0.71 mmol) in MeCN (1.50 mL) and water (1.50 mL) was added lithium hydroxide monohydrate (38.6 mg, 0.920 mmol) at RT. After 30 min, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 390 [M+l],STEP E; CA-3-[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cvclobutyl]-A-(4-methyl-l.l-dioxo-thian-4-yl)-1.2,4-oxadiazole-5-carboxamide and 7ra»5-3-[3-[[5-chloro-3-(2.2-difluoroethoxy)-2-pyridyl1oxy1-3-methyl-cvclobutyl1-A-(4-methyl- LI -dioxo-thian-4-yl)- 1,2.4-oxadiazole-5-carboxamide

[0222] To a mixture of 3-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-l,2,4-oxadiazole-5-carboxylic acid (276 mg, 0.710 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1 -dioxide hydrochloride (156 mg, 0.780 mmol) and DIPEA (495 pL, 2.83 mmol) in DMF (1.50 mL) was added HATU (323 mg, 0.850 mmol) at RT. After 1 h, the reaction mixture w as directly purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) and then further purified by chiral SFC (OJ-H column, 25% / 75%25870MeOH / CCh) to afford the title compounds. 3-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]- / V-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-5-carboxamide (EX-30A, cis-isomer): LC / MS = 535 [M+l],rH NMR (500 MHz, Methanol-d4) 5 7.72 (d, J= 2.2 Hz, 1H), 7.40 (d, J= 2.2 Hz, 1H), 6.21 (tt, J= 54.9. 3.8 Hz, 1H), 4.29 (td, J = 13.7, 3.8 Hz. 2H), 3.57 (p. J= 8.9 Hz. 1H), 3.30 - 3.21 (m, 2H), 3.03 - 2.95 (m, 2H), 2.90 - 2.78 (m, 6H), 2.25 - 2.14 (m, 2H), 1.80 (s, 3H), 1.52 (s, 3H). Human DGAT2 ICso = 2.1 nM. 3-[3-[[5-Chloro-3-(2,2-difluoroethoxy )-2-pyridy 1] oxy] -3-methyl-cy clobuty 1] -JV-(4-methyl- 1, 1 -dioxo-thian-4-yl)-l,2,4-oxadiazole-5-carboxamide (EX-30B, trans-isomer): LC / MS = 535 [M+l], 'll NMR (500 MHz, Methanol-d4) 57.75 (d, J= 2.2 Hz, 1H), 7.42 (d, J= 2.2 Hz, 1H), 6.23 (tt, J = 54.8, 3.8 Hz, 1H), 4.32 (td, J= 13.7, 3.8 Hz, 2H), 3.85 - 3.75 (m, 1H), 3.30 - 3.23 (m, 2H), 3.09 - 2.99 (m, 4H), 2.92 - 2.83 (m, 2H), 2.76 - 2.66 (m, 2H), 2.28 - 2.18 (m, 2H), 1.74 (s, 3H), 1.55 (s, 3H). Human DGAT2 ICso = 41 nM.EXAMPLES 31A and 31BCA-2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-3-methyl- / V-(4-methyl- l,l-dioxo-thian-4-yl)imidazole-4-carboxamide and Tra«5-2-[3-[[5-chloro-3-(2,2,2- trifluoroethoxy)-2-pyridyl]oxy]cy clobuty l]-3-methyl-A-(4-methyl-l, 1 -dioxo-thian-4- yl)imidazole-4-carboxamideEX-31A EX-31BSTEP A: 3-((5-Chloro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)cvclobutane-l-carbonitrile

[0223] To a mixture of 3-hydroxycyclobutane-l-carbonitrile (500 mg, 5.15 mmol) and 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (1.30 g, 5.66 mmol) in DMF (10.0 rnL) was added CS2CO3 (2.01 g. 6.18 mmol), and the resulting mixture was heated to 70 °C. After 4 h, themixture was cooled to RT. filtered, and the filtrate was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 307 [M+l], STEP B; 3-((5-Chloro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)-A-hvdroxycvclobutane-l-carboximidamide

[0224] To a mixture of 3-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutane-l-carbonitrile (667 mg, 2.18 mmol) and NaHCCh (457 mg, 5.44 mmol) in MeOH (13.0 mL) and water (2.00 mL) was added hydroxylamine hydrochloride (332 mg, 4.78 mmol), and the resulting mixture was heated to 75 °C. After 4 h, the mixture was cooled to RT, filtered, and the filtrate was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 340 [M+l],STEP C: Ethyl 2-(3-((5-chloro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-177-imidazole-5-carboxylate

[0225] To a mixture of 3-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-A-hydroxycyclobutane-l-carboximidamide (730 mg, 2.15 mmol) and ethyl propiolate (239 pL. 2.36 mmol) in toluene (14 mL) was added triethylamine (359 pL, 2.58 mmol), and the resulting mixture was heated to 140 °C. After 16 h, the mixture was cooled to RT, filtered, and the filtrate was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 420 [M+l],STEP D; Ethyl 2-(3-((5-chloro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)cvclobutyl)-l-methyl-l / / -imidazole-5-carboxylate

[0226] To a mixture of ethyl 2-(3-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-lL7-imidazole-5 -carboxylate (900 mg, 2.14 mmol) and K2CO3 (593 mg, 4.29 mmol) in DMF (5 mL) was added iodomethane (268 pL, 4.29 mmol) at RT. After 5 h, the mixture was filtered, and the filtrate was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 434 [M+l],STEP E; 2-(3-((5-Chloro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-l-methyl-177-imidazole-5-carboxylic acid

[0227] To a mixture of ethyl 2-(3-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-l-methyl-177-imidazole-5-carboxylate (326 mg, 0.750 mmol) in MeCN (1.50 mL) and water (1.50 mL) was added lithium hydroxide monohydrate (47.3 mg, 1.13 mmol) at RT. After 2 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 406 [M+l],STEP F; CA-2-[3-[[5-Chloro-3-(2.2.2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl1-3-methyl-A-(4-methyl-l,l-dioxo-thian-4-yl)imidazole-4-carboxamide and 7rc»75'-2-[3-[[5-chloro-3-(2.2.2-trifluoroethoxy)-2-pyridyl1oxy1cyclobutyl1-3-methyl-A-(4-methyl-l.l-dioxo-thian-4-yl)imidazole-4-carboxamide

[0228] To a mixture of 2-(3-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-l-methyl-lE7-imidazole-5 -carboxylic acid (300 mg, 0.740 mmol). 4-amino-4-methyltetrahydro-2 / 7-thiopyran 1,1-dioxide hydrochloride (162 mg. 0.810 mmol) and DIPEA (452 pL. 2.59 mmol) in DMF (2.00 mL) was added HATU (309 mg, 0.810 mmol) at RT. After 1 h, the reaction mixture was directly purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) and then further purified by chiral SFC (AS-H column, 30% MeOH with 0.1% HNEt2170% CO2) to afford the title compounds. 2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-3-methyl-A-(4-methyl- 1, l-dioxo-thian-4-yl)imidazole-4-carboxamide (EX-31A, trans-isomer):LC / MS = 551 [M+l],NMR (500 MHz, Methanol-d4) 57.78 (d, J= 2.2 Hz, 1H), 7.61 (s, 1H), 7.48 (d, J= 2.2 Hz, 1H), 5.50 - 5.41 (m, 1H), 4.65 (q, J= 8.5 Hz, 2H), 3.87 - 3.79 (m, 1H), 3.76 (s, 3H), 3.29 - 3.20 (m, 2H), 3.05 - 2.93 (m, 2H), 2.93 - 2.79 (m. 4H), 2.78 - 2.66 (m, 2H), 2.22 - 2.13 (m, 2H), 1.52 (s, 3H). Human DGAT2 IC50 = 2088 nM. 2-[3-[[5-Chloro-3-(2.2.2-trifluoroethoxy)-2-pyridyl]oxy] cyclobutyl] -3-methy l-A-(4-methy I- 1, 1 -dioxo-thian-4-yl)imidazole-4-carboxamide (EX-31B, cis-isomer): LC / MS = 551 [M+l], *HNMR (500 MHz, Methanol-d4) 57.81 (d, J=2.2Hz, 1H), 7.58 (s, 1H), 7.47 (d, J= 2.1 Hz, 1H), 5.32 (p, J= 7.7 Hz. 1H), 4.62 (q. J= 8.5 Hz. 2H), 3.80 (s, 3H), 3.45 - 3.38 (m, 1H), 3.27 - 3.16 (m, 2H), 3.05 -2.95 (m, 4H), 2.89-2.80 (m, 2H), 2.58 -2.48 (m, 2H), 2.21 -2.11 (m, 2H), 1.51 (s, 3H).Human DGAT2 IC50 = 487 nM.Example 32CA-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-5-methyl-A-(4- methyl-l,l-dioxo-thian-4-yl)oxazole-4-carboxamideF STEP EEX-32STEP A: 3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutane-l-carbonyl chloride

[0229] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxylic acid (1.12 g, 3.48 mmol) in DCM (12.0 mL) and DMF (0.06 rnL) was added (COC1)2 (2 M solution in DCM. 1.91 mL. 3.83 mmol) at RT. After 30 min, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification.STEP B; Methyl 2-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-1 -carboxamido)-3 -hvdroxybutanoate

[0230] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-1 -carbonyl chloride (1.16 g, 3.40 mmol) in DCM (12.0 mL) was added methyl 2-amino-3-hydroxybutanoate hydrochloride (692 mg, 4.08 mmol) and DIPEA (1.78 mL, 10.2 mmol) at RT. After 2 h. the reaction mixture was filtered, and the filtrate was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 437 [M+l],STEP C: Methyl 2-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-5-methyloxazole-4-carboxylate

[0231] To a mixture of methyl 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxamido)-3-hydroxybutanoate (263 mg, 0.600 mmol) in DCM (3.00 mL) was added (diethylamino)sulfur trifluoride (0.100 mL, 0.720 mmol) at 0 °C. After 30 min, the mixture w as warmed to RT. After further 1 h, bromotrichloromethane (0.210 mL, 2.11 mmol) and l,8-diazabicyclo[5.4.0]undec-7-ene (0.320 mL, 2.11 mmol) were added. After 30 min, the reaction mixture was filtered, and the filtrate was purified by flash silica gel column chromatography (0-60% EtOAc in hexanes) to afford the title compound. LC / MS = 417 [M+l], STEP D; 2-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-5-methyloxazole-4-carboxylic acid

[0232] To a mixture of methyl 2-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-5-methyloxazole-4-carboxylate (72.0 mg, 0.170 mmol) in MeCN (1.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (10.9 mg, 0.260 mmol) at RT. After 1 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 403 [M+l],STEP E; C / s-2-[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridylloxy]-3-methyl-cvclobutyl]-5-methyl-A-(4-methyl-l.l-dioxo-thian-4-yl)oxazole-4-carboxamide25870

[0233] To a mixture of 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-5-methyloxazole-4-carboxylic acid (69.0 mg, 0.170 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (37.6 mg, 0.190 mmol) and DIPEA (105 pL. 0.600 mmol) in DMF (0.900 mb) was added HATU (71.7 mg, 0.190 mmol) at RT. After 1 h, the reaction mixture was fdtered, and the filtrate was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the title compound. LC / MS = 548 [M+l], NMR (500 MHz, Methanol-d4) 57.72 (d, J= 2.1 Hz, 1H), 7.40 (d, J = 2.1 Hz, 1H), 6.21 (tt, 7= 54.8, 3.8 Hz, 1H), 4.29 (td, J= 13.7, 3.8 Hz, 2H), 3.48 - 3.38 (m, 1H), 3.29 - 3.15 (m. 2H), 3.04 - 2.94 (m. 2H), 2.88 - 2.72 (m, 6H), 2.56 (s, 3H), 2.22 - 2.11 (m, 2H), 1.77 (s, 3H), 1.50 (s, 3H). Human DGAT2 IC50 = 11 nM.

[0234] By using procedures similar to those described in Example 32 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) / ram-2-|3-||5-Chloro-3- (2,2,2-trifluoroethoxy)-2- py ridy 1] oxy] - 1 -methy 1- > / cyclobutyl]-5-methyl- / V-(4- | ~FO"4 HN-V33a methy 1- 1, 1 -dioxo-thian-4- 566 12010yl)oxazole-4-carboxamide(faster eluting on SFC C2-5column, 12% MeOH / 88%CO2)CA-2-[3-[[5-Chloro-3- (2.2,2-trifluoroethoxy)-2- py ridy 1] oxy] - 1 -methy 1- cyclobutyl]-5-methyl- / V-(4- 33b methyl- 1, 1 -dioxo-thian-4- 566 12 yl)oxazole-4-carboxamide(slower eluting on SFC C2- 5 column. 12% MeOH / 88% CO2)CA-2-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- py ridyl] oxy ] cyclobutyl] -N- |FO-\ HN-V \ <0 (4-methyl- 1, 1 -dioxo-thian- 34a 538 234-yl)oxazole-4-carboxamide(faster eluting on SFC ADcolumn, 20% EtOH with0.1% NH4OH / 20% CO2)25870Human LC / MS DGAT2 Example Structure Name[M+l] IC50(nM) 77ran.s'-2-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- pyridyl] oxy ] cyclobutyl] -N- 1Fo-"\ HN-V (4-methyl- 1, 1 -dioxo-thian- 34b 538 211 T n-NO 4-yl)oxazole-4-carboxamide(slower eluting on SFC ADcolumn, 20% EtOH with0.1% NH4OH / 20% CO2)Example 35Cz.y-3-(3-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-V-(4-methyl-l,l- dioxidotetrahydro-2H-thiopyran-4-yl)-l,2,4-thiadiazole-5-carboxamideSTEP A: Methyl 3-((rerr-butyldiphenylsilyl)oxy)cvclobutane-l-carboxylate

[0235] To a mixture of methyl 3-hydroxycyclobutane-l-carboxylate (1.00 g, 7.68 mmol) and imidazole (0.160 g, 2.31 mmol) in DMF (25.0 mL) was added tert-butylchlorodiphenylsilane (2.53 g, 9.22 mmol) at RT. After 16 h, the mixture was poured into water and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 369 [M+l],STEP B; 3-((Ter / -butyldiphenylsilyl)oxy)cvclobutane-l-carboxamide

[0236] To a mixture of methyl 3-((tert-butyldiphenylsilyl)oxy)cyclobutane- 1 -carboxylate (500 mg, 1.36 mmol) in MeOH (1.00 mL) was added a solution of NEL (7 M in MeOH, 15.0 mL, 10525870mmol) at RT. After 16 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 354 [M+l],STEP C: 3-((7'c / 7-butyldiphenylsilyl )oxy )cvclobutane- 1 -carbothioamide

[0237] To a mixture of 3-((tert-butyldiphenylsilyl)oxy)cyclobutane-l-carboxamide (800 mg, 2.26 mmol) in THF (30.0 mL) was added 2.4-bis(4-methoxyphenyl)-1.3,2,4-dithiadiphosphetane 2.4-disulfide (915 mg, 2.26 mmol), and the resulting mixture was heated to 75 °C. After 16 h, the mixture was cooled to RT, and then 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 = 370 [M+l],STEP D: Ethyl 3-(3-((ter / -butyldiphenylsilyl)oxy)cvclobutyl)-L2.4-thiadiazole-5-carboxylate

[0238] To a mixture of 3-((7e / 7-butyldiphenylsilyl)oxy)cyclobutane- 1 -carbothioamide (300 mg, 0.810 mmol) and ethyl 2-amino-2-thioxoacetate (216 mg, 1.62 mmol) in DCM (10.0 mL) was added (diacetoxyiodo)benzene (390 mg, 1.21 mmol) at RT. After 30 min, the mixture 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 = 467 [M+l], STEP E: 3-(3-((7erz-butyldiphenylsilyl)oxy)cyclobutyl)-1.2.4-thiadiazole-5-carboxylic acid

[0239] To a mixture of ethyl 3-(3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)-l,2,4-thiadiazole-5-carboxylate (100 mg, 0.110 mmol) in MeCN (1.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (18.0 mg, 0.430 mmol) at RT. After 18 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 439 [M+l],STEP F: 3-(3-((Terr-butyldiphenylsilyl)oxy)cvclobutyl)-A-(4-methyl-l.l-dioxidotetrahvdro-2 / / -thiopyran-4-yl)-1.2.4-thiadiazole-5-carboxamide

[0240] To a mixture of 3-(3-((tert-butyldiphenylsilyl)oxy)cyclobutyl)- 1,2,4-thiadiazole-5-carboxylic acid (45.0 mg, 0.100 mmol), 4-amino-4-methyltetrahydro-2 / / -thiopyran 1,1-dioxide hydrochloride (20.1 mg, 0.120 mmol) and DIPEA (54.0 pL, 0.310 mmol) in DMF (0.500 mL) was added HATU (58.5 mg. 0.150 mmol) at RT. After 1 h, the reaction mixture was directly purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS=584 [M+H],STEP G: 3-(3-Hydroxycyclobutyl )-A-(4-methyl- 1, 1 -dioxidotetrahvdro-2 / / -thiopyran-4-yl)- 1.2.4-thiadiazole-5-carboxamide

[0241] To a mixture of 3-(3-((terCbutyldiphenylsilyl)oxy)cyclobutyl)-7V-(4-methyl-l,l-dioxidotetrahydro-277-thiopyran-4-yl)-l,2,4-thiadiazole-5-carboxamide (15.0 mg, 0.0300 mmol) in THF (1.00 mL) was added TBAF (1 M solution in THF, 57.0 pL, 0.0600 mmol) at RT. After2587015 h, the mixture 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 = 346 [M+l],STEP H: CA-3-(3-((5-Chloro-3-(2.2.2-trifluoroethoxy)pyridin-2-yl)oxy)cvclobutyl)- / V-(4-methyl- 1, 1 -dioxidotetrahvdro-27 / -thiopyran-4-yl)- 1.2.4-thiadiazole-5-carboxamide

[0242] To a mixture of 3-(3-hydroxycyclobutyl)- -(4-meth\ l-l. l-dioxidotetrahydro-2 / / -thiopyran-4-yl)-l,2,4-thiadiazole-5-carboxamide (9.00 mg, 0.0300 mmol) and 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (9.00 mg, 0.0400 mmol) in DMA (1.00 mL) was added CS2CO3 (17.0 mg, 0.0500 mmol) and the resulting mixture was warmed to 50 °C. After 15 h, the mixture was cooled to RT, poured into water, and the mixture was extracted with EtOAc. The combined organic layers were 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 compounds. LC / MS = 555 [M+l], 'H NMR (400 MHz, CDCh) 6 7.86 (d, J= 2.3 Hz, 1H), 7.26 - 7.29 (m, 1H), 7.06 (s, 1H), 5.32 (quin, J= 7.5 Hz, 1H). 4.45 (q, J= 8.2 Hz, 2H). 3.56 - 3.65 (m, 1H), 3.15 - 3.25 (m, 2H), 2.99 - 3.11 (m, 4H), 2.83 (br s, 2H), 2.64 - 2.74 (m, 2H), 2.32 - 2.42 (m, 2H), 1.64 (s, 3H). Human DGAT2 IC50 = 24 nM.EXAMPLES 36A and 36BCA-5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]methyl]- / V-(4-methyl-l,l- dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide and Trans'-5-[[3-[[5-chloro-3-(2,2- difluoroethoxy)-2 -pyridyl] oxy] cyclobuty l]methy 1] -A-(4-methy 1- 1, 1 -dioxo-thian-4-yl)- 1,2,4- oxadi azole-3 -carboxamideSTEP A: Ethyl 2-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)cvclobutyl)acetate25870

[0243] To a mixture of ethyl 2-(3-hydroxycyclobutyl)acetate (247 mg, 1.56 mmol) in DMF (1.00 mL) was added sodium hydride (60 wt. %, 62.4 mg, 1.56 mmol) at RT. After 5 min, 5-chloro-3-(2,2-difluoroethoxy)-2-fluoropyridine (300 mg, 1.42 mmol) was added. The resulting mixture was heated to 60 °C. After 1 h, the mixture was cooled to RT, fdtered, and the filtrate was purified by flash silica gel column chromatography (0-30% EtOAc in hexanes) to afford the title compound. LC / MS = 350 [M+l],STEP B; 2-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)acetic acid

[0244] To a mixture of ethyl 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)acetate (216 mg, 0.620 mmol) in MeCN (1.50 mL) and water (1.50 mL) was added lithium hydroxide monohydrate (51.8 mg, 1.24 mmol) at RT. After 1 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 322 [M+l],STEP C: Ethyl 5-((3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)methyl)- 1.2,4-oxadiazole-3-carboxylate

[0245] To a mixture of 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)acetic acid (199 mg, 0.620 mmol) in DCM (3.00 mL) was added 1,1'-carbonyldiimidazole (110 mg, 0.680 mmol) at RT. After 5 min, ethyl ( / V-hydroxycarbamimidoyl)formate (90.0 mg. 0.680 mmol) was added. After 1 h, the mixture was concentrated in vacuo, toluene (6.00 mL) was added, and the resulting mixture was heated to 111 °C. After 1 h, the mixture was cooled to RT and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 418 [M+l],STEP D; 5-((3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)cvclobutyl)methyl)-1.2.4-oxadiazole-3 -carboxylic acid

[0246] To a mixture of ethyl 5-((3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)methyl)-l,2,4-oxadiazole-3-carboxylate (169 mg, 0.410 mmol) in MeCN (1.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (25.5 mg, 0.610 mmol) at RT. After 1 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 390 [M+l],STEP E; CA-5-[[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridyl1oxy1cvclobutyl1methyl]- / V-(4-methyl-l.l-dioxo-thian-4-yl)-1.2,4-oxadiazole-3-carboxamide and 7ra / 75-5-[[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl1oxylcvclobutyl]methyl]-V-(4-methyl-l,l-dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide25870

[0247] To a mixture of 5-((3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)methyl)-l,2,4-oxadiazole-3-carboxylic acid (100 mg, 0.260 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (56.4 mg, 0.280 mmol) and DIPEA (157 pL. 0.890 mmol) in DMF (1.20 mL) was added HATU (107 mg, 0.280 mmol) at RT. After 1 h, the mixture was filtered, and the filtrate was purified by reverse phase HPLC (MeCN / water with 0.1% TFA modifier) and then further purified by chiral SFC (AD-H column, 30% / 70% MeOH / CCh) to afford the title compounds. 5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-py ridyl] oxy ] cyclobutyl] methyl] - / V-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3-carboxamide (EX-36A, cis-isomer): LC / MS = 535 [M+l],rH NMR (500 MHz, Methanol-di) 5 7.72 (d, J= 2.1 Hz, 1H), 7.40 (d, J= 2.1 Hz, 1H), 6.22 (tt, J= 54.8, 3.8 Hz, 1H), 5.18 - 5.09 (m, 1H), 4.30 (td, J= 13.7, 3.8 Hz, 2H), 3.28 - 3.17 (m, 4H), 3.07 - 2.97 (m, 2H), 2.92 - 2.83 (m, 2H), 2.83 - 2.75 (m, 2H), 2.61 - 2.50 (m, 1H), 2.27 - 2.17 (m, 2H), 2.05 - 1.96 (m, 2H), 1.55 (s, 3H). Human DGAT2 IC50 = 786 nM. 5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl] oxy ]cy clobutyl]methyl] -A-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3-carboxamide (EX-36B, trans-isomer): LC / MS = 535 [M+l], ’H NMR (500 MHz, Methanol-d4) 57.73 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 2.2 Hz, 1H), 6.34 - 6.09 (m, 1H), 5.42 - 5.35 (m, 1H), 4.36 - 4.27 (m. 2H), 3.29 - 3.20 (m, 4H), 3.07 - 2.99 (m, 2H), 2.98 - 2.91 (m, 2H), 2.90 - 2.80 (m. 2H), 2.50 - 2.39 (m, 3H), 2.26 - 2.17 (m, 2H), 1.55 (s, 3H). Human DGAT2 IC50 = 2.8 nM.

[0248] By using procedures similar to those described in Example 36A / B 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) CA-5-[[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- F pyridyl]oxy]cyclobutyl]methyl]- |^F N-(3 -methyl- 1,1 -di oxo-thietan-3- 37a 507 >9990°'N y 1)- 1,2,4-oxadiazole-3- 'b carboxamide (faster eluting onSFC AD-H column, 40% MeOH / 60% CO2)25870Human LC / MS DGAT2 Example Structure Name-n -n -n -n - - - - [M+1J IC50(nM) b^' °- 7ra«s-5-[[3-[[5-Chloro-3-(2,2- 0 o 0 o o o difluoroethoxy)-2- F pyridyl]oxy]cyclobutyl]methyl]- |^FN-(3 -methyl- 1,1 -di oxo-thietan-3- 37b CI^^O K Zz N. P 507 71IL ^ d iJ—J 'KH' \^-\ yl)- 1,2,4-oxadiazole-3- N cr “^ ° K- KXN20^ i z,N-v$=ocarboxa6 IZ 'b mide (slower eluting onSFC AD-H column, 40% MeOH0 d \ ’Oc>—nb bC0 o'^-rO^. _ O'- Uil\X / / \ / \ / o o / 60% CO2)O O O o5-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- pyridyl]oxymethyl]cyclobutyl]- 38 / V-(4-methy 1- 1, 1 -dioxo-thian-4- 535 17 yl)-l,2,4-oxadiazole-3- carboxamide (6:1 cis: transdiastereomer mixture)5-[3-[[5-Fluoro-3-(2,2,2- trifluoroethoxy)-2- py ridy 1] oxy methyl] cyclobutyl] - 39 jV-(4-methy 1- 1, 1 -dioxo-thian-4- 537 82 yl)- 1,2,4-oxadiazole-3- carboxamide (6:1 cis: transdiastereomer mixture)5-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- pyridyl]oxymethyl]cyclobutyl]- 40 7V-(3 -methyl- 1, 1 -dioxo-thietan-3- 507 288 yl)-l,2,4-oxadiazole-3- carboxamide (6:1 cis: transdiastereomer mixture)5-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- pyridyl] oxymethyl] - 1 - 41 547 21 bicyclo[l.1. l]pentanyl]-JV-(4- methyl- 1, 1 -dioxo-thian-4-y 1)- l,2,4-oxadiazole-3-carboxamide5-[4-[[5-Chloro-3-(2,2- difluoroethoxy)-2- py ri dy 1] oxymethyl] Cuban- 1 -yl]- 42 583 462JV-(4-methy 1- 1, 1 -dioxo-thian-4- yl)-l,2,4-oxadiazole-3- carboxamide5-[3-[[5-Chloro-3-(2,2,2- trifluoroethoxy)-2- 43 pyridyl]oxy]cyclopentyl]-jV-(4- 553 352 methyl- 1.1 -dioxo-thian-4-y 1)-l,2,4-oxadiazole-3 -carboxamide25870EXAMPLES 44a and 44bCzs-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl-jV-(4- methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide and Trans-5-[3-[ [5 -chi oro-3 -(2,2- difluoroethoxy )-2-pyridyl] oxy ]-3-methyl-cy cl obutyl] -2 -methyl-. V-(4-methyl-l. l-dioxo-thian-4- yl)- 1.2,4-triazole-3-carboxamideSTEP A: Cz5,-5-[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridyl1oxy1-3-methyl-cvclobutyl1-2-methyl-jV-(4-methyl-l.l-dioxo-thian-4-yl)-1.2.4-triazole-3-carboxamide and Trans-5-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-1,2,4-triazole-3-carboxamide

[0249] To a mixture of 5-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-jV-(4-methyl-l,l-dioxidotetrahydro-277-thiopyran-4-yl)-l,2,4-oxadiazole-3-carboxamide (95.0 mg, 0.180 mmol) in DMF (1.00 mL) was added methylhydrazine (0.470 mL, 8.88 mmol), and the resulting mixture was heated to 110 °C. After 4 days, the mixture was cooled to RT and concentrated in vacuo. The residue was purified by reverse phase HPLC (10-80% MeCN / water with 0.1 % TFA modifier) and then further purified by chiral SFC (OJ-H column, 10% / 90% MeOH / CCh) to afford the title compounds.

[0250] 5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl- '-(4-methyl-l. I -dioxo-thian-4-yl)- 1,2.4-triazole-3-carboxamide (EX-44A, cis-isomer): LC / MS = 570 [M+Na], 'H NMR (500 MHz, Methanol-d4) 57.72 (d, J= 2.2 Hz, 1H), 7.38 (d, J= 2.2 Hz, 1H), 6.21 (tt, J= 54.9, 3.8 Hz, 1H), 4.29 (td, J= 13.7, 3.8 Hz, 2H), 4.12 (s, 3H), 3.41 - 3.27 (m, 3H), 3.01 - 2.93 (m, 2H), 2.87 - 2.80 (m, 2H), 2.78 - 2.72 (m, 4H), 2.22 - 2.14 (m, 2H), 1.78 (s, 3H), 1.51 (s, 3H). Human DGAT2 IC50 = 10 nM. 5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide (EX-44B, trans-isomer): LC / MS = 570 [M+Na], 'H NMR (500 MHz, Methanol-d4) δ7.74 (d, J=2.2Hz, 1H), 7.41 (d, J= 2.2 Hz, 1H), 6.23 (tt, J = 54.9, 3.8 Hz, 1H), 4.32 (td, J = 13.7, 3.8 Hz, 2H), 4.16 (s, 3H), 3.70 - 3.61 (m, 1H), 3.38 - 3.29 (m, 2H), 3.05 - 2.94 (m, 4H),258702.90 - 2.79 (m. 2H). 2.69 - 2.61 (m. 2H), 2.26 - 2.16 (m. 2H), 1.70 (s. 3H), 1.54 (s, 3H). Human DGAT2 ICso = 110 nM.

[0251] By using procedures similar to those described in Example 44 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) CA-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- pyridyl] oxy ]- 1 -methyl- 45 1FN'N, HN- Y.03JL ' _ / *0 cy clobutyl] -2-methy 1 - AA- (4 - 566 23 P I rrN0 methyl- 1, 1 -dioxo-thian-4- yl)- 1,2,4-triazole-3- pcarboxamideC / s-5-[3-[[5-Chloro-3- (2,2,2-trifluoroethoxy)-2- pyridyl] oxy ] cy clobutyl] -2- 46 552 43 00^^ " methyl- / V-(4-methyl- 1,1- dioxo-thian-4-y 1)- 1,2,4- triazole-3-carboxamide00 5-[3-[[5-chloro-3-(2,2- difluoroethoxy)-2- F py ridy 1] oxy ] -3 -methy 1- cy clobutyl] -2-methyl-N-(4- 47 XFN'N HN-V V° 548 4.9 methy 1- 1, 1 -dioxo-thian-4- yl)-l,2,4-triazole-3- carboxamide (3:1 cis: transdiastereomer mixture)5-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- py ridy 1] oxymethyl] - 1 - 48 bicy clo[ 1.1.1 ]pentanyl] -2- 560 38 methy 1 - / V-(4-methy 1 - 1,1- dioxo-thian-4-yl)- 1,2,4-triazole-3-carboxamideEXAMPLE 49Trans -2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]- / V-(4-methyl-l,l -dioxo- thian-4-yl)triazole-4-carboxamide25870EX-49STEP A: Methyl 2-(3-(benzyloxy)cvclobutyl )-2 / / - l.2.3-triazole-4-carboxylate

[0252] To a mixture of methyl 2 / / -l,2,3-triazole-4-carboxylate (260 mg, 2.05 mmol), 3-(benzyloxy)cyclobutan-l-ol (300 mg, 1.68 mmol) and triphenylphosphine (662 mg, 2.52 mmol) in THF (10.0 mb) was added diisopropyl azodicarboxylate (681 mg, 3.37 mmol) at RT. After 15 h, the mixture was poured into water and the mixture was extracted with DCM. The combined organic layers were washed with saturated aqueous NaCl solution, dried overNa2SO4, then filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford a mixture of the title compounds. LC / MS = 288 [M+l],STEP B: Methyl 2-(3-hvdroxycvclobutyl)-2 / 7-l.2.3-triazole-4-carboxylate

[0253] To a mixture of methyl 2-(3-(benzyloxy)cyclobutyl)-2 / / -l,2,3-triazole-4-carboxylate (350 mg, 1.22 mmol) in MeOH (10.0 mL) was added Pd / C (10 wt. %, 100 mg, 0.940 mmol). A balloon of Eh was placed over the reaction mixture, and the reaction mixture was sparged with H2 for 5 min. Stirring was then continued under H2 atmosphere. After 15 h, the mixture was filtered over Celite, the filter cake was washed with MeOH and DCM, and the filtrate was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 198 [M+l],STEP C: Methyl 2-(3-((5-chloro-3-(2.2-difluoroethoxy )pyri din-2 -yl)oxy)cyclobutyl)-277-l,2,3-triazole-4-carboxylate

[0254] To a mixture of methyl 2-(3-hydroxycyclobutyl)-2 / / -l,2,3-triazole-4-carboxylate (100 mg, 0.510 mmol) and 5-chloro-3-(2,2-difluoroethoxy)-2-fluoropyridine (129 mg, 0.610 mmol) in DMF (2.00 mL) was added CS2CO3 (330 mg, 1.01 mmol). The resulting mixture was heated to 90 °C. After 16 h, the mixture was cooled to RT, filtered, and the filtrate was purified by reverse phase HPLC (10-80% MeCN / water with 0.1% TFA modifier) to afford the title compound. LC / MS = 389 [M+H],25870STEP D: 2-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-2 / / -L2.3-triazole-4-carboxylic acid

[0255] To a mixture of methyl 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-2F7-l,2,3-triazole-4-carboxylate (100 mg, 0.260 mmol) in MeCN (1.50 mL) and water (1.50 mL) was added lithium hydroxide monohydrate (19.6 mg, 0.470 mmol) at RT. After 2 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 375 [M+l],STEP E: 7 / 'a / 75-2-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-A-(4-methyl- 1, 1 -dioxidotetrahy dro-277-thiopyran-4-yl)-2 / / - 1,2.3-triazole-4-carboxamide

[0256] To a mixture of 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-2 / f-l,2,3-triazole-4-carboxylic acid (50.0 mg, 0.130 mmol), 4-amino-4-methyltetrahydro-277-thiopyran 1,1-dioxide hydrochloride (35.0 mg, 0.150 mmol) and DIPEA (100 pL, 0.570 mmol) in DMF (1.50 mL) was added HATU (76.0 mg, 0.200 mmol) at RT. After 1 h, the reaction mixture was filtered, and the filtrate was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 520 [M+l],NMR (500 MHz, Methanol-d4) δ8.05 - 8.18 (m, 1H), 7.75 (br d, J= 2.1 Hz, 1H), 7.45 (br d, J= 2.0 Hz, 1H), 6.09 - 6.43 (m, 1H), 5.64 (br d, J= 4.9 Hz, 1H), 5.34 - 5.50 (m, 1H), 4.23 - 4.45 (m, 2H), 3.20 - 3.28 (m. 2H), 3.11 - 3.19 (m. 2H), 3.02 (br d, J =11.8 Hz, 2H), 2.90 (br d. J= 9.0 Hz. 4H), 2.21 (br t, J= 11.8 Hz, 2H), 1.55 (br s, 3H). Human DGAT2 IC50 = 3.5 nM.

[0257] By using procedures similar to those described in Example 49 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) l-[3-[[5-Chloro-3-(2,2- F difluoroethoxy)-2- pyridyl] oxy ] cyclobutyl] -N- r=\ HN-V \s,050 (4-methyl- 1, 1 -dioxo-thian- 519 11 II T 0 4-yl)pyrazole-3- carboxamide (1:3 cis: transdiastereomer mixture)25870Human LC / MS DGAT2 Example Structure Name[M+1J IC50(nM) l-[3-[[5-Chloro-3-(2,2- F difluoroethoxy)-2- pyridyl] oxy ] cyclobutyl] -N- |^FHN-V V°51 Clx^.0 V_ / % (4-methyl- 1, 1 -dioxo-thian- 519 178I N X CT 7704-yl)imidazole-4- carboxamide (1:3 cis: transdiastereomer mixture)l-[3-[[5-Fluoro-3-(2,2,2- trifluoroethoxy )-2- py ridyl] oxy ] cy cl obuty 11 -N- | ^Fr=\ HN-V52 (4-methyl- 1, 1 -dioxo-thian- 521 949T X JZ704-yl)pyrazole-3- carboxamide (1:3 cis: transdiastereomer mixture)l-[3-[[5-Chloro-3-(2.2- F difluoroethoxy)-2- f^F r=N HN-V py ridyl] oxy ] cyclobutyl] -N- 53 520 2072 C'YV0. Jii T nN x-^ 'bo (4-methyl- 1, 1 -dioxo-thian- 4-yl)-l,2,4-triazole-3- carboxamideEXAMPLE 54(7.s-2-|3-||5-Chloro-3-(2.2-dilluoroethoxy)-2-pyridyl|oxy|-3-methyl-cyclobut l|-A-(4-methyl- 1, 1 -dioxo-thian-4-y l)triazole-4-carboxamideSTEP A: Mesityl-X3-iodanediyl bis(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxylate)25870

[0258] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-1 -carboxylic acid (905 mg, 2.81 mmol) in toluene (30.0 mL) was added iodomesitylene diacetate (500 mg, 1.37 mmol). The mixture was warmed to 55 °C and the solvent was removed under reduced pressure over a period of 5 min. Additional toluene (30.0 mL) was added, and the evaporation step was repeated. Toluene addition and subsequent evaporation was repeated three times. The residue was then dried in vacuo to afford the title compound. The crude product was used without purification.STEP B; Ethyl 2-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobuty’l)-2H- 1,2.3 -tri azole-4-carboxy late

[0259] To a mixture of mesityl-3-iodanediyl bis(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l -carboxylate) (1.26 g, 1.42 mmol), ethyl 277-l,2,3-triazole-4-carboxylate (100 mg, 0.71 mmol), 4,7-diphenyl-l,10-phenanthroline (70.7 mg, 0.210 mmol) and copper(I) thiophene-2-carboxylate (27.0 mg, 0.140 mmol) in dioxane (18.0 mL) was added [(4,4'-di-terLbutyl-2,2'-bipyridine)-bis-(5-methyl-2-(5-fluoro-phenyl)-pyridine)-iridium(iii)] hexafluorophosphate (6.90 mg, 7.10 pmol). The resulting mixture was then irradiated with blue LED at RT. After 12 h, the mixture was filtered over Celite, and the filtrate 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 = 417 [M+l],STEP C: 2-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutyl)-2 / 7-1.2.3-triazole-4-carboxylic acid

[0260] To a mixture of ethyl 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-2H-1,2,3-triazole-4-carboxylate (52.0 mg, 0.130 mmol) in MeCN (1.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (7.90 mg, 0.190 mmol) at RT. After 1 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 389 [M+l],STEP D: CA-2-[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-A-(4-methyl- 1, 1 -dioxo-thian-4-yl)triazole-4-carboxamide

[0261] To a mixture of 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)-2Ef-l,2,3-triazole-4-carboxylic acid (49.0 mg, 0.130 mmol), 4-amino-4-methyltetrahydro-277-thiopyran 1,1-dioxide hydrochloride (28.0 mg, 0.140 mmol) and DIPEA (77.0 pL. 0.440 mmol) in DMF (1.00 mL) was added HATU (53.0 mg. 0.140 mmol) at RT. After 1 h, the reaction mixture was filtered, and the filtrate was purified by reverse phase HPLC (10-80% MeCN / water with 0.1% TFA modifier) to afford the title compound. LC / MS = 534 [M+l], 'H NMR (500 MHz, Methanol-d4) δ8.06 (s, 1H), 7.74 (d, J= 2.2 Hz, 1H), 7.42 (d, J= 2.2 Hz,258701H), 6.22 (tt. J = 54.9. 3.8 Hz. 1H), 5.12 (p. J = 8.2 Hz. 1H), 4.31 (td, J = 13.7. 3.8 Hz. 2H). 3.26 - 3.17 (m, 2H), 3.17 - 3.09 (m, 2H), 3.08 - 2.96 (m, 4H), 2.92 - 2.85 (m, 2H), 2.24 - 2.14 (m, 2H), 1.79 (s, 3H), 1.52 (s, 3H). Human DGAT2 ICso = 0.8 nM.

[0262] By using procedures similar to those described in Example 54 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) €7s 2-| 3-| 15-F1 uoro-3-(2.2- F difluoroethoxy)-2- py ridy 1] oxy ] -3 -methy 1- 55 [ ^FHN-V 518 1.4 cy clobutyl] - A-(4-melhy 1- 1, 1 -dioxo-thian-4- yl)triazole-4-carboxamideCA-2-[3-[[5-chloro-3-(2,2- difluoroethoxy)-2- F py ridy 1] oxy ] -3 -methy 1- cyclobutyl]-5-methyl-JV-(4- 56a N=Z HN-VCIXV° A V_ / <b methyl- 1, 1 -dioxo-thian-4- 548 14 I X " VT0yl)triazole-4-carboxamide(faster eluting on SFC IGcolumn, 15% MeOH with0.1% NH4OH / 85% CO2)T’ra / 75-2-[3-[[5-chloro-3- (2,2-difluoroethoxy)-2- F py ridy 1] oxy ] -3 -methy 1- cyclobuly l]-5-methyl-2V-(4- 56b [FN=\ HN-V V° methy 1- 1, 1 -dioxo-thian-4- 548 153 yl)triazole-4-carboxamide(slower eluting on SFC IGcolumn, 15% MeOH with0.1% NH4OH / 85% CO2)l-[3-[[5-Chloro-3-(2,2- difluoroethoxy)-2- F py ridy 1] oxy ] -3 -methy 1 - cyclobutyl] -N-(4-methyl- 57 HN-V~~VO,^N 534 9.9 T INo 1, 1 -dioxo-thian-4-yl)- 1,2,4- triazole-3 -carboxamide (3: 1cis: trans diastereomermixture)Human LC / MS DGAT2 Example Structure Name[M+l] IC50(nM) Trans- l-[3-[[5-Chloro-3- F (2,2-difluoroethoxy)-2- r==\ HNW pyridyl]oxy]-3-methyl- 58 CI^^O ✓ *o 533 67 ii T "-.n ° cy cl obuty 11 -A-(4-methy 1 - 1, 1 -dioxo-thian-4-yl)pyrazole-3-carboxamideEXAMPLE 59C7s-2-[3-[[5-Chloro-3-(2, 2-di fluoroethoxy )-2-pyridyl |oxy |-3-methyl-cyclobut l |-A-(4-methyl- 1, 1 -dioxo-thian-4-yl)pyrimidine-5-carboxamideEX-59STEP A: Ethyl 2-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutyl)pyrimidine-5-carboxylate

[0263] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxylic acid (300 mg, 0.930 mmol), silver nitrate (634 mg, 3.73 mmol) and ethyl pyrimidine-5-carboxylate (184 mg, 1.21 mmol) in water (6.00 mL) and MeCN (6.00 mL) was added and ammonium persulfate (1.06 g, 4.66 mmol), and the resulting mixture was warmed to 65 °C. After 16 h, the mixture was cooled to RT, poured into water, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 428 [M+l],STEP B: 2-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutyl)pyrimidine-5-carboxylic acid

[0264] To a mixture of ethyl 2-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)pyrimidine-5-carboxylate (25.0 mg, 0.0600 mmol) in MeCN (0.50 mL) and water (0.5 mL) was added lithium hydroxide monohydrate (3.70 mg, 0.0900 mmol) at RT. After1 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 400 [M+l],STEP C: CA-2-[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridyl1oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)pyrimidine-5-carboxamide

[0265] To a mixture of 2-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)pyrimidine-5-carboxylic acid (24.0 mg, 0.0600 mmol), 4-amino-4-methyltetrahydro-277-thiopyran 1,1-dioxide hydrochloride (16.0 mg, 0.0800 mmol) and DIPEA (42.0 pL. 0.240 mmol) in DMF (0.50 mL) was added HATU (30.0 mg, 0.0800 mmol) at RT. After 30 min, the reaction mixture was filtered, and the filtrate was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 545 [M+l],XH NMR (500 MHz, Methanol-d4) 59.09 (s, 2H), 8.17 (s, 1H), 7.72 (d, J=2.1 Hz, 1H), 7.39 (d, J=2.1 Hz, 1H), 6.21 (tt, J= 54.9, 3.8 Hz, 1H), 4.29 (td, J= 13.7, 3.9 Hz, 2H), 3.61 (p, J = 8.8 Hz, 1H), 3.31 - 3.23 (m, 2H), 3.06 - 2.98 (m, 2H). 2.92 - 2.77 (m, 6H), 2.27 - 2.15 (m. 2H), 1.82 (s, 3H), 1.54 (s, 3H). Human DGAT2 ICso = 20 nM.EXAMPLE 60CA-6-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-A-(4-methyl- 1, 1 -dioxo-thian-4-y l)pyridine-3-carboxamideSTEP A: l,3-Dioxoisoindolin-2-yl 3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxylate

[0266] To a mixture of 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l-carboxylic acid (3.05 g, 9.47 mmol), 2-hydroxyisoindoline-l, 3-dione (1.85 g, 11.4 mmol) and 4-(dimethylamino)pyridine (116 mg. 0.950 mmol) in DCM (47.0 mL) was added, V., V'-diisopropylcarbodiimide (1 M solution in DCM, 11.4 mL, 11.4 mmol) at RT. After 2h, the mixture was diluted with saturated aqueous NaHCOs solution. The aqueous layer was extracted with EtOAc. The combined organic layers were then dried over MgSOv filtered, and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0-50% EtOAc in hexanes) to afford the title compound. LC / MS = 467 [M+l], STEP B; Methyl 6-(3-((5-chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutyllnicotinate

[0267] To a mixture of 4.4'-di- / c / 7-butyl-2.2’-dipyridyl (23.0 mg, 0.0900 mmol) in DMA (2.00 rnL) was added nickel(II) bromide ethylene glycol dimethyl ether complex (26.0 mg, 0.0900 mmol) at RT. After 5 min, l,3-dioxoisoindolin-2-yl 3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutane-l -carboxylate (200 mg, 0.430 mmol), zinc (62.0 mg, 0.940 mmol) and methyl 6-iodonicotinate (124 mg, 0.470 mmol) were added and stirring was continued at RT. After 16 h, the reaction mixture was filtered, and the filtrate was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 413 [M+l],STEP C: 6-(3-((5-Chloro-3-(2.2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcvclobutyl)nicotinic acid

[0268] To a mixture of methyl 6-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)nicotinate (94.0 mg. 0.230 mmol) in MeCN (1.00 mL) and water (1.00 mL) was added lithium hydroxide monohydrate (14.0 mg, 0.340 mmol) at RT. After 30 min, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 399 [M+l],STEP D; CA-6-13-[15-chloro-3-(2.2-difluoroethoxy)-2-pyridyl1oxy1-3-methyl-cvclobutyl1- / V-(4-methyl- Ll-dioxo-thian-4-yl)pyridine-3-carboxami de

[0269] To a mixture of 6-(3-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylcyclobutyl)nicotinic acid (90.0 mg, 0.230 mmol), 4-amino-4-methyltetrahydro-27F-thiopyran 1,1-dioxide hydrochloride (50.0 mg, 0.250 mmol) and DIPEA (138 pL, 0.790 mmol) in DMF (1.00 mL) was added HATU (94.0 mg. 0.250 mmol) at RT. After 30 min, the reaction mixture was filtered, and the filtrate was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 544 [M+l],JH NMR (500 MHz, Methanol-d4) 69.06 (s, 1H). 8.68 - 8.62 (m, 1H), 8.26 (s, 1H), 7.91 (d, J = 8.4 Hz. 1H), 7.73 (d. J = 2.1 Hz. 1H), 7.41 (d. J = 2.1 Hz, 1H), 6.33 - 6.07 (m, 1H), 4.29 (td. J = 13.8, 3.7 Hz, 2H), 3.72 (p, J = 9.0 Hz, 1H), 3.31 - 3.25 (m, 2H), 3.07 - 2.98 (m, 2H), 2.98 - 2.91 (m, 2H), 2.91 - 2.77 (m, 4H), 2.28 - 2.16 (m, 2H), 1.83 (s, 3H), 1.55 (s, 3H). Human DGAT2 IC5o = 3.9 nM.25870EXAMPLE 615-[3-(2-Ethoxy-2-methyl-propoxy)cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l:2:4- oxadiazole-3 -carboxamideSTEP A: 3-((7e77-butyldimethylsilyl)oxy)cyclobutane-l-carboxylic acid

[0270] To a mixture of 3-hydroxycyclobutane-l-carboxylic acid (6.30 g, 54.3 mmol) and imidazole (7.76 g, 114 mmol) in DCM (300 mL) was added rert-butyldimethylchlorosilane (17.2 g, 114 mmol) at RT. After 18 h, the mixture was poured into aqueous 1 M HC1 solution, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, then filtered, and concentrated in vacuo. The residue was dissolved in THF (300 mL) whereupon water (60.0 mL) and K.2CO3 (13.5 g, 98.0 mmol) were added at RT. After 4 h, the aqueous layer was neutralized with aqueous 0.1 M HO and then extracted with EtOAc. The combined organic layers were dried over Na2SO4, then filtered, and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 231 [M+l],STEP B; Ethyl 5-(3-((ter / -butyldimethylsilyl)oxy)cvclobutyl)-L2,4-oxadiazole-3-carboxylate

[0271] To a mixture of 3-((terEbutyldimethylsilyl)oxy)cyclobutane-l-carboxylic acid (5.07 g, 22.0 mmol) in DCM (70.0 mL) was added l,l'-carbonyldiimidazole (3.92 g, 24.2 mmol) at RT. After 10 min, ethyl (TV-hydroxycarbamimidoyl)formate (3.49 g, 26.4 mmol) was added. After 2 h, the mixture was concentrated in vacuo, toluene (70.0 mL) was added, and the resulting mixture was heated to 111 °C. After 16 h, the mixture was cooled to RT, poured into saturated aqueous NaHCCL solution, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 327 [M+l],25870STEP C: 5-(3-((7'erLbutyldimethylsilyl)oxy)cvclobutyl)-L2.4-oxadiazole-3-carboxylic acid

[0272] To a mixture of ethyl 5-(3-((tert-butyldimethylsilyl)oxy)cyclobutyl)-l,2,4-oxadiazole-3-carboxylate (7.31 g, 22.4 mmol) in THF (22.0 mL), MeOH (11.0 mL) and water (11.0 mL) was added lithium hydroxide monohydrate (940 mg, 22.4 mmol) at RT. After 2 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 299 [M+l].STEP D: 5-(3-((7erLbutyldimethylsilyl)oxy)cyclobutyl)-A-(4-methyl-l.l-dioxidotetrahvdro-277-thiopyran-4-yl)-1.2,4-oxadiazole-3-carboxamide

[0273] To a mixture of 5-(3-((ter / -butyldimethylsilyl)oxy)cyclobutyl)-l,2,4-oxadiazole-3-carboxylic acid (6.68 g, 22.4 mmol), 4-amino-4-methyltetrahydro-277-thiopyran 1,1-dioxide hydrochloride (4.92 g, 24.6 mmol) and DIPEA (11.7 mL, 67.2 mmol) in DMF (100 mL) was added HATU (10.2 g, 26.9 mmol) at RT. After 12 h, the mixture was poured into water, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, then filtered, and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 444 [M+l], STEP E; 5-(3-Hvdroxycvclobutyl)-. V-(4-methyl-l. l-dioxidotetrahvdro-2 / / -thiopyran-4-yl)-1.2,4-oxadiazole-3-carboxamide

[0274] To a mixture of 5-(3-(( / c77-bulyldimelhylsilyl)oxy)cyclobutyl)-A-(4-methyl- 1.1 -dioxidotetrahydro-277-thiopyran-4-yl)-l,2,4-oxadiazole-3-carboxamide (11.4 g, 25.8 mmol) in THF (100 mL) was added TBAF (I M solution in THF, 51.6 mL, 51.6 mmol) at RT. After 1 h, the mixture was poured into saturated aqueous NaHCO₃ solution, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (0-10% MeOH in DCM) to afford the title compound. LC / MS = 330 [M+l],STEP F; 3-(3-((4-Methyl-l.l-dioxidotetrahvdro-277-thiopyran-4-yl)carbamoyl)-L2.4-oxadiazol-5-yl)cyclobutyl 4-methylbenzenesulfonate

[0275] To a mixture of 5-(3-hydroxycyclobutyl)-7V-(4-methyl-l,l-dioxidotetrahydro-277-thiopyran-4-yl)-l,2,4-oxadiazole-3-carboxamide (200 mg, 0.61 mmol), 4-(dimethylamino)pyridine (7.40 mg, 0.0600 mmol) and triethylamine (0.340 mL, 2.43 mmol) in DCM (2.50 mL) was added -toluenesulfonyl chloride (139 mg, 0.73 mmol) at RT. After 2 h, the mixture was poured into aqueous 1 M HC1 solution, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 484[M+l],25870STEP G: 5-(3-(2-Hvdroxy-2-methylDropoxy)cvclobutyl)-A'-(4-methyl-M-dioxidotelrahvdro-2 / / -thiopyran-4-yl)-1.2.4-oxadiazole-3 -carboxamide

[0276] To a mixture of sodium hydride (60 wt %, 23.0 mg, 0.570 mmol) in 2-methylpropane-1,2-diol (0.500 mL) was added 3-(3-((4-methyl- 1, l-dioxidotetrahydro-2 / 7-thiopyran-4-yl)carbamoyl)-1.2.4-oxadiazol-5-yl)cyclobutyl 4-methylbenzenesulfonate (92.0 mg, 0.190 mmol) at RT. After 18 h, the reaction mixture was filtered, and the filtrate was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the title compound. LC / MS = 402 [M+l],STEP H: 5-[3-(2-Ethoxy-2-methyl-propoxy)cyclobutyl]- / V-(4-methyl-l.l-dioxo-thian-4-yl)- 1.2.4-oxadiazole-3-carboxamide

[0277] To a mixture of 5-(3-(2-hydroxy-2-methylpropoxy)cyclobutyl)-JV-(4-methyl-l,l-dioxidotetrahydro-277-thiopyran-4-yl)-l,2,4-oxadiazole-3-carboxamide (28.0 mg, 0.0700 mmol) and N, NJV', N'- tetramethyl- 1.8-naphthalenediamine (20.0 mg, 0.0900 mmol) in DCM (1.00 mL) was added triethyloxonium tetrafluoroborate (1 M solution in DCM, 84.0 pL, 0.0800 mmol) at RT. After 24 h, the reaction mixture was filtered, and the filtrate was purified by mass triggered reverse phase HPLC (MeCN / water with 0.1% TFA modifier) to afford the title compound.LC / MS = 430 [M+l], ’H NMR (500 MHz, Methanol-d4) 5 8.57 (s, 1H), 4.11 (p, J= 7.4 Hz, 1H), 3.56 - 3.41 (m. 4H), 3.29 - 3.20 (m. 2H), 3.07 - 2.98 (m, 2H), 2.92 - 2.78 (m, 5H), 2.45 - 2.35 (m, 2H), 2.27 - 2.16 (m, 2H), 1.55 (s, 3H), 1.20 (s, 6H), 1.16 (t, J= 7.0 Hz, 3H). Human DGAT2 IC50 > 9900 nM.EXAMPLES 62A and 62BCA-5-[3-(2,2-Difluoroethoxy)-3-methyl-cyclobutyl]- / V-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4- oxadiazole-3-carboxamide and 7'ra / ?s-5-[3-(2,2-difluoroethoxy)-3-methyl-cyclobutyl]-JV-(4- methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamideSTEP A: Benzyl 3-(2.2-difluoroethoxy)-3-methylcvclobutane-l-carboxylate25870

[0278] To a mixture of benzyl 3-hydroxy-3-methylcyclobutane-l-carboxylate (2.00 g, 9.08 mmol) in DMF (10.0 mL) was added NaH (60 wt. %, 1.09 g, 27.2 mmol) at 0 °C. After 30 min, 2,2-difluoroethyl trifluoromethanesulfonate (5.83 g, 27.2 mmol) was added, and the resulting mixture was warmed to RT. After 12 h, the mixture was poured into water, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, then filtered, and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (0-100% EtOAc in hexanes) to afford the title compound. LC / MS = 285 [M+l],STEP B; (3-(2.2-Difluoroethoxy)-3-methylcvclobutane-l -carboxylic acid

[0279] To a mixture of benzyl 3-(2,2-difluoroethoxy)-3-methylcyclobutane-l -carboxylate (700 mg, 2.46 mmol) in MeOH (10.0 mL) was added Pd / C (10 wt. %, 262 mg, 0.250 mmol). A balloon of EE was placed over the reaction mixture, the reaction mixture was sparged with H2 for 5 min, and stirring was then continued under H2 atmosphere. After 1 h, the mixture was filtered over Celite, the filter cake was washed with MeOH and DCM, and the filtrate was concentrated in vacuo to afford the title compound. The crude product was used without purification.STEP C: Ethyl 5-(3-(2.2-difluoroethoxy)-3-methylcyclobutyl)-1.2.4-oxadiazole-3-carboxylate

[0280] To a mixture of 3-(2,2-difluoroethoxy)-3-methylcyclobutane-l-carboxylic acid (450 mg, 2.32 mmol) in DCM (10.0 mL) was added l,l'-carbonyldiimidazole (413 mg, 2.55 mmol) at RT. After 5 min, ethyl (A'-hydroxycarbamimidoyl)formate (306 mg, 2.32 mmol) was added. After 1 h, the mixture was concentrated in vacuo, toluene (50.0 mL) was added, and the resulting mixture was heated to 111 °C. After 16 h, the mixture was cooled to RT and concentrated in vacuo. The residue was purified by reverse phase HPLC (MeCN / water with 0.1% FA modifier) to afford the title compound. LC / MS = 291 [M+l],STEP D: 5-(3-(2.2-Difluoroethoxy)-3-methylcvclobutyl)-A-(4-methyltetrahydro-27 / -thiopyran-4-y 1)- 1,2,4-oxadiazole-3-carboxamide

[0281] To a mixture of 4-methyltetrahydro-27F-thiopyran-4-amine (70.0 mg, 0.530 mmol) in toluene (1.00 mL) was added trimethylaluminium (2 M solution in toluene. 0.300 mL, 0.600 mmol) at 0 °C. After 30 min, ethyl 5-(3-(2,2-difluoroethoxy)-3-methylcyclobutyl)- 1,2,4-oxadiazole-3 -carboxylate (50.0 mg, 0.170 mmol) was added, and the resulting mixture was warmed to 60 °C. After 4 h, the mixture was cooled to RT, and then 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 = 376 [M+l],25870STEP E: 0.s'-5-|3-(2.2-difluoroethoxy)-3-methyl-cvclobutyl|- '-(4-methyl-l. l-dioxo-thian-4-yl)-1.2.4-oxadiazole-3-carboxamide and 7' / Y / m-5-| 3-(2.2-di fluoroethoxy )-3-methyl-cvclobutyl l-A-(4-methy 1- 1, 1 -dioxo-thian-4-y 1)- 1.2.4-oxadiazole-3 -carboxamide

[0282] To a mixture of 5-(3-(2,2-difluoroethoxy)-3-methylcyclobutyl)-jV-(4-methyltetrahydro-2 / / -thiopyran-4-yl)-l, 2, 4-oxadiazole-3 -carboxamide (30.0 mg, 0.0800 mmol) in DME (1.00 mL) and water (0.200 mL) was added oxone (98.0 mg, 0.160 mmol) at RT. After 12 h, the mixture was poured into water, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, then 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 compounds. 5-[3-(2,2- Difluoroethoxy)-3-methyl-cyclobutyl]-7V-(4-methyl-I, I-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide (EX-62A, cis-isomer): LC / MS = 408 [M+l], 'H NMR (400 MHz, CDCh) 56.65 -6.94 (m, 1H), 5.58 - 6.11 (m, 1H). 3.59 (dt, J= 13.9, 4.1 Hz, 2H), 3.39 - 3.49 (m, 1H), 3. O9 -3.24 (m, 2H), 2.94 - 3.06 (m, 2H). 2.79 (br d, J= 14.9 Hz, 2H), 2.58 - 2.69 (m, 2H). 2.45 - 2.56 (m, 2H), 2.27 - 2.41 (m, 2H), 1.55 - 1.67 (m, 3H), 1.48 (s, 3H). Human DGAT2 ICso > 9990 nM. 5-[3-(2,2-Difluoroethoxy)-3-methyl-cyclobutyl ]-A-(4-methyl-l, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3 -carboxamide (EX-62B, trans-isomer): LC / MS = 408 [M+l], ’H NMR (400 MHz, CDCh) 56.58 - 6.97 (m, 1H). 5.58 - 6.17 (m. 1H), 3.80 - 3.99 (m. 1H), 3.60 (dt, J= 13.9, 4.0 Hz, 2H), 3.12 - 3.22 (m, 1H), 3.12 - 3.22 (m, 2H), 2.96 - 3.09 (m, 2H), 2.80 (br d, J= 15.0 Hz, 2H), 2.72 (dd, J= 13.4, 9.7 Hz, 2H), 2.41 - 2.54 (m, 2H), 2.28 - 2.40 (m, 2H), 1.60 (s, 3H), 1.43 (s, 3H). Human DGAT2 ICso > 9990 nM.ASSAYSInsect cell expression and membrane preparation

[0283] 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 ug / 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. Cell debris 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, abl02831) and donkey anti-rabbit IgGH& L Alexa25870Fluor® 647 (Abeam, abl50075) followed by detection using Typhoon FLA9000 (GE Healthcare).LC / MS / MS analysis method

[0284] LC / MS / MS analyses were performed using Thermal 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 80mTorr. Standard reference material (SRM) chromatograms of13Cis-triolein (QI: 920.8> Q3:621.3) and internal standard13C2i-triolein (QI: 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 standard13C2i-triolein was used to generate percentage inhibition and IC50 values. Compound percentage inhibition was calculated by7the following formula: Inhibition %=1- [(compound response - low control ) / (high control - low control)] x 100%. Potent compounds were titrated and ICso were calculated by 4 parameter sigmoidal curve fitting formula.DGAT2 enzymatic activity assay

[0285] DGAT2 activity was determined by measuring the amount of enzymatic product13Cis-triolein (13C-l,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 MgCh.5% ethanol), 25 pM of diolein, 5 pM of13C oleoyl-CoA and 8 ng / pL of DGAT2 membrane.

Claims

CLAIMS:

1. A compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:m is 0 or 1, indicating the absence or presence of a C-H in the ring;n2 is 0 or 1, indicating the absence or presence of a CH2 between theL‘A” ring and Xm is 0 or 1, indicating the absence or presence of a CH2 between the£'A” ring and the oxygen; X is independently selected from C and N;Y independently selected from C-H, C-CH3, N, andN-CHs;V is independently selected from C-H, C-CH3, N, N-CH3, O and S;U is independently selected from C-H, C-CH3, N, N-CH3, O and S;ring ‘’A” is 4 to 8-membered mono-, bridged- or multicyclic cycloalkyl group,R1is(1) 6-membered heteroaryl containing 1, or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R6.(2) -(Ci-6)alkyl-O-(Ci-6)alkyl, or(3) -(Ci-3)haloalkyl,R2is(1) 4- to 7-membered heterocyclyl containing 1. 2 or 3 heteroatoms independently selected from N, O and S,(2) phenyl,(3) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S,(4) -(Ci-6)alkyl-heteroaryl. wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O and S, (5) -(Ci-6)alkyl-aryl,(6) -(Ci-6)heterocyclyl, wherein the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S, (7) -(Ci-6)alkyl,(8) -(C3-6)cycloalkyl,(9) -(Ci-6)hydroxyalkyl,(10) -(C3-6)cyclic amine, or(11) -SO2(Ci-6)alkyl;wherein each alkyl, aryl, cycloalkyl, heteroaryl and heterocyclyl moiety is unsubstituted or substituted with 1, 2. or 3 R5;when present, each R3is independently:(1) halogen,(2) (Ci-3)alkyl, or(3) (Ci-3)haloalkyl,when present, each R5is independently selected from(1) -OCi-ealkyl,(2) -O(Ci-6)haloalkyl,(3) halogen,(4) (Ci-3)alkyl,(5) hydroxy, and(6) oxo;when present, each R6is independently selected from:(1) -OCi-salkyl,(2) -O(Ci-6)haloalkyl,(3) halogen, and(4) (Ci-3)alkyl.

2. A compound of claim 1, of Formula la,Xlaor a pharmaceutically acceptable salt thereof, wherein:X is independently selected from C and N;Y independently selected from C-H, N, and N-CH3;V is independently selected from C-H, N, and O;U is independently selected from C-H, C-CH3, N, O and S;R1is(1) 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1. 2, or 3 R6,(2) -(Ci-6)alkyl-O-(Ci-6)alkyl, or(3) -(Ci-3)haloalkyl;R2is(1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(2) phenyl,(3) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S,(4) -(Ci-e)alkyl,(5) -(C3-6)cycloalkyl, or(6) -(Ci-6)hydroxy alkyl;wherein each alkyd, cycloalkyl, aryl and heterocyclyl moiety is unsubstituted or substituted with 1, 2, or 3 R5;R3is:(1) hydrogen,(2) halogen,(3) (Ci-3)alkyl, or(4) (Ci-3)haloalkyl;25870when present, each R5is independently selected from(1) -OCi-ealkyl,(2) -O(Ci-6)haloalkyl,(3) halogen,(4) (Ci-3)alkyl,(5) hydroxy, and(6) oxo;when present, each R6is independently selected from:(1) -OCi-salkyl,(2) -O(Ci-e)haloalkyl,(3) halogen, and(4) (Ci-3)alkyl.

3. The compound of any one of claims 1-2. or a pharmaceutically acceptable salt thereof, wherein Rxis(1) 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1, 2, or 3 substituents independently selected from -OCH2CHF2, OCH2CF3, OCH2CH3, - OCH2CF2CH3, Cl, F, and CH2CH3;(2) -(Ci-6)alkyl-O-(Ci-6)alkyl; or(3) -(Ci-3)haloalkyl.

4. The compound of any one of claims 1-3. or a pharmaceutically acceptable salt thereof, wherein R1is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1 or 2 substituents independently selected from -OCH2CHF2, -OCH2CF3, -OCH2CH3, OCH2CF2CH3, Cl, F, and -CH2CH3.

5. The compound of any one of claims 1-4. or a pharmaceutically acceptable salt thereof, wherein R2is(1) 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, unsubstituted or substituted with one, two, or three substituents independently selected from (Ci-3)alkyl and oxo;(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O, and S, unsubstituted or substituted with (Ci-3)alkyl;(3) -(C?-6)cycloalkyL unsubstituted or substituted with one, two, or three substituents independently selected from OH, halogen, or (Ci-3)alkyh or(4) -(Ci-6) alky l, unsubstituted or substituted with one two or three halogen substituents.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R2is(1) 4- to 7-membered heterocyclyl containing one sulfur atom, unsubstituted or substituted with one, two, or three substituents independently selected from (Ci- 3)alkyl and oxo;(2) 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected fromN, O. and S, unsubstituted or substituted with (Ci-3)alkyl;(3) -(C3-6)cycloalkyl unsubstituted or substituted with one, two, or three substituents independently selected OH, halogen, or (Ci-s)alkyl; or(4) -(C1-6) alkyl, unsubstituted or substituted with one two or three halogen substituents.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R2iso, o, o, or o8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R5is oxo, (Ciw)alk l. OH, or halogen.

9. The compound of any one of claims 1-8. or a pharmaceutically acceptable salt thereof, wherein X is C or N.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein Y is C-H, C-CH3, N, or N-CH3.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein V is C-H, C-CH3, N, N-CH3, O, or S.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein U is C-H, C-CH3. N, N-CH3, O, or S.

13. A compound of claim 1, of Formula Ic,0, / R2N- / 7— NHR3-fnicR1~» '0, or a pharmaceutically acceptable salt thereof, whereinR1is a 6-membered heteroar l containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1, 2, or 3 substituents independently selected from -OCH2CHF2, -OCH2CF3, -OCH2CH3. -OCH2CF2CH3, Cl, F, and -CH2CH3;R2is 4- to 7-membered heterocyclyl containing 1 sulfur atom, unsubstituted or substituted with one, two, or three substituents independently selected from CHs and oxo; andR3is H, (Ci-3)alkyl, halogen, or (Ci-3)haloalkyl.

14. A compound of claim 1, of Formula Id,, or a pharmaceutically acceptable salt thereof, whereinR1is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is substituted with 1, 2, or 3 substituents independently selected from -OCH2CHF2, -OCH2CF3, -OCH2CH3, -OCH2CF2CH3, Cl, F, and -CH2CH3;R2is 4- to 7-membered heterocyclyl containing 1 sulfur atom, unsubstituted or substituted with one, two, or three substituents independently selected from CH3 and oxo; andR3is H, (Ci-s)alkyl, halogen, or (Ci-s)haloalkyl.

15. A compound of claim 1, of Formula le,x, or a pharmaceutically acceptable salt thereof, wherein:X is independently selected from C and N;Y independently selected from C-H, N, and N-CH3;V is independently selected from C-H, N, and O;U is independently selected from C-H, C-CH3, N, O and S;R1is a 6-membered heteroary 1 containing 1 or 2 nitrogen atoms, wherein the heteroary 1 is substituted with 1, 2, or 3 substituents independently selected from -OCH2CHF2, -OCH2CF3, -OCH2CH3. -OCH2CF2CH3, Cl, F, and -CH2CH3;R2is a 4- to 7-membered heterocyclyl containing 1 sulfur atom, unsubstituted or substituted with one, two, or three substituents independently selected from CH3 and oxo; and R3is H, (Ci-3)alkyl, halogen, or (Ci-3)haloalkyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is:CA-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,7ra / ?s-5-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-A-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,CA-5-[3-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobut l]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-1.2.4-oxadiazole-3-carboxamide,(7.s-5-|3-||5-Chloro-3-(2.2.2-trifluoroethoxy)-2-pyndyl|oxy|-3-methyl-cyclobutyl ]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,7ra -5-|3-||5-Chloro-3-(2.2.2-trinuoroethoxy)-2-pyridyl|oxy|-3-methyl-cyclobutyl|-; V-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,5-[3-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Cz5-5-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutj4]-7V-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,7ra / 7s-5-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-[(LS',2 / ?)-3,3-difluoro-2-hydroxy-cyclohexyl]-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-7V-[(lA,2S)-3,3-difluoro-2-hydroxy-cyclohexyl]-l,2,4-oxadiazole-3-carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-[(3 )-3-methyl-l,l-dioxo-thiolan-3-yl]-l,2,4-oxadiazole-3-carboxamide,Czx-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-2 / -[(3S)-3-methyl-l,l-dioxo-thiolan-3-yl]-l,2,4-oxadiazole-3-carboxamide,Cz3,-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-A^-[(3iS)-tetrahydrofuran- 3-yl]-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-7V-(4,4-difluoro-l-methyl-cyclohexyl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-N-(3,3-difluoro-l-methyl-cyclobutyl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-7V-(2-methylpyrazol-3-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-N-(3,3,3-trifluoropropyl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[(5-chloro-3-ethoxy-2-pyridyl)oxy]cyclobutyl]-N-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3 -carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian- 4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[3-(2,2-Difluoroethoxy)pyrazin-2-yl]oxycyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-A^-(4-methyl-l,l-dioxo-thian- 4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian- 4-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-V-(4-methyl-l,l-dioxo-thian- 4-yl)-l,2,4-oxadiazole-3-carboxamide,Cz5-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-fluoro-cyclobutj4]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,7ra / 7s-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-fluoro-cyclobutyl]-jV-(4-methyl- 1.1-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,7z-a / ?6-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-methyl-cyclobutyl]-JV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,7ra / 7.s,-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-l,3-dimethyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-l,3-dimethyl-cyclobutyl]-JV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1, 2, 4-oxadiazole-3 -carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-l-ethyl-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-ethyl-l-methyl-cyclobutyl]-N-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(tnfluoromethyl)cyclobutyl]-V-(4-methy 1- 1, 1 -dioxo-thian-4-y 1)- 1, 2, 4-oxadiazole-3 -carboxamide,Zra«i-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(trifluoromethyl)cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[(LS’,37?)-3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-2.2-dimethyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[(lJ?,3S)-3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-2,2-dimethyl-cyclobutyl]-JV-(4-methyl- 1, 1 -dioxo-thian-4-y 1)- 1,2,4-oxadiazole-3 -carboxamide,Cz\s-3-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1.1-dioxo-thian-4-yl)-l,2,4-oxadiazole-5-carboxamide,7raw.s-3-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-5-carboxamide,25870(7.s-2-|3-||5-Chloro-3-(2.2.2-trifluoroethoxy)-2-pyridyl|oxy|cyclobutyl|-3-methyl-A'-(4-methyl- 1.1-dioxo-thian-4-yl)imidazole-4-carboxamide and 7ra«s-2-[3-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridy 1] oxy] cy cl obuty 11 -3-methy l-7V-(4-methy 1- 1, 1 -dioxo-thian-4-yl)imidazole-4-carboxamide,Cz5-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-5-methyl-JV-(4-methyl- 1, 1 -dioxo-thian-4-yl)oxazole-4-carboxamide,Trans-2-\3-[ [5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl |oxy ]- 1-methyl-cyclobutyl ]-5-methyl-V-(4-methy 1-1,1 -di oxo-thian-4-yl)oxazole-4-carboxamide,Czs-2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-methyl-cyclobutyl]-5-methyl-JV-(4-methy 1- 1, 1 -dioxo-thian-4-y l)oxazole-4-carboxamide,Czs-2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)oxazole-4-carboxamide,7 / Y? / ?6-2-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-7V-(4-methyl-l.l-dioxo-thian-4-yl)oxazole-4-carboxamide,Czs-3-(3-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)cyclobutyl)-jV-(4-methyl-l,l-dioxidotetrahydro-2H-thiopyran-4-yl)-l,2,4-thiadiazole-5-carboxamide,Czs-5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]methyl]-7V-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Tra«s-5-[[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]methyl]-jV-(4-methyl- 1.1-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,Czs-5-[[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]methyl]-jV-(3-methyl-l,l-dioxo-thietan-3-yl)-l,2,4-oxadiazole-3-carboxamide,7ra / M-5-[[3-[[5-Chloro-3-(2.2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]methyl]-jV-(3-methyl- 1.1-dioxo-thi etan-3 -yl)-l, 2, 4-oxadiazole-3 -carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]cyclobutyl]-7V-(4-methyl-l,l -dioxo-thian-4-yl)-l,2.4-oxadiazole-3-carboxamide,5-[3-ff5-Fluoro-3-(2.2.2-trifluoroethoxy)-2-pyridyl]oxymethyl]cyclobutyl]-zV-(4-methyl-l.l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]cyclobutyl]-jV-(3-methyl-l,l -dioxo-thietan-3-yl)-l,2,4-oxadiazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]-l-bicyclo[l.l.l]pentanyl]-7V-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-oxadiazole-3-carboxamide,5-[4-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]cuban-l-yl]-JV-(4-methyl-l,l -dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,258705-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclopentyl]-JV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide,CA-5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy ]-3-methyl-cyclobutyl]-2-methyl-JV-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-triazole-3-carboxamide,7ra«s-5-[3-f[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl-JV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,Czs-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-l-methyl-cyclobutyl]-2-methyl-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,C / s-5-[3-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-2-methyl-V-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,5-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-2-methyl-N-(4-methyl- 1, 1 -dioxo-thian-4-yl)- 1,2,4-triazole-3-carboxamide,5-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxymethyl]-l-bicyclo[l.l.l]pentanyl]-2-methy l-A'-(4-methy I- 1.1 -dioxo-thian-4-yl)- 1.2.4-tnazole-3-carboxamide.T’raw.s'-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)triazole-4-carboxamide,l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian- 4-yl)pyrazole-3 -carboxamide,l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)imidazole-4-carboxamide,l-[3-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]cyclobutjl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)pyrazole-3-carboxamide,l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,Czs-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)triazole-4-carboxamide,Cz\s-2-[3-f[5-Fluoro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)triazole-4-carboxamide,Czs-2-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-5-methyl-jV-(4-methyl- 1, 1 -dioxo-thian-4-y l)triazole-4-carboxamide,7ra / 7s-2-[3-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-5-methyl-JV- (4-methy 1- 1, 1 -dioxo-thian-4-y 1 )tri azole-4-carboxamide,l-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-zV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-triazole-3-carboxamide,25870 / / / zi.s- 1 -[ 3-| 15-Chl oro-3-(2.2-di fl uoroethoxy)-2-py ri dy 11 oxy | -3-methy 1-cy cl obuty 11 - / V-(4-methyl-1, 1 -dioxo-thian-4-yl)pyrazole-3-carboxamide,Czs-2-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl-1,1 -di oxo-thian-4-yl)pyrimidine-5 -carboxamide,Czis-6-[3-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-cyclobutyl]-jV-(4-methyl- 1, 1 -dioxo-thian-4-yl)pyridine-3-carboxamide,5-[3-(2-Ethoxy-2-methyl-propoxy)cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3 -carboxamide,C / 3-5-[3-(2,2-Difluoroethoxy)-3-methyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide, or7raw.s-5-[3-(2,2-difluoroethoxy)-3-methyl-cyclobutyl]-jV-(4-methyl-l,l-dioxo-thian-4-yl)-l,2,4-oxadiazole-3-carboxamide.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is:25870258702587018. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is:F F19. A composition for treating a condition selected from 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 and heart failure comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically carrier.- Ill -2587020. A composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

21. A method for treating a condition selected from 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 and heart failure comprising administering to a patient in need thereof of a therapeutically effective amount of a compound of any of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

22. Use of a compound of any of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition selected from 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 and heart failure.

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