Preparation of imidazopyridine and imidazopyridazine derivatives as novel diacylglyceride O-acyltransferase 2 inhibitors

Abstract

Provided are compounds of Formula I that are DGAT2 inhibitors, as well as pharmaceutically acceptable salts, esters, and prodrugs thereof. Also provided are methods of making compounds of Formula I, pharmaceutical compositions containing compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure), and related diseases and conditions, comprising administering a compound of Formula I to a patient in need of such treatment. [Formula 1] TIFF2025537514000142.tif26143

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This international application claims the benefit of priority to U.S. Provisional Application No. 63 / 421,362, filed November 1, 2022, the entire contents of which are incorporated herein by reference. The present disclosure relates to novel pharmaceutical compounds that inhibit diacylglyceride O-acyltransferase 2 ("DGAT2") and may be useful in preventing, treating, or acting as reversing agents for hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure) and related diseases and conditions, as well as methods for making such compounds and pharmaceutical compositions comprising such compounds and a pharmaceutical carrier. [Background technology]

[0002] Triacylglycerols ("TGs") serve several functions in the body. One such function of TGs is in energy storage. TGs also play a role in the synthesis of membrane lipids. TG synthesis in cells can protect cells from the potentially toxic effects of excess fatty acids ("FAs"). In enterocytes and hepatocytes, TGs are synthesized for the assembly and secretion of lipoproteins that transport FAs between tissues. TGs play a role in the water barrier at the skin surface, and TGs in adipose tissue provide insulation for the body.

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

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

[0005] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 is largely understood from studies using antisense oligonucleotides (ASOs) in rodents. In this setting, knockdown of DGAT2 in ob / ob mice with DGAT2 gene-specific ASOs resulted in a dose-dependent decrease in very low-density lipoprotein (VLDL) and reduced plasma triglycerides, total cholesterol, and ApoB (Liu, et al., Biochim. Biophys Acta 2008, 1781, 97). In the same study, treatment of ob / ob mice with DGAT2 antisense oligonucleotides demonstrated a reduction in body weight gain, adipose tissue mass, and hepatic triglyceride content. Ibid. In another study, antisense treatment of ob / ob mice improved hepatic steatosis and hyperlipidemia (Yu, et al., Hepatology, 2005, 42, 362). Another study showed that knocking down DGAT2 in rats improved diet-induced hepatic steatosis and insulin resistance. These effects appear to be specific to DGAT2 inhibition, as ASOs against DGAT1 did not produce similar beneficial effects. Although the molecular mechanisms behind these observations remain unclear, collective data suggest that DGAT2 inhibition is associated with decreased expression of lipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative / thermogenic genes (CPT1, UCP2) (Choi et al., J. Bio. Chem., 2007, 282, 22678).

[0006] Inhibitors of DGAT2 are useful for treating diseases associated with metabolic syndrome, such as hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure), and related diseases and conditions.

[0007] DGAT2 inhibitor compounds are described in WO2022050749, WO2021133035, WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, WO2013150416, US20150259323, WO2015077299, WO2017011276, WO2018033832, US201801628 and W2003053363. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO2022050749 [Patent Document 2] WO2021133035 [Patent Document 3] WO2021064590 [Patent Document 4] WO2016036633 [Patent Document 5] WO2016036636 [Patent Document 6] WO2016036638 [Patent Document 7] WO2018093696 [Patent Document 8] WO2018093698 [Patent Document 9] WO2013150416 [Patent Document 10] US20150259323 [Patent Document 11] WO2015077299 [Patent Document 12] WO2017011276 [Patent Document 13] WO2018033832 [Patent Document 14] US201801628 [Patent Document 15] WO2003053363 [Non-patent literature]

[0009] [Non-Patent Document 1] Yen et al., J. Lipid Research, 2008, 49, 2283 [Non-patent document 2] Li et al., Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080 [Non-patent document 3] Liu, et al., Biochim. Biophys Acta 2008, 1781, 97 [Non-patent document 4] Yu, et al., Hepatology, 2005, 42, 362 [Non-patent document 5] Choi et al., J. Bio. Chem., 2007, 282, 22678 Summary of the Invention [Means for solving the problem]

[0010] The present disclosure provides DGAT2 inhibitors, compounds of structural formula I: [ka] and pharmaceutically acceptable salts, esters, and prodrugs thereof. Also provided are methods of making the compounds of Formula I, pharmaceutical compositions containing the compounds of Formula I, and methods of using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease and heart failure), and related diseases and conditions, wherein the method comprises administering a compound of Formula I to a patient in need of such treatment. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present disclosure provides compounds of structural formula I: [ka] [During the ceremony, X, Y and Z are N and C(R 4 ) are independently selected; R 1 teeth, (1) Unsubstituted or 1, 2, or 3 R 5 6-membered aryl substituted with (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R 5 ), which is replaced by (3) -(C 1-6 ) alkyl-aryl (wherein the aryl is unsubstituted or has 1, 2, or 3 R 5 ), which is replaced by (4) -(C 1-6 ) alkyl-heteroaryl (wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and wherein the heteroaryl is unsubstituted or contains 1, 2, or 3 R 5 ), which is replaced by (5) -(C 1-3 ) haloalkyl, or (6) 1, 2 or 3 R 5 may be substituted with -(C 1-6 ) alkyl-O-(C 1-6 ) alkyl and; R 2 teeth, (1) a 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) -(C 1-6 ) alkyl-heterocyclyl, where the heterocyclyl is a 4-, 5-, or 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (5) -(C 1-6 ) alkyl-aryl, (6) -(C 3-6 ) cycloalkyl, (7) -(C 3-6 ) cyclic amines, (8) -(C 3-6 ) cycloalkyl-(C 1-6 )Alkyl-SO2(C 1-6 ) alkyl, or (9) 8-10 membered fused bicyclic heterocyclic rings containing one or two heteroatoms independently selected from N, O, and S, wherein the bicyclic rings are optionally substituted independently with one, two, or three halogens. and wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R 6 is replaced by; R 3 teeth, (1) Hydrogen, (2) halogens, (3) Hydroxy, (4) (C 1-6 ) alkyl, (5) (C 1-6 ) haloalkyl, (6) (C 1-6 ) alkylhydroxy, (7) (C 1-6 ) alkoxyl-, (8) C(=O)NH2, (9) C(=O)OH, or (10) O-(C 1-6 ) alkyl and; If present, each R 4 is, independently, (1) Hydrogen, (2) halogens, (3) (C 1-3 ) alkyl, (4) C 1-3 haloalkyl, or (5) Cyano and; If present, each R 5 is, independently, (1) Hydrogen, (2) halogens, (3) Hydroxy, (4) CN, (5) C(O)OH, (6) (C 1-6 ) alkyl, (7) (C 1-6 ) haloalkyl, (8) (C 1-3 ) alkyl-OH, (9) -OC 1-6 Alkyl, (10) O-(C 1-6 ) haloalkyl, (11) SO2(C 1-6 ) alkyl, (12) N(C 1-6 ) alkyl, (13) (C 3-6 ) cycloalkyl, (14) O-(C 3-7 ) cycloalkyl, (15) -OC optionally substituted with halogen 1-6 alkyl-oxetanyl, or (16) OC optionally substituted with halogen 1-6 Alkyl-(C 3-7 )Cycloalkyl and; If present, each R 6 is, independently, (1) halogens, (2) oxo, (3) OH, (4) C 1-3 Alkyl, (5) C 1-3 haloalkyl, (6) C 1-3 alkyl-CN, (7) OC 1-3 Alkyl, or (8) C(O)C 1-3 Haloalkyl is] or a pharmaceutically acceptable salt thereof.

[0012] In a second embodiment of the present disclosure, the compound of formula I or a pharmaceutically acceptable salt thereof is represented by formula Ib: [ka] [During the ceremony, R 1 teeth, (1) Unsubstituted or 1, 2, or 3 R 5 6-membered aryl substituted with (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R 5 ), which is replaced by (3) -(C 1-6 ) alkyl-aryl (wherein the aryl is unsubstituted or has 1, 2, or 3 R 5 ), which is replaced by (4) -(C 1-6 ) alkyl-heteroaryl (wherein the heteroaryl is a 5- or 6-membered heteroaryl containing one nitrogen atom, where the heteroaryl is unsubstituted or has one, two, or three R 5 ), which is replaced by (5) -(C 1-3 ) haloalkyl, or (6) 1, 2 or 3 R 5 may be substituted with -(C 1-6 ) alkyl-O-(C 1-6 ) alkyl and; R 2 teeth, (1) a 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; (4) -(C 1-6 ) alkyl-heterocyclyl, wherein the heterocyclyl is a 4-, 5-, or 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from S; (5) -(C 1-6 ) alkyl-aryl, (6) -(C 3-6 ) cycloalkyl, (7) -(C 3-6 ) cyclic amines, (8) -(C 3-6 ) cycloalkyl-(C 1-6 )Alkyl-SO2(C 1-6 ) alkyl, or (9) A 10-membered fused bicyclic heterocyclic ring containing one heteroatom independently selected from N, O, and S, wherein the bicyclic ring is optionally substituted independently with one, two, or three halogens. and; wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R 6 is replaced by; R 3 teeth, (1) Hydrogen, (2) halogens, (3) Hydroxy, (4) (C 1-6 ) alkyl, (6) (C 1-6 ) haloalkyl, (7) (C 1-6 ) alkylhydroxy, (8) (C 1-6 ) alkoxyl-, (9) C(=O)NH2, (10) C(=O)OH, or (11) O-(C 1-6 ) alkyl and; If present, each R 4 is, independently, (1) Hydrogen, (2) halogens, (3) (C 1-3 ) alkyl, (4) C 1-3 haloalkyl, or (5) Cyano and; If present, each R 5 is, independently, (1) Hydrogen, (2) halogens, (3) Hydroxy, (4) CN, (5) C(O)OH, (6) (C 1-6 ) alkyl, (7) (C 1-6 ) haloalkyl, (8) (C 1-3 ) alkyl-OH, (9) -OC 1-6 Alkyl, (10) O-(C 1-6 ) haloalkyl, (11) SO2(C 1-6 ) alkyl, (12) N(C 1-6 ) alkyl, (13) (C 3-6 ) cycloalkyl, (14) O-(C 3-7 ) cycloalkyl, (15) -OC optionally substituted with halogen 1-6 alkyl-oxetanyl, or (16) OC optionally substituted with halogen 1-6 Alkyl-(C 3-7 )Cycloalkyl and; If present, each R 6 is, independently, (1) halogens, (2) oxo, (3) OH, (4) C 1-3 Alkyl, (5) C 1-3 haloalkyl, (6) C 1-3 alkyl-CN, (7) OC 1-3 Alkyl, or (8) C(O)C 1-3 Haloalkyl is] or a pharmaceutically acceptable salt thereof.

[0013] Embodiment 3 of the present disclosure is a compound of Formula I or Formula Ib, or Embodiments 1-2, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, (1) Unsubstituted or 1, 2, or 3 R 5 6-membered aryl substituted with (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R 5 ), which is replaced by (3) —CH-aryl, where the aryl is unsubstituted or has 1, 2, or 3 R 5 ), which is replaced by (4) —CH2-heteroaryl (wherein the heteroaryl is a 5- or 6-membered heteroaryl containing one nitrogen atom, where the heteroaryl is unsubstituted or has one, two, or three R 5 ), which is replaced by (5) -(C 1-3 ) haloalkyl, or (6) 1, 2 or 3 R 5 may be substituted with -(C 1-6 ) alkyl-O-(C 1-6 ) alkyl is.

[0014] Embodiment 4 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, (1) Unsubstituted or -OC 1-6 Alkyl or O-(C 1-6 ) a 6-membered aryl substituted with haloalkyl; (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, hydroxy, —O(C 1-6 ) alkyl, (C 1-6 ) alkyl, (C 1-6 ) haloalkyl, O-(C 1-6 ) haloalkyl, (C 1-3 ) alkyl-OH, SO2(C 1-6 ) alkyl, N(C 1-6 ) alkyl, (C 3-6 ) cycloalkyl, O-(C 3-7 ) cycloalkyl, CN, C(O)OH, OC optionally substituted with halogen 1-6 Alkyl-(C 3-7 ) -OC optionally substituted with cycloalkyl and halogen 1-6 substituted with 1, 2, or 3 substituents independently selected from alkyl-oxetanyl; (3) -CH2-aryl (wherein the aryl is selected from the group consisting of halogen, -OC 1-3 Alkyl or -OC 1-3 substituted with 1 or 2 substituents independently selected from haloalkyl; (4) -CH2-heteroaryl (wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, where the heteroaryl is unsubstituted or substituted with halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl and -OC 1-3 haloalkyl), (5) -(C 1-3 ) haloalkyl, or (6) -(C 1-6 ) alkyl-O-(C 1-6 ) alkyl is.

[0015] Embodiment 5 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-4, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, (1) 6-membered aryl, unsubstituted or substituted with OCH2CH3 or OCH2CF3; (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from Cl, F, OH, CN, CH3, CF3, CH2CH3, CH(CH3)2, C(CH3)2OH, C(CH3)2F, CF3, C(F)2CH2CH3, C(O)OH, OCH2CH3, OCH2CF3, OCH2CHF2, OCH2C(F)2CH3, OCH2C(F)2CH(F)2, S(O)2CH3, cyclopropyl, OCH2-cyclopropyl, OCH2-fluorocyclopropyl, O-cyclobutyl, OCH2-oxetanyl-F, and N(CH3)2; (3) -CH-aryl, wherein the aryl is substituted with one or two substituents independently selected from F, OCHCH, and OCHF; (4) -CH-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with one, two, or three substituents selected from OCHCHF, F, Cl, OCHCF, CH, CF, and OCHCH; (5) CH2CH2CF3, or (6) CH2(CH3)2CH2OCH2CH3 is.

[0016] Embodiment 6 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-5 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is unsubstituted or -OC 1-6 Alkyl or O-(C 1-6 ) 6-membered aryl substituted with haloalkyl.

[0017] Embodiment 7 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-6 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered aryl that is unsubstituted or substituted with OCH2CH3 or OCH2CF3.

[0018] Embodiment 8 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, hydroxy, -O(C 1-6 ) alkyl, (C 1-6 ) alkyl, (C 1-6 ) haloalkyl, O-(C 1-6 ) haloalkyl, (C 1-3 ) alkyl-OH, SO2(C 1-6 ) alkyl, N(C 1-6 ) alkyl, (C 3-6 ) cycloalkyl, O-(C 3-7 ) cycloalkyl, optionally substituted with halogen 1-6 Alkyl-(C 3-7 ) cycloalkyl, CN, C(O)OH and -OC optionally substituted with halogen 1-6 It is substituted with 1, 2, or 3 substituents independently selected from alkyl-oxetanyl.

[0019] Embodiment 9 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5 or 8, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from Cl, F, OH, CN, CH, CHCH, CH(CH), C(CH)OH, C(CH)F, CF, C(F)CHCH, C(O)OH, OCHCH, OCHCF, OCHCHF, OCHC(F)CH, OCHC(F)CH(F), S(O)CH, cyclopropyl, OCH-cyclopropyl, OCH-fluorocyclopropyl, O-cyclobutyl, OCH-oxetanyl-F, and N(CH).

[0020] Embodiment 10 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -CH2-aryl (wherein the aryl is selected from the group consisting of halogen, -OC 1-3 Alkyl or -OC 1-3 substituted with 1 or 2 substituents independently selected from haloalkyl.

[0021] Embodiment 11 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5 or 10, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -CH2-aryl, where the aryl is a 6-membered aryl substituted with 1 or 2 substituents independently selected from F, OCH2CH3, and OCHF2.

[0022] Embodiment 12 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1is -CH2-heteroaryl, where the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, where the heteroaryl is unsubstituted or substituted with halogen, C 1-3 Alkyl, -OC 1-3 Alkyl and -OC 1-3 haloalkyl).

[0023] Embodiment 13 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 12, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -CH2-heteroaryl, where the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, where the heteroaryl is unsubstituted or substituted with halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl and -OC 1-3 haloalkyl).

[0024] Embodiment 14 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 12-13, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -CH2-heteroaryl, wherein the heteroaryl is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2 or 3 substituents selected from OCH2CHF2, F, Cl, OCH2CF3, CH3, CF3 and OCH2CH3.

[0025] Embodiment 15 of the present disclosure is a compound of Formula I or Formula Ib, or any of embodiments 1-5 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is CH2CH2CF3.

[0026] Embodiment 16 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-6 ) alkyl-O-(C 1-6 ) alkyl.

[0027] Embodiment 17 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 16, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is CH2(CH3)2CH2OCH2CH3.

[0028] Embodiment 18 of the present disclosure is a compound of Formula I or Formula Ib, or any of Embodiments 1-5, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0029] Embodiment 19 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-18 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) a 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 one or two nitrogen atoms; (4) -CH2-heterocyclyl (wherein the heterocyclyl is a 4-, 5-, or 6-membered heterocyclyl containing 1, 2, or 3 sulfur atoms); (5) —CH2-aryl (wherein the aryl is a 6-membered aryl); (6) -(C 3-6 ) cycloalkyl, (7) -(C 3-6 ) cyclic amine, (8) -(C 3-6 ) cycloalkyl-CH3-SO2CH3, or (9) A 10-membered fused bicyclic heterocyclic ring containing one oxygen atom, wherein the bicyclic ring is optionally substituted independently with one, two, or three halogens. and; wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R 6 is replaced by .

[0030] Embodiment 20 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-19 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) Halogen, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl-CN and C(O)C 1-3 a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1, 2, or 3 substituents independently selected from haloalkyl; (2) phenyl, (3) C 1-3 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, optionally substituted by alkyl; (4) -CH2-heterocyclyl (wherein the heterocyclyl is oxo and C 1-3 a 4- or 6-membered heterocyclyl containing 1, 2, or 3 sulfur atoms, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl; (5) —CH2-aryl (wherein the aryl is a 6-membered aryl); (6) Halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, OC 1-3 -(C3-6 ) cycloalkyl, (7) -(C 3-6 ) cyclic amines, (8) -(C4)cycloalkyl-CH3-SO2CH3, or (9) chroman optionally substituted with 1, 2 or 3 halogens; wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R 6 is replaced by .

[0031] Embodiment 21 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-20, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, (1) a 4- to 7-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from halogen, oxo, CH, CHCF, CH(CH), CHCH, CHCN, C(O)CF, and (CH); (2) phenyl, (3) 5- or 6-membered heteroaryl containing one or two nitrogen atoms, optionally substituted with CH3; (4) -CH2-heterocyclyl (wherein the heterocyclyl is a 4- or 6-membered heterocyclyl containing one sulfur atom, optionally substituted with 1, 2, or 3 substituents independently selected from oxo and CH3); (5) —CH2-aryl (wherein the aryl is a 6-membered aryl); (6) -(C 3-6 ) cycloalkyl, (7) -(C 3-6 ) cyclic amines, (8) -(C4)cycloalkyl-CH3-SO2CH3, or (9) chromans independently substituted with halogens; is.

[0032] Embodiment 22 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is halogen, oxo, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl-CN and C(O)C 1-3 and a 4-7 membered heterocyclyl containing one heteroatom selected from sulfur, nitrogen, and oxygen, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkyl.

[0033] Embodiment 23 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-22 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-7 membered heterocyclyl containing one heteroatom selected from sulfur, nitrogen and oxygen, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from halogen, oxo, CH, CHCF, CH(CH), CHCH, CHCN, C(O)CF and (CH).

[0034] Embodiment 24 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-23 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-7 membered heterocyclyl containing one sulfur atom optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from oxo, CH, CHCF, CH(CH), CHCH, CHCN and (CH).

[0035] Embodiment 25 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-23 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocyclyl containing one nitrogen atom optionally substituted with 1, 2, or 3 substituents independently selected from CH3, CH2CN, and C(O)CF3.

[0036] Embodiment 26 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-23 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4-7 membered heterocyclyl containing one oxygen atom optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from CH3, (CH3)2 and CH2CF3.

[0037] Embodiment 27 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is phenyl.

[0038] Embodiment 28 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms optionally substituted with CH3.

[0039] Embodiment 29 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -CH2-heterocyclyl (wherein the heterocyclyl is oxo and C 1-3 and a 4-6 membered heterocyclyl containing one sulfur atom optionally substituted with 1, 2 or 3 substituents independently selected from alkyl.

[0040] Embodiment 30 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-21, 29, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -CH2-heterocyclyl, wherein the heterocyclyl is a 4-6 membered heterocyclyl containing one sulfur atom optionally substituted with 1, 2 or 3 substituents independently selected from oxo and CH3.

[0041] Embodiment 31 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is CH2-6 membered aryl.

[0042] Embodiment 32 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, OC 1-3 -(C 3-6 ) cycloalkyl.

[0043] Embodiment 33 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-21, 32, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is optionally substituted with 1, 2, or 3 substituents independently selected from halogen, oxo, CH, CHCF, CH(CH), CHCH, CHCN, C(O)CF, and (CH). 3-6 ) cycloalkyl.

[0044] Embodiment 34 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is substituted with oxo -(C3-6 ) cyclic amine.

[0045] Embodiment 35 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -(C4)cycloalkyl-CH3-SO2CH3.

[0046] Embodiment 36 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, [ka] is.

[0047] Embodiment 37 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-21 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, [ka] is.

[0048] Embodiment 38 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-37 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, halogen, C 1-6 Alkyl, OH, C(O)OH, C(O)NH2, OC 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 It is alkyl-OH.

[0049] Embodiment 39 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-38 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, halogen, C 1-3Alkyl, OH, C(O)OH, C(O)NH2, OC 1-3 Alkyl, C 1-3 Haloalkyl or C 1-3 It is alkyl-OH.

[0050] Embodiment 40 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-39 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, Cl, F, CH3, CH(CH3)2, CH2CH3, OH, C(O)OH, C(O)NH2, OCH3, CF3 or CH2OH.

[0051] Embodiment 41 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-40 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen or CH3.

[0052] Embodiment 42 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-41 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen.

[0053] Embodiment 43 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-41 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is CH3.

[0054] Embodiment 44 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-43 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 is hydrogen, halogen, C 1-3 Alkyl, C 1-3 Independently selected from haloalkyl and CN.

[0055] Embodiment 45 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-44 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 are independently selected from hydrogen, CH3, F, Cl, CH(CH3)2, CF3, CH2CH3, and CN.

[0056] Embodiment 46 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-43 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 are independently selected from hydrogen, halogen, and CH3.

[0057] Embodiment 47 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-44 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 are independently selected from hydrogen, Cl, F and CH3.

[0058] Embodiment 48 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-47 or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 are independently selected from hydrogen and CH3.

[0059] Embodiment 49 of the present disclosure is a compound of Formula I or Formula Ib or embodiments 1-47 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 4 are independently selected from hydrogen, F and Cl.

[0060] Embodiment 50 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, 19-49, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 5 is hydrogen, halogen, hydroxy, CN, C(O)OH, (C 1-6 ) alkyl, (C 1-6) haloalkyl, (C 1-3 ) Alkyl-OH, -OC 1-6 Alkyl, O-(C 1-6 ) haloalkyl, SO2(C 1-6 ) alkyl, N(C 1-6 ) alkyl, (C 3-6 ) cycloalkyl, O-(C 3-7 ) cycloalkyl, optionally substituted with halogen -OC 1-6 Alkyl-oxetanyl and OC optionally substituted with halogen 1-6 Alkyl-(C 3-7 ) cycloalkyl.

[0061] Embodiment 51 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-3, 19-50, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 5 are hydrogen, Cl, F, OH, CN, CH3, CF3, CH2CH3, CH(CH3)2, C(CH3)2OH, C(CH3)2F, CF3, C(F)2CH2CH3, C(O)OH, OCH2CH3, OCHF2, OCH2CF3, OCH2CHF2, OCH2C(F)2CH3, OCH2C(F)2CH(F)2, S(O)2CH3, cyclopropyl, OCH2-cyclopropyl, OCH2-fluorocyclopropyl, O-cyclobutyl, OCH2-oxetanyl-F and N(CH3)2.

[0062] Embodiment 52 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-20, 38-51, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 6 is halogen, oxo, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl-CN, OC 1-3 Alkyl and C(O)C 1-3 haloalkyl.

[0063] Embodiment 53 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-20, 38-52, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein, if present, each R 6 are independently selected from halogen, oxo, CH3, CF3, OH, CH2CF3, CH(CH3)2, CH2CH3, OCH3, CH2CN, C(O)CF3, and (CH3)2.

[0064] Embodiment 54 of the present disclosure is a compound of Formula I or embodiments 1, 3-53 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ) and Y is C(R 4 ) and Z is C(R 4 )

[0065] Embodiment 55 of the present disclosure is a compound of Formula I or embodiments 1, 3-53 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N and Y is C(R 4 ) and Z is C(R 4 )

[0066] Embodiment 56 of the present disclosure is a compound of Formula I or embodiments 1, 3-53 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ), Y is N, and Z is C(R 4 )

[0067] Embodiment 57 of the present disclosure is a compound of Formula I or embodiments 1, 3-53 or classes thereof or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ) and Y is C(R 4 ) and Z is N.

[0068] Embodiment 58 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 8-9, 19-57, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0069] Embodiment 59 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 11-5, 8-9, 19-57, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0070] Embodiment 60 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 8-9, 19-57, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0071] Embodiment 61 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 8-9, 19-57, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0072] Embodiment 62 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-5, 8-9, 19-57, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 teeth, [ka] is.

[0073] Embodiment 63 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-24, 36-62, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, [ka] is.

[0074] Embodiment 64 of the present disclosure is a compound of Formula I or Formula Ib, or embodiments 1-24, 36-62, or classes thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 teeth, [ka] is.

[0075] In embodiment 65, the present disclosure provides a method for manufacturing a semiconductor device, comprising: [ka] The compound is selected from

[0076] In embodiment 66, the present disclosure provides a method for manufacturing a semiconductor device comprising: [ka] or a pharmaceutically acceptable salt thereof.

[0077] Embodiment 67 is [ka] or a pharmaceutically acceptable salt thereof.

[0078] Embodiment 68 is [ka] or a pharmaceutically acceptable salt thereof.

[0079] Embodiment 69 is [ka] or a pharmaceutically acceptable salt thereof.

[0080] Embodiment 70 is [ka] or a pharmaceutically acceptable salt thereof.

[0081] Embodiment 71 is [ka] or a pharmaceutically acceptable salt thereof.

[0082] Embodiment 72 is [ka] or a pharmaceutically acceptable salt thereof.

[0083] Embodiment 73 is [ka] or a pharmaceutically acceptable salt thereof.

[0084] Embodiment 74 is [ka] or a pharmaceutically acceptable salt thereof.

[0085] In embodiment 75, the compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, is 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(2,2,4-trimethyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4,4-difluoro-1-methyl-cyclohexyl)-6-[(3-ethoxy-2-pyridyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 8-Fluoro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]-7-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 7-chloro-6-[5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide; 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide; N-(3,3-difluoro-1-methyl-cyclobutyl)-6-[(3-ethoxy-2-pyridyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide; 8-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-7-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 5-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(1R,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(2,2,6,6-tetramethyltetrahydropyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 5-Fluoro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-5,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(3-fluorooxetan-3-yl)methoxy]-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(3-methyl-1,1-dioxo-thietan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 8-Fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-phenyl-imidazo[1,2-a]pyridine-2-carboxamide; 2,2,2-trifluoroacetate; 6-[3-(2,2-difluoroethoxy)pyrazin-2-yl]oxy-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-((3-(2,2-difluoropropoxy)-5-fluoropyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-Isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(4-methyl-1,1-dioxo-thian-4-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide; N-(6,8-difluorochroman-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; N-benzyl-6-[(3-ethoxy-2-pyridyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(3-pyridyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(6-methylpyridazin-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(1,1-difluoropropyl)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-hydroxy-2-pyridyl)oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-isopropyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-ethyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3-ethyl-1,1-dioxo-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-isopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-[4-(cyanomethyl)-1,1-dioxo-thian-4-yl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; N-(4-ethyl-1,1-dioxo-thian-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[5-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(2,2-dimethyl-1,1-dioxo-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-[3-methoxy-3-(trifluoromethyl)cyclobutyl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-[3-methyl-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(4,4-difluoro-1-methyl-cyclohexyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[3-methyl-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-isopropyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(2,2-dimethyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-ethoxy-5-(trifluoromethyl)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-6-[5-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-[3-(trifluoromethyl)cyclobutyl]imidazo[1,2-a]pyridine-2-carboxamide; N-[3-(cyanomethyl)-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]-6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[4-methyl-1-(2,2,2-trifluoroacetyl)-4-piperidyl]imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-6-[3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,3,3-tetrafluoropropoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(2,2-dimethyl-1,1-dioxo-thian-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; N-(4-ethyl-1,1-dioxo-thian-4-yl)-3-methyl-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[4-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[6-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[4-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[(3-methyl-1,1-dioxo-thietan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[6-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[3-(2,2,2-trifluoroethyl)tetrahydropyran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-[(3S)-6-oxo-3-piperidyl]-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-3-ethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-Ethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-Isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 8-Fluoro-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-fluoro-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-fluoro-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-Fluoro-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]methoxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(2-ethoxyphenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(4-fluorophenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[2-(difluoromethoxy)phenyl]methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-2-carboxamide; 6-(3-ethoxy-2,2-dimethyl-propoxy)-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-chloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-Hydroxy-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 2-((4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)carbamoyl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid; N2-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2,3-dicarboxamide; 3-Methoxy-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methoxy-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide;2,2,2-trifluoroacetate; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; 3-(hydroxymethyl)-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-7-cyano-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-chloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-cyclopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-(1-hydroxy-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-(1-fluoro-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-hydroxy-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-cyano-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-Methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[5-methylsulfonyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[3-methyl-2-[(4-methyl-1,1-dioxo-thian-4-yl)carbamoyl]imidazo[1,2-a]pyridin-6-yl]oxy-5-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid; 6-[5-(dimethylamino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(cyclopropylmethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(cyclobutoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-[1-(methylsulfonylmethyl)cyclobutyl]imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-7-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)-6-((3-(2,2-difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-8-methylimidazo[1,2-b]pyridazine-2-carboxamide; 3,7-Dichloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-chloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3,7-Dichloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide; 3-chloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide; 3,7-Dichloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[2-(difluoromethoxy)-6-fluoro-phenyl]methoxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]methoxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((1,4-dimethyl-1H-pyrazol-3-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; (S)-6-(2-ethoxyphenoxy)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrazine-2-carboxamide; or 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide; is.

[0086] In embodiment 76, the compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, is [ka] TIFF2025537514000026.tif200145TIFF2025537514000027.tif204149TIFF2025537514000028.tif207149TIFF2025537514000029.tif202146TIFF2025537514000030.tif125146

[0087] The present disclosure includes pharmaceutically acceptable salts of the compounds defined herein.

[0088] In one embodiment, the disclosure is a composition comprising an effective amount of at least one compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0089] The present disclosure further provides pharmaceutical compositions comprising an effective amount of at least one compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0090] The present disclosure also provides pharmaceutical compositions comprising an effective amount of at least one compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (e.g., a chemotherapeutic agent).

[0091] The present disclosure also provides pharmaceutical compositions comprising an effective amount of at least one compound of Formula I or Formula Ib or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (e.g., a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

[0092] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, or cardiorenal disease (e.g., chronic kidney disease or heart failure), comprising an acceptable carrier and a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0093] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, or cardiorenal disease (e.g., chronic kidney disease or heart failure), comprising a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0094] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, or cardiorenal disease (e.g., chronic kidney disease or heart failure), comprising a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0095] In one embodiment, the present disclosure provides a method of treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease or heart failure) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0096] In one embodiment, the present disclosure provides a method of treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease (e.g., chronic kidney disease or heart failure) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0097] The methods of the disclosure include administering a pharmaceutical composition comprising at least one compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0098] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0099] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0100] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a composition comprising a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof.

[0101] In another embodiment, the present disclosure encompasses a method of treating NASH and / or fibrosis, comprising administering to a patient in need of such treatment a composition comprising a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0102] In another embodiment, the present disclosure provides the use of a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating NASH and / or fibrosis.

[0103] In another embodiment, the present disclosure encompasses the use of a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of NASH and / or fibrosis.

[0104] "Alkyl," when specified, refers to both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. If no number is specified, 1 to 6 carbon atoms is intended for straight-chain alkyl groups, and 3 to 7 carbon atoms for branched-chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, and tert-butyl, pentyl, hexyl, octyl, nonyl, and the like. For example, the term "C 1-6 "Alkyl" means a group having a C 1-4 "C" includes all "alkyl" groups as well as straight or branched alkyl groups having 5 or 6 carbon atoms (including all possible isomers). 1-6 "Alkyl" means a straight or branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, including all possible isomers, and 1-6 Within the scope of alkyl are included each of the alkyl groups, including each of the hexyl and pentyl isomers, as well as n-, iso-, sec-, and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively "C4 alkyl"; Bu = butyl), n- and i-propyl (propyl, i-propyl, collectively "C3 alkyl"; Pr = propyl), ethyl (Et) and methyl (Me). Commonly used abbreviations for alkyl groups are used throughout the specification, for example, methyl is represented by conventional abbreviations including "Me" or CH3, or by a symbol that is an extended bond as a terminal group, for example: [ka] where ethyl can be represented by "Et" or CH2CH3, propyl can be represented by "Pr" or CH2CH2CH3, and butyl can be represented by "Bu" or CH2CH2CH2CH3. For example, the structure [ka] have equivalent meanings. If no number is specified, 1 to 6 carbon atoms is intended for straight or branched chain alkyl groups.

[0105] "Alkoxy" refers to an alkyl group attached to an oxygen. Examples of alkoxy groups include methoxy, ethoxy, and propoxy.

[0106] "Aryl" refers to a monocyclic or polycyclic aromatic ring moiety containing 6 to 14 ring carbon atoms. In one embodiment, an aryl group contains about 6 to 10 ring carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl. Polycyclic rings include, but are not limited to, naphthyl and bicyclic rings (e.g., 8-10 membered fused bicyclic heterocyclic rings). Aryl groups may be substituted with one or more substituents as defined herein. Attachment may be via any carbon atom of either ring.

[0107] "Halogen" or "halo" includes fluorine, chlorine, bromine and iodine.

[0108] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic ring system containing about 3 to 10 ring carbon atoms. If no number of atoms is specified, 3 to 10 carbon atoms are intended. Cycloalkyls can also be fused to form 1 to 3 carbocyclic rings. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C 1-6 The term "cycloalkyl" refers to a cycloalkyl group having 1 to 6 ring carbon atoms. 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 ring carbon atoms. Thus, for example, "C 3-6 "Cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups are unsubstituted or substituted with one or more ring system substituents, which may be the same or different, as defined herein. When cycloalkyl is a substituent on an alkyl group, the cycloalkyl substituent may be attached to any available carbon within the alkyl group. The following describes -C on an alkyl group: 3-6 An example of a cycloalkyl substituent where the substituent is a bold cyclopropyl: [ka] "Haloalkyl" refers to an alkyl group, as defined herein, in which one or more of the alkyl group's hydrogen atoms has been replaced with a halogen. In one embodiment, a haloalkyl group has 1 to 6 carbon atoms. Non-limiting examples of haloalkyl groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CH2CH3, CF2CHF2, -C(CH3)2F, CH2Cl, and CCl3. The term "C 1-6 Haloalkyl" or "HaloC 1-6 "Alkyl" refers to a haloalkyl group having 1 to 6 carbons.

[0109] "Haloalkoxy", "haloalkyl-O" and derived forms (e.g., "halo(C 1-6 ")alkoxy" are used interchangeably and refer to a halo-substituted alkyl group attached through an oxygen atom. Haloalkoxy includes mono- and multiply halo-substituted alkoxy groups. For example, OCH2CF3, OCH2CHF2, OCF2CF3, OCH2CF2CH3, OCH2CF2CHF2, OCHF2, and OCF2CHF2, as well as trifluoromethoxy, chloromethoxy, and bromomethoxy are included.

[0110] "Heterocyclyl," "heterocycle," or "heterocyclic" refers to a monocyclic ring system in which one or more atoms in the ring (heteroatoms) are elements other than carbon. The heteroatom is typically an O atom, a S atom, or a N atom. Heterocycles containing multiple heteroatoms may contain different heteroatoms. Bicyclic ring moieties include fused bicyclic rings, spirocyclic bicyclic rings, and bridged bicyclic rings, and any of the rings may contain one or more heteroatoms. The ring bonded to the rest of the molecule may or may not contain heteroatoms. Either ring of a bicyclic heterocycle can be saturated, partially unsaturated, or unsaturated. The heterocycle can be bonded to the rest of the molecule through a ring carbon atom, a ring oxygen atom, or a ring nitrogen atom. Examples of heterocyclyl groups include piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, oxiranyl, or aziridinyl.

[0111] "Bicyclic heterocyclyl," "bicyclic heterocycle," or "bicyclic heterocyclic" refers to a heterocyclic ring fused to another ring system, which fusion may be bridged or unbridged.

[0112] Unless otherwise specified, the term "heteroaryl," as used herein, refers to a stable monocyclic, bicyclic, or tricyclic ring having up to 10 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of O, N, and S. Heteroaryl groups within this definition include, but are not limited to, the following: benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthopyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazolyl. phenyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline.

[0113] "Oxo" means an oxygen attached to an atom by a double bond. Examples of oxo groups are the double-bonded oxygen in a ketone, sulfoxide, sulfone, sulfate, or the double-bonded oxygen fused to a non-aromatic cycloalkyl or heteroalkyl.

[0114] "Hydroxyalkyl" or "hydroxy(C 1-3 ")alkyl-" means an alkyl group in which one or more hydrogen atoms have been replaced with a hydroxyl (-OH) group. Examples of hydroxyalkyl are CH2OH, C(CH3)2OH, CH2CH2OH, or CH(OH)CH3.

[0115] "Cyanoalkyl" means an alkyl group in which one or more hydrogen atoms is replaced with a cyano (-CN) group.

[0116] The term "composition" is intended to encompass a product containing the specified ingredients in the specified amounts, as well as any product resulting directly or indirectly from combining the specified ingredients in the specified amounts.

[0117] The term "at least one" means one or more. The meaning of "at least one" with respect to the number of compounds of the present disclosure is independent of its meaning with respect to the number of chemotherapeutic agents.

[0118] The term "chemotherapeutic agent" refers to a drug (medicine or pharmaceutically active ingredient) for treating cancer (i.e., an anti-tumor drug).

[0119] The term "effective amount" means a "therapeutically effective amount." The term "therapeutically effective amount" means that amount of an active compound or drug that elicits the biological or pharmacological response in a tissue, system, animal, or human that is desired by a researcher, veterinarian, medical doctor, or other clinician.

[0120] The terms "treating cancer" or "treatment of cancer" refer to administration to a mammal suffering from a cancerous condition and refer to an effect that alleviates the cancerous condition by killing cancerous cells, as well as an effect that results in the inhibition of cancer growth and / or metastasis.

[0121] Except as otherwise stated herein, the term "carbocycle" (and variations thereof, e.g., "carbocyclic" or "carbocyclyl") as used herein, unless otherwise indicated, refers to a C3-C6 monocyclic ring, e.g., C 3-6 Monocyclic carbocyclic rings are shown. The carbocyclic ring can be attached to the rest of the molecule at any carbon atom that results in a stable compound. Saturated carbocyclic rings include, for example, "cycloalkyl" rings, e.g., cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings include, for example, [ka] is included.

[0122] A "stable" compound is one that can be prepared and isolated, and whose structure and properties remain essentially unchanged or can remain essentially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).

[0123] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I or Formula Ib and embodiments thereof. For example, a particular moiety defined in Formula I or Formula Ib may be unsubstituted or substituted, where the latter is intended to encompass any substitution pattern (i.e., number and type of substituents) that is chemically possible for that moiety and results in a stable compound.

[0124] The term "substituted" means that one or more hydrogens on the specified atom have been replaced with the indicated group, provided that the replacement does not exceed the normal valence of the specified atom in its existing environment and that the substitution results in a stable compound. When multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted single or multiple times with one or more of the disclosed or claimed substituent moieties. Independently substituted means that the (two or more) substituents can be the same or different. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. When a substituent is itself substituted with multiple groups, it is understood that these multiple groups can be on the same carbon or on different carbons, so long as a stable structure results. "Optionally substituted" refers to compounds containing the specified optional substituents and compounds that do not contain such optional substituents.

[0125] Wavy line [ka] As used herein, indicates the point of attachment to the remainder of the compound. For example, [ka] When a ring atom is represented by a variable moiety such as "X", e.g. [ka] The variables are defined by showing the atom located at the variable position on the ring without showing the ring bond associated with that atom. For example, if X in the ring above is nitrogen, the definition would show "N" and no bond associated with it, e.g., no "=N-" is shown. Similarly, if X is a carbon atom substituted with bromide, the definition would show "C-Br" and no bond associated with it, e.g., [ka] is not displayed.

[0126] The present disclosure also encompasses derivatives of compounds of Formula I or Formula Ib that act as prodrugs and solvates. Pharmaceutically acceptable prodrug modifications of compounds of Formula I or Formula Ib that are converted in vivo to compounds within the scope of Formula I or Formula Ib are also within the scope of the present disclosure. After administration to a patient, prodrugs are converted to compounds of Formula I or Formula Ib in the body by normal metabolic or chemical processes (e.g., hydrolysis in the blood). Such prodrugs include those that exhibit enhanced bioavailability, tissue specificity, and / or cellular delivery to improve drug absorption of compounds of Formula I. The effect of such prodrugs can be achieved by altering physicochemical properties (e.g., lipophilicity, molecular weight, charge, and other physicochemical properties that determine the permeation characteristics of a drug).

[0127] For example, esters can be prepared by esterification of an available carboxylic acid group, or by forming an ester on an available hydroxy group in the compound, as the case may be. Similarly, easily convertible amides can be made. Pharmaceutically acceptable esters or amides of compounds of Formula I or Formula Ib can be prepared to act as prodrugs, particularly those that can be hydrolyzed in vivo to the acid form (or -COO- form, depending on the pH of the body fluid or tissue where the conversion occurs) or the hydroxy form, and as such are included within the scope of the present invention. Included are esters and acyl groups known in the art for modifying solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 -C substituted with alkyl esters and phenyl esters 1-6 Alkyl, etc.

[0128] "Celite®" (Fluka) diatomaceous earth is diatomaceous earth, also called "celite."

[0129] Any variable part (e.g., R 1 When a group (e.g., R ) occurs more than one time in any constituent or in Formula I or Formula Ib or other general formulae herein, its definition at each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. In selecting compounds of Formula I or Formula Ib, one of ordinary skill in the art will appreciate the various substituents (i.e., R ). 1 It will be recognized that the substituents (e.g., aryl, heteroaryl, or saturated heterocyclic rings) should be selected based on well-known principles of connectivity and stability of the chemical structure. Unless expressly stated to the contrary, substitution by a named substituent is permissible on any atom within the ring (e.g., an aryl ring, heteroaryl ring, or saturated heterocyclic ring) provided that such ring substitution is chemically permissible and results in a stable compound.

[0130] It should be noted that if there is a discrepancy between a chemical name and a structure, the structure is understood to control.

[0131] Compounds of Formula I or Formula Ib can contain one or more asymmetric centers and thus can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereoisomers. Any asymmetric centers present in a compound of Formula I or Formula Ib can, independently of one another, have either the S or R configuration. When a bond to a chiral carbon is depicted as a straight line in a structural formula herein, it is understood that both the (R) and (S) configurations of that chiral carbon, and thus both enantiomers and mixtures thereof, are encompassed by the formula. Similarly, when a compound name is given without explicitly stating that a chiral carbon is chiral, it is understood that both the (R) and (S) configurations of that chiral carbon, and thus individual enantiomers and mixtures thereof, are encompassed by the name. The preparation of a particular stereoisomer or mixture thereof can be confirmed in the examples in which such stereoisomer or mixture is obtained, but this is in no way intended to limit the scope of the present disclosure to include all stereoisomers and mixtures thereof.

[0132] The compounds of the present disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers in all ratios (e.g., mixtures of enantiomers and / or diastereomers). Thus, enantiomers in enantiomerically pure form (as both levorotatory and dextrorotatory enantiomers), in the form of racemates, and in the form of mixtures of two enantiomers in all ratios are subject of the present invention. The present disclosure is intended to encompass all such stereoisomeric forms of the compounds of structural formula I or structural formula Ib.

[0133] The compounds of formula I or formula Ib can be separated into their individual diastereoisomers, for example, by fractional crystallization from a suitable solvent (e.g., MeOH or EtOAc, or mixtures thereof) or by chiral chromatography using an optically active stationary phase. In some cases, derivatization can be carried out prior to the separation of stereoisomers. Separation of a mixture of stereoisomers can be carried out at the intermediate stage during the synthesis of a compound of formula I or formula Ib, or can be carried out on the final racemic product. Absolute stereochemistry can be confirmed by X-ray crystallography of a crystalline product or a crystalline intermediate, which is 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 or formula Ib can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. The present disclosure of Formula I and Formula Ib includes all such isomers, as well as salts, solvates (which includes hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

[0134] If necessary, the racemic mixture of the compound can be separated so that the individual enantiomers are isolated. This separation can be carried out by methods well known in the art, for example, by coupling the racemic mixture of the compound with an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereoisomers by standard methods such as fractional crystallization or chromatography. The coupling reaction is often the formation of a salt with an enantiomerically pure acid or base. The diastereomeric derivative can then be converted to a pure enantiomer by cleavage of the added chiral residue. The racemic mixture of the compound can also be directly separated by chromatographic methods utilizing chiral stationary phases, and such methods are well known in the art.

[0135] For compounds of Formula I or Formula Ib described herein that contain olefinic double bonds, unless otherwise specified, they are intended to include both E and Z geometric isomers.

[0136] Some of the compounds described herein can exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. The individual tautomers and mixtures thereof are encompassed by the compounds of Formula I or Formula Ib.

[0137] In compounds of structural formula I or structural formula Ib, the atoms may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The invention described and claimed herein is intended to encompass all appropriate isotopic variations of compounds of structural formula I or structural formula Ib and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protium (H) and deuterium (H, also referred to herein as D). Protium is the predominant hydrogen isotope found in nature. Enrichment with deuterium may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced dose requirements) or provide a compound useful as a standard for characterizing biological samples. Isotopically enriched compounds within the scope of formula I or formula Ib 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.

[0138] It will be understood that the compounds of formula I or formula Ib can be prepared as pharmaceutically acceptable salts, or as pharmaceutically unacceptable salts when used as free compounds or precursors to their pharmaceutically acceptable salts or in other synthetic procedures. The compounds of the present invention, including the compounds of the Examples, can also include all salts of compounds of formula I or formula Ib that are not directly suitable for use in medicine due to poor physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for preparing physiologically acceptable salts.

[0139] The compounds of Formula I or Formula Ib can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic or organic bases and inorganic or inorganic acids.

[0140] Salts of basic compounds encompassed by the term "pharmaceutically acceptable salts" are non-toxic salts of compounds of Formula I or Formula Ib, generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of Formula I or Formula Ib include, but are not limited to, acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, and hydroxyl. Sinaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucoate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, acetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, valerate, and the like. Furthermore, when a compound of Formula I or Formula Ib contains an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases such as aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like.In one embodiment, the salts of acidic compounds are as follows: ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts.

[0141] The compounds of formula I or formula Ib form stable alkali metal salts, alkaline earth metal salts or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides and ammonia, organic bases or basic amino acids.

[0142] Salts derived from pharmaceutically acceptable non-toxic organic bases include salts of primary, secondary, and tertiary amines, salts of cyclic amines, dicyclohexylamine, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Furthermore, basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates, e.g., dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides, e.g., decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides, e.g., benzyl and phenethyl bromides, and the like.

[0143] Preparation of pharmacologically acceptable salts from salt-forming compounds of formula I or formula Ib (including stereoisomers thereof) can be carried out by known methods, for example, by mixing an equivalent amount of the compound of formula I or formula Ib with a solution containing the desired acid or base, and then recovering the desired salt by filtering the salt or by distilling off the solvent. Compounds of formula I and formula Ib and their salts can form solvates with solvents such as water, ethanol, or glycerol. Compounds of formula I or formula Ib can simultaneously form acid addition salts and base salts depending on the type of substituents on the side chain.

[0144] When a compound of formula I or formula Ib contains simultaneously an acidic and a basic group in the molecule, the present disclosure encompasses, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). Salts can be obtained from compounds of formula I or formula Ib by conventional methods known to those skilled in the art, for example, by combination with organic or inorganic acids or bases in solvents or dispersants, or by anion or cation exchange from other salts.

[0145] Compounds of formula I or formula Ib, as well as salts thereof (particularly pharmaceutically acceptable salts), solvates of the compounds and solvated salt forms thereof, are disclosed herein, and unless otherwise indicated, such forms are possible.

[0146] Furthermore, the compounds of Formula I and Formula Ib can exist in amorphous form and / or one or more crystalline forms, and therefore, all amorphous and crystalline forms of the compounds of Formula I or Formula Ib, including the Examples, and mixtures thereof, are intended to be encompassed within the scope of this disclosure. Additionally, some of the compounds of this disclosure can form solvates (i.e., hydrates) with water or common organic solvents (e.g., but not limited to, EtOAc). Such solvates and hydrates (particularly pharmaceutically acceptable solvates and hydrates) of the compounds of the present invention, along with unsolvated and anhydrous forms, are also encompassed within the scope of this disclosure.

[0147] Thus, compounds encompassed by the general structural formulae, specific compounds described in the embodiments and examples, and specific compounds claimed herein include their salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvates and hydrates, and any combination of these forms, as well as their salts, prodrug forms, and salts of their prodrug forms, where such forms are possible unless otherwise indicated.

[0148] Furthermore, there is also provided a medicament containing at least one compound of formula I or formula Ib and / or a pharmaceutically acceptable salt of a compound of formula I or formula Ib and / or optionally a stereoisomeric form of a compound of formula I or formula Ib or a pharmaceutically acceptable salt of a stereoisomeric form of a compound of formula I or formula Ib or a pharmaceutically acceptable solvate of a compound of formula I or formula Ib or a pharmaceutically acceptable salt of a pharmaceutically acceptable solvate of a compound of formula I or formula Ib or a prodrug of a compound of formula I or formula Ib or a pharmaceutically acceptable salt or solvate of a prodrug of a compound of formula I or formula Ib or a polymorphic form of a compound of formula I or formula Ib or a pharmaceutically acceptable salt, solvate or prodrug of a polymorphic form of a compound of formula I or formula Ib, together with a pharmaceutically acceptable vehicle, carrier, excipient and / or other active substances and adjuvants.

[0149] The agents described herein can be administered orally, by inhalation, rectally, or transdermally, or by subcutaneous, intraarticular, intraperitoneal, or intravenous injection. Oral administration is preferred.

[0150] Also provided is a method for producing a medicament, which method comprises forming at least one compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt, solvate, prodrug or polymorphic form thereof, into a suitable dosage form using a pharmaceutically acceptable carrier and optionally further suitable active substances, additives or auxiliaries.

[0151] Also provided are methods for preparing compounds of Formula I or Formula Ib, which are described below and by which compounds of Formula I and Formula Ib or pharmaceutically acceptable salts, solvates, prodrugs or polymorphic forms thereof can be obtained.

[0152] The term "therapeutically effective (or effective) amount" and similar descriptions, such as "therapeutically effective amount," are intended to mean an amount of a pharmaceutical agent that alleviates the symptoms of the disorder, condition, or disease being treated in an animal or human (i.e., a disorder, condition, or disease associated with DGAT2 activity). The term "prophylactically effective (or effective) amount" and similar descriptions, such as "prophylactically effective amount," are intended to mean an amount of a pharmaceutical agent that prevents or reduces the symptoms or onset of the disorder, condition, or disease being treated in an animal or human (i.e., a disorder, condition, or disease associated with DGAT2 activity). Dosage regimens utilizing a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt, solvate, prodrug, or polymorphic form thereof, are selected according to various factors, such as the type, species, age, weight, sex, and medical condition of the patient; the severity of the condition being treated; the potency of the selected compound being administered; the route of administration; and the patient's renal and hepatic function. Consideration of these factors is well within the purview of an ordinarily skilled clinician for purposes of determining the therapeutically or prophylactically effective dose necessary to prevent, counter, or arrest the progression of the condition. It is understood that a particular daily dosage may simultaneously be both a therapeutically effective amount (e.g., a therapeutically effective amount for treating hepatic steatosis, diabetes, obesity, hyperlipidemia, hypercholesterolemia) and a prophylactically effective amount (e.g., a prophylactically effective amount for treating NASH).

[0153] Disorders, conditions, and diseases that can be treated or prevented by inhibiting DAGT2 with a compound of Formula I or Formula Ib include, for example, nonalcoholic steatohepatitis (NASH), liver fibrosis, hyperlipidemia, type I diabetes, type II diabetes, cognitive decline, dementia, coronary heart disease, ischemic stroke, restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial dyslipidemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic nephropathy, glomerular filtration rate, and the like. Diseases that may be treated include, but are not limited to, sclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue disorders, hyperapo B lipoproteinemia, non-alcoholic fatty liver disease, and cardio-renal diseases (e.g., chronic kidney disease and heart failure), as well as related diseases and conditions.

[0154] The compounds of Formula I or Formula Ib and their pharmaceutically acceptable salts, solvates, prodrugs, and polymorphic forms can be administered alone, in admixture with each other, or in the form of pharmaceutical preparations to animals, preferably mammals, particularly humans, as pharmaceuticals. The compounds of Formula I or Formula Ib and their pharmaceutically acceptable salts, solvates, prodrugs, and polymorphic forms can be administered alone, in admixture with each other, or in the form of pharmaceutical preparations to animals, including dogs and cats, as pharmaceuticals. The term "patient" includes animals, preferably mammals, particularly humans, that use the active agents of the present invention for the prevention or treatment of a medical condition. Administration of a drug to a patient includes both self-administration and administration to the patient by another person. The patient may need or desire treatment for an existing disease or medical condition, or may need or desire prophylactic treatment to prevent or reduce the risk of developing the disease or medical condition. As used herein, a patient "in need" of therapeutic or prophylactic treatment for an existing condition encompasses both a determination of need by a medical professional and the patient's desire for such treatment.

[0155] Further provided herein are pharmaceutical preparations (or pharmaceutical compositions) comprising, as an active ingredient, a therapeutically effective dose of at least one compound of Formula I or Formula Ib and / or a pharmaceutically acceptable salt, solvate, prodrug, or polymorphic form thereof, and a conventional pharmaceutically acceptable carrier (i.e., one or more pharmaceutically acceptable carrier substances) and / or excipients.

[0156] Thus, one aspect of the present disclosure is, for example, the compounds and pharmaceutically acceptable salts thereof for use as medicaments, pharmaceutical formulations comprising a therapeutically effective dose of the compounds and / or pharmaceutically acceptable salts thereof as active ingredients and a conventional pharmaceutically acceptable carrier, as well as the use of the compounds and / or pharmaceutically acceptable salts thereof in the treatment or prevention of the syndromes described above, and their use for preparing medicaments for these purposes.

[0157] The medicaments described herein can be administered orally, for example, in the form of pills, tablets, lacquered tablets, dragees, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be parenterally, for example, subcutaneously, intramuscularly or intravenously, in the form of solutions for injection or infusion. Other suitable administration forms are, for example, transdermal or topical administration, for example, in the form of ointments, tinctures, sprays or transdermal therapeutic systems, or inhalation administration in the form of nasal sprays or aerosol mixtures, or, for example, microcapsules, implants or rods. The preferred administration form depends, for example, on the disease to be treated and its severity.

[0158] For the preparation of pills, tablets, dragees, and hard gelatin capsules, lactose, starch (e.g., corn starch) or starch derivatives, talc, stearic acid, or its salts, can be used. Carriers for soft gelatin capsules and suppositories include, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carriers for preparing solutions (e.g., injectable solutions), emulsions, or syrups include, for example, water, saline, alcohols (e.g., ethanol, glycerin, polyols), sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. Furthermore, the compounds of Formula I or Formula Ib and their pharmaceutically acceptable salts, solvates, solvates, and prodrugs can be lyophilized, and the resulting lyophilizates can be used, for example, to prepare preparations for injection or infusion. Suitable carriers for microcapsules, implants, or rods include, for example, glycolic acid and lactic acid copolymers.

[0159] Suitable solid or galenical formulation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, infusions or injection solutions, and formulations with sustained release of active substances, for the preparation of which customary excipients are used, such as vehicles, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavorings, sweeteners, solubilizers, etc. Commonly used auxiliaries that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol, and solvents, such as sterilized water and mono- or polyhydric alcohols (e.g., glycerol).

[0160] In addition to the active compound and carrier, the pharmaceutical formulations may also contain conventional additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, fragrances, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for changing osmotic pressure, coating agents or antioxidants.

[0161] The dosage of the active compound of formula I or formula Ib and / or its pharmaceutically acceptable salts, solvates, prodrugs or polymorphic forms to be administered will depend on each individual case and should, as a rule, be adapted to the individual circumstances to achieve the optimum effect. It will therefore depend on the nature and severity of the disorder, condition or disease to be treated, as well as the sex, age, weight and individual response of the human or animal being treated, the potency and duration of action of the compound used, whether the therapy is acute or chronic or prophylactic, or whether other active compounds are administered in addition to the compound of formula I or formula Ib.

[0162] Combination drugs The compounds of Formula I and Formula Ib, their salts, solvates, prodrugs, and polymorphic forms, 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. Thus, in some embodiments, one or more compounds of Formula I or Formula Ib are co-administered with other agents described herein. When used in combination therapy, the compounds described herein are administered simultaneously with the second agent or separately. This combined administration can include simultaneous administration of the two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound of Formula I or Formula Ib and any of the agents described above can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of Formula I or Formula Ib and any of the agents described above can be administered simultaneously, where both agents are present in separate formulations. In another alternative, the compound of Formula I or Formula Ib can be administered immediately followed by any of the agents described above, or vice versa. In some embodiments of the separate administration protocol, the compound of Formula I or Formula Ib and any of the agents described above are administered minutes apart, hours apart, or days apart.

[0163] The present disclosure contemplates the treatment of diseases / conditions with a combination of pharmaceutically active compounds that can be administered separately. The present disclosure further relates to combining separate pharmaceutical compositions in the form of a kit. The kit includes two separate pharmaceutical compositions, i.e., a compound of Formula I or Formula Ib and a second pharmaceutical compound. The kit includes a container for housing the separate compositions, such as a divided bottle or a divided foil packet. Further examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for use of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral, parenteral; IV, transdermal, and subcutaneous), administered at different dosage intervals, or when titration of the individual components of the combination by the prescribing medical professional is desired.

[0164] One or more additional pharmacologically active agents can be administered in combination with a compound of Formula I or Formula Ib. An additional active agent is intended to mean a pharmaceutically active agent (different from the compound of Formula I or Formula Ib, and including the free acid, free base, and pharmaceutically acceptable salts of the additional active agent) that is active in the body, including prodrugs that are converted into a pharmaceutically active form after administration. Generally, any suitable additional active agent (including, but not limited to, antihypertensive agents, antiobesity agents, anti-inflammatory agents, antifibrotic agents, and antiatherosclerotic agents, such as lipid-modifying compounds, antidiabetic agents, and / or antiobesity agents) can be used in any combination with a compound of Formula I or Formula Ib in a single formulation (fixed-dose drug combination), or can be administered to a patient in one or more separate formulations that allow for simultaneous or sequential administration of the active agents (co-administration of separate active agents).

[0165] Examples of additional active agents that may be used include, but are not limited to, angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, cipirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., in combination with losartan, i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan, and hydrochlorothiazide, such as HYZAAR®), any of these drugs that can be used in combination with other drugs; neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., di- and tri-peptide urea derivatives, amino acids and derivatives, amino acid chains linked by non-peptide bonds, di- and tri-peptide derivatives, peptidyl aminodiols and peptidyl beta-aminoacyl aminodiol carbamates); and, further, small molecule renin inhibitors such as diol sulfonamides, N-morpholino derivatives, N-heterocyclic alcohols and pyrrolimidazolones;Furthermore, pepstatin derivatives and fluoro- and chloro-derivatives of statin-containing peptides, enalkrein, remikiren, A 65317, terlakiren, ES 1005, ES 8891, SQ 34017, aliskiren, SPP600, SPP630 and SPP635, endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalfil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, gallopamil, niludipine, nimodipine, nicardipine), potassium channel activators (e.g., nicola diuretics (e.g., hydrochlorothiazide), sympatholytics, beta-adrenergic blocking agents (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartrate), alpha-adrenergic blocking agents (e.g., doxazosin, prazosin, or alpha-methyldopa), central alpha-adrenergic blocking agents phospholipid agonists, peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, such as HMG-CoA reductase inhibitors, e.g., simvastatin and lovastatin (which are marketed in lactone prodrug form as ZOCOR® and MEVACOR® and function as inhibitors after administration), and pharmaceutically acceptable salts of dihydroxy open-acid HMG-CoA reductase inhibitors, such as atorvastatin (particularly the calcium salt sold as LIPITOR®), rosuvastatin (particularly the calcium salt sold as CRESTOR®), pravastatin (particularly the sodium salt sold as PRAVACHOL®), fluvastatin (particularly the sodium salt sold as LESCOL®), cerivastatin, and pravastatin;Cholesterol absorption inhibitors, for example, ezetimibe (ZETIA®), and ezetimibe in combination with any other lipid-lowering agent, such as the HMG-CoA reductase inhibitors described above, in particular ezetimibe in combination with simvastatin (VYTORIN®) or atorvastatin calcium; niacin in immediate-release or controlled-release form and / or niacin with an HMG-CoA reductase inhibitor; niacin receptor agonists, for example, acipimox and acifran, and niacin receptor partial agonists; anticholesterol drugs, for example, PCSK9 inhibitors (alirocumab, evolocumab), Nexletol; TM(bempedoic acid, an ACL inhibitor), Vascepa® (icosapent ethyl); metabolic altering agents), such as insulin and insulin mimetics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, such as (i) β-klotho / FGFR1 activating monoclonal antibodies (e.g., MK-3655), pan FGFR1-4 / KLB modulators, FGF19 analogs (e.g., aldafermin), (ii) PPARγ agonists, such as glitazones (e.g., pioglitazone, AMG131, mitoglitazone, lobeglitazone, rosiglitazone, and balaglitazone), and other PPAR ligands, such as (i) PPARα / γ dual agonists (e.g., ZYH2, ZYH1, GFT505, Tiglitazar, muraglitazar, aleglitazar, soderglitazar, and naveglitazar; (2) PPARα agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, and bezafibrate); (3) selective PPARγ modulators (SPPARγMs), (e.g., WO02 / 060388, WO02 / 08188, (4) PPARγ partial agonists; (5) PPARα / δ dual agonists (e.g., elafibranor); (iii) biguanides, such as metformin and its pharmaceutically acceptable salts, particularly metformin hydrochloride, and sustained release formulations thereof, such as Glumetza. TM , Fortamet TM and GlucophageXR TMand (iv) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, insulin degludec, insulin glargine, insulin lispro, and inhaled formulations of each); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipidamide, amide, glimepiride, mitiglinide, meglitinides, nateglinide, and repaglinide; α-glucosidase inhibitors (e.g., acarbose, voglibose, and miglitol); glucagon receptor antagonists (e.g., MK-3577, MK-0893, LY-2409021, and KT6-971); incretin mimetics, e.g., GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC -1131 and BIM-51077, e.g., their nasal, transdermal and once-weekly formulations); bile acid sequestrants (e.g., colestilan, colestimide, colesevalam hydrochloride, colestipol, cholestyramine and dialkylaminoalkyl derivatives of cross-linked dextran), acyl-CoA:cholesterol acyltransferase inhibitors (e.g., avasimibe); anti-obesity compounds; drugs intended for use in inflammatory conditions, e.g., aspirin, nonsteroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and Selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (e.g., those disclosed in U.S. Pat. No. 6,730,690 and LY-2523199); CETP inhibitors (e.g., anacetrapib, torcetrapib, and evacetrapib); inhibitors of fructose 1,6-bisphosphatase (e.g., U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748;Nos. 6,399,782 and 6,489,476; inhibitors of acetyl-CoA carboxylase-1 or -2 (ACC1 or ACC2); AMP-activated protein kinase (AMPK) activators; other agonists of G protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., those disclosed in WO2009 / 001836); neuromedin U receptor agonists (e.g., those disclosed in WO2009 / 042053, e.g., These include, but are not limited to, neuromedin S (NMS); SCD modulators (e.g., aramchol); GPR-105 antagonists (e.g., those disclosed in WO2009 / 000087); glucose pathway modulators, such as SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2, e.g., empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, BI-10773, remogliflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); dual SGLT-1 / 2 inhibitors (e.g., licogliflozin), glucose-6-P dehydrogenase inhibitors (e.g., fluasterone). LAPS glucagon combo (e.g., HM14320), SGLT-1 inhibitors (e.g., SGL5213); inhibitors of acyl-coenzyme A carboxylase (ACC, MK-4074); inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid synthase; inhibitors of acyl-coenzyme A:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2) inhibitors; agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; IL-1b antibodies (e.g., XOMA052 and canakinumab); anti-fibrotic and / or anti-inflammatory drugs (CCR2 / CCR5 dual receptor antagonists (e.g., cenicriviroc));Galectin 3 inhibitors (e.g., belapectin, GB-1107, GB-1211), siRNA against HSP47 (e.g., BMS-986263); NSAIDs derived from pirfenidone (e.g., hydronidone), A3AR agonists (e.g., namodenoson, FM101); TGFTX4 (e.g., nitazoxanide); 5-lipoxygenase inhibitors (e.g., tipelukast), bifunctional urate inhibitors (e.g., ACQT1127), adiponectin receptor agonists (e.g., ALY688), TNF receptor antagonists (e.g., atrocimab), autotaxin inhibitors (e.g., BLD-0409) , TJC0265, TJC0316), CCL24 blocking monoclonal antibodies (e.g., CM101), IL-11 inhibitors (e.g., ENx108A), LPA1 receptor antagonists (e.g., EPGN696), dual JAK1 / 2 inhibitors (e.g., EX76545), GPR antagonists (e.g., GPR91 antagonists), integrin avb1, avb3 and avb6 inhibitors (e.g., IDL2965), NLRP3 antagonists (e.g., IFM-514), inflammasome inhibitors (e.g., JT194, JT349), cell membrane permeability inhibitors (e.g., larazotide), CCR5 antagonists (e.g., Leron; limab), TNF inhibitors (e.g., LIVNate), integrin avβ6 inhibitors (e.g., MORFbeta6), NLRP inflammasome antagonists, siRNA (e.g., OLX701), dual TFGβ / hedgehog inhibitors (e.g., Oxy200), GPR40 agonists / GPR84 antagonists (e.g., PBI-4547), neutrophil elastase inhibitors (e.g., PHP-303), integrin inhibitors (e.g., PLN-1474), TGFβ1 modulators (e.g., PRM-151), CCK receptor antagonists (e.g., proglumide), LOX L2 inhibitors (e.g., PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitors (e.g., cGAS / STING antagonists), kinase inhibitors, RNase, membrane protein mAbs, tumor necrosis factor inhibitors, NRF2 activators (e.g., SCO116), SSAO inhibitors (e.g., TERN201), TRAIL2 agonists (e.g., TLY012), IL-6 receptor antagonists (e.g., TZLS501), AOC3 inhibitors (e.g., UD-014), SSAO / VAP-1 inhibitors, TREM2; antioxidants (e.g., vitamin E) Anti-inflammatory drugs (e.g., norfloxacin, ciprofloxacin, ceftriaxone); coagulation modulating drugs (e.g., anticoagulants, antiplatelet drugs, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonists (e.g., tirzepeptide); dual GLP-1 / GRA (e.g., cotadutide, ALT-801, DD01, G49, PB-718); dual GLP-1 (e.g., CT868); GLP-1 / GRA / GIP triple agonists (e.g., HM15211); GRP120 stimulators / inflammasome modulators / PPARγ dual agonists (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonists (e.g., Ozempic (subcutaneous semaglutide), XW003); selective thyroid hormone receptor beta agonists (e.g., resmetirom); apoptosis modulators (JNK-1 inhibitors (e.g., CC-90001), peroxidase inhibitors (e.g., AZM198), ASK-1 inhibitors (e.g., CS-17919, SRT015)); erythropoietin stimulators (erythropoietin receptor agonists (e.g., sibinetide)); immunomodulators (TLR4 inhibitors (e.g.,GBK-233), immunomodulatory polyclonal antibodies (e.g., IMM-124E), TLR4 antagonists (e.g., JKB-122), CD3 monoclonal antibodies (e.g., foralarumab), TLR4 antagonists (e.g., JKB133), TLR4 inhibitors (e.g., mocedipimod), macrophage inhibitors by CD206 targeting (e.g., MT2002), TLR2 / 4 antagonists (e.g., VB-201, VB-703), immunomodulatory polyclonal antibodies (e.g., IMM-124E); incretin-based therapies (GLP-1 agonists (e.g., ozen Pic (semaglutide sc), XW003), GLP-1 / glucagon dual receptor agonists (e.g., HM12525A), prandial insulin (e.g., ORMD0801); lipid modulators (AMPK activators / glutathione transferase inhibitors (e.g., oltipraz), THR-β agonists (e.g., resmetirom, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN501), IBAT inhibitors (e.g., elobixibat, CJ1419), omega-6 fatty acids (e.g., epereuton (e peleuton), FASN inhibitors (e.g., TVB2640, FT4101, FT8225), ANGPTL3 inhibitors (e.g., bupanorsen), PNPLA3 inhibitors (e.g., AZD2693), RAS domain kinase inhibitors (e.g., BioE1115), NTCP inhibitors (e.g., brevirtide), P2Y13 receptor agonists (e.g., CER-209), omega-3 fatty acids, HSD17β13 inhibitors, metabolic regulators (FXR agonists (e.g., Ocaliva (obeticholic acid), IOT022), recombinant variants of FGF19 (e.g., Aldafermi), ), bispecific FGFR1 / KLB antibodies (e.g., BFKB8488A), mTOT modulators (e.g., MSDC-0602K), pegylated analogs of FGF21 (e.g., pegbelfermin, BMS-986171), non-biliary FXR agonists (e.g., cilofexor, EDP-305, EYP001, tropifexor, MET409, AGN-242256, AGN-242266, EDP297, HPG1860, MET642, RDX023, TERN101), ACC inhibitors (e.g., filsocostat, PF-05221304),Ketohexokinase inhibitors (e.g., PF-06835919), AMPK activators (e.g., PXL770, MSTM101, O304), bile acid modulators (e.g., Albiero), FGF21 analogs (e.g., BIO89-100), MOTSc analogs (e.g., CB4211), cyclophilin inhibitors (e.g., CRV431), FGF19 (e.g., DEL30), mitochondrial uncouplers (e.g., GEN3026), FXR / GPCR dual agonists (e.g., INT-767), cysteamine derivatives (e.g., KB-GE- 001), dual amylin and calcitonin receptor agonists (e.g., KBP-089), transient FXR agonists (e.g., M1217), anti-β-klotho (KLB)-FGFR1c receptor complex mAb (e.g., MK3655), GDF15 mimetics (e.g., NGM395), cyclophilin inhibitors (e.g., NV556), LXR modulators (e.g., PX329, PX655, PX788), LXR inverse agonists (e.g., PX016), deuterated obeticholic acid (e.g., ZG5216); PPAR modulators (dual PPAR α / γ agonists (e.g., elafibranor), PPARpan agonists (e.g., lanifibranor), PPARα agonists (e.g., Palmodia), PPARγ agonists (e.g., CHS131), MPC inhibitors (e.g., PXL065), PPARδ / γ agonists (e.g., T3D959); RAASmIM modulators (mineralocorticoid receptor antagonists (e.g., aparenone, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulators, including CB1 receptor antagonists (e.g., CRB-4001, IM-102, nimasimab), TPH1 inhibitors (e.g., CU02), GPR120 agonists (e.g., KBR2001), and combinations of cannabinoids and botanical anti-inflammatory compounds (e.g., SCN002); PDE modulators (PDE4 inhibitors (e.g., ART648)); CYP2E1 inhibitors (e.g., SNP-610); cell therapy (e.g., HepaStem), and bromocriptine mesylate and its rapid-release formulations; or nitroprusside and diazoxide.Combination with other drugs useful in the prevention or treatment of the above diseases (where chemically possible, the free acid, free base and pharmaceutically acceptable salt forms of the above active drugs).

[0166] The present invention includes pharmaceutically acceptable salts of the compounds defined herein, including pharmaceutically acceptable salts of all structural formulas, embodiments, and classes defined herein. Reference to a compound of structural formula I or structural formula Ib includes compounds of other general structural formulas, such as formulas and embodiments falling within the scope of formula I or formula Ib.

[0167] Dosage of Compounds of Formula I or Formula Ib After completion of a treatment cycle, if the patient is responding or stable, the treatment cycle can be repeated according to the judgment of a skilled clinician. After completion of a treatment cycle, the patient can continue on the compound of the present invention at the same dose administered in the treatment protocol. This maintenance dose can be continued until the patient progresses or is no longer able to tolerate the dose (in which case the dose can be reduced and the patient can continue on the reduced dose).

[0168] Those skilled in the art will recognize that the actual dosages and administration protocols used in the methods disclosed herein may be varied according to the judgment of a skilled clinician. The actual dosage used may vary depending on the needs of the patient and the severity of the condition being treated. Determination of the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. The decision to vary the dosage and administration protocol may be made by a skilled clinician after considering factors such as the age, condition, and size of the patient, as well as the severity of the condition being treated and the patient's response to treatment.

[0169] Dosage regimens utilizing the compounds of Formula I and Formula Ib or pharmaceutically acceptable salts, solvates, prodrugs, or polymorphic forms thereof are selected according to a variety of factors, including the type, species, age, weight, sex, and condition of the patient; the severity of the condition being treated; the potency of the compound selected for administration; the route of administration; and the patient's renal and hepatic function. Consideration of these factors is within the skill of the clinician in determining the therapeutically or prophylactically effective dose necessary to prevent, inhibit, or inhibit the progression of the condition. It is understood that a particular daily dosage may simultaneously be both a therapeutically effective amount (e.g., a therapeutically effective amount for treating an oncological condition) and a prophylactically effective amount (e.g., a prophylactically effective amount for preventing an oncological condition).

[0170] While individual needs vary, determination of optimal ranges of effective amounts of the compounds of Formula I or Formula Ib, or pharmaceutically acceptable salts, solvates, prodrugs or polymorphic forms thereof, is within the skill of one of ordinary skill in the art. For example, when administered to humans in the therapeutic or prophylactic treatment of the conditions and disorders identified herein, a typical dosage of a compound of Formula I or Formula Ib will be from about 0.05 mg / kg / day to about 50 mg / kg / day, e.g., at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, and preferably not more than 50 mg / kg, not more than 40 mg / kg, not more than 30 mg / kg, not more than 20 mg / kg, or not more than 10 mg / kg, which can be, for example, from about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dosage of the compound may be about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.05 mg / kg / day to about 10 mg / kg / day, about 0.05 mg / kg / day to about 5 mg / kg / day, about 0.05 mg / kg / day to about 3 mg / kg / day, about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / kg / day, or about 0.05 mg / kg / day to about 0.1 mg / kg / day. g / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. Such doses can be administered in a single dose or can be divided into multiple doses.

[0171] Pharmaceutical Composition The compounds of Formula I or Formula Ib, or pharmaceutically acceptable salts, solvates, prodrugs, or polymorphic forms thereof, can be administered to animals, preferably mammals, and particularly humans, as pharmaceuticals on their own, mixed with each other, or in the form of pharmaceutical compositions. The term "subject" or "patient" includes animals, preferably mammals, and particularly humans, who use the active agents to prevent or treat a medical condition.

[0172] Administration of a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt, solvate, prodrug, or polymorphic form thereof, to a subject includes both self-administration and administration to the patient by another person. The subject may be in need of 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 developing said disease or medical condition. As used herein, a subject "in need" of treatment for an existing condition or prophylactic treatment includes both identification of the need by a medical professional and the patient's desire for such treatment.

[0173] If the patient is responding or stable after completion of a treatment cycle, the treatment cycle can be repeated according to the judgment of a skilled clinician. After completion of a treatment cycle, the patient can continue receiving the compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt, solvate, prodrug, or polymorphic form thereof, at the same dose as administered in the treatment protocol. This maintenance dose can be continued until the patient progresses or is no longer able to tolerate the dose (in which case the dose can be reduced and the patient can continue on the reduced dose).

[0174] Those skilled in the art will recognize that the actual dosages and administration protocols used in the methods described herein may vary according to the judgment of a skilled clinician. The actual dosage used may vary depending on the needs of the patient and the severity of the condition being treated. Determination of the appropriate dosage for a particular situation is within the skill of one of ordinary skill in the art. The decision to vary the dosage and administration protocol may be made by a skilled clinician after considering factors such as the age, condition, and size of the patient, as well as the severity of the condition being treated and the patient's response to treatment.

[0175] The dosage and frequency of administration of the compound of Formula I or Formula Ib and the additional agent will be regulated according to the judgment of the attending clinician (physician), taking into account factors such as the age, condition, and size of the patient, and the severity of the condition being treated.

[0176] The compounds of Formula I or Formula Ib and pharmaceutically acceptable salts, solvates, prodrugs or polymorphic forms thereof are further useful in the preparation of medicaments useful in the treatment of NASH and fibrosis.

[0177] The compounds of the present invention are also useful in combination with therapeutic, chemotherapeutic, and anti-cancer agents for treating hepatocellular carcinoma. Combinations of the compounds of the present disclosure with therapeutic, chemotherapeutic, and anti-cancer agents are within the scope of the present disclosure. Examples of such agents are described in "Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 9 thedition (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: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death-ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other anti-angiogenesis agents, HIV protease inhibitors, reverse transcriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, gamma-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), and agents that interfere with cell cycle checkpoints.

[0178] The chemotherapeutic agent can be administered according to treatment protocols well known in the art. It will be apparent to those skilled in the art that the administration of the chemotherapeutic agent can be varied depending on the cancer being treated and the known effects of the chemotherapeutic agent on that disease. Furthermore, according to the knowledge of a skilled clinician, the treatment protocol (e.g., dosage and frequency of administration) can be modified taking into account the observed effects of the administered therapeutic agent on the patient and the observed response of the cancer to the administered therapeutic agent. The particular choice of chemotherapeutic agent depends on the diagnosis of the attending physician and their judgment of the patient's condition and the appropriate treatment protocol.

[0179] Initial administration can be according to established protocols known in the art, after which the dose, mode of administration and frequency of administration can be modified by a skilled clinician based on the observed effects.

[0180] The determination of the sequence of administration of chemotherapeutic agents and the number of repetitions of administration during a treatment protocol is within the knowledge of a skilled physician after evaluation of the condition being treated and the condition of the patient.

[0181] Thus, according to experience and knowledge, the practitioner may modify each protocol for administration of chemotherapy agents according to the needs of the individual patient as treatment progresses, and all such modifications are within the scope of this disclosure.

[0182] The agents can be administered according to treatment protocols well known in the art. It will be apparent to those skilled in the art that the administration of the anti-cancer agent can vary depending on the cancer being treated and the known effects of the anti-cancer agent on that disease.

[0183] Initial administration can be according to established protocols known in the art, after which the dose, mode of administration and frequency of administration can be modified by a skilled clinician based on the observed effects.

[0184] The particular choice of medication will depend on the attending physician's diagnosis and their judgment of the patient's condition and the appropriate treatment protocol.

[0185] The determination of the order of administration of agents and the number of repetitions of administration during a treatment protocol is within the knowledge of a skilled physician after evaluation of the cancer being treated and the condition of the patient.

[0186] In determining whether treatment is effective at a given dosage, the attending physician will consider not only the patient's general health, but also more specific signs such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual shrinkage of the tumor, or inhibition of metastasis. Tumor size can be measured by standard methods, such as radiological tests (e.g., CAT or MRI scans), and serial measurements can be used to determine whether tumor growth is slowing or reversing. Relief of disease-related symptoms (e.g., pain) and improvement in overall condition can also help determine the effectiveness of treatment.

[0187] The compounds, compositions, and methods provided herein are useful for treating cancer. Cancers that may be treated by the compounds, compositions, and methods disclosed herein include, but are not limited to, the following: Liver: liver cancer (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

[0188] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL inhibitors include atezolizumab, avelumab, and durvalumab.

[0189] Also provided is a method of treating hepatocellular carcinoma in a human patient, comprising administering to the patient a compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt, solvate, prodrug, or polymorphic form thereof, and a PD-1 antagonist. The compound of Formula I or Formula Ib and the PD-1 antagonist can be administered simultaneously or sequentially.

[0190] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody or antigen-binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody or antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA TM , Merck & Co., Inc., Rahway, NJ, USA), nivolumab (OPDIVO TM , Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO TM , Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab (TECENTRIQ TM , Genentech, San Francisco, CA, USA), durvalumab (IMFINZI TM, AstraZeneca Pharmaceuticals LP, Wilmington, DE) or avelumab (BAVENCIO TM , Merck KGaA, Darmstadt, Germany).

[0191] In some embodiments, the PD-1 antagonist is pembrolizumab. In certain subembodiments, the method comprises administering 200 mg of pembrolizumab to the patient about every three weeks. In other subembodiments, the method comprises administering 400 mg of pembrolizumab to the patient about every six weeks.

[0192] In a further subembodiment, the method comprises administering 2 mg / kg of pembrolizumab to the patient about every 3 weeks. In a particular subembodiment, the patient is a pediatric patient.

[0193] In some embodiments, the PD-1 antagonist is nivolumab. In certain subembodiments, the method comprises administering 240 mg of nivolumab to the patient about every two weeks. In other subembodiments, the method comprises administering 480 mg of nivolumab to the patient about every four weeks.

[0194] In some embodiments, the PD-1 antagonist is cemiplimab. In certain embodiments, the method comprises administering 350 mg of cemiplimab to the patient about every 3 weeks.

[0195] In some embodiments, the PD-1 antagonist is atezolizumab. In certain subembodiments, the method comprises administering 1200 mg of atezolizumab to the patient about every 3 weeks.

[0196] 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.

[0197] In some embodiments, the PD-1 antagonist is avelumab. In certain subembodiments, the method comprises administering 800 mg of avelumab to the patient about every two weeks.

[0198] The compounds of Formula I or Formula Ib, or pharmaceutically acceptable salts thereof, may also be useful in treating cancer in combination with the following therapeutic agents: Pembrolizumab (Keytruda®), abarelix (Plenaxisdepot®); aldesleukin (Prokine®); aldesleukin (Proleukin®); alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene Gel (Targretin®); Bleomycin (Blenoxane®); Bortezomib (Velcade®); Busulfan intravenous (Busulfex®); Busulfan oral (Myleran®); Calsterone (Methosarb®); Capecitabine (Xeloda®); Carboplatin (Paraplatin®); Carmustine (BCNU®, BiCNU®); Carmustine (Gliadel®); Carmustine and polifeprosan 20 Implants (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®); dacarbazine (DTIC-Dome®);Dactinomycin, Actinomycin D (Cosmegen®); Darbepoetin alfa (Aranesp®); Daunorubicin liposomal (DanuoXome®); Daunorubicin, daunomycin (Daunorubicin®); Daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); Dexrazoxane (Zinecard®); Docetaxel (Taxotere®); Doxorubicin (Adriamycin PFS®); Doxorubicin (Adriamycin®, Rubex®); Doxorubicin (Adriamycin PFS Injection®); Doxorubicin Liposomal (Doxil®); dromostanolone propionate (Dromostanolone®); dromostanolone propionate (Masterone injection®); Elliott's B Solution®; epirubicin (Ellence®); epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®); exemestane (Aromasin®); filgrastim (Neupogen®); floxuridine (intra-arterial) (FUDR®); fludarabine (Fludara) (registered trademark); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelinimplant®); hydroxyurea (Hydrea®); ibritumomab tiusetan (Zevalin®);Idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alpha-2a (RoferonA®); interferon alpha-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); leucovorin acetate Prolide (Eligard®); Levamisole (Ergamisol®); Lomustine, CCNU (CeeBU®); Mechlorethamine, Nitrogen Mustard (Mustargen®); Megestrol Acetate (Megace®); Melphalan, L-PAM (Alkeran®); Mercaptopurine, 6-MP (Purinethol®); Mesna (Mesnex®); Mesna (Mesnextabs®); Methotrexate (Methotrex®) ate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); nofetumomab (Verluma®); opelvequin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®) paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase (Adagen (Pegademase Bovine)®); pegaspargas (Oncaspar®); pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);Pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®); rasuburicase (Elitek®); rituximab (Rituxan®); ridaforolimus; sargramostim (Leukine®); sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®) trademark); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); tositumomab (Bexxar®); tositumomab / I-131 tositumomab (Bexxar®); trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); uracil mustard (Uracil Mustard Capsules®; valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®), and zoledronate (Zometa®), or pharmaceutically acceptable salts thereof;

[0199] Methods for Preparing Compounds of Formula I and Formula Ib The following examples are provided so that the present disclosure might be more fully understood. Unless otherwise indicated, starting materials were commercially available. They should not be construed as limiting the invention in any way.

[0200] Several methods for preparing compounds of Formula I or Formula Ib are illustrated in the following schemes and examples. Starting materials and intermediates are either commercially available, prepared from known procedures, or as otherwise described. Some frequently used routes to compounds of Formula I or Formula Ib are also illustrated by the schemes below. In some cases, the order in which the steps of the reaction schemes are carried out can be varied to facilitate the reaction or to avoid undesired reaction products. With respect to stereoisomers, Enantiomer A refers to the enantiomer that elutes earlier / faster upon separation, and Enantiomer B refers to the enantiomer that elutes later / later upon separation; this nomenclature is maintained throughout the remaining synthetic procedures for a given enantiomeric series, regardless of whether subsequent intermediates and final compounds may have the same or opposite elution order. [Table 1] TIFF2025537514000040.tif133144LCMS conditions: Column: ACQUITY UPLC-QDa BEH C18, 1.7 mm, 2.1 x 50 mm; Solvent system: A: water (0.1% FA), B: ACN (0.1%) FA.

[0201] Gradient conditions: 10-90% B in 1.7 min, total run time 2.4 min.

[0202] General synthetic scheme In addition to the specific examples given below, many alternatives, modifications, and variations thereof will be apparent to those skilled in the art. In some cases, the order of carrying out the steps of the reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. All such alternatives, modifications, and variations are intended to be within the spirit and scope of the present disclosure.

[0203] General scheme [ka] Compounds of formula 1-4 can be prepared by the reaction of 1-1 with R via SN2, SNAr or copper-mediated CO coupling. 1 -X. Saponification of 1-2 gave the corresponding carboxylic acid (1-3), followed by the addition of the appropriate amine (R 2 Amide coupling with 1-NH afforded compounds of formula (1-4) as described in the general scheme. In some cases, the order of steps can be altered to facilitate the synthesis. [Example]

[0204] Intermediates Intermediate 1: 3-ethoxy-2-fluoropyridine [ka] Iodoethane (6.4 mL, 80 mmol) was added to a stirring solution of 2-fluoropyrid-3-ol (5.0 g, 44 mmol) and KCO (9.8 g, 71 mmol) in DMF (45 mL) at room temperature, and the reaction mixture was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-10% EtOAc / PE) to give the title compound.

[0205] LC / MS = 142 [M+H] Using the appropriate reagents, the following intermediates were synthesized using a procedure similar to that described for Intermediate 1. These intermediates were characterized by LC / MS. [Table 2] TIFF2025537514000044.tif89164 Intermediate 19: 5-ethyl-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine [ka] Step A: 2-Fluoro-3-(2,2,2-trifluoroethoxy)-5-vinylpyridine 4,4,6-Trimethyl-2-vinyl-1,3,2-dioxaborinane (365 mg, 2.37 mmol) was added to a stirring solution of 5-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (500.0 mg, 1.83 mmol), K2CO3 (757 mg, 5.47 mmol), and PdCl2(dppf) (107 mg, 0.146 mmol) in 1,4-dioxane (730.0 μL) and water (183 μL) at room temperature. The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated under reduced pressure. The crude residue was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0206] LC / MS = 222 [M+H] Step B: 5-ethyl-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine Pd(OH)-C (73.3 mg, 104.0 μmol) was added to a stirred solution of 2-fluoro-3-(2,2,2-trifluoroethoxy)-5-vinylpyridine (330.0 mg, 1.49 mmol) in MeOH (7.46 mL) at room temperature under a N atmosphere. Triethylsilane (715 μL, 4.48 mmol) was then added dropwise. The reaction mixture was sparged with N and then filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0207] LC / MS = 224 [M+H] Using the appropriate reagents, the following intermediates were synthesized using a procedure similar to that described for Intermediate 19. The intermediates were characterized by LC / MS. [Table 3] Intermediate 21: 5-(azetidin-1-yl)-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine [ka] Step A: 3-Bromo-5-(2,2,2-trifluoroethoxy)pyridine To a stirred solution of 5-bromopyridin-3-ol (1.50 g, 8.62 mmol) and K2CO3 (1.55 g, 11.2 mmol) in DMF (30.0 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.40 g, 10.4 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (20% EtOAc / PE) to provide the title compound.

[0208] LC / MS = 256 [M+H] Step B: 3-(azetidin-1-yl)-5-(2,2,2-trifluoroethoxy)pyridine Azetidine hydrochloride (128 mg, 1.37 mmol) was added to a stirred solution of 3-bromo-5-(2,2,2-trifluoroethoxy)pyridine (350.0 mg, 1.37 mmol), CsCO (1.16 g, 3.55 mmol), Pd(dba) (125 mg, 137 μmol), and XantPhos (79.0 mg, 137 μmol) in 1,4-dioxane (20.0 mL) at room temperature under a N atmosphere. The resulting solution was stirred at 120 °C for 12 h, and then the reaction mixture was filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (17% EtOAc / PE) to provide the title compound.

[0209] LC / MS = 233 [M+H] Step C: 5-(azetidin-1-yl)-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine To a stirred solution of 3-(azetidin-1-yl)-5-(2,2,2-trifluoroethoxy)pyridine (80.0 mg, 345 μmol) in ACN (4.00 mL) was added NIS (81.0 mg, 362 μmol) at room temperature. The resulting mixture was stirred at room temperature for 12 hours and then directly purified by silica preparative thin-layer chromatography (25% EtOAc / PE) to give the title compound.

[0210] LC / MS = 359 [M+H] Intermediate 22: 3-(cyclopropylmethoxy)-5-fluoro-2-iodopyridine [ka] Step A: 5-Fluoro-2-iodopyridin-3-ol To a stirred solution of 5-fluoropyridin-3-ol (3.50 g, 30.9 mmol) in water (50 mL) at room temperature, Na2CO3 (6.56 g, 61.9 mmol) and KI (6.17 g, 37.1 mmol) were added, followed by the dropwise addition of a solution of iodine (7.85 g, 30.9 mmol) in water (20 mL). The resulting mixture was stirred at room temperature for 2 hours, and then the pH was adjusted to 5-6 with 4 M aqueous HCl. The resulting precipitate was collected by filtration and dried under reduced pressure. The crude material was purified by preparative HPLC to provide the title compound.

[0211] LC / MS = 239 [M+H] Step B: 3-(cyclopropylmethoxy)-5-fluoro-2-iodopyridine To a stirred solution of 5-fluoro-2-iodopyridin-3-ol (0.800 g, 3.35 mmol) in DMF (3.00 mL) at room temperature was added KCO (694 mg, 5.02 mmol) and (bromomethyl)cyclopropane (678 mg, 5.02 mmol). The resulting solution was stirred at 80 °C for 12 h. The mixture was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0212] LC / MS 294 [M+H] Intermediate 23: 2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyrazine [ka] To a stirred solution of 2-chloro-6-(trifluoromethyl)pyrazine (2.00 g, 11.0 mmol) and CsCO (4.28 g, 13.2 mmol) in DMF (11.0 mL) was added 2,2,2-trifluoroethan-1-ol (860 μL, 12.1 mmol) at room temperature. The resulting solution was stirred at 50 °C for 2 h. The mixture was then filtered through a pad of Celite, and the filtrate was directly purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0213] LC / MS = 247 [M+H] Intermediate 24: 3-(1,1,2,2-tetrafluoroethoxy)pyridine 1-oxide [ka] Step A: 3-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridine To a stirred solution of pyridin-3-ol (0.500 g, 5.26 mmol) and CsCO (3.43 g, 10.5 mmol) in DMF (26.3 mL) was added 1,3-dibromo-1,1,2,2,3,3-hexafluoropropane (750 μL, 5.26 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 h. The mixture was diluted with water, and the aqueous layer was extracted with EtO. The combined organic layers were washed with water and brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0214] LC / MS = 275 [M+H] Step B: 3-(1,1,2,2-tetrafluoroethoxy)pyridine Zinc (1.03 g, 15.8 mmol) was added to a stirred solution of 3-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridine (1.44 g, 5.26 mmol) in HOAc (5.26 mL) at room temperature. The resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was diluted with water, neutralized with saturated aqueous NaHCO, and the aqueous layer was extracted with DCM. The combined organic fractions were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0215] LC / MS = 196 [M+H] Step C: 3-(1,1,2,2-tetrafluoroethoxy)pyridine 1-oxide To a stirred solution of 3-(1,1,2,2-tetrafluoroethoxy)pyridine (1.03 g, 5.26 mmol) in DCM (11.1 mL) was added mCPBA (1.09 g, 6.31 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with water, neutralized with saturated aqueous NaHCO, and the aqueous layer was extracted with DCM. The combined organic fractions were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-10% MeOH / DCM) to provide the title compound.

[0216] LC / MS = 212 [M+H] Using the appropriate reagents, the following intermediates were synthesized using a procedure similar to that described for Intermediate 24. The intermediates were characterized by LC / MS. [Table 4] Intermediate 26: 2-chloro-5-methyl-3-(2,2,2-trifluoroethoxy)pyrazine [ka] To a stirred solution of 2,3-dichloro-5-methylpyrazine (1.00 g, 6.13 mmol) and CsCO (2.40 g, 7.36 mmol) in DMF (6.13 mL) was added 2,2,2-trifluoroethan-1-ol (0.526 mL, 7.36 mmol) at room temperature. After 15 min, the resulting mixture was stirred at 50 °C for 45 min, then filtered through a pad of Celite, washed with EtOAc, and concentrated under reduced pressure to provide the title compound.

[0217] LC / MS = 227 [M+H] The following intermediates were synthesized using the appropriate reagents and a procedure similar to that described for Intermediate 26. These intermediates were characterized by LC / MS. [Table 5] Intermediate 29: 2,4-Dichloro-3-(2,2,2-trifluoroethoxy)pyridine [ka] To a stirring solution of 2,4-dichloropyridin-3-ol (330 mg, 2.01 mmol) and KCO (556 mg, 4.02 mmol) in DMF (2.00 mL) at room temperature was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (350 μL, 2.42 mmol). After 10 min, the resulting mixture was stirred at 50 °C for 45 min, then filtered through a pad of Celite, washed with EtOAc, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0218] LC / MS = 246 [M+H] Using the appropriate reagents, the following intermediates were synthesized using a procedure similar to that described for Intermediate 29. These intermediates were characterized by LC / MS. [Table 6] Intermediate 32: 2-chloro-3-(1,1-difluoropropyl)pyridine [ka] DAST (0.779 mL, 5.90 mmol) was added dropwise to a stirred solution of 1-(2-chloropyridin-3-yl)propan-1-one (500.0 mg, 2.95 mmol) in DCM (6.00 mL) at room temperature under a N atmosphere. The resulting mixture was stirred at 50° C. for 12 hours, then quenched with MeOH and stirred at room temperature for an additional 0.5 hours. The reaction mixture was diluted with saturated aqueous NaHCO and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed with water, then brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (5% EtOAc / hexanes) to provide the title compound.

[0219] LC / MS = 192 [M+H] Intermediate 33: (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate [ka] Step A: 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine To a mixture of 5-chloro-2-iodopyridin-3-ol (2.7 g, 10.6 mmol) and K2CO3 (1.9 g, 13.7 mmol) in DMF (8.8 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (1.7 mL, 11.6 mmol) at room temperature. After 1 h, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0220] LC / MS = 320 [M+1]. Step B: (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol To a mixture of 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (0.88 g, 2.8 mmol) in toluene (15.3 mL) was added n-butyllithium solution (2.5 M in hexane, 1.3 mL, 3.3 mmol) at −78 °C. After 30 min, DMF (0.32 mL, 4.1 mmol) was added at −78 °C. After 1 h, methanol (3.1 mL) was added, followed by sodium borohydride (0.21 g, 5.5 mmol), and the resulting mixture was allowed to warm to room temperature. After 20 min, the mixture was diluted with saturated aqueous NH4Cl, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layers were then dried over MgSO4(s), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to afford the title compound.

[0221] LC / MS = 224 [M+1] Step C: (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate To a mixture of (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol (0.10 g, 0.45 mmol) and triethylamine (0.14 mL, 0.98 mmol) in DCM (2.2 mL) was added methanesulfonyl chloride (48.8 μL, 0.63 mmol) at −78 °C. After 5 min, the mixture was allowed to warm to room temperature. After an additional 15 min, the mixture was diluted with saturated aqueous NaCl, and the aqueous layer was extracted once with DCM. The combined organic layers were dried over MgSO(s), filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0222] LC / MS = 302 [M+1]. Using the appropriate reagents and procedures similar to those described for Intermediate 33, the following intermediates were synthesized and characterized by LC / MS. [Table 7] Intermediate 35: (3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol [ka] Step A: Methyl 3-fluoro-5-(2,2,2-trifluoroethoxy)picolinate To a mixture of methyl 3,5-difluoropicolinate (1.1 g, 6.4 mmol) and 2,2,2-trifluoroethan-1-ol (0.51 mL, 7.0 mmol) in DMF (6.4 mL) was added CsCO (2.5 g, 7.6 mmol) at room temperature. After 30 min, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to give the title compound.

[0223] LC / MS = 254 [M+H]. Step B: (3-fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol To a mixture of methyl 3-fluoro-5-(2,2,2-trifluoroethoxy)picolinate (870 mg, 3.4 mmol) in THF (17 mL) was added LiAlH solution (2 M in THF, 2.6 mL, 5.2 mmol) at 0 °C. After 30 min, the mixture was diluted with EtO, HO, and 1 M aqueous NaOH solution and then allowed to warm to room temperature. After 15 min, MgSO was added, and the mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0224] LC / MS = 226 [M+H]. Using the appropriate reagents, the following intermediates were synthesized using a procedure similar to that described for Intermediate 35. These intermediates were characterized by LC / MS. [Table 8] Intermediate 42: (3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl methanesulfonate [ka] Step A: (3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol To a mixture of 2-(hydroxymethyl)pyridin-3-ol hydrochloride (500 mg, 3.1 mmol) and KCO (1.3 g, 9.3 mmol) in DMF (3.1 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.6 mL, 4.0 mmol) at room temperature. After 15 h, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0225] LC / MS = 208 [M+1]. Step B: (3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl methanesulfonate To a mixture of (3-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol (330 mg, 1.6 mmol) and triethylamine (0.29 mL, 2.1 mmol) in DCM (5.3 mL) was added methanesulfonyl chloride (0.15 mL, 1.8 mmol) at 0 °C. After 5 min, the mixture was allowed to warm to room temperature. After 17 h, the mixture was diluted with saturated aqueous NaCl, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0226] LC / MS = 286 [M+H] Using the appropriate reagents and procedures similar to those described for Intermediate 42, the following intermediates were synthesized and characterized by LC / MS. [Table 9] Intermediate 43: 2-(4-amino-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)acetonitrile [ka] Step A: 2-(1,1-dioxidetetrahydro-4H-thiopyran-4-ylidene)acetonitrile To a mixture of potassium tert-butoxide solution (1 M in THF, 6.1 mL, 6.1 mmol) in THF (15 mL) was added diethyl cyanomethylphosphonate (0.98 mL, 6.1 mmol) at 0 °C. After 15 min, the mixture was allowed to warm to room temperature. After 30 min, the mixture was cooled to 0 °C, and then a solution of tetrahydro-4H-thiopyran-4-one 1,1-dioxide (0.90 g, 6.1 mmol) in THF (15 mL) was added. After 1 h, the mixture was allowed to warm to room temperature. 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, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0227] LC / MS = 172 [M+1] Step B: 2-(4-amino-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)acetonitrile To a mixture of 2-(1,1-dioxidetetrahydro-4H-thiopyran-4-ylidene)acetonitrile (0.40 g, 2.3 mmol) in MeOH (1.1 mL) was added aqueous NH (29 wt%, 3.0 mL, 46.7 mmol) at room temperature. The resulting mixture was heated to 100 °C. After 3 h, the mixture was cooled to room temperature and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0228] LC / MS = 189 [M+1] Intermediate 44: 4-amino-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran 1,1-dioxide [ka] Step A: 4-nitro-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran 1,1-dioxide To a mixture of 1,1,1-trifluoro-3-nitropropane (1.0 g, 7.2 mmol) and DBU (0.9 mL, 6.3 mmol) in DCM (40 mL) was added divinyl sulfone (0.6 mL, 6.0 mmol) at room temperature. After 15 h, the mixture was poured into 1 M aqueous HCl, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound. The crude product was used without purification.

[0229] LC / MS = 262 [M+1]. Step B: 4-amino-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran 1,1-dioxide To a mixture of 4-nitro-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran 1,1-dioxide (960 mg, 3.7 mmol) in MeOH (18 mL) was added Rh / C (5 wt%, 378 mg, 0.2 mmol) at room temperature. A balloon of H was placed over the reaction mixture, and the reaction mixture was sparged with H for 5 minutes, then stirring was continued under an H atmosphere. After 72 hours, the mixture was filtered through Celite, the filter cake was washed with methanol and DCM, and the filtrate was concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0230] LC / MS = 232 [M+1]. Using the appropriate reagents and procedures similar to those described for Intermediate Int-44, the following intermediates were synthesized and characterized by LC / MS. [Table 10] Intermediate 47: 4-amino-2,2,4-trimethyltetrahydro-2H-thiopyran 1,1-dioxide [ka] Step A: 4-((2,4-di-tert-butyl-6-hydroxyphenyl)amino)-2,2,4-trimethyltetrahydro-2H-thiopyran 1,1-dioxide To a mixture of 4-amino-2,2-dimethyltetrahydro-2H-thiopyran 1,1-dioxide (1.5 g, 8.5 mmol) in DCE (40 mL) was added a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (1.9 g, 8.5 mmol) in DCE (40 mL) at room temperature. After 5 min, the resulting mixture was warmed to 40 °C. After 15 h, the mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in PhMe (80 mL) and N,N,N',N'-tetramethylethane-1,2-diamine (1.3 mL, 8.5 mmol), and the resulting solution was added to a solution of MeLi solution (3.1 M in DME, 16.4 mL, 50.8 mmol) in EtO (100 mL) at -78 °C. After 1 hour, the mixture was allowed to warm to room temperature. After 3 hours, the mixture was poured into saturated aqueous NH4Cl, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0231] LC / MS = 396 [M+1] Step B: 4-amino-2,2,4-trimethyltetrahydro-2H-thiopyran 1,1-dioxide To a mixture of 4-((2,4-di-tert-butyl-6-hydroxyphenyl)amino)-2,2,4-trimethyltetrahydro-2H-thiopyran 1,1-dioxide (3.4 g, 8.5 mmol) in water (42 mL) and ACN (42 mL) was added H5IO6 (2.1 g, 9.3 mmol) at 0 °C. After 30 min, the organic solvent was removed under reduced pressure. The aqueous layer was extracted with Et2O / hexane (1:1) and concentrated under reduced pressure. The residue was dissolved in 1 M aqueous NaOH, and the mixture was extracted with DCM / MeOH. The combined organic layers were washed with saturated aqueous NaCl, dried over Na2SO4, then filtered and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0232] LC / MS = 192 [M+1] Intermediate 48: 3-amino-3-ethylthietane 1,1-dioxide [ka] Step A: 2-ethyl-2-nitropropane-1,3-diyl bis(4-methylbenzenesulfonate) To a mixture of 2-ethyl-2-nitropropane-1,3-diol (10.0 g, 67.0 mmol) in DCM (130 mL) and pyridine (21.7 mL, 268 mmol) was added p-toluenesulfonyl chloride (32.0 g, 168 mmol) at 0 °C. After 10 min, the mixture was allowed to warm to room temperature. After 15 h, the mixture was poured into 1 M aqueous HCl, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0233] LC / MS = 458 [M+1]. Step B: 3-Ethyl-3-nitrothietane To a mixture of 2-ethyl-2-nitropropane-1,3-diyl bis(4-methylbenzenesulfonate) (10.5 g, 23.0 mmol) in DMSO (115 mL) was added NaS at room temperature. After 5 min, the resulting mixture was heated to 100 °C. After 16 h, the mixture was cooled to room temperature and poured into saturated aqueous NaCl, and the mixture was extracted with EtOAc. The combined organic layers were dried over NaSO, then filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0234] LC / MS = 148 [M+1]. Step C: 3-Ethyl-3-nitrothietane 1,1-dioxide To a mixture of 3-ethyl-3-nitrothietane (150 mg, 1.0 mmol) in DCM (4 mL) was added m-chloroperoxybenzoic acid (685 mg, 3.1 mmol) at room temperature. After 24 h, the mixture was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound.

[0235] LC / MS = 180 [M+1]. Step D: 3-amino-3-ethylthietane 1,1-dioxide To a mixture of 3-ethyl-3-nitrothietane 1,1-dioxide (190 mg, 1.1 mmol) and DIPEA (0.9 mL, 5.3 mmol) in ACN (5.3 mL) was added trichlorosilane (0.4 mL, 3.7 mmol) at room temperature. After 24 h, the mixture was poured into 1 M aqueous NaOH, and the mixture was extracted with DCM / MeOH. The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound. The crude product was used without purification.

[0236] LC / MS = 150 [M+1]. Example The following experimental procedures detail the preparation of certain examples of the present disclosure, which are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.

[0237] Example 1: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: Ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate To a mixture of 5-bromopyridin-2-amine (6.00 g, 34.7 mmol) and NaHCO (5.83 g, 69.4 mmol) in dioxane (20 mL) was added ethyl 3-bromo-2-oxopropanoate (10.1 g, 52.0 mmol) at room temperature. The resulting mixture was then heated to 90 °C. After 16 h, the mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-50% EtOAc / hexane) to provide the title compound.

[0238] LC / MS = 268 [M+1]. Step B: Ethyl 6-hydroxyimidazo[1,2-a]pyridine-2-carboxylate To a mixture of ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (200 mg, 0.74 mmol), potassium acetate (219 mg, 2.23 mmol), and bis(pinacolato)diboron (425 mg, 1.67 mmol) in dioxane (11 mL), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (54.4 mg, 0.07 mmol) was added at room temperature. The resulting mixture was then heated to 100 °C. After 2 h, the mixture was cooled to 0 °C, and then water (0.2 mL) and HOAc (0.1 mL) were added. After 1 h, aqueous hydrogen peroxide (32 wt%, 0.15 mL, 1.49 mmol) was added, and the resulting mixture was allowed to warm to room temperature. After 18 h, MgSO(s) was added, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to give the title compound.

[0239] LC / MS = 207 [M+1]. Step C: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate To a mixture of ethyl 6-hydroxyimidazo[1,2-a]pyridine-2-carboxylate (500 mg, 2.43 mmol) in DMF (12 mL) was added sodium hydride (60 wt%, 126 mg, 3.15 mmol) at room temperature. After 5 minutes, 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (724 mg, 3.15 mmol) was added, and the resulting mixture was heated to 80° C. After 48 hours, the mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0240] LC / MS = 416 [M+1] Step D: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate (1.01 g, 2.43 mmol) in ACN (4 mL) and water (4 mL) was added lithium hydroxide monohydrate (0.31 g, 7.28 mmol) at room temperature. After 30 minutes, the mixture was concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0241] LC / MS = 388 [M+1] Step E: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide To a mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylic acid (70.0 mg, 0.11 mmol), 3-amino-3-methylthietane 1,1-dioxide hydrochloride (22.3 mg, 0.13 mmol), and DIPEA (76.0 μL, 0.43 mmol) in DMF (0.7 mL) was added HATU (49.4 mg, 0.13 mmol) at room temperature. After 1 h, the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0242] LC / MS = 505 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 8.56 (d, J = 1.5 Hz, 1H), 8.33 (s, 1H), 7.79 (d, J = 2.1 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 9.8 Hz, Human DGAT2 IC 50 = 5.0 nM. Using the appropriate reagents, the following compounds were synthesized using procedures similar to those described in Example 1. The compounds were characterized by LC / MS. [Table 11] TIFF2025537514000070.tif242166TIFF2025537514000071.tif231168TIFF2025537514000072.tif247165 TIFF2025537514000073.tif244165TIFF2025537514000074.tif248167TIFF2025537514000075.tif123166 Example 59: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: 5-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridin-2-amine To a mixture of 5-bromo-4-chloropyridin-2-amine (3 g, 14.5 mmol) in DMF (40 mL) was added NaH (60 wt%, 1.74 g, 43.4 mmol) at 0 °C. After 30 min, 1-(chloromethyl)-4-methoxybenzene (6.79 g, 43.4 mmol) was added, and the mixture was allowed to warm to room temperature. After 18 h, saturated aqueous NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic layers were washed with water and brine. The organic layers were then dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0243] LC / MS = 447 [M+1] Step B: (6-(bis(4-methoxybenzyl)amino)-4-chloropyridin-3-yl)boronic acid To a mixture of 5-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridin-2-amine (3.8 g, 8.49 mmol) in dioxane (50 mL) was added bis(pinacolato)diboron (3.23 g, 12.73 mmol), potassium acetate (2.50 g, 25.5 mmol), and PdCl(dppf) (0.62 g, 0.85 mmol). The resulting mixture was then heated to 80 °C. After 3 h, the mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0244] LC / MS = 413 [M+1]. Step C: 6-(bis(4-methoxybenzyl)amino)-4-chloropyridin-3-ol To a mixture of (6-(bis(4-methoxybenzyl)amino)-4-chloropyridin-3-yl)boronic acid (2 g, 4.85 mmol) in THF (10 mL) and water (10 mL) was added sodium perborate tetrahydrate (2.24 g, 14.54 mmol) at room temperature. After 2 h, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0245] LC / MS = 385 [M+1] Step D: 6-(bis(4-methoxybenzyl)amino)-4-vinylpyridin-3-ol To a mixture of 6-(bis(4-methoxybenzyl)amino)-4-chloropyridin-3-ol (1.2 g, 3.12 mmol) in dioxane (4 mL) and water (4 mL), NaCO (0.99 g, 9.35 mmol), potassium vinyltrifluoroborate (2.09 g, 15.59 mmol), and PdCl(dppf) (0.23 g, 0.31 mmol) were added at room temperature. The resulting mixture was then heated to 100 °C. After 12 h, the mixture was cooled to room temperature and poured into water, and the mixture was extracted with EtOAc. The combined organic layers were dried over NaSO(s), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0–100% EtOAc / hexanes) to provide the title compound.

[0246] LC / MS = 377 [M+1] Step E: 6-(bis(4-methoxybenzyl)amino)-4-ethylpyridin-3-ol To a mixture of 6-(bis(4-methoxybenzyl)amino)-4-vinylpyridin-3-ol (510 mg, 1.36 mmol) in MeOH (5 mL) was added Pd / C (10 wt%, 144 mg, 0.135 mmol). The reaction flask was evacuated and filled with H, and stirring was continued under an H atmosphere. After 2 h, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0247] LC / MS = 379 [M+1]. Step F: 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-ethyl-N,N-bis(4-methoxybenzyl)pyridin-2-amine To a mixture of 6-(bis(4-methoxybenzyl)amino)-4-ethylpyridin-3-ol (410 mg, 1.08 mmol) in DMF (3 mL) was added CsCO (529 mg, 1.63 mmol) and 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (298 mg, 1.30 mmol) at room temperature. After 2 h, the mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over NaSO(s), filtered, and concentrated under reduced pressure. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0248] LC / MS = 589 [M+1]. Step G: 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-ethylpyridin-2-amine To a mixture of 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-ethyl-N,N-bis(4-methoxybenzyl)pyridin-2-amine (560 mg, 0.95 mmol) in DCM (4 mL) was added TFA (2 mL) at room temperature. After 5 h, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and then washed with saturated aqueous NaHCO. The organic layer was dried over NaSO, then filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0249] LC / MS = 348 [M+1]. Step H: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethylimidazo[1,2-a]pyridine-2-carboxylate To a mixture of 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-ethylpyridin-2-amine (100 mg, 0.288 mmol) in dioxane (3 mL) was added ethyl 3-bromo-2-oxopropanoate (112 mg, 0.575 mmol) at room temperature. The resulting mixture was then heated to 100° C. After 12 h, the mixture was cooled to room temperature and then concentrated under reduced pressure. The crude product was purified by RP HPLC (ACN / water with 0.1% FA modifier) ​​to afford the title compound as the TFA salt.

[0250] LC / MS = 444 [M+1]. Step I: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethylimidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethylimidazo[1,2-a]pyridine-2-carboxylate (45 mg, 0.101 mmol) in THF (2 mL) and water (2 mL) was added lithium hydroxide hydrate (8.51 mg, 0.203 mmol) at room temperature. After 2 h, the mixture was concentrated under reduced pressure and then dissolved in water. Aqueous 1 M HCl was added to adjust the pH to 4, and then the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0251] LC / MS = 416 [M+1]. Step J: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide To a mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethylimidazo[1,2-a]pyridine-2-carboxylic acid (35 mg, 0.084 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (20.61 mg, 0.126 mmol), and DIPEA (0.044 mL, 0.253 mmol) in DMF (2 mL) was added HATU (48.0 mg, 0.126 mmol) at room temperature. After 1 h, the reaction mixture was filtered, and the filtrate was purified by RP HPLC (ACN / water with 0.1% TFA modifier) ​​to give the title compound as the TFA salt.

[0252] LC / MS = 561 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 8.88 (s, 1H), 8.47 - 8.68 (m, 1H), 7.79 - 7.86 (m, 2H), 7.71 - 7.77 (m, 1H), 4.78 - 4.84 (m, 2H), 3.25 - 3.32 (m, 2H), 3.00 - 3.12 (m, 2H), 2.84 - 2.97 (m, 2H), 2.78 (q, J = 7.48 Hz, 2H), 2.20 - 2.37 (m, 2H), 1.54 - 1.70 (m, 3H), 1.33 (t, J = 7.48 Hz, 3H). Human DGAT2 IC 50 = 9.0 nM Example 60: 6-[(3-hydroxy-2-pyridyl)oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] To a mixture of 6-((3-(benzyloxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (7.0 mg, 0.01 mmol) in DCM (0.5 mL) was added BCl solution (1 M in DCM, 30.0 μL, 0.03 mmol) at 0° C. The resulting mixture was then allowed to warm to room temperature. After 3 h, DCM / MeOH (9:1) was added, and the resulting mixture was concentrated. The crude product was purified by mass-triggered RP HPLC (ACN / water with 0.1% FA modifier) ​​to give the title compound.

[0253] LC / MS = 417 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 8.57 (s, 1H), 8.51 (d, J = 1.9 Hz, 1H), 8.31 (s, 1H), 7.64 (d, J = 9.8 Hz, 1H), 7.59 (dd, J = 4.8, 1.4 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.05 (dd, J = 7.8, 4.9 Hz, 1H), 3.40 - 3.34 (m, 2H), 3.08 - 3.00 (m, 2H), 2.96 - 2.86 (m, 2H), 2.30 - 2.18 (m, 2H), 1.58 (s, 3H). Human DGAT2 IC 50 = >9990 nM. Example 61: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: Ethyl 6-(benzyloxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylate To a stirring solution of 5-(benzyloxy)pyridin-2-amine (4.90 g, 24.5 mmol) in 1,4-dioxane (100.0 mL) was added methyl 3-bromo-2-oxobutanoate (7.16 g, 36.7 mmol) at room temperature. The resulting mixture was heated to 80 °C for 13 h. The mixture was diluted with saturated aqueous NH4Cl, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (100% EtOAc / hexanes) to provide the title compound.

[0254] LC / MS = 311 [M+H] Step B: Ethyl 6-hydroxy-3-methylimidazo[1,2-a]pyridine-2-carboxylate To a stirred solution of ethyl 6-(benzyloxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylate (3.60 g, 11.6 mmol) in DCM (100.0 mL) was added TEA (4.85 mL, 34.8 mmol), triethylsilane (5.56 mL, 34.8 mmol), and palladium(II) chloride (0.411 g, 2.32 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by mass-triggered RP HPLC (C18, 100% ACN, 0.1% FA modifier) ​​to provide the title compound.

[0255] LC / MS = 221 [M+H]. Step C: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylate Sodium hydride (16.5 mg, 0.413 mmol, 60 wt%) was added to a stirred solution of ethyl 6-hydroxy-3-methylimidazo[1,2-a]pyridine-2-carboxylate (70.0 mg, 0.318 mmol) in DMF (0.795 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (88.0 mg, 0.381 mmol) was added. The resulting reaction mixture was heated to 100° C. for 18 hours, then cooled to room temperature and directly purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0256] LC / MS = 430 [M+H]. Step D: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylate (137 mg, 0.319 mmol) in MeOH (0.50 mL), water (1.4 mL), and THF (1.4 mL) at room temperature was added lithium hydroxide monohydrate (40.1 mg, 0.956 mmol). The resulting mixture was stirred at room temperature for 1.5 hours and then lyophilized to provide the title compound.

[0257] LC / MS = 402 [M+H]. Step E: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (50.0 mg, 0.100 mmol) and HATU (41.6 mg, 0.110 mmol) in DMF (1.00 mL) and DCM (1.00 mL) was added DIPEA (60.9 μL, 0.348 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (21.9 mg, 0.110 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then diluted with EtOAc, filtered through Celite, and washed with EtOAc. The filtrate was concentrated and the crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound.

[0258] 1 H NMR (500 MHz, methanol-d4) δ 8.35 (d, J = 1.8 Hz, 1H), 7.78 (d, J = 2.0 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 9.8 Hz, 1H), 7.34 (dd, J = 9.8, 2.0 Hz, 1H), 4.78 (q, J = 8.4 Hz, 2H), 3.39 (m, J = 12.5 Hz, 2H), 3.03 (d, J = 14.0 Hz, 2H), 2.90 (d, J = 15.1 Hz, 2H), 2.78 (s, 3H), 2.24 (t, J = 12.5 Hz, 2H), 1.58 (s, 3H). LC / MS = 547 [M+H]. Human DGAT2 IC 50 = 3.0 nM Using the appropriate reagents and procedures similar to those described in Example 61, the following compounds were synthesized and characterized by LC / MS. [Table 12] TIFF2025537514000080.tif241165TIFF2025537514000081.tif247165TIFF2025537514000082.tif237165TIFF2025537514 000083.tif247164TIFF2025537514000084.tif243164TIFF2025537514000085.tif245168TIFF2025537514000086.tif59165 Example 123: 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]methoxy]imidazo[1,2-a]pyridine-2-carboxamide [ka] To a stirring solution of 6-hydroxy-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (30.0 mg, 0.0890 mmol) and KCO (24.6 mg, 0.178 mmol) in DMF (445 μL) was added 2-(chloromethyl)-3-(2,2,2-trifluoroethoxy)pyridine (30.1 mg, 0.133 mmol) at room temperature. The resulting mixture was heated to 50 °C for 2 h. The reaction was cooled to room temperature, and the mixture was directly purified by mass-triggered RP HPLC (C18, 20 → 60% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0259] 1H NMR (500 MHz, methanol-d4) δ 8.31 (d, J = 4.7 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.55 - 7.43 (m, 2H), 7.26 (dd, J = 9.8, 2.2 Hz, 1H), 5.33 (s, 2H), 4.76 (q, J = 8.4 Hz, 2H), 3.40 - 3.34 (m, 2H), 3.02 (d, J = 13.4 Hz, 2H), 2.88 (d, J = 14.3 Hz, 2H), 2.78 (s, 3H), 2.22 (t, J = 13.6 Hz, 2H), 1.57 (s, 3H). LC / MS = 527 [M+H]. Human DGAT2 IC 50 = 93 nM Using the appropriate reagents and procedures similar to those described in Example 123, the following compounds were synthesized and characterized by LC / MS. [Table 13] Example 128: 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: 6-Bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylate (340.0 mg, 1.20 mmol) in MeOH (3.00 mL), water (1.00 mL), and THF (2.00 mL) at room temperature was added lithium hydroxide monohydrate (101 mg, 2.40 mmol). The resulting mixture was stirred at room temperature for 5 hours and then lyophilized to provide the title compound.

[0260] LC / MS = 255 / 257 [M+H]. Step B: 6-Bromo-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred mixture of 6-bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (650.0 mg, 2.55 mmol) and HATU (1.45 g, 3.82 mmol) in DMF (10.0 mL) was added DIPEA (1.33 mL, 7.64 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (611 mg, 3.06 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (60% EtOAc / hexanes) to provide the title compound.

[0261] LC / MS = 400 / 402 [M+H]. Step C: 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-2-carboxamide To a stirred solution of 6-bromo-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (80.0 mg, 0.200 mmol), sodium tert-butoxide (23.1 mg, 0.240 mmol), N,N'-bis(2-phenylethyl)ethanediamide (11.9 mg, 0.040 mmol), and copper(I) iodide (7.61 mg, 0.040 mmol) in 1,4-dioxane (2.00 mL) was added 3,3,3-trifluoro-1-propanol (114 mg, 0.999 mmol) under N2 atmosphere at room temperature. The resulting mixture was heated to 80 °C for 18 h. The reaction mixture was cooled to room temperature, diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was directly purified by mass-triggered RP HPLC (C18, 30→50% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0262] 1H NMR (500 MHz, methanol-d4) δ 7.83 (d, J = 1.96 Hz, 1H), 7.50 (d, J = 9.78 Hz, 1H), 7.21 (dd, J = 2.35, 9.78 Hz, 1H), 4.32 (t, J = 5.87 Hz, 2H), 3.32 - 3.39 (m, 2H), 2.98 - 3.01 (m, 2H), 2.84 - 2.88 (m, 2H), 2.72 - 2.82 (m, 5H), 2.17 - 2.24 (m, 2H), 1.55 (s, 3H). LC / MS = 434 [M+H]. Human DGAT2 IC 50 >9990 nM Using the appropriate reagents and procedures similar to those described in Example 128, the following compounds were synthesized and characterized by LC / MS. [Table 14] Example 130: 3-chloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: Ethyl 3-chloro-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate To a stirring mixture of ethyl 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate (100.0 mg, 0.262 mmol) in DMF (2.00 mL) at room temperature was added NCS (70.0 mg, 0.525 mmol). The resulting mixture was stirred at room temperature for 15 hours, then diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by preparative silica thin-layer column chromatography (50% EtOAc / PE) to provide the title compound.

[0263] LC / MS = 416 [M+H]. Step B: 3-chloro-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 3-chloro-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate (100.0 mg, 0.241 mmol) in MeOH (1.50 mL), THF (1.00 mL), and water (0.500 mL) at room temperature was added lithium hydroxide monohydrate (20.2 mg, 0.481 mmol), diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0264] LC / MS = 388 [M+H]. Step C: 3-chloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 2,2,2-trifluoroacetate To a stirring mixture of 3-chloro-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylic acid (70.0 mg, 0.181 mmol) in DMF (2.00 mL) was added DIPEA (95.0 μL, 0.542 mmol) and HATU (103 mg, 0.271 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (45.0 mg, 0.225 mmol). The resulting mixture was stirred at room temperature for 0.5 hours and then directly purified by mass-triggered reverse-phase HPLC (C18, 40→60% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0265] 1H NMR (500 MHz, methanol-d4) δ 8.44 (d, J = 1.53 Hz, 1H), 7.79 (dd, J = 1.37, 4.88 Hz, 1H), 7.70 (d, J = 9.77 Hz, 1H), 7.61 (dd, J = 1.22, 7.93 Hz, 1H), 7.43 (dd, J = 2.14, 9.77 Hz, 1H), 7.17 (dd, J = 4.88, 8.09 Hz, 1H), 4.73 (q, J = 8.49 Hz, 2H), 3.33 - 3.36 (m, 2H), 3.01 - 3.03 (m, 2H), 2.87 - 2.90 (m, 2H), 2.19 - 2.26 (m, 2H), 1.57 (s, 3H). LC / MS = 533 [M+H]. Human DGAT2 IC 50 = 3.3 nM. Example 131: 3-hydroxy-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-((2-(trimethylsilyl)ethoxy)methoxy)imidazo[1,2-a]pyridine-2-carboxamide To a stirred mixture of 2-(trimethylsilyl)ethan-1-ol (10.2 mg, 0.0870 mmol), 3-bromo-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide (50.0 mg, 0.0870 mmol), and sodium 2-methylpropan-2-olate (16.7 mg, 0.173 mmol) was added copper(I) iodide (1.65 mg, 8.66 μmol) in 1,4-dioxane (4.00 mL) at room temperature. The resulting mixture was stirred at 50° C. for 16 hours and then concentrated under reduced pressure. The crude material was purified by preparative silica thin layer column chromatography (17% EtOAc / PE) to afford the title compound.

[0266] LC / MS = 615 [M+H]. Step B: 3-hydroxy-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 2,2,2-trifluoroacetate To a stirred mixture of N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(2-(trimethylsilyl)ethoxy)imidazo[1,2-a]pyridine-2-carboxamide (40.0 mg, 0.0650 mmol) in THF (2.00 mL) was added dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified directly by mass-triggered RP HPLC (C18, 20→60% ACN in water, 0.1% FA modifier) ​​to afford the title compound.

[0267] 1 H NMR (500 MHz, chloroform-d) δ 13.45 (br s, 1H), 8.65 (s, 1H), 8.32 (s, 1H), 7.82 (d, J = 5.08 Hz, 1H), 7.55 (br d, J = 9.54 Hz, 1H), 7.47 (dd, J = 1.83, 9.66 Hz, 1H), 7.37 (d, J = 7.34 Hz, 1H), 7.07 (dd, J = 4.89, 7.82 Hz, 1H), 4.50 (q, J = 7.99 Hz, 2H), 3.23 - 3.37 (m, 2H), 2.99 (br d, J = 9.78 Hz, 4H), 2.15 - 2.34 (m, 2H), 1.64 (s, 3H). LC / MS = 515 [M+H]. Human DGAT2 IC 50 = 34 nM. Example 132 and Example 133: Example 132: 2-((4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)carbamoyl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid Example 133: N2-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2,3-dicarboxamide [ka] Step A: 3-(furan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide PdCl(dppf) (6.00 mg, 8.20 μmol) was added to a stirred solution of 3-bromo-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide (50.0 mg, 0.0870 mmol), KCO (48.0 mg, 0.347 mmol), and furan-2-ylboronic acid (12.0 mg, 0.107 mmol) in 1,4-dioxane (1.00 mL) and water (0.100 mL) at room temperature. The resulting mixture was stirred at 150° C. for 20 minutes under microwave heating. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparative silica thin layer column chromatography (100% EtOAc) to afford the title compound.

[0268] LC / MS = 565 [M+H]. Step B (Example 132): 2-((4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)carbamoyl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid To a stirred solution of 3-(furan-2-yl)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide (35.0 mg, 0.0620 mmol) in acetone (3.00 mL) and water (1.80 mL) was added KMnO (69.0 mg, 0.434 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 5 h. The mixture was filtered through a pad of Celite, washed with MeOH, and the filtrate was concentrated under reduced pressure to provide the title compound.

[0269] LC / MS = 543 [M+H]. Human DGAT2 IC 50 > 9990 nM, Step C (Example 133): N2-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2,3-dicarboxamide To a stirred solution of 2-((4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)carbamoyl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid (30.0 mg, 0.0550 mmol) in DMF (1.00 mL) was added NHCl (9.00 mg, 0.166 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (42.0 mg, 0.111 mmol), and N-ethyl-N-isopropylpropan-2-amine (36.0 mg, 0.277 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour and then purified directly by mass-triggered RP HPLC (C18, 30→60% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0270] 1 H NMR (500 MHz, methanol-d4) δ 9.79 (br s, 1H), 7.71 - 7.83 (m, 2H), 7.59 (br d, J = 7.83 Hz, 1H), 7.52 (br d, J = 8.80 Hz, 1H), 7.14 (dd, J = 4.89, 8.07 Hz, 1H), 4.70 (q, J = 8.31 Hz, 2H), 3.33 (br s, 2H), 3.02 (m, 2H), 2.91 (m, 2H), 2.18 - 2.28 (m, 2H), 1.57 (s, 3H). LC / MS = 542 [M+H]. Human DGAT2 IC 50 = 28 nM. Example 134: 3-Methoxy-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide [ka] To a stirred solution of 3-bromo-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide (20.0 mg, 0.0350 mmol), sodium 2-methylpropan-2-olate (6.66 mg, 0.0690 mmol), copper(I) iodide (0.660 mg, 3.46 μmol), and N1,N2-diphenethyloxalamide (1.03 mg, 3.46 μmol) in 1,4-dioxane (1.00 mL) was added MeOH (69.4 μg, 1.73 mmol) under N2 atmosphere at room temperature. The resulting mixture was stirred at 60 °C for 16 h. The reaction was concentrated under reduced pressure and the crude material was purified by mass-triggered RP HPLC (C18, 10 mM aqueous NH4HCO3 in ACN) to afford the title compound.

[0271] 1 H NMR (500 MHz, methanol-d4) δ 8.20 (d, J = 1.47 Hz, 1H), 7.75 (dd, J = 1.22, 4.89 Hz, 1H), 7.57 (dd, J = 1.22, 7.83 Hz, 1H), 7.49 (d, J = 9.78 Hz, 1H), 7.23 (dd, J = 2.08, 9.90 Hz, 1H), 7.13 (dd, J = 4.89, 7.83 Hz, 1H), 4.69 (q, J = 8.31 Hz, 2H), 4.58 (br s, 1H), 4.17 (s, 3H), 3.31 - 3.38 (m, 1H), 2.99 (m, 2H), 2.86 (m, 2H), 2.14 - 2.24 (m, 2H), 1.54 (s, 3H). LC / MS = 529 [M+H]. Human DGAT2 IC 50 = 6.2 nM Using the appropriate reagents and procedures similar to those described in Example 134, the following compounds were synthesized and characterized by LC / MS. [Table 15] Example 136: N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: Ethyl 6-hydroxy-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate To a stirred solution of ethyl 6-hydroxyimidazo[1,2-a]pyridine-2-carboxylate (41.2 mg, 0.200 mmol), pyridine N-oxide (57.1 mg, 0.600 mmol), and tris(2,2'-bipyridyl)ruthenium(II) chloride hexahydrate (1.50 mg, 2.000 μmol) in ACN (412 μL) was added TFAA (83.0 μL, 0.600 mmol) at room temperature. The resulting mixture was irradiated with a blue LED (50% light at 800 rpm) for 16 h. The reaction mixture was concentrated under reduced pressure and purified by silica flash column chromatography (0-90% EtOAc / hexanes) to give the title compound.

[0272] LC / MS = 275 [M+H]. Step B: Ethyl 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate To a stirred solution of 3-(2,2,2-trifluoroethoxy)pyridine 1-oxide (16.3 mg, 0.0840 mmol) and ethyl 6-hydroxy-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (22.0 mg, 0.0800 mmol) in THF (1.00 mL) was added DIPEA (42.0 μL, 0.241 mmol) and PyBrop (48.6 mg, 0.104 mmol) at room temperature. The resulting solution was stirred at room temperature for 18 h. The mixture was diluted with DCM and washed with 1 M aqueous NaOH, water, and brine. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0273] LC / MS = 450 [M+H]. Step C: 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate (22.0 mg, 0.0490 mmol) in THF (57.6 μL), MeOH (28.8 μL), and water (11.5 μL) at room temperature was added lithium hydroxide monohydrate (2.06 mg, 0.0490 mmol). The resulting mixture was stirred at room temperature for 1.5 hours and then lyophilized to provide the title compound.

[0274] LC / MS = 422 [M+H]. Step D: N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred mixture of 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid (20.6 mg, 0.0490 mmol) and HATU (37.3 mg, 0.0980 mmol) in DMF (1.00 mL) was added DIPEA (26.0 μL, 0.147 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (10.8 mg, 0.0540 mmol). The resulting mixture was stirred at room temperature for 2 hours and then directly purified by mass-triggered RP HPLC (C18, 50→98% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0275] 1 H NMR (500 MHz, methanol-d4) δ 8.58 (s, 1H), 7.94 - 7.74 (m, 2H), 7.70 - 7.47 (m, 2H), 7.19 (dd, J = 8.0, 4.9 Hz, 1H), 4.75 (q, J = 8.4 Hz, 2H), 3.41 - 3.33 (m, 2H), 3.03 (d, J = 13.5 Hz, 2H), 2.86 (d, J = 14.4 Hz, 2H), 2.23 (t, J = 13.6 Hz, 2H). LC / MS = 567 [M+H]. Human DGAT2 IC 50= 146 nM. Example 137: 3-(hydroxymethyl)-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-vinylimidazo[1,2-a]pyridine-2-carboxamide PdCl(dppf) (5.07 mg, 6.93 μmol) was added to a stirred solution of 3-bromo-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide (40.0 mg, 0.0690 mmol) and potassium trifluoro(vinyl)borate (27.8 mg, 0.208 mmol) in 1,4-dioxane (1.00 mL) and water (0.100 mL) at room temperature under a N atmosphere. The resulting solution was stirred at 100° C. for 4 h. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by preparative silica thin layer column chromatography (100% EtOAc) to afford the title compound.

[0276] LC / MS = 525 [M+H]. Step B: 3-formyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide To a stirred solution of N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-vinylimidazo[1,2-a]pyridine-2-carboxamide (30.0 mg, 0.0570 mmol) in THF (3.00 mL) and water (0.600 mL) was added 4-methylmorpholine N-oxide (6.70 mg, 0.0570 mmol), sodium periodate (24.5 mg, 0.114 mmol), and osmium(VIII) oxide (1.45 mg, 5.72 μmol) at room temperature. The resulting mixture was stirred at 30° C. for 2 hours. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound.

[0277] LC / MS = 527 [M+H]. Step C: 3-(hydroxymethyl)-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide To a stirring solution of 3-formyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide (30.0 mg, 0.0570 mmol) in THF (0.800 mL) and MeOH (0.800 mL) was added NaBH (2.10 mg, 0.0570 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by mass-triggered RP HPLC (C18, ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0278] 1H NMR (400 MHz, methanol-d4) δ 8.74 (s, 1H), 7.70 - 7.84 (m, 3H), 7.61 (dd, J = 1.22, 8.07 Hz, 1H), 7.17 (dd, J = 5.01, 7.95 Hz, 1H), 5.23 (s, 2H), 4.67 - 4.83 (m, 2H), 2.95 - 3.11 (m, 2H), 2.77 - 2.88 (m, 2H), 2.22 (m 2H), 1.56 (s, 3H). LC / MS = 529 [M+H]. Human DGAT2 IC 50 = 11 nM. Example 138: 6-[5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-7-cyano-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: 2-amino-5-bromoisonicotinonitrile NBS (3.29 g, 18.5 mmol) was added to a stirring solution of 2-aminoisonicotinonitrile (2.00 g, 16.8 mmol) in THF (60.0 mL) at room temperature. The resulting solution was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NaSO, and the aqueous layer was extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0279] LC / MS = 198 and 200 [M+H]. Step B: 2-(bis(4-methoxybenzyl)amino)-5-bromoisonicotinonitrile Sodium hydride (1.40 g, 35.0 mmol, 60 wt%) was added to a stirred solution of 2-amino-5-bromoisonicotinonitrile (3.00 g, 15.2 mmol) in DMF (50.0 mL) under a N atmosphere at 0°C. The resulting solution was stirred at 0°C for 0.5 h, and then 1-(chloromethyl)-4-methoxybenzene (5.22 g, 33.3 mmol) was added. The mixture was stirred at 0°C for an additional 1.5 h. The reaction mixture was quenched with saturated aqueous NH4Cl, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0280] LC / MS = 438 and 440 [M+H]. Step C: (6-(bis(4-methoxybenzyl)amino)-4-cyanopyridin-3-yl)boronate PdCl(dppf) (0.501 g, 0.684 mmol) was added to a stirred solution of 2-(bis(4-methoxybenzyl)amino)-5-bromoisonicotinonitrile (3.00 g, 6.84 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.48 g, 13.7 mmol), and potassium acetate (2.02 g, 20.5 mmol) in 1,4-dioxane (60.0 mL) at room temperature under a N atmosphere. The resulting mixture was stirred at 95 °C for 12 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc, and the filtrate was concentrated under reduced pressure to provide the title compound.

[0281] LC / MS = 404 and 486 [M+H] Step D: 2-(bis(4-methoxybenzyl)amino)-5-hydroxyisonicotinonitrile 4-Methylmorpholine N-oxide (3.00 g, 25.6 mmol) was added to a stirred solution of 2-(bis(4-methoxybenzyl)amino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isonicotinonitrile (6-(bis(4-methoxybenzyl)amino)-4-cyanopyridin-3-yl)boronate (4.00 g, 4.50 mmol) in THF (80.0 mL) at room temperature under a N atmosphere. The resulting solution was stirred at 80 °C for 3 h. The reaction mixture was quenched with saturated aqueous NH Cl, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0282] LC / MS = 376 [M+H]. Step E: 2-(bis(4-methoxybenzyl)amino)-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)isonicotinonitrile CsCO (911 mg, 2.80 mmol) was added to a stirring solution of 2-(bis(4-methoxybenzyl)amino)-5-hydroxyisonicotinonitrile (700.0 mg, 1.87 mmol) in DMF (7.00 mL) at room temperature. The resulting mixture was stirred at 20 °C for 10 min, after which 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (556 mg, 2.42 mmol) was added. The mixture was stirred at 60 °C for 12 h. The reaction mixture was quenched with saturated aqueous NHCl, and the aqueous layer was extracted with DCM. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0283] LC / MS = 585 [M+H]. Step F: 2-amino-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)isonicotinamide To a stirred solution of 2-(bis(4-methoxybenzyl)amino)-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)isonicotinonitrile (230.0 mg, 0.393 mmol) in DCM (3.00 mL) was added TFA (1.00 mL) at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The solution was concentrated under reduced pressure to provide the title compound.

[0284] LC / MS = 345 [M+H]. Step G: Methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylate Methyl 3-bromo-2-oxobutanoate (200 mg, 1.026 mmol) was added to a stirring solution of 2-amino-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)isonicotinonitrile (120 mg, 0.349 mmol) in 1,4-dioxane (4.00 mL) at room temperature under a N atmosphere. The resulting mixture was stirred at 90 °C for 13 h. The reaction mixture was quenched with saturated aqueous NH Cl, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The crude material was purified by preparative silica thin-layer column chromatography (33% EtOAc / PE) to provide the title compound.

[0285] LC / MS = 441 [M+H]. Step H: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid To a stirred solution of methyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylate (10.0 mg, 0.0230 mmol) in MeOH (1.50 mL) and water (0.150 mL) was added lithium hydroxide monohydrate (4.00 mg, 0.0950 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, and then the mixture was concentrated under reduced pressure to provide the title compound.

[0286] LC / MS = 427 [M+H]. Step I: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-cyano-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-cyano-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (9.00 mg, 0.0210 mmol) and HATU (34.6 mg, 0.0910 mmol) in DMF (1.00 mL) was added DIPEA (24.0 μL, 0.136 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (21.9 mg, 0.110 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then diluted with EtOAc, filtered through Celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure and the crude material was purified by mass-triggered RP HPLC (C18, ACN in water, 0.1% FA modifier) ​​to afford the title compound.

[0287] 1 H NMR (400 MHz, methanol-d4) δ 8.48 (s, 1H), 8.15 (s, 1H), 7.66 - 7.68 (m, 1H), 7.66 (s, 1H), 4.65 - 4.72 (m, 2H), 3.24 (br d, J = 3.10 Hz, 1H), 3.17 (br s, 1H), 2.92 (br d, J = 16.93 Hz, 2H), 2.75 - 2.84 (m, 2H), 2.64 - 2.71 (m, 3H), 2.04 - 2.19 (m, 2H), 1.43 - 1.48 (m, 3H). LC / MS = 572 [M+H]. Human DGAT2 I C 50 = 25 nM. Example 139: 3,5-dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: Ethyl 3,5-dichloro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate NCS (647 mg, 4.85 mmol) was added to a stirring solution of ethyl 6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate (968 mg, 2.42 mmol) in DMF (15.0 mL) at room temperature. The resulting solution was stirred at room temperature for 72 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to provide the title compound.

[0288] LC / MS = 468 [M+H] Step B: 3,5-dichloro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylic acid Lithium hydroxide monohydrate (0.0240 g, 0.563 mmol) was added to a stirred solution of ethyl 3,5-dichloro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylate (0.264 g, 0.563 mmol) in THF (0.663 mL), MeOH (0.331 mL), and water (0.133 mL) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, and then the mixture was concentrated under reduced pressure to provide the title compound.

[0289] LC / MS = 441 [M+H]. Step C: 3,5-dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide HATU (16.0 mg, 0.0420 mmol) was added to a stirred solution of 3,5-dichloro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxylic acid (20.0 mg, 0.0450 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide dihydrochloride (9.98 mg, 0.0300 mmol), and DIPEA (0.0140 mL, 0.0770 mmol) in DMF (0.800 mL) at room temperature. The resulting solution was stirred at room temperature for 1.5 hours, and then the mixture was directly purified by mass-triggered RP HPLC (C18, 20→60% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0290] 1 H NMR (400 MHz, methanol-d4) δ 7.74 (s, 2H), 7.52 (d, J = 9.7 Hz, 1H), 7.28 (d, J = 9.7 Hz, 1H), 4.80 (q, J = 8.3 Hz, 2H), 3.44 - 3.33 (m, 2H), 3.04 (d, J = 14.3 Hz, 2H), 2.93 (s, 5H), 2.23 (t, J = 14.1 Hz, 2H), 1.58 (s, 3H). LC / MS = 586 [M+H]. Human DGAT2 IC 50 = 0.7 nM Using the appropriate reagents and procedures similar to those described in Example 139, the following compounds were synthesized and characterized by LC / MS. [Table 16] Example 141: 3-chloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] NCS (25.6 mg, 0.192 mmol) was added to a stirred solution of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-5-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (100.0 mg, 0.183 mmol) in THF (914 μL) at room temperature under light protection. The resulting solution was stirred at 80° C. under light protection for 18 hours and then directly purified by mass-triggered RP HPLC (C18, 55→98% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0291] 1 H NMR (400 MHz, methanol-d4) δ 7. LC / MS = 582 [M+H]. Human DGAT2 IC 50 = 2.6 nM. Using the appropriate reagents and procedures similar to those described in Example 141, the following compounds were synthesized and characterized by LC / MS. [Table 17] Example 144: 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: Ethyl 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylate Sodium hydride (47.2 mg, 1.18 mmol, 60 wt%) was added to a stirred solution of ethyl 6-hydroxy-3-methylimidazo[1,2-a]pyridine-2-carboxylate (200.0 mg, 0.908 mmol) in DMF (2.27 mL) at room temperature. The resulting mixture was stirred at room temperature for 5 minutes, and then 5-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (299 mg, 1.09 mmol) was added. The reaction mixture was heated to 80° C. for 18 hours, then cooled to room temperature and diluted with brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0292] LC / MS = 474 [M+H]. Step B: 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylate (431 mg, 0.909 mmol) in MeOH (1.30 mL), water (3.90 mL), and THF (3.90 mL) at room temperature was added lithium hydroxide monohydrate (76.0 mg, 1.82 mmol). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to provide the title compound.

[0293] LC / MS = 446 [M+H] Step C: 6-[[5-bromo-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred mixture of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid (406 mg, 0.910 mmol) and HATU (346 mg, 0.910 mmol) in DMF (2.18 mL) and DCM (1.46 mL) was added DIPEA (556 μL, 3.18 mmol), followed by 4-methyltetrahydro-2H-thiopyran-4-aminium 1,1-dioxide chloride (182 mg, 0.910 mmol) at room temperature. The resulting mixture was stirred at room temperature for 18 hours, then diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to afford the title compound.

[0294] LC / MS = 593 [M+H]. Step D: 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide PdCl(dppf) (7.42 mg, 10.2 μmol) was added to a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (40.0 mg, 0.0680 mmol), KCO (28.0 mg, 0.203 mmol), and potassium methyltrifluoroborate (20.6 mg, 0.169 mmol) in 1,4-dioxane (564 μL) and water (113 μL) under a N atmosphere at room temperature. The resulting mixture was stirred at 100° C. for 1 h, then cooled to room temperature and directly purified by silica flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound.

[0295] 1H NMR (500 MHz, methanol-d4) δ 8.29 (d, J = 1.7 Hz, 1H), 7.62 (s, 1H), 7.60 (s, 1H), 7.48 (s, 1H), 7.31 (dd, J = 9.8, 2.1 Hz, 1H), 4.71 (q, J = 8.4 Hz, 2H), 3.38 (t, J = 13.7 Hz, 2H), 3.03 (d, J = 13.5 Hz, 2H), 2.90 (d, J = 14.4 Hz, 2H), 2.77 (s, 3H), 2.34 (s, 3H), 2.23 (t, J = 12.6 Hz, 2H), 1.58 (s, 3H). LC / MS = 527 [M+H]. Human DGAT2 IC 50 = 8.9 nM. Using the appropriate reagents and procedures similar to those described in Example 144, the following compounds were synthesized and characterized by LC / MS. [Table 18] Example 146: 6-[[5-(1-hydroxy-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: 6-((5-acetyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (350.0 mg, 0.592 mmol) in toluene (1.97 mL) was added tributyl(1-ethoxyvinyl)tin (300.0 μL, 0.888 mmol) and (PPh3)4Pd (68.4 mg, 0.0590 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 7 hours, then cooled to 45° C., and THF (2.00 mL) and 4 M aqueous HCl (2.00 mL) were added. The solution was stirred at 45° C. for 1 h, then diluted with saturated aqueous NaHCO and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to provide the title compound.

[0296] LC / MS = 555 [M+H]. Step B: 6-[[5-(1-hydroxy-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide Methylmagnesium bromide (721 μL, 2.16 mmol) was added to a stirred solution of 6-((5-acetyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (300.0 mg, 0.541 mmol) in THF (5.00 mL) at 0° C. The resulting mixture was stirred at 0° C. for 10 min, then quenched with saturated aqueous NaHCO, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by mass-triggered RP HPLC (C18, 40→80% CAN in water, 0.1% FA modifier) ​​to give the title compound.

[0297] 1H NMR (500 MHz, methanol-d4) δ 8.33 (d, J = 1.6 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.70 (d, J = 1.9 Hz, 1H), 7.62 (d, J = 9.9 Hz, 1H), 7.33 (dd, J = 9.8, 2.1 Hz, 1H), 4.75 (q, J = 8.5 Hz, 2H), 3.39 (d, J = 12.5 Hz, 2H), 3.03 (d, J = 13.6 Hz, 2H), 2.90 (d, J = 14.4 Hz, 2H), 2.78 (s, 3H), 2.24 (t, J = 12.3 Hz, 2H), 1.58 (d, J = 5.8 Hz, 9H). LC / MS = 571 [M+H]. Human DGAT2 IC 50 = 102 nM. Example 147: 6-[[5-(1-fluoro-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] DAST (31.3 μL, 0.237 mmol) was added to a stirred solution of 6-((5-(2-hydroxypropan-2-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (45.0 mg, 0.0790 mmol) in DCM (526 μL) at −78° C. The resulting mixture was stirred at room temperature for 20 minutes, then cooled to 0° C. and quenched with MeOH and water. The resulting solution was concentrated under reduced pressure and directly purified by mass-triggered RP HPLC (C18, 20→60% ACN in water, 0.1% FA modifier) ​​to provide the title compound.

[0298] 1H NMR (500 MHz, methanol-d4) δ 8.35 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 1.6 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.34 (dd, J = 9.7, 2.1 Hz, 1H), 4.78 (q, J = 8.4 Hz, 2H), 3.43 - 3.35 (m, 2H), 3.03 (d, J = 13.8 Hz, 2H), 2.90 (d, J = 14.4 Hz, 2H), 2.78 (s, 3H), 2.24 (t, J = 12.5 Hz, 2H), 1.72 (d, J = 21.9 Hz, 6H), 1.58 (s, 3H). LC / MS = 573 [M+H]. Human DGAT2 IC 50 = 41 nM. Example 148: 6-[[5-hydroxy-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] To a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (70.0 mg, 0.118 mmol), PdCl(dppf) (13.0 mg, 0.0180 mmol), and KOAc (34.8 mg, 0.355 mmol) in 1,4-dioxane (395 μL) was added bis(pinacolato)diboron (67.6 mg, 0.266 mmol) at room temperature. The resulting mixture was stirred at 100° C. for 1 h, then cooled to room temperature and quenched with water (0.100 mL) and HOAc (20.3 μL, 0.355 mmol). The mixture was stirred at room temperature for an additional 1 h, then HO (31.1 μL, 0.355 mmol) was added. After 2 h, the reaction mixture was diluted with brine and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to provide the title compound.

[0299] 1 H NMR (500 MHz, methanol-d4) δ 8.19 (s, 1H), 7.59 (d, J = 9.7 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.29 (dd, J = 9.8, 2.1 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H), 4.68 (q, J = 8.4 Hz, 2H), 3.42 - 3.35 (m, 2H), 3.02 (d, J = 13.5 Hz, 2H), 2.90 (d, J = 14.2 Hz, 2H), 2.76 (s, 3H), 2.23 (t, J = 13.5 Hz, 2H), 1.58 (s, 3H). LC / MS = 529 [M+H]. Human DGAT2 IC 50 = 80 nM. Example 149: 6-[[5-cyano-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Zinc cyanide (35.7 mg, 0.304 mmol) was added to a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (60.0 mg, 0.101 mmol), PdCl(dppf) (7.42 mg, 0.0102 mmol), and zinc (1.33 mg, 0.0200 mmol) in DMF (338 μL) at room temperature. The resulting mixture was stirred at 120° C. in a microwave for 1 h, then filtered and purified directly by mass-triggered RP HPLC (C18, 20→60% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0300] 1H NMR (500 MHz, methanol-d4) δ 8.42 (d, J = 1.6 Hz, 1H), 8.16 (d, J = 1.7 Hz, 1H), 7.95 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 9.8 Hz, 1H), 7.37 (dd, J = 9.8, 2.1 Hz, 1H), 4.86 - 4.77 (m, 3H), 3.38 (t, J = 10.5 Hz, 2H), 3.03 (d, J = 13.5 Hz, 2H), 2.90 (d, J = 14.8 Hz, 2H), 2.78 (s, 3H), 2.24 (t, J = 12.4 Hz, 2H), 1.58 (s, 3H). LC / MS = 538 [M+H]. Human DGAT2 IC 50 = 33 nM. Example 150: 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[5-methylsulfonyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide [ka] Sodium methanesulfinate (57.0 mg, 0.558 mmol) was added to a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (110.0 mg, 0.186 mmol) and copper(I) iodide (106 mg, 0.558 mmol) in DMSO (620 μL) at room temperature. The resulting mixture was stirred at 110 °C for 18 h, then saturated aqueous NaHCO was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes, then 0-10% MeOH / DCM) to afford the title compound.

[0301] 1H NMR (500 MHz, methanol-d4) δ 8.43 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.66 (d, J = 9.8 Hz, 1H), 7.39 (dd, J = 9.8, 2.1 Hz, 1H), 4.88 (s, 2H), 3.39 (d, J = 12.6 Hz, 2H), 3.23 (s, 3H), 3.03 (d, J = 13.7 Hz, 2H), 2.90 (d, J = 14.3 Hz, 2H), 2.79 (s, 3H), 2.24 (t, J = 13.4 Hz, 2H), 1.58 (s, 3H). LC / MS = 591 [M+H]. Human DGAT2 IC 50 = 58 nM. Example 151: 6-[3-methyl-2-[(4-methyl-1,1-dioxo-thian-4-yl)carbamoyl]imidazo[1,2-a]pyridin-6-yl]oxy-5-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid [ka] To a stirred solution of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (30.0 mg, 0.0550 mmol), KCO (15.2 mg, 0.110 mmol), Pd(OAc) (1.23 mg, 5.49 μmol), and DCPP (3.35 mg, 5.49 μmol) in DMSO (2.00 mL) and water (0.200 mL) was added CO (15 psi) at room temperature. The resulting mixture was stirred at 110° C. for 12 h and then purified directly by mass-triggered RP HPLC (C18, 31→51% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0302] 1H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J = 1.56 Hz, 1H), 8.29 (d, J = 1.96 Hz, 1H), 8.01 (d, J = 1.56 Hz, 1H), 7.90 (s, 1H), 7.66 (d, J = 9.78 Hz, 1H), 7.37 (dd, J = 2.15, 9.59 Hz, 1H), 5.05 (q, J = 8.87 Hz, 2H), 3.06 (br s, 4H), 2.83 (br d, J= 14.09 Hz, 2H), 2.69 (s, 3H), 1.94 - 2.13 (m, 2H), 1.43 (s, 3H). LC / MS = 557 [M+H]. Human DGAT2 IC 50 = >9990 nM. Example 152: 6-[5-(dimethylamino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide [ka] Step A: 3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide PdCl(dppf) (64.9 mg, 0.0890 mmol) was added to a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide (500.0 mg, 0.888 mmol), bis(pinacolato)diboron (451 mg, 1.78 mmol), and KOAc (174 mg, 1.78 mmol) in 1,4-dioxane (10.0 mL) under a N atmosphere at room temperature. The resulting mixture was stirred at 100 °C for 3 h, then cooled to room temperature, diluted with water, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-100% EtOAc / hexanes) to afford the title compound.

[0303] LC / MS = 611 [M+H] Step B: 6-((5-((4-methoxybenzyl)amino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidethietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred solution of 3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide (450.0 mg, 0.737 mmol) and (4-methoxyphenyl)methanamine (303 mg, 2.21 mmol) in ACN (5.00 mL) was added copper(II) acetate (26.8 mg, 0.147 mmol), boric acid (91.0 mg, 1.47 mmol), and 4 Å molecular sieves at room temperature. The resulting mixture was stirred at 80 °C under an O atmosphere for 16 h and then concentrated under reduced pressure. The residue was dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica preparative thin-layer chromatography (33% EtOAc / hexanes) to provide the title compound.

[0304] LC / MS = 620 [M+H]. Step C: 6-((5-amino-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidethietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide At room temperature, 6-((5-((4-methoxybenzyl)amino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide (10.0 mg, 0.0160 mmol) was dissolved in TFA (0.500 mL). The resulting mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The crude material was purified by silica preparative thin layer chromatography (100% EtOAc) to provide the title compound.

[0305] LC / MS = 500 [M+H] Step D: 6-((5-(dimethylamino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidethietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide To a stirred solution of 6-((5-amino-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide (25.0 mg, 0.0500 mmol) in MeOH (0.500 mL) was added formaldehyde (6.62 mg, 0.220 mmol) and sodium triacetoxyborohydride (53.0 mg, 0.250 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then diluted with water, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by mass-triggered RP HPLC (C18, 31→51% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0306] 1 H NMR (500 MHz, methanol-d4) δ 8.32 (s, 1H), 7.69 (d, J = 9.78 Hz, 1H), 7.52 (br d, J = 9.78 Hz, 1H), 7.31 (d, J = 2.35 Hz, 1H), 7.07 (d, J = LC / MS = 528 [M+H]. Human DGAT2 IC 50 = 63 nM Example 153: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide [ka] Step A: Ethyl 6-hydroxyimidazo[1,2-b]pyridazine-2-carboxylate To a stirring mixture of ethyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (5.00 g, 22.16 mmol), N-hydroxyacetamide (3.33 g, 44.3 mmol), and KCO (9.19 g, 66.5 mmol) was added DMF (111 mL), and the reaction mixture was heated to 80° C. After 16 h, the reaction mixture was treated with hydrogen chloride (111 mL, 111 mmol) (1 M, aqueous solution), and the precipitated solid was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure to give the desired product.

[0307] LC / MS = 208 [M+1] Step B: Ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylate 5-Chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (648 mg, 2.03 mmol) was added to a stirred solution of ethyl 6-hydroxyimidazo[1,2-b]pyridazine-2-carboxylate (200 mg, 965 μmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (127 mg, 386 μmol), CuI (46.0 mg, 241 μmol), and K3PO4 (512 mg, 2.41 mmol) in DMSO (4.8 mL), and the reaction mixture was heated to 80 °C. After 16 h, the reaction mixture was diluted with ethyl acetate and filtered through a plug of SiO2. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with LiCl (1 M, aq.) and NaCl (sat., aq.), dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to afford the title compound.

[0308] LC / MS = 399 [M+1] Step C: Lithium 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylate To a stirring solution of ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylate (111 mg, 278 μmol) in acetonitrile (1.9 mL) and water (930 μL) was added lithium hydroxide (6.67 mg, 278 μmol). After 30 minutes, the reaction mixture was concentrated under reduced pressure to provide the title compound.

[0309] LC / MS = 371 [M-5] Step D: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide To a stirred solution of lithium 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylate (30 mg, 80 μmol), DIPEA (42 μL, 239 μmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (16.70 mg, 84 μmol) in DMF (797 μL) was added HATU (31.8 mg, 84 μmol). After 18 h, the reaction mixture was filtered, and the filtrate was purified by RP HPLC (10-80% ACN / water with 0.1% FA modifier) ​​to give the title compound. LC / MS analysis showed high conversion to the desired product.

[0310] LC / MS = 516 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.46 (s, 1H), 8.28 (d, J = 9.8 Hz, 1H), 8.04 - 7.99 (m, 2H), 7.95 (s, 1H), 7.36 (d, J = 9.8 Hz, 1H), 6.44 - 6.12 (m, 1H), 4.50 (td, J = 14.6, 3.3 Hz, 2H), 3.12 - 3.03 (m, 4H), 2.83 (d, J = 13.9 Hz, 2H), 2.03 (dt, J = 14.5, 7.0 Hz, 2H), 1.44 (s, 3H). Human DGAT2 IC 50 = 3.2 nM Using the appropriate reagents and procedures similar to those described in Example 153, the following compounds were synthesized and characterized by LC / MS. [Table 19] TIFF2025537514000114.tif76170 Example 166: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide [ka] Step A: Ethyl 3-bromo-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylate To a stirring solution of ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylate (468 mg, 1.17 mmol) in DCE (5868 μL) was added 1-bromopyrrolidine-2,5-dione (230 mg, 1.29 mmol) in one portion at 20° C. After 1 h, the reaction mixture was warmed to 40° C. After 16 h, the crude residue was cooled to room temperature and purified by silica gel flash column chromatography using a gradient of 0-90% ethyl acetate in hexanes to provide the title compound.

[0311] LC / MS = 478 [M+1] Step B: Ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-b]pyridazine-2-carboxylate To a 5 mL screw-cap vial containing a magnetic stir bar, ethyl 3-bromo-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylate (548 mg, 1.15 mmol), and CatAXium A Pd G2 (77 mg, 115 μmol) was charged tetrahydrofuran (11.5 mL) and trimethylaluminum (1 M in toluene, 1.15 mL, 2.30 mmol) at 20 °C. The reaction mixture was heated to 60 °C. After 16 h, the reaction mixture was diluted with EtOAc and quenched with MeOH, followed by water. The reaction mixture was filtered through Celite and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq.), dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was subjected to SiO2 flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to afford the title compound.

[0312] LC / MS = 413 [M+1] Step C: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-b]pyridazine-2-carboxylic acid Lithium hydroxide (10.50 mg, 0.44 mmol) was added to a stirring solution of ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-b]pyridazine-2-carboxylate (181 mg, 0.44 mmol) in tetrahydrofuran (2.5 mL), methanol (1.3 mL), and water (600 μL) at 20° C. After 16 h, the reaction mixture was acidified with HCl (1 M, aq), diluted with water, and extracted with EtOAc. The combined organic fractions were washed with NaCl (sat. aq.), dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound.

[0313] LC / MS = 385 [M+1] Step D: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide To a stirring solution of 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-b]pyridazine-2-carboxylic acid (33 mg, 86 μmol), DIPEA (37 μL, 214 μmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (17 mg, 86 μmol) in DCM (572 μL) was added HATU (33 mg, 86 μmol). After 18 h, the reaction mixture was subjected to SiO flash column chromatography using a gradient of 0-10% MeOH in DCM to give the title compound.

[0314] LC / MS = 530 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.23 ​​(d, J = 9.7 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.98 (d, J = 2.1 Hz, 1H), 7.91 (s, 1H), 7.31 (d, J = 9.7 Hz, 1H), 6.45 - 6.19 (m, 1H), 4.51 (td, J = 14.7, 3.3 Hz, 2H), 3.07 (d, J = 5.6 Hz, 4H), 2.85 (d, J = 15.0 Hz, 2H), 2.56 (s, 3H), 2.03 (dt, J = 14.1, 7.0 Hz, 2H), 1.45 (s, 3H). Human DGAT2 IC 50 = 6.8 nM Using the appropriate reagents and procedures similar to those described in Example 166, the following compounds were synthesized and characterized by LC / MS. [Table 20] Example 168: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide [ka] Step A: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate At 20° C., 6-chloro-5-methylpyridazin-3-amine (5.00 g, 34.8 mmol) was dissolved in dioxane (232 mL) and ethyl 3-bromo-2-oxopropanoate (4.37 mL, 34.8 mmol). The mixture was heated to 100° C. After 6 h, the solvent was removed under reduced pressure, and the crude residue was dissolved with ethyl acetate. The organic phase was washed with LiCl (1 M, aq.), NaCl (sat., aq.), dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was subjected to SiO flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to provide the title compound.

[0315] LC / MS = 240 [M+1]. Step B: Ethyl 6-hydroxy-7-methylimidazo[1,2-b]pyridazine-2-carboxylate To a stirring mixture of ethyl 6-chloro-7-methylimidazo[1,2-b]pyridazine-2-carboxylate (4.50 g, 18.78 mmol), N-hydroxyacetamide (2.82 g, 37.6 mmol), and KCO (7.79 g, 56.3 mmol) was added DMSO (94 mL), and the reaction mixture was heated to 80 °C for 16 h. LC / MS showed high conversion to the desired product. The reaction mixture was treated with hydrogen chloride (94 mL, 94 mmol) (1 M aqueous solution), and the precipitated solid was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure to give the title compound.

[0316] LC / MS = 222 [M+1] Step C: Ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methylimidazo[1,2-b]pyridazine-2-carboxylate 5-Chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (1.21 g, 3.80 mmol) was added to a stirred solution of ethyl 6-hydroxy-7-methylimidazo[1,2-b]pyridazine-2-carboxylate (400 mg, 1.81 mmol), N1,N2-bis(4-hydroxy-2,6-dimethylphenyl)oxalamide (238 mg, 723 μmol), CuI (86 mg, 452 μmol), and K3PO4 (960 mg, 4.52 mmol) in DMSO (9.04 mL), and the reaction mixture was heated to 80 °C. After 16 h, the reaction mixture was diluted with ethyl acetate and filtered through a plug of SiO2. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with LiCl (1 M, aq.) and NaCl (sat., aq.), dried over MgSO, filtered, and concentrated under reduced pressure. The crude residue was subjected to silica gel flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to afford the title compound.

[0317] LC / MS = 413 [M+1] Step D: Lithium 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methylimidazo[1,2-b]pyridazine-2-carboxylate To a stirred solution of ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methylimidazo[1,2-b]pyridazine-2-carboxylate (77 mg, 187 μmol) in acetonitrile (1.2 mL) and water (622 μL) was added lithium hydroxide (4.47 mg, 187 μmol) at 20° C. After 30 minutes, the reaction mixture was concentrated under reduced pressure to give the crude title compound.

[0318] LC / MS = 385 [M-5] Step E: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide To a stirring solution of lithium 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methylimidazo[1,2-b]pyridazine-2-carboxylate (36 mg, 92 μmol), DIPEA (48.3 μL, 276 μmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (19.32 mg, 97 μmol) in DMF (922 μL) was added HATU (36.8 mg, 97 μmol). After 18 h, the solvent was removed under reduced pressure, and the crude residue was subjected to silica gel flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to provide the title compound.

[0319] 1 H NMR (500 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.12 (s, 1H), 8.02 (q, J = 2.1 Hz, 2H), 7.96 (s, 1H), 7.90 (s, 1H), 6.25 (tt, J = 54.0, 3.2 Hz, 1H), 4.48 (td, J = 14.7, 3.2 Hz, 2H), 3.09 - 3.04 (m, 4H), 2.83 (d, J = 14.2 Hz, 2H), 2.35 (s, 3H), 2.02 (dt, J = 14.6, 6.6 Hz, 2H), 1.43 (s, 3H).LC / MS = 530 [M+1]. Human DGAT2 IC 50 = 1.0 nM. Using the appropriate reagents and procedures similar to those described in Example 168, the following compounds were synthesized and characterized by LC / MS. [Table 21] Example 175: 3,7-dichloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide [ka] At 20° C., 6-chloro-5-methylpyridazin-3-amine (5.00 g, 34.8 mmol) was dissolved in dioxane (232 mL) and ethyl 3-bromo-2-oxopropanoate (4.37 mL, 34.8 mmol). The mixture was heated to 100° C. After 6 h, the solvent was removed under reduced pressure, and the crude residue was dissolved with ethyl acetate. The organic phase was washed with LiCl (1 M, aq.), NaCl (sat., aq.), dried over MgSO, filtered, and concentrated under reduced pressure. The crude material was subjected to SiO flash column chromatography using a gradient of 0-100% ethyl acetate in hexanes to provide the title compound.

[0320] 1 H NMR (500 MHz, methanol-d4) δ 8.55 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.95 (d, J = 1.8 Hz, 1H), 6.31 - 6.04 (m, 1H), 4.69 (d, J = 14.7 Hz, 2H), 4.48 (td, J = 14.2, 3.3 Hz, 2H), 4.30 (d, J = 14.8 Hz, 2H), 1.87 (s, 4H). LC / MS = 557 [M+1]. Human DGAT2 IC 50 = 0.4 nM Using the appropriate reagents and procedures similar to those described in Example 175, the following compounds were synthesized and characterized by LC / MS. [Table 22] Example 180: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide [ka] Step A: Methyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine-2-carboxylate A solution of (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol (174 mg, 780 μmol) in DMF (2.4 mL) was treated sequentially with NaH (34.0 mg, 851 μmol) and methyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (150 mg, 709 μmol) at room temperature. After 15 min, the mixture was subjected to silica gel flash column chromatography using a gradient of 0 to 100% EtOAc / hexanes to give the title compound.

[0321] LC / MS = 399 [M+1]. Step B: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine-2-carboxylic acid A mixture of methyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine-2-carboxylate (236 mg, 0.592 mmol) and LiOH·water (37.3 mg, 888 μmol) in water (1.5 mL) and acetonitrile (1.5 mL) was stirred at 40° C. After 15 min, the solvent was removed under reduced pressure to give the title compound.

[0322] LC / MS = 385 [M+1] Step C: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide A mixture of 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)imidazo[1,2-b]pyridazine-2-carboxylic acid (70 mg, 82 μmol) and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (43.6 mg, 218 μmol) in DMF (910 μL) and DIPEA (111 μL, 637 μmol) was treated with HATU (83 mg, 0.218 mmol) at room temperature. After 30 min, the mixture was subjected to silica gel flash column chromatography using a gradient of 0 to 100% EtOAc / hexanes, followed by 0 to 10% methanol in DCM to give the title compound.

[0323] 1H NMR (500 MHz, methanol-d4) δ 8.32 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 9.8 Hz, 1H), 7.76 - 7.71 (m, 1H), 7.03 (d, J = 9.8 Hz, 1H), 6.23 (tt, J = 54.6, 3.5 Hz, 1H), 5.57 (s, 2H), 4.44 (td, J = 13.8, 3.5 Hz, 2H), 3.03 (d, J = 13.8 Hz, 2H), 2.90 (d, J = 14.5 Hz, 2H), 2.23 (t, J = 13.7 Hz, 2H), 1.57 (s, 3H). LC / MS = 530 [M+1]. Human DGAT2 IC 50 = 53 nM. Using the appropriate reagents and procedures similar to those described in Example 180, the following compounds were synthesized and characterized by LC / MS. [Table 23] Example 184: (S)-6-(2-ethoxyphenoxy)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-2-carboxamide [ka] Step A: Ethyl 6-(2-ethoxyphenoxy)imidazo[1,2-a]pyridine-2-carboxylate A mixture of 2-ethoxylphenol (51.3 mg, 372 μmol), copper(II) acetate (7.08 mg, 37.2 μmol), cesium carbonate (242 mg, 743 μmol), 1,10-phenanthroline (6.70 mg, 37.2 μmol), and ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate (100 mg, 372 μmol) in DMSO (1.9 mL) was stirred at 100° C. for 18 h, after which the mixture was cooled to room temperature and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (0-10% MeOH / DCM) to provide the title compound.

[0324] LC / MS = 327 [M+H] Step B: 6-(2-ethoxyphenoxy)imidazo[1,2-a]pyridine-2-carboxylic acid To a mixture of ethyl 6-(2-ethoxyphenoxy)imidazo[1,2-a]pyridine-2-carboxylate (121 mg, 0.372 mmol) in THF (2.2 mL), MeOH (1.1 mL), and water (0.44 mL) was added lithium hydroxide monohydrate (16.0 mg, 0.372 mmol) at room temperature. After 18 h, the mixture was concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0325] LC / MS = 299 [M+1]. Step C: (S)-6-(2-ethoxyphenoxy)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-2-carboxamide To a mixture of 6-(2-ethoxyphenoxy)imidazo[1,2-a]pyridine-2-carboxylic acid (111 mg, 0.372 mmol), (S)-tetrahydrofuran-3-aminium chloride (55.2 mg, 0.446 mmol), and DIPEA (195 μL, 1.12 mmol) in DMF (1.5 mL) was added HATU (184 mg, 0.484 mmol) at room temperature. After 2 h, the reaction mixture was concentrated under reduced pressure. The crude material was purified by mass-triggered RP HPLC (C18, 30→60% ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0326] LC / MS = 368 [M+1]. 1H NMR (500 MHz, methanol-d4) δ 8.18 (s, 1H), 8.00 - 7.87 (m, 1H), 7.54 (d, J = 9.8 Hz, 1H), 7.31 - 7.15 (m, 2H), 7.15 - 7.09 (m, 2H), 6.99 (td, J = 7.7, 1.5 Hz, 1H), 4.60 (ddd, J = 9.6, 7.6, 3.8 Hz, 1H), 4.16 - 3.89 (m, 4H), 3.85 (td, J = 8.4, 5.6 Hz, 1H), 3.75 (dd, J = 9.2, 3.6 Hz, 1H), 2.32 (dq, J = 13.0, 7.7 Hz, 1H), 2.07 - 1.94 (m, 1H), 1.21 (t, J = 7.0 Hz, 3H). Human DGAT2 IC 50 = 6342 nM Example 185: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrazine-2-carboxamide [ka] Step A: Ethyl 6-bromoimidazo[1,2-a]pyrazine-2-carboxylate To a mixture of 5-bromopyrazin-2-amine (2.00 g, 11.5 mmol) in 1,4-dioxane (20 mL) was added ethyl 3-bromo-2-oxopropanoate (3.36 g, 17.2 mmol). The resulting mixture was stirred at 100 °C for 12 h, after which the mixture was cooled to room temperature and filtered. The filtrate was diluted with saturated aqueous NaHCO to pH = 8, and the solution was extracted with EtOAc. The combined organic layers were washed with water, then brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash column chromatography (20% EtOAc / hexanes) to provide the title compound.

[0327] LC / MS = 270 and 272 [M+H] Step B: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrazine-2-carboxylate A mixture of ethyl 6-bromoimidazo[1,2-a]pyrazine-2-carboxylate (100 mg, 0.370 mmol), 5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-ol (101 mg, 0.444 mmol), KCO (102 mg, 0.741 mmol), N,N-dimethylglycine (7.64 mg, 0.0741 mmol), and copper(I) iodide (7.05 mg, 0.0371 mmol) in DMSO (2.0 mL) was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction mixture was directly purified by RP HPLC (C18, ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0328] LC / MS = 417 [M+H] Step C: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrazine-2-carboxylic acid To a mixture of ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrazine-2-carboxylate (15 mg, 0.037 mmol) in MeOH (1.0 mL) and water (1.0 mL) was added lithium hydroxide monohydrate (2.7 mg, 0.11 mmol) at room temperature. After 1 h, the mixture was dissolved in water, acidified with 1 M HCl to pH = 4, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0329] LC / MS = 389 [M+1] Step D: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrazine-2-carboxamide To a mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrazine-2-carboxylic acid (13 mg, 0.033 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (8.0 mg, 0.049 mml), and DIPEA (29 μL, 0.17 mmol) in DMF (1.0 mL) was added HATU (25 mg, 0.067 mmol) at 30° C. After 2 h, the reaction mixture was concentrated under reduced pressure. The crude material was purified by RP HPLC (C18, ACN in water, 0.1% FA modifier) ​​to give the title compound.

[0330] LC / MS = 534 [M+1]. 1 H NMR (400 MHz, methanol-d4) δ 8.89 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 8.08 (br s, 1H), 7.79 (br d, J = 1.96 Hz, 1H), 7.73 (br d, J = 1.96 Hz, 1H), 4.71 (q, J = 8.31 Hz, 2H), 3.30 - 3.34 (m, 1H), 3.26 (br s, 1H), 3.01 (br d, J = 14.18 Hz, 2H), 2.89 (br d, J = 14.67 Hz, 2H), 2.17 - 2.25 (m, 2H), 1.54 (s, 3H). Human DGAT2 IC 50 = 5.3 nM Example 186: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide [ka] Step A: tert-butyl (tert-butoxycarbonyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamate To a suspension of tert-butyl (5-bromopyrimidin-2-yl)(tert-butoxycarbonyl)carbamate (500 mg, 1.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (407 mg, 1.60 mmol), and potassium acetate (393 mg, 4.01 mmol) in DMF (8.0 mL) was added Pd(OAc) (150 mg, 0.668 mmol). The mixture was stirred at 85 °C for 16 h, after which the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0331] LCMS-B(OH)2=184.0 [M+H-156] Step B: tert-Butyl (tert-butoxycarbonyl)(5-hydroxypyrimidin-2-yl)carbamate To a suspension of tert-butyl (tert-butoxycarbonyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamate (560 mg, 1.33 mmol) in THF (4.0 mL) and water (4 mL) was added NaBO 4H O (422 mg, 3.99 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure to give the title compound. The crude product was used without purification.

[0332] LC / MS=312 [M+H] Step C: tert-butyl (tert-butoxycarbonyl)(5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-yl)carbamate A mixture of tert-butyl (tert-butoxycarbonyl)(5-hydroxypyrimidin-2-yl)carbamate (180 mg, 0.578 mmol), 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (159 mg, 0.694 mmol), and CsCO (377 mg, 1.16 mmol) in DMA (8.0 mL) was stirred at 50 °C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was purified by preparative TLC (25% EtOAc / PE) to provide the title compound.

[0333] LC / MS= 321 [M+H-200] Step D: 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-amine To a mixture of tert-butyl (tert-butoxycarbonyl)(5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-yl)carbamate (170 mg, 0.326 mmol) in DCM (5.0 mL) was added TFA (1.0 mL) and stirred at room temperature for 1 h, after which the reaction was concentrated under reduced pressure. The mixture was diluted with water and EtOAc, then diluted with saturated aqueous Na2CO3 and adjusted to pH = 7. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0334] LC / MS=321 [M+H] Step E: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrimidine-2-carboxylate To a mixture of 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-amine (100 mg, 0.312 mmol) in 1,4-dioxane (10.0 mL) was added ethyl 3-bromo-2-oxopropanoate (73.0 mg, 0.374 mmol). The mixture was stirred at 80° C. for 12 hours, after which the mixture was concentrated under reduced pressure. The residue was directly purified by preparative TLC (20% EtOAc / PE) to provide the title compound.

[0335] LC / MS=417 [M+H] Step F: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrimidine-2-carboxylic acid To a mixture of ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrimidine-2-carboxylate (40.0 mg, 0.096 mmol) in THF (3.0 mL) and water (1.0 mL) was added LiOH.HO (4.03 mg, 0.096 mmol). The reaction was stirred at room temperature for 1 h, after which the mixture was diluted with water and acidified with 1 M HCl to pH = 4. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound. The crude product was used without purification.

[0336] LC / MS=389 [M+H] Step G: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide To a mixture of 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrimidine-2-carboxylic acid (38 mg, 0.033 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (19 mg, 0.12 mml), and DIPEA (34 μL, 0.20 mmol) in DMF (3.0 mL) was added HATU (56 mg, 0.15 mmol) at room temperature. After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC (20% EtOAc / PE) to provide the title compound.

[0337] LC / MS = 534 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 8.61 (d, J=7.00 Hz, 2H), 8.07 (s, 1H), 7.79 (s, 1H), 7.27-7.46 (m, 2H), 4.52 (q, J=7.93 Hz, 2H), 3.21-3.30 (m, 2H), 2.97 (br d, J=12.97 Hz, 2H), 2.86 (br d, J=14.50 Hz, 2H), 2.26-2.36 (m, 2H), 1.57 (br s, 3H). Human DGAT2 IC 50 = 33 nM Assay Insect cell expression and membrane preparation Sf-9 insect cells were maintained in Grace's insect cell medium containing 10% heat-inactivated fetal bovine serum, 1% Pluronic F-68, and 0.14 μg / mL kanamycin sulfate at 27°C in a shaking incubator. Cells were harvested after infection with an untagged baculovirus expressing human DGAT2 (hDGAT2) at a multiplicity of infection (MOI) of 3 for 48 hours. The cell pellet was suspended in a buffer containing 10 mM Tris-HCl (pH 7.5), 1 mM EDTA, 250 mM sucrose, and a complete protease inhibitor cocktail (Sigma-Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2,000 × g for 15 minutes. Membrane fractions were isolated by ultracentrifugation (100,000 × g), resuspended in the same buffer, and frozen (−80°C) for later use. Protein concentrations were measured using the Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific). Protein expression was analyzed by immunoblotting with rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa Fluor® 647 (Abcam, ab150075), followed by detection using a Typhoon FLA9000 (GE Healthcare).

[0338] LC / MS / MS analysis method LC / MS / MS analysis was performed using a Thermal Fisher LX4-TSQ Vantage system. This system consisted of an Agilent binary high-performance liquid chromatography (HPLC) pump and a TSQ Vantage triple quadrupole MS / MS instrument. For each sample, 2 μL of sample from the upper organic layer of the in-plate liquid-liquid extraction was injected onto a Thermo Betabasic C4 column (2.1 mm × 20 mm, 5 μm particle size). The sample was then eluted using the following conditions: mobile phase: isopropanol:acetonitrile / 10 mM ammonium formate = 50 / 35 / 15 (v / v / v), flow rate: 0.8 mL / min, temperature: 25 °C. Data were acquired in positive mode using a heated electrospray ionization (HESI) interface. The operating parameters for the TSQ Vantage MS / MS instrument were as follows: spray voltage 3000 V, capillary temperature 280°C, vaporizer temperature 400°C, sheath gas 40 arbitrary units, auxiliary gas 10 arbitrary units, S-lens 165, and collision gas 1.0 mTorr. 13 C 18 - Triolein (Q1: 920.8>Q3: 621.3) and internal standard 13 C 21 - Standard Reference Material (SRM) chromatograms of triolein (Q1: 923.8>Q3: 617.3) were collected for 33 seconds. Peak areas were integrated using Xcalibur Quan software. 13 C 18 -Triolein and internal standard 13 C 21 The ratio between the 100% ATP spiked with 100% triolein and that spiked with 100% triolein was used to obtain the percent inhibition and IC50 values. The percent compound inhibition was calculated by the following formula: % Inhibition = 1 - [(compound response - low control) / (high control - low control)] x 100%.

[0339] Potent compounds were titrated and IC 50 was calculated by a four-parameter sigmoidal curve fitting equation.

[0340] DGAT2 enzyme activity assay Using the membrane preparation described above, the enzyme product 13 C 18 -Triolein ( 13 DGAT2 activity was determined by measuring the amount of C-1,2,3-tri(cis-9-octadecenoyl)glycerol. The assay was performed in an ABgene 384-well assay plate at room temperature in a final volume of 25 μL. The assay mixture contained the following: assay buffer (100 mM Tris Cl, pH 7.0, 20 mM MgCl, 5% ethanol), 25 μM diolein, 5 μM C-oleoyl-CoA, and 8 ng / μL DGAT2 membranes.

Claims

1. Formula I: 【Chemistry 1】 [During the ceremony, X, Y and Z are N and C(R ４ ) independently selected from; R １ teeth, (1) Unsubstituted or 1, 2 or 3 R ５ 6-membered aryl substituted with (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R ５ ), which is replaced by (3) -(C １－６ ) alkyl-aryl (wherein the aryl is unsubstituted or has 1, 2 or 3 R ５ ), which is replaced by (4) -(C １－６ ) alkyl-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and wherein the heteroaryl is unsubstituted or contains 1, 2, or 3 R ５ ), which is replaced by (5) -(C １－３ ) haloalkyl, or (6) R 1, 2 or 3 ５ -(C １－６ ) alkyl-O—(C １－６ ) alkyl and R ２ teeth, (1) a 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) -(C １－６ ) alkyl-heterocyclyl, wherein the heterocyclyl is a 4-, 5-, or 6-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; (5) -(C １－６ ) alkyl-aryl, (6) -(C ３－６ ) cycloalkyl, (7) -(C ３－６ ) cyclic amines, (8) -(C ３－６ ) cycloalkyl-(C １－６ ) alkyl-SO ２ (C １－６ ) alkyl, or (9) An 8- to 10-membered fused bicyclic heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, wherein the bicyclic ring is optionally substituted independently with one, two, or three halogens. and wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R ６ is substituted with; R ３ teeth, (1) hydrogen, (2) halogens, (3) hydroxy, (4) (C １－６ ) alkyl, (5) (C １－６ ) haloalkyl, (6) (C １－６ ) alkylhydroxy, (7) (C １－６ ) alkoxyl-, (8) C(=O)NH ２ 、 (9) C(═O)OH, or (10) O-(C １－６ ) alkyl and If present, each R ４ is, independently, (1) hydrogen, (2) halogens, (3) (C １－３ ) alkyl, (4) C １－３ haloalkyl, or (5) Cyano and If present, each R ５ is, independently, (1) hydrogen, (2) halogens, (3) hydroxy, (4) CN, (5) C(O)OH, (6) (C １－６ ) alkyl, (7) (C １－６ ) haloalkyl, (8) (C １－３ ) alkyl-OH, (9) -OC １－６ Alkyl, (10) O-(C １－６ ) haloalkyl, (11) Special Order ２ (C １－６ ) alkyl, (12) N (C １－６ ) alkyl, (13) (C ３－６ ) cycloalkyl, (14) O-(C ３－７ ) cycloalkyl, (15) —OC optionally substituted with halogen １－６ alkyl-oxetanyl, or (16) O—C optionally substituted with halogen １－６ Alkyl-(C ３－７ ) cycloalkyl and If present, each R ６ is, independently, (1) halogens, (2) oxo, (3) OH, (4) C １－３ Alkyl, (5) C １－３ haloalkyl, (6) C １－３ alkyl-CN, (7) O.C. １－３ Alkyl, or (8) C(O)C １－３ Haloalkyl is] or a pharmaceutically acceptable salt thereof.

2. Formula Ib: 【Chemistry 2】 [During the ceremony, R １ teeth, (1) Unsubstituted or 1, 2 or 3 R ５ 6-membered aryl substituted with (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R ５ ), which is replaced by (3) -(C １－６ ) alkyl-aryl (wherein the aryl is unsubstituted or has 1, 2 or 3 R ５ ), which is replaced by (4) -(C １－６ ) alkyl-heteroaryl (wherein the heteroaryl is a 5- or 6-membered heteroaryl containing one nitrogen atom, where the heteroaryl is unsubstituted or has one, two, or three R ５ ), which is replaced by (5) -(C １－３ ) haloalkyl, or (6) R 1, 2 or 3 ５ -(C １－６ ) alkyl-O—(C １－６ ) alkyl and R ２ teeth, (1) a 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; (4) -(C １－６ ) alkyl-heterocyclyl, wherein the heterocyclyl is a 4-, 5-, or 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from S; (5) -(C １－６ ) alkyl-aryl, (6) -(C ３－６ ) cycloalkyl, (7) -(C ３－６ ) cyclic amines, (8) -(C ３－６ ) cycloalkyl-(C １－６ ) alkyl-SO ２ (C １－６ ) alkyl, or (9) A 10-membered fused bicyclic heterocyclic ring containing one heteroatom independently selected from N, O, and S, wherein the bicyclic ring is optionally substituted independently with one, two, or three halogens. and wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R ６ is substituted with; R ３ teeth, (1) hydrogen, (2) halogens, (3) hydroxy, (4) (C １－６ ) alkyl, (5) (C １－６ ) haloalkyl, (6) (C １－６ ) alkylhydroxy, (7) (C １－６ ) alkoxyl-, (8) C(=O)NH ２ 、 (9) C(=O)OH, or (10) O-(C １－６ ) alkyl and If present, each R ４ is, independently, (1) hydrogen, (2) halogens, (3) (C １－３ ) alkyl, (4) C １－３ haloalkyl, or (5) Cyano and If present, each R ５ is, independently, (1) hydrogen, (2) halogens, (3) hydroxy, (4) CN, (5) C(O)OH, (6) (C １－６ ) alkyl, (7) (C １－６ ) haloalkyl, (8) (C １－３ ) alkyl-OH, (9) -OC １－６ Alkyl, (10) O-(C １－６ ) haloalkyl, (11) Special Order ２ (C １－６ ) alkyl, (12) N (C １－６ ) alkyl, (13) (C ３－６ ) cycloalkyl, (14) O-(C ３－７ ) cycloalkyl, (15) —OC optionally substituted with halogen １－６ alkyl-oxetanyl, or (16) O—C optionally substituted with halogen １－６ Alkyl-(C ３－７ ) cycloalkyl and If present, each R ６ is, independently, (1) halogens, (2) oxo, (3) OH, (4) C １－３ Alkyl, (5) C １－３ haloalkyl, (6) C １－３ alkyl-CN, (7) O.C. １－３ Alkyl, or (8) C(O)C １－３ Haloalkyl is] The compound according to claim 1, represented by:

3. R １ teeth, (1) Unsubstituted or 1, 2 or 3 R ５ 6-membered aryl substituted with (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or contains one, two, or three R ５ ), which is replaced by (3) -CH ２ -aryl, wherein the aryl is unsubstituted or has 1, 2 or 3 R ５ ), which is replaced by (4) -CH ２ -heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing one nitrogen atom, wherein the heteroaryl is unsubstituted or has one, two or three R ５ ), which is replaced by (5) -(C １－３ ) haloalkyl, or (6) R 1, 2 or 3 ５ -(C １－６ ) alkyl-O—(C １－６ ) alkyl The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein:

4. R １ teeth, (1) Unsubstituted or -OC １－６ Alkyl or O—(C １－６ ) a 6-membered aryl substituted with haloalkyl; (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, hydroxy, —O(C １－６ ) alkyl, (C １－６ ) alkyl, (C １－６ ) haloalkyl, O—(C １－６ ) haloalkyl, (C １－３ ) alkyl-OH, SO ２ (C １－６ ) alkyl, N(C １－６ ) alkyl, (C ３－６ ) cycloalkyl, O—(C ３－７ ) cycloalkyl, CN, C(O)OH, O—C optionally substituted with halogen １－６ Alkyl-(C ３－７ ) —OC optionally substituted with cycloalkyl and halogen １－６ substituted with 1, 2, or 3 substituents independently selected from alkyl-oxetanyl; (3) -CH ２ -aryl, wherein the aryl is selected from the group consisting of halogen, -OC １－３ Alkyl or -OC １－３ substituted with 1 or 2 substituents independently selected from haloalkyl; (4) -CH ２ -heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with halogen, C １－３ Alkyl, C １－３ Haloalkyl, —OC １－３ Alkyl and —OC １－３ haloalkyl); (5) -(C １－３ ) haloalkyl, or (6) -(C １－６ ) alkyl-O—(C １－６ ) alkyl The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein:

5. R １ teeth, (1) Unsubstituted or OCH ２ CH ３ or OCH ２ CF ３ 6-membered aryl substituted with (2) 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with Cl, F, OH, CN, CH ３ , C.F. ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ２ OH, C(CH ３ ) ２ F, CF ３ , C(F) ２ CH ２ CH ３ ,C(O)OH,OCH ２ CH ３ , OCH ２ CF ３ , OCH ２ CHF ２ , OCH ２ C (F) ２ CH ３ , OCH ２ C (F) ２ CH(F) ２ , S(O) ２ CH ３ , cyclopropyl, OCH ２ -cyclopropyl, OCH ２ -fluorocyclopropyl, O-cyclobutyl, OCH ２ -oxetanyl-F and N(CH ３ ) ２ substituted with 1, 2, or 3 substituents independently selected from: (3) -CH ２ -aryl (wherein the aryl is F, OCH ２ CH ３ and OCHF ２ and substituted with one or two substituents independently selected from (4) -CH ２ -heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or OCH ２ CHF ２ , F, Cl, OCH ２ CF ３ , C.H. ３ , C.F. ３ and OCH ２ CH ３ substituted with one, two or three substituents selected from (5) CH ２ CH ２ CF ３ , or (6) CH ２ (CH) ３ ) ２ CH ２ OCH ２ CH ３ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein:

6. R ２ teeth, (1) a 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 or 2 nitrogen atoms; (4) -CH ２ heterocyclyl, wherein the heterocyclyl is a 4-, 5- or 6-membered heterocyclyl containing 1, 2 or 3 sulfur atoms; (5) -CH ２ -aryl, wherein the aryl is a 6-membered aryl; (6) -(C ３－６ ) cycloalkyl, (7) -(C ３－６ ) cyclic amines, (8) -(C ３－６ ) cycloalkyl-CH ３ -SO ２ CH ３ , or (9) A 10-membered fused bicyclic heterocyclic ring containing one oxygen atom, wherein the bicyclic ring is optionally substituted independently with one, two, or three halogens. and wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R ６ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, substituted with:

7. R ２ teeth, (1) Halogen, oxo, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkyl-CN and C(O)C １－３ a 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted with 1, 2 or 3 substituents independently selected from haloalkyl; (2) phenyl, (3) C １－３ a 5- or 6-membered heteroaryl containing one or two nitrogen atoms, optionally substituted by alkyl; (4) -CH ２ -heterocyclyl, where the heterocyclyl is oxo and C １－３ a 4- or 6-membered heterocyclyl containing 1, 2, or 3 sulfur atoms, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkyl; (5) -CH ２ -aryl, wherein the aryl is a 6-membered aryl; (6) Halogen, C １－３ Alkyl, C １－３ Haloalkyl, OC １－３ -(C ３－６ ) cycloalkyl, (7) -(C) optionally substituted with 1, 2, or 3 substituents independently selected from oxo ３－６ ) cyclic amines, (8) -(C ４ ) cycloalkyl-CH ３ -SO ２ CH ３ , or (9) chroman optionally substituted with 1, 2 or 3 halogens; wherein each alkyl, aryl, cycloalkyl, heteroaryl, cyclic amine, and heterocyclyl is unsubstituted or has 1, 2, 3, 4, or 5 R ６ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, substituted with:

8. R ２ teeth, (1) Halogen, oxo, CH ３ , C.H. ２ CF ３ , CH(CH ３ ) ２ , C.H. ２ CH ３ , C.H. ２ CN, C(O)CF ３ and (CH ３ ) ２ a 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from (2) phenyl, (3) CH ３ a 5- or 6-membered heteroaryl containing one or two nitrogen atoms, optionally substituted with (4) -CH ２ -heterocyclyl, where the heterocyclyl is oxo or CH ３ and a 4- or 6-membered heterocyclyl containing one sulfur atom, optionally substituted with 1, 2, or 3 substituents independently selected from (5) -CH ２ -aryl, wherein the aryl is a 6-membered aryl; (6) F, CH ３ , C.F. ３ , OH, F ２ and OCH ３ -(C ３－６ ) cycloalkyl, (7) -(C) optionally substituted with oxo ３－６ ) cyclic amines, (8) -(C ４ ) cycloalkyl-CH ３ -SO ２ CH ３ , or (9) chromans independently substituted with halogens; The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein:

9. R ２ is halogen, oxo, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkyl-CN and C(O)C １－３ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocyclyl containing one heteroatom selected from sulfur, nitrogen, and oxygen, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from haloalkyl.

10. R ２ is halogen, oxo, CH ３ , C.H. ２ CF ３ , CH(CH ３ ) ２ , C.H. ２ CH ３ , C.H. ２ CN, C(O)CF ３ and (CH ３ ) ２ The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocyclyl containing one heteroatom selected from sulfur, nitrogen, and oxygen, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

11. R ２ is oxo, CH ３ , C.H. ２ CF ３ , CH(CH ３ ) ２ , C.H. ２ CH ３ , C.H. ２ CN and (CH ３ ) ２ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocyclyl containing one sulfur atom, optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from:

12. R ２ is CH ３ , C.H. ２ CN and C(O)CF ３ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocyclyl containing one nitrogen atom, optionally substituted by 1, 2, or 3 substituents independently selected from:

13. R ２ is CH ３ , (CH ３ ) ２ and CH ２ CF ３ The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is a 4- to 7-membered heterocyclyl containing one oxygen atom, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

14. R ２ is a halogen, C １－３ Alkyl, C １－３ Haloalkyl, OC １－３ -(C ３－６ 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

15. R ２ is halogen, oxo, CH ３ , C.H. ２ CF ３ , CH(CH ３ ) ２ , C.H. ２ CH ３ , C.H. ２ CN, C(O)CF ３ and (CH ３ ) ２ -(C ３－６ 15. The compound according to any one of claims 1 to 8 and 14, or a pharmaceutically acceptable salt thereof, wherein:

16. R ３ is hydrogen, halogen, C １－６ Alkyl, OH, C(O)OH, C(O)NH ２ , O.C. １－６ Alkyl, C １－６ Haloalkyl or C １－６ The compound according to any one of claims 1 to 15, which is alkyl-OH, or a pharmaceutically acceptable salt thereof.

17. R ３ is hydrogen, halogen, C １－３ Alkyl, OH, C(O)OH, C(O)NH ２ , O.C. １－３ Alkyl, C １－３ Haloalkyl or C １－３ The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, which is alkyl-OH.

18. R ３ is hydrogen, Cl, F, CH ３ , CH(CH ３ ) ２ , C.H. ２ CH ３ , OH, C(O)OH, C(O)NH ２ , OCH ３ , C.F. ３ or CH ２ 18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R is OH.

19. R ３ is hydrogen or CH ３ The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein:

20. R ３ The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

21. R ３ is CH ３ 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein:

22. If present, each R ４ is hydrogen, halogen, C １－３ Alkyl, C １－３ 22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, independently selected from haloalkyl and CN.

23. If present, each R ４ is hydrogen, CH ３ ,F,Cl,CH(CH ３ ) ２ , C.F. ３ , C.H. ２ CH ３ 23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, independently selected from:

24. If present, each R ４ is hydrogen, Cl, F and CH ３ 22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, independently selected from:

25. If present, each R ５ is hydrogen, halogen, hydroxy, CN, C(O)OH, (C １－６ ) alkyl, (C １－６ ) haloalkyl, (C １－３ ) alkyl-OH, —OC １－６ Alkyl, O—(C １－６ ) haloalkyl, SO ２ (C １－６ ) alkyl, N(C １－６ ) alkyl, (C ３－６ ) cycloalkyl, O—(C ３－７ ) cycloalkyl, optionally substituted with halogen, —OC １－６ Alkyl-oxetanyl and O—C optionally substituted with halogen １－６ Alkyl-(C ３－７ 25. The compound according to any one of claims 1 to 3 and 6 to 24, or a pharmaceutically acceptable salt thereof, wherein R is 1 or 2;

26. If present, each R ５ are hydrogen, Cl, F, OH, CN, CH ３ , C.F. ３ , C.H. ２ CH ３ , CH(CH ３ ) ２ , C(CH ３ ) ２ OH, C(CH ３ ) ２ F, CF ３ , C(F) ２ CH ２ CH ３ ,C(O)OH,OCH ２ CH ３ , OCHF ２ , OCH ２ CF ３ , OCH ２ CHF ２ , OCH ２ C (F) ２ CH ３ , OCH ２ C (F) ２ CH(F) ２ , S(O) ２ CH ３ , cyclopropyl, OCH ２ -cyclopropyl, OCH ２ -fluorocyclopropyl, O-cyclobutyl, OCH ２ -oxetanyl-F and N(CH ３ ) ２ The compound according to any one of claims 1 to 3 and 6 to 25, or a pharmaceutically acceptable salt thereof, wherein

27. If present, each R ６ is halogen, oxo, OH, C １－３ Alkyl, C １－３ Haloalkyl, C １－３ Alkyl-CN, OC １－３ Alkyl and C(O)C １－３ 27. The compound of any one of claims 1 to 7, 16 to 26, or a pharmaceutically acceptable salt thereof, independently selected from haloalkyl.

28. If present, each R ６ is halogen, oxo, CH ３ , C.F. ３ , OH, CH ２ CF ３ , CH(CH ３ ) ２ , C.H. ２ CH ３ , OCH ３ , C.H. ２ CN, C(O)CF ３ and (CH ３ ) ２ The compound according to any one of claims 1 to 7 and 16 to 27, or a pharmaceutically acceptable salt thereof, independently selected from:

29. X is C(R ４ ) and Y is C(R ４ ) and Z is C(R ４ 29. The compound according to any one of claims 1, 3 to 28, or a pharmaceutically acceptable salt thereof, wherein

30. X is N and Y is C(R ４ ) and Z is C(R ４ 29. The compound according to any one of claims 1, 3 to 28, or a pharmaceutically acceptable salt thereof, wherein

31. X is C(R ４ ), Y is N, and Z is C(R ４ 29. The compound according to any one of claims 1, 3 to 28, or a pharmaceutically acceptable salt thereof, wherein

32. X is C(R ４ ) and Y is C(R ４ ) and Z is N, or a pharmaceutically acceptable salt thereof.

33. R １ teeth, 【Transformation 3】 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein:

34. R １ teeth, 【Chemistry 4】 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein:

35. R １ teeth, 【Transformation 5】 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein:

36. R １ teeth, 【Transformation 6】 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein:

37. R １ teeth, 【Transformation 7】 33. The compound according to any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein:

38. R ２ teeth, 【Transformation 8】 The compound according to any one of claims 1 to 11 and 16 to 32, or a pharmaceutically acceptable salt thereof, wherein

39. R ２ teeth, 【Chemistry 9】 The compound according to any one of claims 1 to 11 and 16 to 32, or a pharmaceutically acceptable salt thereof, wherein

40. below 【Chemistry 10】 【change】 【change】 【change】 【change】 2. The compound of claim 1, wherein:

41. below, 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(2,2,4-trimethyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4,4-difluoro-1-methyl-cyclohexyl)-6-[(3-ethoxy-2-pyridyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 8-fluoro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]-7-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 7-chloro-6-[5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide; 7-fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide; N-(3,3-difluoro-1-methyl-cyclobutyl)-6-[(3-ethoxy-2-pyridyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide; 8-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-7-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(1R,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(2,2,6,6-tetramethyltetrahydropyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 5-fluoro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-5,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(3-fluorooxetan-3-yl)methoxy]-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(3-methyl-1,1-dioxo-thietan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-phenyl-imidazo[1,2-a]pyridine-2-carboxamide; 2,2,2-trifluoroacetate; 6-[3-(2,2-difluoroethoxy)pyrazin-2-yl]oxy-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-((3-(2,2-difluoropropoxy)-5-fluoropyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-Isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(4-methyl-1,1-dioxo-thian-4-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide; N-(6,8-difluorochroman-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; N-benzyl-6-[(3-ethoxy-2-pyridyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(3-pyridyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-isopropyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-N-(6-methylpyridazin-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(1,1-difluoropropyl)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-hydroxy-2-pyridyl)oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thian-4-yl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-isopropyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-ethyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3-ethyl-1,1-dioxo-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(5-chloro-3-ethoxy-2-pyridyl)oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-isopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-[4-(cyanomethyl)-1,1-dioxo-thian-4-yl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; N-(4-ethyl-1,1-dioxo-thian-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[5-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(2,2-dimethyl-1,1-dioxo-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-[3-methoxy-3-(trifluoromethyl)cyclobutyl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-[3-methyl-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(4,4-difluoro-1-methyl-cyclohexyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[3-methyl-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-isopropyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(2,2-dimethyl-1,1-dioxo-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-ethoxy-5-(trifluoromethyl)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-6-[5-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-N-[3-(trifluoromethyl)cyclobutyl]imidazo[1,2-a]pyridine-2-carboxamide; N-[3-(cyanomethyl)-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]-6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(3-fluoro-1-bicyclo[1.1.1]pentanyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[4-methyl-1-(2,2,2-trifluoroacetyl)-4-piperidyl]imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)-6-[3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,3,3-tetrafluoropropoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; N-(2,2-dimethyl-1,1-dioxo-thian-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide; N-(4-ethyl-1,1-dioxo-thian-4-yl)-3-methyl-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[4-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[6-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[[4-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-[(3-methyl-1,1-dioxo-thietan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[6-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[3-(2,2,2-trifluoroethyl)tetrahydropyran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-[(3S)-6-oxo-3-piperidyl]-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)oxy]-3-ethyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-ethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-Isopropyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 8-fluoro-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 7-fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-fluoro-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-fluoro-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 7-fluoro-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]methoxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[(2-ethoxyphenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(3-ethoxy-2-pyridyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[(4-fluorophenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[2-(difluoromethoxy)phenyl]methoxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-2-carboxamide; 6-(3-ethoxy-2,2-dimethyl-propoxy)-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-chloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 3-hydroxy-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 2-((4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)carbamoyl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid; N2-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2,3-dicarboxamide; 3-Methoxy-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methoxy-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide; 2,2,2-trifluoroacetate; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide; 3-(hydroxymethyl)-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide; 6-[5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-7-cyano-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3,5-dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3,5-dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-chloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-cyclopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-(1-hydroxy-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-(1-fluoro-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-hydroxy-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-[[5-cyano-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide; 3-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[[5-methylsulfonyl-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 6-[3-methyl-2-[(4-methyl-1,1-dioxo-thian-4-yl)carbamoyl]imidazo[1,2-a]pyridin-6-yl]oxy-5-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid; 6-[5-(dimethylamino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-3-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(cyclopropylmethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(cyclobutoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-[1-(methylsulfonylmethyl)cyclobutyl]imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxidothietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-7-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-8-methyl-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; N-((1S,2R)-3,3-difluoro-2-hydroxycyclohexyl)-6-((3-(2,2-difluoroethoxy)-5-fluoropyridin-2-yl)oxy)-8-methylimidazo[1,2-b]pyridazine-2-carboxamide; 3,7-dichloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3-chloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 3,7-dichloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide; 3-chloro-N-(4-methyl-1,1-dioxo-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide; 3,7-dichloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[2-(difluoromethoxy)-6-fluoro-phenyl]methoxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]methoxy]-N-(4-methyl-1,1-dioxo-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; 6-((1,4-dimethyl-1H-pyrazol-3-yl)methoxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide; (S)-6-(2-ethoxyphenoxy)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-2-carboxamide; 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrazine-2-carboxamide; Or, 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxidetetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide; 2. The compound of claim 1, wherein: 。

42. below 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

43. below 【Chemistry 12】 42. The compound of claim 41, wherein:

44. 42. A composition for treating a condition selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease, and heart failure, comprising a compound of any of claims 1 to 41, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

45. 42. A composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof.

46. 42. A method for treating a condition selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease and heart failure, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of any of claims 1 to 41 or a pharmaceutically acceptable salt thereof.

47. 42. Use of a compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a condition selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease, and heart failure.

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