Preparation of imidazopyridine and imidazopyridazine derivatives as novel diacylglycerol o-acyltransferase 2 inhibitors

Abstract

Compounds of Formula (I) and pharmaceutically acceptable salts, esters, and prodrugs thereof are provided, which are DGAT2 inhibitors. Also provided are methods of preparing the compounds of Formula I, pharmaceutical compositions comprising the compounds of Formula I, and use of these compounds in the treatment of liver steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, reduced cognitive ability, dementia, heart and kidney disease ( The present invention relates to methods for treating chronic kidney disease and heart failure, such as chronic kidney disease and heart failure, and related diseases and disorders, comprising administering to a patient in need thereof a compound of Formula I. # imgabs0 #

Description

[0001] Cross-reference to related applications

[0002] This international application claims the benefit of priority of U.S. Provisional Application No. 63 / 421,362, filed on November 1, 2022, the entire content of which is incorporated herein by reference. Technical Field

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

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

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

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

[0007] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been understood mainly through the results of studies of antisense oligonucleotides (ASO) in rodents. In this context, knockdown of DGAT2 in ob / ob mice with DGAT2 gene-specific ASO led to a dose-dependent decrease in very low density lipoprotein (“VLDL”) and a reduction in plasma TG, total cholesterol, and ApoB (Liu, et al., Biochim. Biophys Acta 2008, 1781, 97). In the same study, treatment of ob / ob mice with DGAT2 antisense oligonucleotides showed a decrease in body weight gain, fat mass, and liver TG content. Id. In another study, antisense treatment of ob / ob mice improved hepatic steatosis and hyperlipidemia (Yu, et al., Hepatology, 2005, 42, 362). Another study showed that diet-induced hepatic steatosis and insulin resistance were improved by knockdown of DGAT2 in rats. These effects appear to be unique to the inhibition of DGAT2, as ASO directed against DGAT1 did not produce similar beneficial effects. Although the molecular mechanisms underlying these observations remain uncertain, the combined data suggest that inhibition of DGAT2 is associated with a decrease in the expression of lipogenic genes (SREBPlc, ACC1, SCD1, and mtGPAT) and an increase in the expression of oxidative / thermogenic genes (CPT1, UCP2) (Choi et al., J. Bio.Chem., 2007, 282, 22678).

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

[0009] DGAT2 inhibitor compounds are described in WO2022050749, WO2021133035, WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, W02013150416, US20150259323, WO2015077299, W02017011276, WO2018033832, US201801628 and W02003053363. Summary of the Invention

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

[0011]

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

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

[0014]

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

[0016] X, Y, and Z are independently selected from N and C(R 4 );

[0017] R 1 is

[0018] (1) a 6-membered aryl that is unsubstituted or substituted with 1, 2, or 3 R 5 substituents,

[0019] (2) a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted with 1, 2, or 3 R 5 substituents,

[0020] (3)-(C 1-6 )alkyl-aryl, wherein the aryl is unsubstituted or substituted with 1, 2, or 3 R 5 substituents,

[0021] (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 substituted by 1, 2 or 3 R 5 substituents,

[0022] (5)-(C 1-3 )haloalkyl, or

[0023] (6)optionally substituted by 1, 2 or 3 R 5 substituents of -(C 1-6 )alkyl - O-(C 1-6 )alkyl;

[0024] R 2 is

[0025] (1)a 4 - to 7 - membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0026] (2)phenyl,

[0027] (3)a 5 - or 6 - membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0028] (4)-(C 1-6 )alkyl - heterocyclic group, wherein the heterocyclic group is a 4 -, 5 - or 6 - membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0029] (5)-(C 1-6 )alkyl - aryl,

[0030] (6)-(C 3-6 )cycloalkyl,

[0031] (7)-(C 3-6 )cycloamine,

[0032] (8)-(C 3-6 )cycloalkyl-(C 1-6 )alkyl - SO2(C 1-6 )alkyl, or

[0033] (9)an 8 - to 10 - membered fused bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from N, O and S, and wherein optionally the bicyclic is independently substituted by one, two or three halogens,

[0034] wherein each alkyl, aryl, cycloalkyl, heteroaryl, cycloamine and heterocyclic group is unsubstituted or substituted by 1, 2, 3, 4 or 5 R 6 substituents;

[0035] R3 For

[0036] (1) hydrogen,

[0037] (2) halogen,

[0038] (3) hydroxyl,

[0039] (4) (C 1-6 ) alkyl,

[0040] (5) (C 1-6 ) haloalkyl,

[0041] (6) (C 1-6 ) alkylhydroxy,

[0042] (7) (C 1-6 ) alkoxy-,

[0043] (8) C(=O)NH2,

[0044] (9) C(=O)OH, or

[0045] (10) O-(C 1-6 ) alkyl;

[0046] When present, each R 4 is independently

[0047] (1) hydrogen,

[0048] (2) halogen,

[0049] (3) (C 1-3 ) alkyl,

[0050] (4) C 1-3 haloalkyl, or

[0051] (5) cyano;

[0052] When present, each R 5 is independently:

[0053] (1) hydrogen,

[0054] (2) halogen,

[0055] (3) hydroxyl,

[0056] (4) CN,

[0057] (5) C(O)OH,

[0058] (6) (C 1-6 ) alkyl,

[0059] (7) (C 1-6 ) haloalkyl,

[0060] (8)(C 1-3 ) alkyl-OH,

[0061] (9) -OC 1-6 alkyl,

[0062] (10) O-(C 1-6 ) haloalkyl,

[0063] (11) SO2(C 1-6 ) alkyl,

[0064] (12) N(C 1-6 ) alkyl,

[0065] (13)(C 3-6 ) cycloalkyl,

[0066] (14) O-(C 3-7 ) cycloalkyl,

[0067] (15) Optionally halogen-substituted -OC 1-6 alkyl-oxetanyl, or

[0068] (16) Optionally halogen-substituted O-C 1-6 alkyl-(C 3-7 ) cycloalkyl;

[0069] When present, each R 6 is independently:

[0070] (1) halogen,

[0071] (2) oxo,

[0072] (3) OH,

[0073] (4) C 1-3 alkyl,

[0074] (5) C 1-3 haloalkyl,

[0075] (6) C 1-3 alkyl-CN,

[0076] (7) OC 1-3 alkyl, or

[0077] (8) C(O)C 1-3 haloalkyl.

[0078] In Embodiment 2 of the present disclosure, the compound of Formula I or a pharmaceutically acceptable salt thereof is a compound of Formula Ib:

[0079]

[0080] or a pharmaceutically acceptable salt thereof, wherein:

[0081] R 1 is:

[0082] (1) a 6-membered aryl group which is unsubstituted or substituted with 1, 2 or 3 R 5 substituents,

[0083] (2) a 6-membered heteroaryl group containing 1 or 2 nitrogen atoms, wherein the heteroaryl group is unsubstituted or substituted with 1, 2 or 3 R 5 substituents,

[0084] (3)-(C 1-6 )alkyl-aryl, wherein the aryl group is unsubstituted or substituted with 1, 2 or 3 R 5 substituents,

[0085] (4)-(C 1-6 )alkyl-heteroaryl, wherein the heteroaryl group is a 5- or 6-membered heteroaryl group containing 1 nitrogen atom, and the heteroaryl group is unsubstituted or substituted with 1, 2 or 3 R 5 substituents,

[0086] (5)-(C 1-3 )haloalkyl, or

[0087] (6)-(C 5 )alkyl-O-(C 1-6 )alkyl optionally substituted with 1, 2 or 3 R 1-6 substituents;

[0088] R 2 is:

[0089] (1) a 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0090] (2) phenyl,

[0091] (3) a 5- or 6-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently selected from N,

[0092] (4)-(C 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 4-, 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms independently selected from S,

[0093] (5)-(C 1-6 )alkyl-aryl,

[0094] (6)-(C 3-6 )cycloalkyl,

[0095] (7)-(C 3-6 )cycloamine,

[0096] (8)-(C 3-6 ) cycloalkyl-(C 1-6 ) alkyl-SO2(C 1-6 ) alkyl, or

[0097] (9) a 10-membered fused bicyclic heterocycle containing 1 heteroatom independently selected from N, O, and S, and wherein optionally the bicyclic ring is independently substituted by one, two, or three halogens,

[0098] wherein each alkyl, aryl, cycloalkyl, heteroaryl, cycloamine, and heterocyclic group is unsubstituted or substituted by 1, 2, 3, 4, or 5 R 6 substituents;

[0099] R 3 is:

[0100] (1) hydrogen,

[0101] (2) halogen,

[0102] (3) hydroxy,

[0103] (4) (C 1-6 ) alkyl,

[0104] (6) (C 1-6 ) haloalkyl,

[0105] (7) (C 1-6 ) alkylhydroxy,

[0106] (8) (C 1-6 ) alkoxy-,

[0107] (9) C(=O)NH2,

[0108] (10) C(=O)OH, or

[0109] (11) O-(C 1-6 ) alkyl;

[0110] When present, each R 4 is independently:

[0111] (1) hydrogen,

[0112] (2) halogen,

[0113] (3) (C 1-3 ) alkyl,

[0114] (4) C 1-3 haloalkyl, or

[0115] (5) cyano;

[0116] When present, each R 5Independently for:

[0117] (1) Hydrogen,

[0118] (2) Halogen,

[0119] (3) Hydroxyl,

[0120] (4) CN,

[0121] (5) C(O)OH,

[0122] (6) (C 1-6 ) Alkyl,

[0123] (7) (C 1-6 ) Haloalkyl,

[0124] (8) (C 1-3 ) Alkyl-OH,

[0125] (9) -OC 1-6 Alkyl,

[0126] (10) O-(C 1-6 ) Haloalkyl,

[0127] (11) SO2(C 1-6 ) Alkyl,

[0128] (12) N(C 1-6 ) Alkyl,

[0129] (13) (C 3-6 ) Cycloalkyl,

[0130] (14) O-(C 3-7 ) Cycloalkyl,

[0131] (15) Optionally halogen-substituted -OC 1-6 Alkyl-oxetanyl, or

[0132] (16) Optionally halogen-substituted O-C 1-6 Alkyl-(C 3-7 ) Cycloalkyl;

[0133] When present, each R 6 Independently for:

[0134] (1) Halogen,

[0135] (2) Oxo,

[0136] (3) OH,

[0137] (4) C 1-3 Alkyl,

[0138] (5) C 1-3haloalkyl,

[0139] (6)C 1-3 alkyl-CN,

[0140] (7)OC 1-3 alkyl, or

[0141] (8)C(O)C 1-3 haloalkyl.

[0142] In Embodiment 3 of the present disclosure, a compound of Formula I or Formula Ib, or a compound of Embodiment 1 - 2 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is:

[0143] (1) a 6 - membered aryl which is unsubstituted or substituted by 1, 2 or 3 R 5 substituents,

[0144] (2) a 6 - membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents,

[0145] (3) - CH2aryl, wherein the aryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents,

[0146] (4) - CH2 - heteroaryl, wherein the heteroaryl is a 5 - or 6 - membered heteroaryl containing 1 nitrogen atom, and the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents,

[0147] (5) - (C 1-3 ) haloalkyl, or

[0148] (6) - (C 5 ) alkyl - O - (C 1-6 ) alkyl optionally substituted by 1, 2 or 3 R 1-6 substituents.

[0149] Embodiment 4 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiment 1 - 3 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is:

[0150] (1) a 6 - membered aryl which is unsubstituted or substituted by - OC 1-6 alkyl or O - (C 1-6 ) haloalkyl,

[0151] (2) a 6 - membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from the following: halogen, hydroxy, - O(C 1-6An alkyl group, (C 1-6 ) alkyl group, (C 1-6 ) haloalkyl group, O-(C 1-6 ) haloalkyl group, (C 1-3 ) alkyl-OH group, SO2(C 1-6 ) alkyl group, N(C 1-6 ) alkyl group, (C 3-6 ) cycloalkyl group, O-(C 3-7 ) cycloalkyl group, CN, C(O)OH, O-C 1-6 alkyl group-(C 3-7 ) cycloalkyl group, and -OC 1-6 alkyl group-oxetanyl group,

[0152] (3) -CH2-aryl group, wherein the aryl group is substituted by one or two substituents independently selected from halogen,

[0153] -OC 1-3 alkyl group or -OC 1-3 haloalkyl group,

[0154] (4) -CH2-heteroaryl group, wherein the heteroaryl group is a 5- or 6-membered heteroaryl group containing 1 or 2 nitrogen atoms, and the heteroaryl group is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-3 alkyl group, C 1-3 haloalkyl group, -OC 1-3 alkyl group and -OC 1-3 haloalkyl group,

[0155] (5) -(C 1-3 ) haloalkyl group, or

[0156] (6) -(C 1-6 ) alkyl group-O-(C 1-6 ) alkyl group.

[0157] Embodiment 5 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-4 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is:

[0158] (1) A 6-membered aryl group that is unsubstituted or substituted by OCH2CH3 or OCH2CF3,

[0159] (2) A 6-membered heteroaryl group containing one or two nitrogen atoms, wherein the heteroaryl group is unsubstituted or substituted by one, two or three substituents independently selected from the following:

[0160] 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,

[0161] (3) -CH2-aryl, wherein the aryl is substituted with one or two substituents independently selected from F, OCH2CH3, and OCHF2,

[0162] (4) -CH2-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is unsubstituted or substituted with 1, 2, or 3 substituents selected from the following: OCH2CHF2, F, Cl, OCH2CF3, CH3, CF3, and OCH2CH3,

[0163] (5) CH2CH2CF3, or

[0164] (6) CH2(CH3)2CH2OCH2CH3.

[0165] Embodiment 6 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is an unsubstituted or -OC 1-6 alkyl or O-(C 1-6 ) haloalkyl-substituted 6-membered aryl.

[0166] Embodiment 7 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-6 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is an unsubstituted or OCH2CH3- or OCH2CF3-substituted 6-membered aryl.

[0167] Embodiment 8 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or a class 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, and the heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from the following: halogen, hydroxyl, -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 halogen-substituted -C 1-6 Alkyl-(C 3-7 ) Cycloalkyl, CN, C(O)OH and optionally halogen-substituted -OC 1-6 Alkyl-oxetanyl.

[0168] Embodiment 9 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or 8 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from: Cl, F, OH, CN, CN, CH3, 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.

[0169] Embodiment 10 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -CH2-aryl, wherein the aryl is substituted by one or two substituents independently selected from halogen, -OC 1-3 alkyl or OC 1-3 haloalkyl.

[0170] Embodiment 11 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or 10 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -CH2-aryl, wherein the aryl is a 6-membered aryl substituted by one or two substituents independently selected from F, OCH2CH3 and OCHF2.

[0171] Embodiment 12 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1is -CH2-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-3 alkyl, -OC 1-3 alkyl and -OC 1-3 haloalkyl.

[0172] Embodiment 13 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5, 12 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -CH2-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and the heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, -OC 1-3 alkyl and -OC 1-3 haloalkyl.

[0173] Embodiment 14 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5, 12-13 or a class 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, and the heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents selected from OCH2CHF2, F, Cl, OCH2CF3, CH3, CF3 and OCH2CH3.

[0174] Embodiment 15 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is CH2CH2CF3.

[0175] Embodiment 16 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is -(C 1-6 )alkyl - O - (C 1-6 )alkyl.

[0176] Embodiment 17 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-5, 16 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is CH2(CH3)2CH2OCH2CH3.

[0177] Embodiment 18 of the present disclosure is a compound of formula I or formula Ib, or any one of embodiments 1-5, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is:

[0178]

[0179]

[0180] Embodiment 19 of the present disclosure is a compound of formula I or formula Ib, or any one of embodiments 1-18, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is:

[0181] (1) a 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S,

[0182] (2) phenyl,

[0183] (3) a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms,

[0184] (4) -CH2-heterocyclic group, wherein the heterocyclic group is a 4-, 5- or 6-membered heterocyclic group containing 1, 2 or 3 sulfur atoms,

[0185] (5) -CH2-aryl, wherein the aryl is a 6-membered aryl,

[0186] (6) -(C 3-6 ) cycloalkyl,

[0187] (7) -(C 3-6 ) cycloamine,

[0188] (8) -(C 3-6 ) cycloalkyl-CH3-SO2CH3, or

[0189] (9) a 10-membered fused bicyclic heterocycle containing 1 oxygen atom, wherein optionally the bicyclic is independently substituted by one, two or three halogens,

[0190] wherein each alkyl, aryl, cycloalkyl, heteroaryl, cycloamine and heterocyclic group is unsubstituted or substituted by 1, 2, 3, 4 or 5 R 6 substituents.

[0191] Embodiment 20 of the present disclosure is a compound of formula I or formula Ib, or a compound of any one of embodiments 1-19 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is:

[0192] (1) containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted by one, two or three independently selected from halogen, oxo, C1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-CN and C(O)C 1-3 a 4- to 7-membered heterocyclic group substituted with a substituent of haloalkyl,

[0193] (2) phenyl,

[0194] (3) a 5- or 6-membered heteroaryl optionally substituted with C 1-3 alkyl and containing one or two nitrogen atoms,

[0195] (4) -CH2-heterocyclic group, wherein the heterocyclic group is a 4- or 6-membered heterocyclic group containing one, two or three sulfur atoms and optionally substituted with one, two, three, four or five substituents independently selected from oxo and C 1-3 alkyl,

[0196] (5) -CH2-aryl, wherein the aryl is a 6-membered aryl,

[0197] (6) -(C 1-3 optionally substituted with one, two or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, OC 3-6 ) cycloalkyl,

[0198] (7) -(C 3-6 ) cycloamine optionally substituted with one, two or three substituents independently selected from oxo,

[0199] (8) -(C4) cycloalkyl-CH3-SO2CH3, or

[0200] (9) a chromane optionally substituted with one, two or three halogens,

[0201] wherein each alkyl, aryl, cycloalkyl, heteroaryl, cycloamine and heterocyclic group is unsubstituted or substituted with 1, 2, 3, 4 or 5 R 6 substituents.

[0202] Embodiment 21 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-20 or a class thereof, or any of the foregoing pharmaceutically acceptable salts, wherein R 2 is:

[0203] (1) a 4- to 7-membered heterocyclic group containing one, two or three heteroatoms independently selected from N, O and S and optionally substituted with one, two, three, four or five substituents independently selected from halogen, oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN, C(O)CF3 and (CH3)2,

[0204] (2) phenyl,

[0205] (3) a 5- or 6-membered heteroaryl optionally substituted with CH3 and containing 1 or 2 nitrogen atoms,

[0206] (4) -CH2-heterocyclyl, wherein the heterocyclyl is a 4- or 6-membered heterocycle optionally substituted with one, two or three substituents independently selected from oxo and CH3 and containing 1 sulfur atom,

[0207] (5) -CH2-aryl, wherein the aryl is a 6-membered aryl,

[0208] (6) -(C 3-6 ) cycloalkyl optionally substituted with one, two or three substituents independently selected from F, CH3, CF3, OH, F2 and OCH3,

[0209] (7) -(C 3-6 ) cycloamine optionally substituted with oxo,

[0210] (8) -(C4) cycloalkyl-CH3-SO2CH3, or

[0211] (9) chromane independently substituted with halogen.

[0212] Embodiment 22 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocycle containing 1 heteroatom selected from sulfur, nitrogen and oxygen and optionally substituted with one, two, three, four or five substituents independently selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-CN and C(O)C 1-3 haloalkyl.

[0213] Embodiment 23 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-22 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is a 4- to 7-membered heterocycle containing 1 heteroatom selected from sulfur, nitrogen and oxygen and optionally substituted with one, two, three, four or five substituents independently selected from halogen, oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN, C(O)CF3 and (CH3)2.

[0214] Embodiment 24 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-23 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2A 4- to 7-membered heterocyclic group containing 1 sulfur atom and optionally substituted by one, two, three, four or five substituents independently selected from oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN and (CH3)2.

[0215] Embodiment 25 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-23 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 A 4- to 7-membered heterocyclic group containing 1 nitrogen atom and optionally substituted by one, two or three substituents independently selected from CH3, CH2CN and C(O)CF3.

[0216] Embodiment 26 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-23 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 A 4- to 7-membered heterocyclic group containing 1 oxygen atom and optionally substituted by one, two, three, four or five substituents independently selected from CH3, (CH3)2 and CH2CF3.

[0217] Embodiment 27 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 Is phenyl.

[0218] Embodiment 28 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 Is a 5- or 6-membered heteroaryl optionally substituted by CH3 and containing 1 or 2 nitrogen atoms.

[0219] Embodiment 29 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 Is -CH2-heterocyclic group, wherein the heterocyclic group is a 4- or 6-membered heterocyclic group containing 1 sulfur atom and optionally substituted by one, two or three substituents independently selected from oxo and C 1-3 Alkyl substituents.

[0220] Embodiment 30 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21, 29 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 Is -CH2-heterocyclic group, wherein the heterocyclic group is a 4- or 6-membered heterocyclic group containing 1 sulfur atom and optionally substituted by one, two or three substituents independently selected from oxo and CH3.

[0221] Embodiment 31 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is CH2-6-membered aryl.

[0222] Embodiment 32 of the present disclosure is a compound of formula I or formula Ib, or a compound of Examples 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is optionally substituted by one, two or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, OC 1-3 alkyl and OH of -(C 3-6 ) cycloalkyl.

[0223] Embodiment 33 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21, 32 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is optionally substituted by one, two or three substituents independently selected from halogen, oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN, C(O)CF3 and (CH3)2 of -(C 3-6 ) cycloalkyl.

[0224] Embodiment 34 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -(C 3-6 ) cycloamine substituted by oxo.

[0225] Embodiment 35 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is -(C4) cycloalkyl-CH3-SO2CH3.

[0226] The compound of formula I or formula Ib in Embodiment 36 of the present disclosure, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

[0227] The compound of formula I or formula Ib in Embodiment 37 of the present disclosure, or a compound of Embodiments 1-21 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

[0228] Embodiment 38 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-37 or a class 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 alkyl-OH.

[0229] Embodiment 39 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-38 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen, halogen, C 1-3 alkyl, OH, C(O)OH, C(O)NH2, OC 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkyl-OH.

[0230] Embodiment 40 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-39 or a class 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.

[0231] Embodiment 41 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-40 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen or CH3.

[0232] Embodiment 42 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-41 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is hydrogen.

[0233] Embodiment 43 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-41 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 is CH3.

[0234] Embodiment 44 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-43 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is independently selected from hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl and CN.

[0235] Embodiment 45 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-44 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is independently selected from hydrogen, CH3, F, Cl, CH(CH3)2, CF3, CH2CH3, and CN.

[0236] Embodiment 46 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-43 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is independently selected from hydrogen, halogen, and CH3.

[0237] Embodiment 47 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-44 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is independently selected from hydrogen, Cl, F, and CH3.

[0238] Embodiment 48 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-47 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is independently selected from hydrogen and CH3.

[0239] Embodiment 49 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-47 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 4 is independently selected from hydrogen, F, and Cl

[0240] Embodiment 50 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-3, 19-49 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when 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 halogen-substituted -OC 1-6 alkyl-oxetanyl and optionally halogen-substituted O-C 1-6 alkyl-(C 3-7 )cycloalkyl.

[0241] Embodiment 51 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-3, 19-50 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 5 is 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. Embodiment 52 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-20, 38-51 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 6 is independently selected from halogen, 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.

[0242] Embodiment 53 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1-20, 38-52 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein when present, each R 6 is independently selected from halogen, oxo, CH3, CF3, OH, CH2CF3, CH(CH3)2, CH2CH3, OCH3, CH2CN, C(O)CF3 and (CH3)2.

[0243] Embodiment 54 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1, 3-53 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ), Y is C(R 4 ), and Z is C(R 4 ).

[0244] Embodiment 55 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiments 1, 3-53 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is C(R 4 ), and Z is C(R 4 ).

[0245] Embodiment 56 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 1, 3 - 53 or a class 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 ).

[0246] Embodiment 57 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 1, 3 - 53 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein X is C(R 4 ), Y is C(R 4 ), and Z is N.

[0247] Embodiment 58 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 1 - 5, 8 - 9, 19 - 57 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0248] Embodiment 59 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 11 - 5, 8 - 9, 19 - 57 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0249] Embodiment 60 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 1 - 5, 8 - 9, 19 - 57 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0250] Embodiment 61 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 1 - 5, 8 - 9, 19 - 57 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0251] Embodiment 62 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 1 - 5, 8 - 9, 19 - 57 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 is

[0252] Embodiment 63 of the present disclosure is a compound of formula I or formula Ib, or a compound of Embodiment 1 - 24, 36 - 62 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

[0253] Embodiment 64 of the present disclosure is a compound of Formula I or Formula Ib, or a compound of Embodiments 1-24, 36-62 or a class thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2 is

[0254] In Embodiment 65, the present disclosure is a compound selected from the following:

[0255]

[0256] In Embodiment 66, the present disclosure is a compound selected from the following:

[0257]

[0258] Embodiment 67 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0259] Embodiment 68 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0260] Embodiment 69 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0261] Embodiment 70 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0262]

[0263] Embodiment 71 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0264]

[0265] Embodiment 72 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0266]

[0267] Embodiment 73 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0268]

[0269] Embodiment 74 is a compound of the following formula or a pharmaceutically acceptable salt thereof:

[0270]

[0271] In Embodiment 75, the compound of Formula I or Formula Ib or a pharmaceutically acceptable salt thereof is:

[0272] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0273] 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(2,2,4-trimethyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0274] N-(4,4-difluoro-1-methyl-cyclohexyl)-6-[(3-ethoxy-2-pyridinyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0275] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[l,2-a]pyridine-2-carboxamide,

[0276] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[1,1-dioxido-4-(2,2,2-trifluoroethyl)thian-4-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0277] 6-[(3-ethoxy-2-pyridinyl)oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0278] 8-fluoro-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0279] 6-[(5-chloro-3-ethoxy-2-pyridinyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0280] 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0281] 6-[[5-chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0282] 6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0283] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[1,1-dioxido-4-(2,2,2-trifluoroethyl)thiacyclohexan-4-yl]-7-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0284] 7-chloro-6-[5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0285] N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0286] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0287] N-[(1S,2R)-3,3-difluoro-2-hydroxy-cyclohexyl]-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0288] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0289] 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0290] 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0291] 7-Methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy)pyrazin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide,

[0292] 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxo-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0293] 6-[(3-Ethoxypyridin-2-yl)oxy]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide,

[0294] N-(3,3-Difluoro-1-methyl-cyclobutyl)-6-[(3-ethoxypyridin-2-yl)oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0295] 8-Methyl-N-(4-methyl-1,1-dioxo-thiane-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0296] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-7-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0297] 6-[(3-Ethoxypyridin-2-yl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide,

[0298] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxo-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0299] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-5-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0300] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxo-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0301] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0302] 6-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0303] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thiacyclobutan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0304] 6-[[5-Fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0305] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0306] 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-[(3S)-3-methyl-1,1-dioxido-thiacyclopentan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0307] 5-Methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0308] 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-[(1R,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide,

[0309] 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-(2,2,6,6-tetramethyltetrahydropyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0310] 5-Fluoro-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0311] 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridyl]oxy]-5,7-dimethyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0312] 6-[[5-chloro-3-[(3-fluoroxetane-3-yl)methoxy]-2-pyridyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0313] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-N-[(3-methyl-1,1-dioxido-thiacyclobutan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide,

[0314] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]-7-isopropyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0315] 8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0316] 6-[(3-ethoxypyridin-2-yl)oxy]-N-phenyl-imidazo[1,2-a]pyridine-2-carboxamide; 2,2,2-trifluoroacetate,

[0317] 6-[3-(2,2-difluoroethoxy)pyrazin-2-yl]oxy-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0318] 6-((3-(2,2-difluoropropoxy)-5-fluoropyridin-2-yl)oxy)-7-fluoro-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0319] 7-isopropyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0320] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-isopropyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0321] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[(4-methyl-1,1-dioxido-thian-4-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide,

[0322] N-(6,8-Difluorochroman-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0323] 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0324] N-Benzyl-6-[(3-ethoxy-2-pyridinyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0325] 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-(3-pyridinyl)imidazo[1,2-a]pyridine-2-carboxamide,

[0326] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-isopropyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0327] N-(4-Methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide,

[0328] 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-(6-methylpyridazin-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0329] 6-[[3-(1,1-Difluoropropyl)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0330] 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0331] 6-[(3-Hydroxy-2-pyridinyl)oxy]-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0332] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0333] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thiacyclohexan-4-yl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0334] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0335] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0336] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-isopropyl-1,1-dioxo-thiacyclohexan-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0337] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-ethyl-1,1-dioxo-thiacyclohexan-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0338] 6-[[5-Ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0339] 6-[[5-Fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0340] 6-[(5-Chloro-3-ethoxy-2-pyridinyl)oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0341] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(3-ethyl-1,1-dioxido-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0342] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0343] 6-[(5-Chloro-3-ethoxy-2-pyridinyl)oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0344] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0345] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0346] 6-[[5-Isopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0347] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-[4-(cyanomethyl)-1,1-dioxido-thiacyclohexan-4-yl]-3-methyl-imidazo[1,2-a]-pyridine-2-carboxamide,

[0348] N-(4-Ethyl-1,1-dioxido-thian-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0349] 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[5-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-α]pyridine-2-carboxamide,

[0350] 6-[[5-Ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0351] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(2,2-dimethyl-1,1-dioxido-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0352] 6-[[5-Chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-3-methyl]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]-pyridine-2-carboxamide,

[0353] 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0354] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-[3-methoxy-3-(trifluoromethyl)cyclobutyl]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0355] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0356] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-[3-methyl-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0357] 6-[[3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(4,4-difluoro-1-methylcyclohexyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0358] 3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0359] 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0360] 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-[3-methyl-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0361] 6-[[3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0362] 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-isopropyl-1,1-dioxido-thiane-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0363] 3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0364] 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(2,2-dimethyl-1,1-dioxido-thiane-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0365] 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0366] 6-[[3-Ethoxy-5-(trifluoromethyl)-2-pyridyloxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0367] 3-Methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)-6-[5-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0368] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridyloxy]-3-methyl-N-[3-(trifluoromethyl)cyclobutyl]imidazo[l,2-a]pyridine-2-carboxamide,

[0369] N-[3-(Cyanomethyl)-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]-6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridyloxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0370] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridyloxy]-N-(3-fluoro-1-bicyclo[1.1.1]pentyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0371] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridyloxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0372] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyloxy]-3-methyl-N-[(3R)-3-methyl-1,1-dioxido-thiolan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0373] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridyloxy]-3-methyl-N-[4-methyl-1-(2,2,2-trifluoroacetyl)-4-piperidyl]imidazo[1,2-a]pyridine-2-carboxamide,

[0374] 3-Methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)-6-[3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0375] 6-[[5-Fluoro-3-(2,2,3,3-tetrafluoropropoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0376] N-(2,2-Dimethyl-1,1-dioxido-thian-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide,

[0377] N-(4-Ethyl-1,1-dioxido-thian-4-yl)-3-methyl-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0378] 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[4-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0379] 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[6-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0380] 6-[[4-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0381] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-[(3-methyl-1,1-dioxido-thietan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide,

[0382] 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[6-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0383] 3-Methyl-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[3-(2,2,2-trifluoroethyl)tetrahydropyran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide,

[0384] 3-Methyl-N-[(3S)-6-oxo-3-piperidinyl]-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0385] 6-[(3-Ethoxy-2-pyridinyl)oxy]-3-ethyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0386] 3-Ethyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0387] 3-Isopropyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0388] 8-Fluoro-3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0389] 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0390] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-fluoro-3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0391] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-fluoro-3-methyl]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0392] 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0393] 7-Fluoro-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0394] 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]methoxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0395] 6-[(2-Ethoxyphenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0396] 6-[(3-Ethoxy-2-pyridinyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0397] 6-[(4-Fluorophenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0398] 6-[[2-(Difluoromethoxy)phenyl]methoxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0399] 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-2-carboxamide,

[0400] 6-(3-Ethoxy-2,2-dimethyl-propoxy)-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0401] 3-Chloro-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0402] 3-Hydroxy-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0403] 2-((4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)carbamoyl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid

[0404] N2-(4-Methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2,3-dicarboxamide,

[0405] 3-Methoxy-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0406] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methoxy-N-(3-methyl-1,1-dioxo-thiacyclobutan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide; 2,2,2-trifluoroacetate,

[0407] N-(4-Methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide,

[0408] 3-(Hydroxymethyl)-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide,

[0409] 6-[5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-7-cyano-3-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0410] 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0411] 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxo-thiacyclobutan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0412] 3-Chloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0413] 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0414] 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0415] 3-Methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0416] 6-[[5-cyclopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0417] 6-[[5-(1-hydroxy-1-methylethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0418] 6-[[5-(1-fluoro-1-methylethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0419] 6-[[5-hydroxy-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0420] 6-[[5-cyano-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0421] 3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[5-methylsulfonyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide,

[0422] 6-[3-methyl-2-[(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)carbamoyl]imidazo[1,2-a]pyridin-6-yl]oxy-5-(2,2,2-trifluoroethoxy)pyridine-3-carboxylic acid,

[0423] 6-[5-(dimethylamino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-3-methyl-N-(3-methyl-1,1-dioxido-thiacyclobutan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide,

[0424] 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0425] 6-[[5-chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0426] 6-[[5-fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0427] 6-[[3-(2,2-difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0428] 6-[[3-(cyclopropylmethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0429] 6-[[3-(Cyclobutyloxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0430] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0431] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0432] 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,

[0433] 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0434] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-[1-(methylsulfonylmethyl)cyclobutyl]imidazo[1,2-b]pyridazine-2-carboxamide,

[0435] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0436] N-(4-Methyl-1,1-dioxido-thian-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide,

[0437] 6-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0438] 6-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxothietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0439] 6-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0440] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-7-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0441] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxo-thiacyclohexane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0442] 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxo-thiacyclohexane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0443] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-8-methyl-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0444] 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-8-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0445] 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,

[0446] 3,7-Dichloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxo-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0447] 3-Chloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0448] 3,7-Dichloro-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide,

[0449] 3-Chloro-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-b]pyridazine-2-carboxamide,

[0450] 3,7-Dichloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0451] 6-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0452] 6-[[2-(Difluoromethoxy)-6-fluorophenyl]methoxy]-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0453] 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]methoxy]-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0454] 6-((1,4-Dimethyl-1H-pyrazol-3-yl)methoxy)-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide,

[0455] (S)-6-(2-Ethoxyphenoxy)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-2-carboxamide,

[0456] 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrazine-2-carboxamide, or

[0457] 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide.

[0458] In embodiment 76, the compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof is:

[0459]

[0460]

[0461]

[0462]

[0463]

[0464] The present disclosure includes pharmaceutically acceptable salts of the compounds defined herein.

[0465] In one embodiment, the present 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.

[0466] The present disclosure also provides a pharmaceutical composition 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.

[0467] The present disclosure also provides a pharmaceutical composition 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).

[0468] The present disclosure also provides a pharmaceutical composition 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.

[0469] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (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.

[0470] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (such as chronic kidney disease or heart failure), comprising a compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof.

[0471] In one embodiment, the present disclosure provides a composition for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (such as chronic kidney disease or heart failure), comprising a compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0472] In one embodiment, the present disclosure provides a method for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (such as chronic kidney disease or heart failure) in a subject in need 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.

[0473] In one embodiment, the present disclosure provides a method for treating hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases (such as chronic kidney disease or heart failure) in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of at least one compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0474] The methods of the present 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.

[0475] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, comprising administering to a patient in need thereof a compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof.

[0476] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, comprising administering to a patient in need thereof a compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0477] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, which comprises administering to a patient in need thereof a composition comprising a compound of Formula I or Formula Ib or a pharmaceutically acceptable salt thereof.

[0478] In another embodiment, the present disclosure includes a method for treating NASH and / or fibrosis, which comprises administering to a patient in need thereof a composition comprising a compound of Formula I or Formula Ib or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0479] 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 preparation of a medicament for treating NASH and / or fibrosis.

[0480] In another embodiment, the present disclosure includes the use of a compound of Formula I or Formula Ib or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH and / or fibrosis.

[0481] "Alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. If no number is specified, the straight-chain alkyl has 1-6 carbon atoms and the branched-chain alkyl has 3-7 carbon atoms. Examples of alkyl include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl and tert-butyl, pentyl, hexyl, octyl, nonyl, etc. For example, the term "C 1-6 alkyl" includes all "C 1-4 alkyl" as defined below, plus straight-chain or branched-chain alkyls having 5 or 6 carbon atoms, including all possible isomers. "C 1-6 alkyl" refers to straight-chain or branched-chain alkyls having 1, 2, 3, 4, 5 or 6 carbon atoms, including all possible isomers, and includes each alkyl within C 1-6 alkyl, including each hexyl and pentyl is as well as n-butyl, iso-butyl, sec-butyl and tert-butyl (n-butyl, isobutyl, sec-butyl, tert-butyl, collectively referred to as "C4 alkyl"; Bu = butyl), n-propyl and iso-propyl (n-propyl, isopropyl, collectively referred to as "C8 alkyl"; Pr = propyl), ethyl (Et) and methyl (Me). The common abbreviations for alkyl are used throughout the specification. For example, methyl can be represented by conventional abbreviations, including "Me" or CH3 or an extended bond symbol as a terminal group, such as ethyl can be represented as "Et" or CH2CH3, propyl can be represented as "Pr" or CH2CH2CH3, butyl can be represented as "Bu" or CH2CH2CH2CH3, etc. For example, the structure has an equivalent meaning. If no number is specified, it is a straight-chain or branched-chain alkyl.

[0482] "Alkoxy" means an alkyl group attached to oxygen. Examples of alkoxy groups include methoxy, ethoxy, propoxy, etc.

[0483] "Aryl" means an aromatic monocyclic or polycyclic moiety containing 6 to 14 ring carbon atoms. In one embodiment, aryl contains about 6 to 10 ring carbon atoms. Monocyclic aromatic rings include, but are not limited to, phenyl. Polycycles include, but are not limited to, naphthyl and bicyclics, such as 8- to 10-membered fused bicyclic heterocycles. Aryl may optionally be substituted with one or more substituents as defined herein. Bonding can occur through any carbon atom on any ring.

[0484] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine.

[0485] "Cycloalkyl" means a non-aromatic monocyclic or polycyclic system containing about 3 to 10 ring carbon atoms. If no atom number is specified, it means 3 - 10 carbon atoms. Cycloalkyl can also be fused to form 1 - 3 carbon rings. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C 1-6 cycloalkyl" means a cycloalkyl having 1 to 6 ring carbon atoms. The term "C 3-6 cycloalkyl" means a cycloalkyl having 3 to 6 ring carbon atoms. Thus, for example, "C 3-6 cycloalkyl" includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl is unsubstituted or substituted with one or more ring system substituents, which may be the same or different and as defined therein. When cycloalkyl is a substituent on an alkyl group, the cycloalkyl substituent can be bonded to any available carbon atom on the alkyl group. The following is an illustration of a -C 3-6 cycloalkyl substituent on an alkyl group, where the substituent is cyclopropyl and is shown in bold:

[0486] "Haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen. In one embodiment, haloalkyl has 1 to 6 carbon atoms. Non-limiting examples of haloalkyls include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CH2CH3, CF2CHF2, -C(CH3)2F, CH2Cl, and CCl3. The term "C 1-6 haloalkyl" or "halo C 1-6 alkyl" means a haloalkyl having 1 to 6 carbons.

[0487] "Haloalkoxy", "haloalkyl - O", and its derivatives such as "halo(C 1-6The terms “haloalkoxy” and “alkoxy” are used interchangeably and refer to a halogen-substituted alkyl group linked through an oxygen atom. Haloalkoxy groups include mono-halogen-substituted alkoxy groups and poly-halogen-substituted alkoxy groups. For example, they include trifluoromethoxy, chloromethoxy, bromomethoxy, as well as OCH2CF3, OCH2CHF2, OCF2CF3, OCH2CF2CH3, OCH2CF2CHF2, OCHF2, and OCF2CHF2.

[0488] “Heterocyclic group”, “heterocycle” or “heterocyclic” refers to a monocyclic structure in which one or more atoms in the ring, i.e., heteroatoms, are elements other than carbon. Heteroatoms are typically O, S or N atoms. Heterocycles containing more than one heteroatom may contain different heteroatoms. Bicyclic moieties include fused bicyclics, spirocycles and bridged bicyclics, and may contain one or more heteroatoms in either ring. The ring attached to the remainder of the molecule may or may not contain heteroatoms. Either ring of a bicyclic heterocycle may be saturated, partially unsaturated or unsaturated. The heterocycle may be attached to the remainder of the molecule via a ring carbon atom, a ring oxygen atom or a ring nitrogen atom. Examples of heterocyclic groups include: piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, azetidinyl, oxiranyl or aziridinyl, etc.

[0489] “Bicyclic heterocyclic group”, “bicyclic heterocycle” or “bicyclic heterocyclic” refers to a heterocycle fused to another ring system. The fusion may be bridged or unbridged.

[0490] Unless otherwise specified, the term “heteroaryl” as used herein denotes 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 O, N and S. Heteroaryls within the scope of this definition include, but are not limited to: benzimidazolyl, benzofuranyl, benzofurazanyl, benzpyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrazolyl, tetrazolopyridinyl, thiadiazolyl, thiazolyl, thiophenyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothiophenyl, quinolinyl, isoquinolinyl, oxazolyl and tetrahydroquinoline.

[0491] "Oxo" refers to an oxygen atom attached by a double bond. An example of an oxo group is the double bond oxygen in a ketone, sulfoxide, sulfone, sulfate, or the double bond oxygen fused to a non-aromatic cycloalkyl or heteroalkyl group.

[0492] "Hydroxyalkyl" or "hydroxy(C 1-3 )alkyl-" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group (-OH). Examples of hydroxyalkyl groups are CH2OH, C(CH3)2OH, CH2CH2OH, or CH(OH)CH3.

[0493] "Cyanoalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a cyano group (-CN).

[0494] The term "composition" is intended to cover a product consisting of specified amounts of specific ingredients, as well as any product directly or indirectly resulting from the combination of specified amounts of specific ingredients.

[0495] The term "at least one" means one or more than one. In terms of the number of compounds of the present disclosure, the meaning of "at least one" is independent of the meaning in terms of the number of chemotherapeutic agents.

[0496] The term "chemotherapeutic agent" refers to a drug (agent or pharmaceutically active ingredient) used to treat cancer (i.e., an anti-tumor agent).

[0497] The term "effective amount" means "therapeutically effective amount". The term "therapeutically effective amount" refers to the amount of an active compound or agent that elicits a biological or pharmaceutical response sought by a researcher, veterinarian, physician, or other clinician in a tissue, system, animal, or human.

[0498] The term "treating cancer" or "treatment of cancer" refers to administering a treatment to a mammal suffering from a cancerous condition and refers to reducing the effects of the cancerous condition by killing cancer cells, and also refers to causing an effect that inhibits cancer growth and / or metastasis.

[0499] Unless otherwise specified herein, the term "carbocyclic" (and its variants such as "carbocyclic" or "carbocyclic group") refers to a C3 to C6 monocyclic ring, such as C 3-6 monocyclic carbocyclic ring. The carbocyclic ring can be attached to any carbon atom of the rest of the molecule to form a stable compound. Saturated carbocyclic rings include, for example, "cycloalkyl" rings such as cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings include, for example

[0500] A "stable" compound is a compound that can be prepared and isolated and whose structure and properties remain unchanged or substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., for therapeutic or prophylactic administration to a subject).

[0501] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I or Formula Ib and their embodiments. For example, certain moieties defined in Formula I or Formula Ib may be unsubstituted or substituted, and the latter is intended to cover the chemically feasible substitution patterns (i.e., the number and types of substituents) of the moiety and produce stable compounds.

[0502] The term "substituted" means that one or more hydrogens on the specified atom are replaced by a group selected from the specified group, provided that there is no exceeding the normal valence of the specified atom in the existing situation and the substitution results in a stable compound. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently substituted by one or more of the disclosed or claimed substituent moieties (single or multiple). Substituted independently means that (two or more) substituents may be the same or different. Such combinations are permitted only when the combination of substituents and / or variables can produce a stable compound. If the substituent itself is substituted by more than one group, it should be understood that these multiple groups may be located on the same carbon or different carbons, as long as a stable structure can be obtained. Optionally substituted means a compound containing the specified optional substituent and a compound not containing the optional substituent.

[0503] The wavy line used herein represents the point of attachment to the remainder of the compound, for example

[0504] When a ring atom is represented by a variable (such as "X"), for example the definition of the variable indicates the atom located at the variable ring position and does not describe the ring bonds associated with that atom. For example, when X in the above ring is nitrogen, the definition will show "N" and will not describe the bonds associated with it, for example, will not show "=N-". Similarly, when X is a carbon atom substituted by bromine, the definition will show "C-Br" and will not depict the bonds associated with it, for example, will not show

[0505] The present disclosure also includes derivatives of the compounds of Formula I or Formula Ib that are used as prodrugs and solvates. Any pharmaceutically acceptable prodrug modification of the compounds of Formula I or Formula Ib that results in the conversion in vivo to a compound within the scope of Formula I or Formula Ib is also within the scope of the present disclosure. After administration to a patient, the prodrug is converted in vivo to a compound of Formula I or Formula Ib through normal metabolic or chemical processes, such as hydrolysis in the blood. Such prodrugs include those that exhibit enhanced bioavailability, tissue specificity, and / or cellular delivery to improve the drug absorption of the compounds of Formula I. The effects of such prodrugs may result from changes in physicochemical properties, such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine the drug permeation properties.

[0506] For example, esters can optionally be prepared by esterification of available carboxylic acid groups or formation of esters on available hydroxyl groups in the compound. Similarly, labile amides can be prepared. Pharmaceutically acceptable esters or amides of the compounds of formula I or formula Ib can be prepared as prodrugs, which can be hydrolyzed back to the acid (or -COO - , depending on the pH of the liquid or tissue in which the conversion occurs) or the hydroxyl form, particularly in vivo, and are thus also included within the scope of the present invention. Also included are those esters and acyl groups known in the art for modifying solubility or hydrolysis characteristics for use in sustained release or prodrug formulations. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 alkyl esters and –C 1-6 alkyl-substituted phenyl esters.

[0507] “Celite ” (Fluka) is diatomaceous earth and can be referred to as “diatomite”.

[0508] When any variable (e.g., R 1 , etc.) occurs more than once in any component or in formula I or formula Ib or other general formula herein, its definition at each occurrence is independent of its definition at all other occurrences. Such combinations are permitted only if the combination of substituents and / or variables results in a stable compound. In selecting the compounds of formula I or formula Ib, one of ordinary skill in the art will recognize that the various substituents (i.e., R 1 , etc.) should be selected in accordance with well-known principles of chemical structure connectivity and stability. Unless otherwise expressly stated to the contrary, substitution of the designated substituents is permitted on any atom in a ring (e.g., aryl, heteroaryl or saturated heterocycle), provided that such ring substitution is chemically permissible and results in a stable compound.

[0509] It should be noted that if there is a difference between the chemical name and the structure, the structure shall prevail.

[0510] Compounds of Structural Formula I or Structural Formula Ib may contain one or more asymmetric centers and thus may occur as racemates and racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. Each of the asymmetric centers present in the compounds of Formula I or Formula Ib may independently have the S configuration or the R configuration. When the bonds at a chiral carbon are depicted as straight lines in the structural formulas herein, it is to be understood that the (R) or (S) configuration of the chiral carbon, as well as its enantiomers and mixtures, are included in the chemical formula. Similarly, when a compound name is recited without a chiral name for a chiral carbon, it is to be understood that the name encompasses the (R) and (S) configurations of the chiral carbon, as well as the individual enantiomers and mixtures thereof. The production of specific stereoisomers or mixtures thereof can be determined in the examples in which such stereoisomers or mixtures are obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof within the scope of the present disclosure.

[0511] The compounds of the present disclosure include all possible enantiomers and diastereomers and mixtures of two or more stereoisomers in all proportions, such as mixtures of enantiomers and / or diastereomers. Thus, enantiomers are the subject of the present invention in the form of enantiomerically pure form, levorotatory and dextrorotatory enantiomer forms, racemic forms, and mixtures of the two enantiomers in various proportions. In the case of cis / trans isomers, the present invention includes cis and trans, as well as mixtures of these forms in various proportions. The present disclosure is intended to cover all such stereoisomeric forms of the compounds of Structural Formula I or Formula Ib.

[0512] The compounds of Structural Formula I or Formula Ib can be separated into their individual diastereomers, for example, by fractional crystallization from a suitable solvent (such as MeOH or EtOAc or mixtures thereof), or via chiral chromatography using an optically active stationary phase. Optionally, derivatization can be carried out prior to the separation of stereoisomers. The separation of a stereoisomer mixture can be carried out in an intermediate step during the synthesis of the compounds of Formula I or Formula Ib, or can be carried out on the final racemic product. The absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, and if desired, it can be derivatized with a reagent containing an asymmetric center of known absolute configuration. Alternatively, any stereoisomer or isomer of the compounds of Formula I or Formula Ib can be obtained by stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. The Formulas I and Ib of the present disclosure include all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers, and tautomers, and mixtures thereof.

[0513] If desired, a racemic mixture of a compound can be separated to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, such as coupling the racemic mixture of the compound with an enantiomerically pure compound to form a mixture of diastereomers, and then separating the individual diastereomers by standard methods (e.g., fractional crystallization or chromatography). The coupling reaction typically uses an enantiomerically pure acid or base to form a salt. The diastereomeric derivatives can then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the compound can also be directly separated by chromatography using a chiral stationary phase, which methods are well known in the art.

[0514] For compounds of formula I or formula Ib containing an olefinic double bond as described herein, unless otherwise specified, they are meant to include both the E and Z geometric isomers.

[0515] Certain compounds described herein may exist in tautomeric forms, which have different hydrogen attachment points and are accompanied by one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Compounds of formula I or formula Ib encompass the individual tautomers and mixtures thereof.

[0516] In the structural formulas of compounds of formula I or formula Ib, atoms can exhibit their natural isotopic abundances, or one or more atoms can be artificially enriched with specific isotopes having the same atomic number but an atomic mass or mass number different from that predominantly found in nature. The present invention as described and claimed herein is intended to include all suitable isotopic variants of the structural formulas of compounds of formula I or formula Ib and their embodiments. For example, different isotopic forms of hydrogen (H) include protium ( 1 H) and deuterium ( 2 H, also referred to herein as D). Protium is the major hydrogen isotope found in nature. Enrichment with deuterium may have certain therapeutic advantages, such as increasing the in vivo half-life or reducing the dose requirement, or it can provide compounds that can be used as standards for characterizing biological samples. Isotopically enriched compounds within structural formulas I or Ib can be prepared by conventional techniques well known to those skilled in the art or by methods similar to those described in the protocols and examples herein using appropriate isotopically enriched reagents and / or intermediates.

[0517] It should be understood that when compounds of formula I or formula Ib are used as precursors of the free compound or its pharmaceutically acceptable salts or for other synthetic operations, they can be prepared as pharmaceutically acceptable salts or non-pharmaceutically acceptable salts. The compounds of the present invention, including the compounds of the examples, can also include all salts of the compounds of formula I or formula Ib, which are not directly suitable for use as drugs due to low physiological compatibility but can be used, for example, as intermediates in chemical reactions or for preparing physiologically acceptable salts.

[0518] 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 organic acids).

[0519] Salts of basic compounds covered by the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of formula I or formula Ib, which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of formula I or formula Ib include, but are not limited to, the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, dextrocamphorsulfonate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, ethanedisulfonate, propionate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothiocyanate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, acetalate, naphthalenesulfonate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, teoclate, thiocyanate, toluenesulfonate, triethyl iodide, valerate, etc. In addition, when the compound of formula I or formula Ib bears an acidic moiety, its suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganous, potassium, sodium, zinc, etc. In one embodiment, the salts of acidic compounds are as follows: ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts.

[0520] Together with basic reagents (such as hydroxides, carbonates, bicarbonates, alkoxides, and ammonia), organic bases, or basic amino acids, the compounds of formula I or formula Ib form stable alkali metal salts, alkaline earth metal salts, or optionally substituted ammonium salts.

[0521] Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, cyclic amines, dicyclohexylamine, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. It also includes quaternization with reagents such as lower alkyl halides, such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl; dialkyl sulfates, such as dimethyl, diethyl, dibutyl; and dipentyl sulfates; long-chain halides, such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl; aralkyl halides, such as bromides of benzyl and phenethyl, etc.

[0522] The preparation of pharmaceutically acceptable salts from the compounds of formula I and formula Ib capable of forming salts (including their stereoisomeric forms) is carried out by known methods, for example, by mixing an equal amount of the compound of formula I or formula Ib with a solution containing the required acid, base, etc., and then collecting the required salt by filtering the salt or distilling off the solvent. The compounds of formula I and formula Ib and their salts can form solvates with solvents such as water, ethanol or glycerol. Depending on the type of side chain substituents, the compounds of formula I and formula Ib can form acid addition salts and salts with bases simultaneously.

[0523] If the compound of formula I or formula Ib contains both acidic and basic groups in the molecule, in addition to the above salt forms, the present disclosure also includes inner salts or betaines (zwitterions). The salts can be obtained from the compounds of formula I or formula Ib by conventional methods known to those skilled in the art, such as by combining with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

[0524] Compounds of formula I or formula Ib and their salts are disclosed, especially pharmaceutically acceptable salts, solvates of such compounds and their solvated salt forms, all of which are possible unless otherwise stated.

[0525] In addition, the compounds of Formula I and Formula Ib can exist in amorphous form and / or one or more crystalline forms. Therefore, all amorphous and crystalline forms of the compounds of Formula I or Formula Ib and their mixtures (including the examples) are intended to be included within the scope of the present disclosure. In addition, some of the compounds in the present disclosure can form solvates with water (i.e., hydrates) or common organic solvents (such as but not limited to EtOAc). Such solvates and hydrates of the compounds of the present disclosure, especially pharmaceutically acceptable solvates and hydrates, as well as non-solvated and anhydrous forms, are equally covered within the scope of the present disclosure.

[0526] Therefore, the compounds within the structural formulas, embodiments and specific compounds described in the examples and claims herein cover salts, all possible stereoisomers and tautomers, physical forms (such as amorphous and crystalline forms), solvate and hydrate forms, and any combination of these forms, as well as salts, prodrug forms and salts of prodrug forms, and these forms are possible unless otherwise stated.

[0527] There are also provided drugs comprising: at least one compound of Formula I or Formula Ib, and / or a pharmaceutically acceptable salt of the compound of Formula I or Formula Ib, and / or an optional stereoisomeric form of the compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt of the stereoisomeric form of the compound of Formula I or Formula Ib, or a pharmaceutically acceptable solvate of the compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt of the pharmaceutically acceptable solvate of the compound of Formula I or Formula Ib, or a prodrug of the compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt or solvate of the prodrug of the compound of Formula I or Formula Ib, or a polymorphic form of the compound of Formula I or Formula Ib, or a pharmaceutically acceptable salt, solvate or prodrug of the polymorphic form of the compound of Formula I or Formula Ib, and a pharmaceutically acceptable carrier, vehicle, additive and / or other active substances and excipients.

[0528] The drugs described herein can be administered orally, by inhalation, rectally or transdermally or by subcutaneous, intra-articular, intraperitoneal or intravenous injection. Oral administration is preferred.

[0529] There is also provided a method for producing a drug, which comprises making at least one compound of Formula I or Formula Ib, or its pharmaceutically acceptable salt, solvate, prodrug or polymorphic form into a suitable administration form using a pharmaceutically acceptable carrier and optionally other suitable active substances, additives or adjuvants.

[0530] There is provided herein a method for preparing the compounds of Formula I or Formula Ib as described below, by which the compounds of Formula I and Formula Ib and their pharmaceutically acceptable salts, solvates, prodrugs or polymorphic forms can be obtained.

[0531] The terms "therapeutically effective (or efficacious) amount" and like descriptions such as "effective therapeutic amount" are intended to mean an amount of a drug capable of alleviating the symptoms of a disorder, condition or disease being treated in an animal or human (i.e., a disorder, condition or disease associated with DGAT2 activity). The terms "preventively effective (or efficacious) amount" and like descriptions, such as "effective preventive amount", are intended to mean an amount of a drug that can prevent or alleviate the symptoms or occurrence of a disorder, condition or disease being treated in an animal or human (i.e., a disorder, condition or disease associated with DGAT2 activity). A dosage regimen using the compounds of Formula I or Ib or a pharmaceutically acceptable salt, solvate, prodrug or polymorphic form thereof is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound selected for administration; the route of administration; and the renal and hepatic function of the patient. These factors can be fully considered by a general clinician in order to determine the therapeutically effective dose or preventive effective dose required to prevent, combat or arrest the progression of a condition. It should be understood that a specific daily dose can be both a therapeutically effective amount (e.g., for treating hepatic steatosis, diabetes, obesity, hyperlipidemia, hypercholesterolemia) and a preventive effective amount (e.g., for treating NASH).

[0532] Disorders, conditions and diseases that can be treated or prevented by inhibiting DGAT2 with a compound of Formula I or Ib are, for example, the following diseases: non-alcoholic steatohepatitis (NASH), liver fibrosis, hyperlipidemia, type I diabetes, type II diabetes, cognitive decline, dementia, coronary heart disease, ischemic stroke, vascular restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial lipemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral arterial disease, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, impaired glucose tolerance, erectile dysfunction, skin and connective tissue diseases, hyperapo B lipoproteinemia, non-alcoholic fatty liver disease, cardio-renal diseases (such as chronic kidney disease and heart failure) and related diseases and conditions.

[0533] Compounds of formula I or formula Ib and their pharmaceutically acceptable salts, solvates, prodrugs and polymorphic forms can be administered to animals, preferably mammals, especially humans, either as the drug itself, as a mutual mixture or in the form of a pharmaceutical preparation. Compounds of formula I or formula Ib and their pharmaceutically acceptable salts, solvates, prodrugs and polymorphic forms can be administered to animals, including dogs and cats, either as the drug itself, as a mutual mixture or in the form of a pharmaceutical preparation. The term "patient" includes animals, preferably mammals, especially humans, who use the active agent of the present invention to prevent or treat a medical condition. Administering a drug to a patient includes self - administration by the patient and administration to the patient by others. A patient may need or wish to treat an existing disease or medical condition, or may need or wish to receive prophylactic treatment to prevent or reduce the risk of occurrence of the said disease or medical condition. As used herein, a patient "needing" treatment of an existing condition or prophylactic treatment includes both the need determined by a medical professional and the patient's desire for such treatment.

[0534] In addition, the present disclosure provides pharmaceutical preparations (or pharmaceutical compositions) comprising a therapeutically effective dose of at least one compound of formula I or formula Ib and / or its pharmaceutically acceptable salt, solvate, prodrug or polymorphic form as an active ingredient and a conventional pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0535] Thus, one aspect of the present disclosure is, for example, the use of the compounds and their pharmaceutically acceptable salts as drugs, pharmaceutical preparations comprising a therapeutically effective dose of the compounds and / or their pharmaceutically acceptable salts as active ingredients and a conventional pharmaceutically acceptable carrier, and the use of the compounds and / or their pharmaceutically acceptable salts in the treatment or prevention of the above - mentioned syndromes and their use in the preparation of drugs for these purposes.

[0536] The drugs described herein can be administered orally, for example, in the form of pills, tablets, film - coated tablets, sugar - coated tablets, granules, hard and soft capsules, aqueous solutions, alcoholic solutions or oil solutions, syrups, emulsions or suspensions, or rectally, for example, in the form of suppositories. Administration can also be parenteral, for example, subcutaneously, intramuscularly or intravenously in the form of injection or infusion solutions. Other suitable forms of administration are, for example, percutaneous 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 form of administration depends, for example, on the disease to be treated and its severity.

[0537] For the production of pills, tablets, sugar-coated tablets and hard gelatin capsules, it is possible to use, for example, lactose, starch (such as corn starch or starch derivatives), talc, stearic acid or its salts, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, etc. Suitable carriers for the preparation of solutions (such as injection solutions or emulsions or syrups) are, for example, water, physiological sodium chloride solution, alcohols (such as ethanol, glycerol, polyols), sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. The compounds of formula I or Ib and their pharmaceutically acceptable salts, solvates, solvates and prodrugs can also be lyophilized and the resulting lyophilizates can be used, for example, for the preparation of injection or infusion preparations. Suitable carriers for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.

[0538] Suitable solid or galenical preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injection solutions and preparations with extended release of the active substance, in which conventional excipients are used, such as carriers, disintegrants, binders, coating agents, swelling agents, glidants or lubricants, flavoring agents, sweeteners and solubilizers. Frequently 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 glycols and solvents (such as, for example, sterile water) and monoalcohols or polyols such as glycerol.

[0539] In addition to the active compound and the carrier, the pharmaceutical preparation can also contain conventional additives, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavoring agents, fragrances, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a sustained release effect, salts for changing the osmotic pressure, coating agents or antioxidants.

[0540] The dose of the active compound of formula I or Ib and / or its pharmaceutically acceptable salt, solvate, prodrug or polymorphic form administered depends on the individual case and, as a rule, has to be adapted to the individual case to achieve the best effect. Thus, it depends on the nature and severity of the disorder, condition or disease to be treated, also on the sex, age, weight and individual response of the human or animal to be treated, on the efficacy and duration of action of the compound used, on whether the treatment is acute, chronic or prophylactic, or on whether other active compounds are administered in addition to the compound of formula I or Ib.

[0541] Combination medicaments

[0542] 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 or other suitable agents disclosed herein, depending on the condition being treated. Thus, in some embodiments, one or more compounds of Formula I or Formula Ib will be co-administered with other agents described herein. When used in combination therapy, the compounds described herein are administered simultaneously or separately from the second agent. Such co-administration can include co-administering the two agents in the same dosage form, co-administering in separate dosage forms, and separate administration. That is, the compound of Formula I or Ib and any of the above agents can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of Formula I or Ib and any of the above agents can be administered simultaneously, where the two agents are present in separate formulations. In another alternative, the compound of Formula I or Ib can be administered first, followed immediately by any of the above agents, or vice versa. In some embodiments of the separate administration scenario, the compound of Formula I or Ib and any of the above agents are administered at intervals of minutes, hours or days.

[0543] The present disclosure contemplates the use of combinations of pharmaceutically active compounds that can be administered alone to treat a disease / condition. The present disclosure also relates to combining separate pharmaceutical compositions into a kit form. The kit contains two separate pharmaceutical compositions: a compound of Formula I or Ib, and a second pharmaceutical compound. The kit includes containers for holding the separate compositions, such as separate bottles or separate foil packs. Other 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), at different dosing intervals, or when the prescribing healthcare professional needs to titrate the individual components of the combination.

[0544] One or more additional pharmaceutically active agents can be co-administered with the compound of Formula I or Formula Ib. An additional active agent (or additional active agents) is intended to mean a pharmaceutically active agent (or pharmaceutically active agents) that is active in vivo, including prodrugs that are converted to a pharmaceutically active form after administration, which is different from the compound of Formula I or Formula Ib, and also includes the free acids, free bases and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable one or more additional active agents, including but not limited to anti-hypertensive agents, anti-obesity agents, anti-inflammatory agents, anti-fibrotic agents and anti-atherosclerotic agents (e.g., lipid-regulating compounds), anti-diabetic agents and / or anti-obesity agents, can be used with the compound of Formula I or Formula Ib in any combination in a single dosage formulation (fixed-dose drug combination), or can be administered to a patient in one or more separate dosage formulations, which allows for simultaneous or sequential administration of the active agents (co-administering the separate active agents).

[0545] Examples of additional active agents that can be employed include, but are not limited to, angiotensin converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, ceronapril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveltipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., losartan, i.e., COZAAR , valsartan, candesartan, olmesartan, telmesartan, and those in combination with hydrochlorothiazide (e.g., HYZAAR )Any of these drugs used in combination); neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., urea derivatives of dipeptides and tripeptides, amino acids and derivatives, amino acid chains linked by non-peptide bonds, dipeptide and tripeptide derivatives, peptidyl amino diols and peptidyl β-aminoacyl amino diol carbamates; also, and small molecule renin inhibitors, including diol sulfonamides and N-morpholino derivatives, N-heterocyclic alcohols and pyrolimidazolones; also, pepstatin derivatives and fluoro- and chloro-derivatives of statone-containing peptides, enalkrein, remikiren, A65317, terlakiren, ES1005, ES8891, SQ34017, aliskiren, SPP600, SPP630 and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, nifedipine, veraparmil, diltiazem, gallopamil, niludipine, nimodipins, nicardipine), potassium channel activators (e.g., nicorandil, pinacidil, cromakalim, minoxidil, aprilkalim, loprazolam), diuretics (e.g., hydrochlorothiazide), sympatholitics, β-adrenergic blockers (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol or metoprolol tartrate), α-adrenergic blockers (e.g., doxazosin, prazosin or alpha methyldopa) central α-adrenergic agonists, peripheral vasodilators (e.g., hydralazine);Hypolipidemic agents, such as HMG-CoA reductase inhibitors, such as simvastatin and lovastatin, which are in the form of lactone prodrugs as ZOCOR; and MEVACOR sold and act as inhibitors after administration, and pharmaceutically acceptable salts of dihydroxy open-ring acid HMG-CoA reductase inhibitors, such as atorvastatin (especially the calcium salt sold as LIPITOR ), rosuvastatin (especially the calcium salt sold as CRESTOR ), pravastatin (especially the sodium salt sold as PRAVACHOL ), fluvastatin (especially the sodium salt sold as LESCOL ), cerivastatin, and pitavastatin; cholesterol absorption inhibitors such as ezetimibe (ZETIA ) and ezetimibe in combination with any other hypolipidemic agent such as the above-mentioned HMG-CoA reductase inhibitors and especially with simvastatin (VYTORIN ) or in combination with atorvastatin calcium; immediate-release or controlled-release forms of niacin, and / or in combination with HMG-CoA reductase inhibitors; niacin receptor agonists such as acipimox and acifran, and niacin receptor partial agonists; anti-cholesterol agents such as PCSK9 inhibitors (alirocumab, evolocumab, Nexletol TM (bempedoic acid, ACL inhibitor) and Vascepa (Eicosapentaenoic acid ethyl ester); metabolic modifiers, including insulin and insulin analogs (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omarigliptin, linagliptin, vildagliptin); insulin sensitizers, including (i) 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, including (1) PPARα / γ dual agonists (e.g., ZYH2, ZYH1, GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, and naveglitazar); (2) PPARα agonists, such as fenofibric acid derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (2) selective PPARγ modulators (SPPARγM’s), (e.g., those disclosed in, for example, WO02 / 060388, WO02 / 08188, WO2004 / 019869, WO2004 / 020409, WO2004 / 020408, and WO2004 / 066963); (4) PPARγ partial agonists; (5) PPARα / δ dual agonists (e.g., Elafibranor); (iii) biguanides, such as metformin and its pharmaceutically acceptable salts, particularly metformin hydrochloride, and its sustained release formulations, such as Glumetza TM , Fortamet TM and GlucophageXR TM; and (iv) protein tyrosine phosphatase-IB (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisine, degludec insulin, insulin glargine, insulin lispro, and their inhalation formulations); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylureas and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, 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 analogs, such as GLP-1, GLP-1 analogs, derivatives, and mimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide, CJC-1131, and BIM-51077, including 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; agents intended for inflammatory conditions, such as aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g., AZD6370); 11β-hydroxysteroid dehydrogenase type 1 inhibitors (e.g., those disclosed in U.S. Patent No. 6,730,690 and LY-2523199);CETP inhibitors (such as anacetrapib, torcetrapib, and evacetrapib); inhibitors of fructose 1,6-bisphosphatase (such as those disclosed in, for example, U.S. Patent Nos. 6,054,587, 6,110,903, 6,284,748, 6,399,782, and 6,489,476); inhibitors of acetyl-CoA carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated protein kinase (AMPK) activators; other agonists of G protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (such as MBX2982 and PSN821), and (iii) GPR-40 (such as TAK875); SSTR3 antagonists (such as those disclosed in, for example, WO2009 / 001836); neuromedin U receptor agonists (such as those disclosed in, for example, WO2009 / 042053, including but not limited to neuromedin S (NMS)); SCD modulators (such as Aramchol); GPR-105 antagonists (such as those disclosed in, for example, WO2009 / 000087); glucose pathway modulators, such as SGLT inhibitors (such as ASP1941, SGLT-3, SGLT-2, such as empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, BI-10773, remogloflozin, TS-071, tofogliflozin, ipragliflozin, and LX-4211); dual SGLT-1 / 2 inhibitors (such as licogliflozin); glucose-6-P dehydrogenase inhibitors (such as fluasterone); LAPS glucagon combination (such as HM14320); SGLT-1 inhibitors (such as SGL5213); acyl-CoA carboxylase inhibitors (ACC, MK-4074); inhibitors of diacylglycerol acyltransferase 1 and 2 (DGAT-1 and DGAT-2); fatty acid synthase inhibitors; inhibitors of acyl-CoA:monoacylglycerol acyltransferase 1 and 2 (MGAT-1 and MGAT-2); TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR) agonists; ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimetics, and PACAP receptor 3 agonists; IL-1b antibodies (such as XOMA052 and canakinumab);Anti-fibrotic and / or anti-inflammatory agents (CCR2 / CCR5 dual receptor antagonists (e.g., cenicriviroc); galectin-3 inhibitors (e.g., belapectin, GB-1107, GB-1211), siRNA against HSP 47 (e.g., BMS-986263); NSAIDs derived from pirfenidone (e.g., hydronidone), A3AR agonists (e.g., namodenoson, FM101); TGFTX4 (e.g., nitazoxanide);5-lipoxygenase inhibitors (such as tipelukast), dual-functional urate inhibitors (such as ACQT1127), adiponectin receptor agonists (such as ALY688), TNF receptor antagonists (such as atrosimab), autotaxin inhibitors (such as BLD-0409, TJC0265, TJC0316), CCL24-blocking monoclonal antibodies (such as CM101), IL-11 inhibitors (such as ENx108A), LPA1 receptor antagonists (such as EPGN696), dual JAK1 / 2 inhibitors (such as EX76545), GPR antagonists (such as GPR91 antagonists), integrin avb1, avb3, and avb6 inhibitors (such as IDL2965), NLRP3 antagonists (such as IFM-514), inflammasome inhibitors (such as JT194, JT349), cell membrane permeability inhibitors (such as Larazotide), CCR5 antagonists (such as Ieronlimab), TNF inhibitors (such as LIVNate), integrin avβ6 inhibitors (such as MORFbeta6), NLRP inflammasome antagonists, siRNA (such as OLX701), dual TGFβ / Hedgehog inhibitors (such as Oxy200), GPR40 agonist / GPR84 antagonist (such as PBI-4547), neutrophil elastase inhibitors (such as PHP-303), integrin inhibitors (such as PLN-1474), TGFβ1 regulators (such as PRM-151), CCK receptor antagonists (such as proglumide), LOXL2 inhibitors (such as PXS-5338K, PXS-5382A), IL-11 inhibitors, MPY protein inhibitors (such as cGAS / STING antagonists), kinase-inhibiting RNase, membrane protein mAb, tumor necrosis factor inhibitors, NRF2 activators (such as SCO116), SSAO inhibitors (such as TERN201), TRAIL2 agonists (such as TLY012), IL-6 receptor antagonists (such as TZLS501), AOC3 inhibitors (such as UD-014), SSAO / VAP-1 inhibitors, TREM2); antioxidants (such as vitamin E); anti-inflammatory agents (such as norfloxacin, ciprofloxacin, ceftriaxone); blood coagulation regulators (such as anticoagulants, antiplatelets, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonists (such as tirzepetide);Dual GLP-1 / GRA agonists (e.g., cotadutide, ALT-801, DD 01, G49, PB-718); dual GLP-1 (e.g., CT 868); GLP-1 / GRA / GIP triple agonists (e.g., HM15211); GRP120 stimulator / inflammasome regulator / PPAR dual agonists (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW 003); selective thyroid hormone receptor-β agonists (e.g., resmetirom); apoptosis regulators (JNK-1 inhibitors (e.g., CC-90001), peroxidase inhibitors (e.g., AZM198), ASK-1 inhibitors (e.g., CS-17919, SRT 015)); erythropoietin stimulators (erythropoietin receptor agonists (e.g., cibinetide)); immunomodulators (TLR4 inhibitors (e.g., GBK-233), immunomodulatory polyclonal antibodies (e.g., IMM-124E), TLR4 antagonists (e.g., JKB-122), anti-CD3 monoclonal antibodies (e.g., foralumab), TLR4 antagonists (e.g., JKB 133), TLR4 inhibitors (e.g., mosedipimod), macrophage inhibitors targeting CD206 (e.g., MT2002), TLR2 / 4 antagonists (e.g., VB-201, VB-703), immunomodulatory polyclonal antibodies (e.g., IMM-124E)); incretin-based therapies (GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW 003), GLP-1 / glucagon dual receptor agonists (e.g., HM12525A), prandial insulin (e.g., ORMD 0801));Lipid regulators (AMPK activators / glutathione transferases (e.g., oltipraz), THR-β agonists (e.g., remeglurant, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN 501), IBAT inhibitors (e.g., elobixibat, CJ 14199), ω-6-fatty acids (e.g., epeleuton), FASN inhibitors (e.g., TVB2640, FT 4101, FT 8225), ANGPTL3 inhibitors (e.g., vupanorsen), PNPLA3 inhibitors (e.g., AZD2693), RAS domain kinase inhibitors (e.g., BioE1115), NTCP inhibitors (e.g., bulevirtide), P2Y13 receptor agonists (e.g., CER-209), ω-3 fatty acids, HSD17β13 inhibitors;Metabolic regulators (FXR agonists (such as Ocaliva (obeticholic acid), IOT022), FGF19 recombinant variants (such as aldafermin), bispecific FGFR1 / KLB antibodies (such as BFKB8488A), mTOT regulators (such as MSDC-0602K), polyethylene glycolated FGF21 analogs (such as pegbelfermin, BMS-986171), non-bile FXR agonists (such as cilofexor, EDP-305, EYP 001, tropifexor, MET409, AGN-242256, AGN-242266, EDP 297, HPG 1860, MET642, RDX023, TERN 101), ACC inhibitors (such as firsocostat, PF-05221304), hexokinase inhibitors (such as PF-06835919), AMPK activators (such as PXL770, MSTM 101, O304), bile acid regulators (such as Albiero), FGF21 analogs (such as BIO89-100), MOTSc analogs (such as CB4211), cyclophilin inhibitors (such as CRV 431), FGF19 (such as.DEL 30), mitochondrial uncouplers (such as GEN 3026), FXR / GPC dual agonists (such as INT-767), cysteamine derivatives (such as KB-GE-001), amylin and calcitonin dual receptor agonists (such as KBP-089), transient FXR agonists (such as M1217), anti-β-klotho (KLB)-FGFRlc receptor complex mAb (such as MK3655), GDF15 analogs (such as NGM395), cyclophilin inhibitors (such as NV556), LXR regulators (such as PX 329, PX 655, PX 788), LXR inverse agonists (such as PX016), deuterated obeticholic acid (such as ZG 5216)); PPAR regulators (dual PPARα / γ agonists (such as elafibranor), PPAR pan-agonists (such as lanifibranor), PPARα agonists (such as Parmodia), PPARγ agonists (such as CHS131), MPC inhibitors (such as PXL065), PPARδ / γ agonists (such as T3D 959));RAAS modulators (mineralocorticoid receptor antagonists (e.g., apararenone, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulators, CB1 receptor antagonists (e.g., CRB-4001, IM-102, nimacimab), TPH1 inhibitors (e.g., CU 02), GPR120 agonists (e.g., KBR2001), combinations of cannabinoids and phytochemical anti-inflammatory compounds (e.g., SCN 002)); PDE modulators (PDE4 inhibitors (e.g., ART 648)); CYP2E1 inhibitors (e.g., SNP-610); cell therapies (e.g., HepaStem) and bromocriptine mesylate and its immediate release formulations; or other drugs beneficial for the prevention or treatment of the above diseases including nitroprusside and diazoxide and free acids, free bases and pharmaceutically acceptable salt forms of the above active agents that are chemically feasible.;

[0546] The present invention includes pharmaceutically acceptable salts of the compounds defined herein, including pharmaceutically acceptable salts of all structural formulas, embodiments and classes defined herein. References to compounds of structural formula I or Ib include other general structural formulas, such as compounds of formulas and embodiments falling within the scope of formula I or Ib.

[0547] Dosage of the compound of formula I or Ib

[0548] If the patient responds or is stable after completing a treatment cycle, the treatment cycle can be repeated at the discretion of a skilled clinician. After completing a treatment cycle, the patient can continue to use the same dose of the compound of the present invention as administered in the treatment regimen. This maintenance dose can be continued until the patient's condition progresses or the patient can no longer tolerate the dose (in which case the dose can be reduced and the patient can continue to take the reduced dose).

[0549] Those skilled in the art will recognize that the actual doses and administration regimens employed in the methods disclosed herein can vary at the discretion of a skilled clinician. The actual doses used may vary depending on the requirements of the patient and the severity of the condition being treated. Determining the appropriate dose for a particular situation is within the ability of those skilled in the art. A skilled clinician can decide to change the dose and administration regimen after considering factors such as the patient's age, condition and body size, as well as the severity of the condition being treated and the patient's response to the treatment.

[0550] The dosage regimen for using a compound of formula I or formula Ib or a pharmaceutically acceptable salt, solvate, prodrug or polymorphic form thereof is selected based on a variety of factors, including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the potency of the compound selected for administration; the route of administration; and the renal and hepatic function of the patient. In order to determine the therapeutically effective dose or prophylactically effective dose required to prevent, combat or arrest the progression of the condition, these factors can be fully considered by an ordinary clinician. It should be understood that a specific daily dose can simultaneously be a therapeutically effective amount (e.g., for treating a tumor condition) and a prophylactically effective amount (e.g., for preventing a tumor condition).

[0551] Although individual requirements vary, it is within the ability of those skilled in the art to determine the optimal range of the effective amount of a compound of formula I or formula Ib or a pharmaceutically acceptable salt, solvate, prodrug or polymorphic form thereof. For example, for administration to humans in the therapeutic or prophylactic treatment of the conditions and disorders identified herein, a typical dose of a compound of formula I or formula Ib can be from about 0.05 mg / kg / day to about 50 mg / kg / day, such as at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, which can be, for example, from about 2.5 mg / day (0.5 mg / kg × 5 kg) to about 5000 mg / day (50 mg / kg × 100 kg). For example, the dose of the compound can be from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about 5 mg / kg / day, from about 0.05 mg / kg / day to about 3 mg / kg / day, from about 0.07 mg / kg / day to about 3 mg / kg / day, from about 0.09 mg / kg / day to about 3 mg / kg / day, from about 0.05 mg / kg / day to about 0.1 mg / kg / day, from about 0.1 mg / kg / day to about 1 mg / kg / day, from about 1 mg / kg / day to about 10 mg / kg / day, from about 1 mg / kg / day to about 5 mg / kg / day, from about 1 mg / kg / day to about 3 mg / kg / day, from about 3 mg / day to about 500 mg / day, from about 5 mg / day to about 250 mg / day, from about 10 mg / day to about 100 mg / day, from about 3 mg / day to about 10 mg / day, or from about 100 mg / day to about 250 mg / day. Such doses can be administered as a single dose or can be divided into multiple doses.

[0552] Pharmaceutical composition

[0553] Compounds of formula I or formula Ib and their pharmaceutically acceptable salts, solvates, prodrugs and polymorphic forms can be administered to animals, preferably mammals, especially humans, either as the drug itself, in admixture with each other or in the form of a pharmaceutical composition. The terms "subject" or "patient" include animals, preferably mammals, especially humans, who use the active agent of the present invention to prevent or treat a medical condition.

[0554] Administering a compound of formula I or formula Ib or a pharmaceutically acceptable salt, solvate, prodrug or polymorphic form thereof to a subject includes self - administration and administration to the patient by another person. The subject may need or desire treatment of an existing disease or medical condition, or may need or desire prophylactic treatment to prevent or reduce the risk of occurrence of said disease or medical condition. As used herein, a subject who "needs" treatment of an existing condition or prophylactic treatment includes both the need determined by a medical professional and the desire of the patient for such treatment.

[0555] If the patient responds or is stable after completion of a treatment cycle, the treatment cycle can be repeated at the discretion of a skilled clinician. After completion of a treatment cycle, the patient can continue to take a 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 regimen. This maintenance dose can be continued until the patient's condition progresses or the patient can no longer tolerate the dose (in which case the dose can be reduced and the patient can continue to take the reduced dose).

[0556] Those skilled in the art will recognize that the actual dosage and administration regimen employed in the methods disclosed herein can vary according to the discretion of a skilled clinician. The actual dose used may vary according to the requirements of the patient and the severity of the condition being treated. Determining an appropriate dose for a particular situation is within the ability of those skilled in the art. A skilled clinician can decide to change the dose and administration regimen after considering factors such as the age, condition and body size of the patient, as well as the severity of the condition being treated and the patient's response to the treatment.

[0557] The dosage and frequency of administration of a compound of formula I or formula Ib and any additional medicaments will be adjusted according to the judgment of the attending clinician (physician) after considering factors such as the age, condition and body size of the patient, as well as the severity of the condition being treated.

[0558] Compounds of formula I or formula Ib and their pharmaceutically acceptable salts, solvates, prodrugs or polymorphic forms can also be used in the preparation of a medicament for the treatment of NASH and fibrosis.

[0559] The compounds of the present invention can also be used in combination with therapeutic agents, chemotherapeutic agents, and anti-cancer agents for the treatment of hepatocellular carcinoma. Combinations of the presently disclosed compounds with therapeutic agents, chemotherapeutic agents, and anti-cancer agents are all within the scope of this disclosure. Examples of such agents can be found in Cancer Principles and Practice of Oncology, 9th Edition (May 16, 2011), edited by V.T. DeVita and S. Hellman, published by Lippincott Williams & Wilkins. One of ordinary skill in the art can discern which combination of agents is useful based on the specific characteristics of the drug and the cancer involved. Such agents include the following: estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed death ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic / cell growth inhibitors, anti-proliferative agents, isoprenyl protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, cell proliferation and survival signaling inhibitors, bisphosphonates, aromatase inhibitors, siRNA therapeutic agents, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs), and agents that interfere with cell cycle checkpoints.

[0560] Chemotherapeutic agents can be administered according to treatment regimens known in the art. It will be apparent to those skilled in the art that the administration of chemotherapeutic agents can vary depending on the cancer being treated and the known effects of the chemotherapeutic agent on the disease. Moreover, based on the knowledge of a skilled clinician, the treatment regimen (e.g., dose and administration time) can be altered based on the observed effects of the administered therapeutic agent on the patient and based on the observed response of the cancer to the administered therapeutic agent. The specific choice of chemotherapeutic drugs will depend on the diagnosis of the attending physician and their judgment of the patient's condition and the appropriate treatment regimen.

[0561] The initial administration can be carried out according to established protocols known in the art, and then, based on the observed effects, the dose, mode of administration, and administration time can be modified by a skilled clinician.

[0562] After evaluating the condition being treated and the patient's status, a skilled physician is fully aware of the determination of the order of administration and the number of administration repetitions of chemotherapeutic agents during the treatment regimen.

[0563] Thus, based on experience and knowledge, a practicing physician can modify the regimen for each administration of chemotherapeutic drugs according to the needs of an individual patient as the treatment progresses. All such modifications are within the scope of this disclosure.

[0564] The agent can be administered according to treatment regimens well-known in the art. It will be apparent to those skilled in the art that the administration of the anti-cancer agent can vary depending on the cancer being treated and the known effects of the anti-cancer agent on the disease.

[0565] The initial administration can be carried out according to established regimens known in the art, and then, based on the observed effects, the dose, mode of administration, and administration time can be modified by a skilled clinician.

[0566] The specific choice of agent will depend on the diagnosis of the attending physician and their judgment of the patient's condition and the appropriate treatment regimen.

[0567] After evaluating the cancer being treated and the patient's condition, a skilled physician is fully aware of the determination of the order of administration and the number of administration repetitions during the treatment regimen.

[0568] When judging whether the treatment with the administered dose is effective, the attending physician will consider the patient's overall health condition and more specific signs, such as alleviating cancer-related symptoms (such as pain), inhibiting tumor growth, actual shrinkage of the tumor, or inhibiting metastasis. The size of the tumor can be measured by standard methods, such as radiological studies, such as CAT or MRI scans, and serial measurements can be used to judge whether the growth of the tumor has slowed down or even reversed. The alleviation of disease-related symptoms such as pain and the improvement of the overall condition can also be used to help judge the effectiveness of the treatment.

[0569] The compounds, compositions, and methods provided herein can be used to treat cancer. Cancers that can be treated by the compounds, compositions, and methods disclosed herein include, but are not limited to: Liver: Hepatocellular carcinoma (hepatoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma.

[0570] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL inhibitors include atezolizumab, avelumab, and durvalumab.

[0571] Also provided is a method for treating hepatocellular carcinoma in a human patient, which comprises 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.

[0572] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody or an antigen-binding fragment thereof. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody or an antigen-binding fragment thereof. In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA TM , Merck&Co., Inc., Rahway, NJ, USA), nivolumab (OPDIVO TM , Bristol-Myers Squibb Company, Princeton, NJ, USA), cemiplimab (LIBTAYO TM , Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab (TECENTRIQ TM , Genentech, San Francisco, CA, USA), durvalumab (IMFINZI TM , AstraZeneca Pharmaceuticals LP, Wilmington, DE) or avelumab (BAVENCIO TM , MerckKGaA, Darmstadt, Germany).

[0573] In some embodiments, the PD-1 antagonist is pembrolizumab. In a specific sub-embodiment, the method comprises administering 200 mg of pembrolizumab to a patient approximately every three weeks. In other sub-embodiments, the method comprises administering 400 mg of pembrolizumab to a patient approximately every six weeks.

[0574] In a further sub-embodiment, the method comprises administering 2 mg / kg of pembrolizumab to a patient approximately every three weeks. In a specific sub-embodiment, the patient is a pediatric patient.

[0575] In some embodiments, the PD-1 antagonist is nivolumab. In a specific sub-embodiment, the method comprises administering 240 mg of nivolumab to a patient approximately every two weeks. In other sub-embodiments, the method comprises administering 480 mg of nivolumab to a patient approximately every four weeks.

[0576] In some embodiments, the PD-1 antagonist is cemiplimab. In a specific embodiment, the method comprises administering 350 mg of cemiplimab to a patient approximately every 3 weeks.

[0577] In some embodiments, the PD-1 antagonist is atezolizumab. In a specific sub-embodiment, the method comprises administering 1200 mg of atezolizumab to a patient approximately every three weeks.

[0578] In some embodiments, the PD-1 antagonist is durvalumab. In a specific sub-embodiment, the method comprises administering 10 mg / kg of durvalumab to a patient approximately every two weeks.

[0579] In some embodiments, the PD-1 antagonist is avelumab. In a specific sub-embodiment, the method comprises administering 800 mg of avelumab to a patient approximately every two weeks.

[0580] The compound of formula I or formula Ib or a pharmaceutically acceptable salt thereof can also be used in combination with the following therapeutic agents for treating cancer: pembrolizumab (Keytruda ), abarelix (Plenaxis depot ), aldesleukin (Prokine ), aldesleukin (Proleukin ), alemtuzumab (Campath ), alitretinoin (Panretin ), allopurinol (Zyloprim ), altretamine (Hexalen ), amifostine (Ethyol ), anastrozole (Arimidex ), arsenic trioxide (Trisenox ), asparaginase (Elspar ), azacitidine (Vidaza ), bevacizumab (Avastin ), bexarotene capsules (Targretin ), bexarotene gel (Targretin ), bleomycin (Blenoxane ), bortezomib (Velcade ), busulfan for intravenous injection (Busulfex ), oral busulfan (Myleran ), Calusterone (Methosarb ), Capecitabine (Xeloda ), Carboplatin (Paraplatin ), Carmustine (BCNU , BiCNU ), Carmustine (Gliadel ), Carmustine with Polifeprosan 20 Implant (Gliadel Wafer ), Celecoxib (Celebrex ), Cetuximab (Erbitux ), Chlorambucil (Leukeran ), Cisplatin (Platinol ), Cladribine (Leustatin , 2-CdA ), Clofarabine (Clolar ), Cyclophosphamide (Cytoxan , Neosar ), Cyclophosphamide (Cytoxan Injection ), Cyclophosphamide (Cytoxan Tablet ), Cytarabine (Cytosar-U ), Liposomal Cytarabine (DepoCyt ), Dacarbazine (DTIC-Dome ), Dactinomycin, Actinomycin D (Cosmegen ), Darbepoetin alfa (Aranesp ), Liposomal Daunorubicin (DanuoXome ), Daunorubicin ), Daunorubicin (Cerubidine ), Denileukin diftitox (Ontak ), Dexrazoxane (Zinecard ), docetaxel (Taxotere ), doxorubicin (Adriamycin PFS ), doxorubicin (Adriamycin , Rubex ), doxorubicin PFS Injection ), liposomal doxorubicin (Doxil ), dromostanolone propionate (Dromostanolone ), dromostanolone propionate (Masterone injection ), Elliott's B Solution (Elliott's B Solution ), epirubicin (Ellence ), epoetin alfa (epogen ), erlotinib (Tarceva ), estramustine (Emcyt ), etoposide phosphate (Etopophos ), etoposide, VP-16 (Vepesid ), exemestane (Aromasin ), filgrastim (Neupogen ), floxuridine (intra-arterial) (FUDR ), fludarabine (Fludara ), fluorouracil, 5-FU (Adrucil ), fulvestrant (Faslodex ), gefitinib (Iressa ), gemcitabine (Gemzar ), gemtuzumab ozogamicin (Mylotarg ), goserelin acetate (Zoladex Implant ), goserelin acetate (Zoladex ), histrelin acetate (Histrelin implant ), hydroxyurea (Hydrea ), ibritumomab tiuxetan (Zevalin ), idarubicin (Idamycin ), ifosfamide (IFEX ), imatinib mesylate (Gleevec ), interferon α2a (Roferon A ), interferon α-2b (Intron A ), irinotecan (Camptosar ), lenalidomide (Revlimid ), letrozole (Femara ), leucovorin (Wellcovorin , Leucovorin ), leuprolide acetate (Eligard ), levamisole (Ergamisol ), lomustine, CCNU (CeeBU ), mechlorethamine, nitrogen mustard (Mustargen ), megestrol acetate (Megace ), melphalan, L-PAM (Alkeran ), mercaptopurine, 6-MP (Purinethol ), mesna (Mesnex ), mesna (Mesnex tabs ), methotrexate (Methotrexate ), methoxsalen (Uvadex ), mitomycin C (Mutamycin ), Mitotane (Lysodren ), Mitoxantrone (Novantrone ), Nandrolone phenpropionate (Durabolin-50 ), Nelarabine (Arranon ), Nofetumomab (Verluma ), Oprelvekin (Neumega ), Oxaliplatin (Eloxatin ), Paclitaxel (Paxene ), Paclitaxel (Taxol ), Paclitaxel albumin-bound particles (Abraxane ), Palifermin (Kepivance ), Pamidronate (Aredia ), Pegademase (Adagen (Pegademase Bovine) ), Pegaspargase (Oncaspar ), Pegfilgrastim (Neulasta ), Pemetrexed disodium (Alimta ), Pentostatin (Nipent ), Pipobroman (Vercyte ), Plicamycin (mithramycin) (Mithracin ), Porfimer sodium (Photofrin ), Procarbazine (Matulane ), Quinacrine (Atabrine ), Rasburicase (Elitek ), Rituximab (Rituxan ), Ridaforolimus, Sargramostim (Leukine ), sargramostim (Prokine ), sorafenib (Nexavar ), streptozocin (Zanosar ), sunitinib maleate (Sutent ), talc (Sclerosol ), tamoxifen (Nolvadex ), temozolomide (Temodar ), teniposide, VM-26 (Vumon ), testolactone (Teslac ), thioguanine, 6-TG (Thioguanine ), thiotepa (Thioplex ), topotecan (Hycamtin ), toremifene (Fareston ), tositumomab (Bexxar ), tositumomab / I-131 tositumomab (Bexxar ), trastuzumab (Herceptin ), tretinoin, ATRA (Vesanoid ), uracil mustard (Uracil Mustard Capsules ), valrubicin (Valstar ), vinblastine (Velban ), vincristine (Oncovin ), vinorelbine (Navelbine ), vorinostat (Zolinza ), and zoledronate (Zometa ), or a pharmaceutically acceptable salt thereof.

[0581] Preparation Formula I and Formula Ib Method for preparing a compound

[0582] The following examples are provided to more fully understand the present disclosure. Unless otherwise noted, starting materials are commercially available. They should not be construed as limiting the invention in any way.

[0583] Several methods for preparing compounds of formula I or formula Ib are described in the following schemes and examples. Starting materials and intermediates are purchased, prepared by known procedures, or otherwise specified. Some of the frequently used routes for preparing compounds of formula I or formula Ib are also described by the following schemes. In some cases, the order of execution of the individual steps in the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. For stereoisomers, enantiomer A refers to the enantiomer that elutes faster / earlier at the separation point, while enantiomer B refers to the enantiomer that elutes slower / later at the separation point, and for a given enantiomer series, this nomenclature remains the same throughout the remaining synthetic sequence, regardless of whether the subsequent intermediates and final compounds may have the same or opposite elution order.

[0584] List of abbreviations:

[0585] ACN = acetonitrile

[0586] aq. = aqueous solution

[0587] ℃ = degree Celsius

[0588] CatAXium A Pd G2 = chloro[(di(1-adamantyl)-N-butylphosphine)-2-(2-aminobiphenyl)]palladium(II)

[0589] DAST = diethylaminosulfur trifluoride

[0590] DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene

[0591] DCPP = 2,3-dichlorophenylpiperazine

[0592] DMF = dimethylformamide

[0593] DCM = dichloromethane

[0594] DCE = 1,2-dichloroethane

[0595] DIPEA = N,N-diisopropylethylamine

[0596] DMSO = dimethyl sulfoxide

[0597] Et = ethyl

[0598] EtOAc = ethyl acetate

[0599] FA = formic acid

[0600] RP HPLC = Reversed-phase high performance liquid chromatography

[0601] H or hrs = hour or hours

[0602] HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0603] HCl = Hydrogen chloride

[0604] HOAc = Acetic acid

[0605] HPLC = High performance liquid chromatography

[0606] LCMS or LC / MS = Liquid chromatography mass spectrometry

[0607] Me = Methyl

[0608] mCPBA = meta-Chloroperoxybenzoic acid

[0609] MgSO4 = Magnesium sulfate

[0610] MTBE = Methyl tert-butyl ether

[0611] RT or rt = Room temperature

[0612] NBS = N-Bromosuccinimide

[0613] NCS = N-Chlorosuccinimide

[0614] NIS = N-Iodosuccinimide

[0615] NMR = Nuclear magnetic resonance

[0616] PE or pet.ether = Petroleum ether

[0617] Pd(OAc)2 = Palladium(II) acetate

[0618] PdCl2(dppf) = Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)

[0619] PyBroP = Bromotripyrrolidinophosphonium hexafluorophosphate

[0620] TBAF = Tetra-n-butylammonium fluoride

[0621] THF = Tetrahydrofuran

[0622] TFA = Trifluoroacetic acid

[0623] TFAA = Trifluoroacetic anhydride

[0624] TLC = Thin layer chromatography

[0625] PhMe = Toluene

[0626] wt.% = Weight percentage

[0627] x g = Multiple of gravity

[0628] % w / v = Percentage of the weight of the former agent relative to the volume of the latter agent

[0629] Sat. = Saturated

[0630] Soln. = Solution

[0631] LCMS conditions: Column: ACQUITY UPLC-QDa BEH C18, 1.7 mm, 2.1 x 50 mm.

[0632] Solvent system: A: Water 0.1% FA, B: ACN 0.1% FA

[0633] Gradient conditions: 10 - 90% B, within 1.7 minutes, total run time 2.4 minutes General synthetic scheme

[0634] Except for the specific embodiments presented below, many alternatives, modifications, and variations will be apparent to those of ordinary skill in the art. In some cases, the order of execution of steps in the reaction scheme can be changed to facilitate the reaction or avoid unwanted reaction products. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the present disclosure.

[0635] General Scheme 1

[0636]

[0637] The compounds of Formula 1-4 are prepared from 1-1 and R 1 -X via SN2, SNAr, or copper-mediated C-O coupling. 1-2 is saponified to give the corresponding carboxylic acid (1-3), which is then subjected to amide coupling with an appropriate amine (R 2 -NH2) to give the compound of formula (1-4) as described in the general scheme. The order of steps in some embodiments may be different to facilitate the synthesis.

[0638] Intermediate

[0639] Intermediate 1: 3-Ethoxy-2-fluoropyridine

[0640]

[0641] Under RT, to a stirred solution of 2-fluoropyridin-3-ol (5.0 g, 44 mmol) and K2CO3 (9.8 g, 71 mmol) in DMF (45 mL) was added iodoethane (6.4 mL, 80 mmol), 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 Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 10% EtOAc / PE) to give the title compound. LC / MS = 142 [M+H].

[0642] The following intermediates were synthesized by using procedures similar to those described for Intermediate 1 and appropriate reagents. These intermediates were characterized by LC / MS.

[0643]

[0644]

[0645] Intermediate 19: 5-Ethyl-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine

[0646]

[0647] Step A: 2-Fluoro-3-(2,2,2-trifluoroethoxy)-5-vinylpyridine

[0648] Under RT, to a stirred 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) was added 4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborolane (365 mg, 2.37 mmol). The resulting mixture was stirred at 100 °C for 1 h. The reaction mixture was cooled to room temperature, filtered through a Celite pad, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 222 [M+H].

[0649] Step B: 5-Ethyl-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine

[0650] Under RT, in an N2 atmosphere, Pd(OH)2-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). Then triethylsilane (715 μl, 4.48 mmol) was added dropwise. N2 was bubbled through the reaction mixture, which was then filtered through a pad of diatomaceous earth, washed with MeOH, and the filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 224 [M+H].

[0651] Using a procedure similar to that described for Intermediate 19 and appropriate reagents, the following intermediate was synthesized. The intermediate was characterized by LC / MS.

[0652]

[0653] Intermediate 21: 5-(oxetan-1-yl)-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine

[0654]

[0655] Step A: 3-Bromo-5-(2,2,2-trifluoroethoxy)pyridine

[0656] Under RT, 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.40 g, 10.4 mmol) was added 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). The resulting mixture was stirred at RT 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 in vacuo. The crude material was purified by flash column chromatography on silica gel (20% EtOAc / PE) to afford the title compound. LC / MS = 256 [M+H].

[0657] Step B: 3-(Azetidin-1-yl)-5-(2,2,2-trifluoroethoxy)pyridine

[0658] Under RT, in an N2 atmosphere, 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), Cs2CO3 (1.16 g, 3.55 mmol), Pd2(dba)3 (125 mg, 137 μmol), and XantPhos (79.0 mg, 137 μmol) in 1,4-dioxane (20.0 mL). The resulting solution was stirred at 120 °C for 12 hours, then the reaction mixture was filtered through a Celite pad, washed with EtOAc, and the filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (17% EtOAc / PE) to give the title compound. LC / MS = 233 [M+H].

[0659] Step C: 5-(Azetidin-1-yl)-2-iodo-3-(2,2,2-trifluoroethoxy)pyridine

[0660] Under RT, NIS (81.0 mg, 362 μmol) was added 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). The resulting mixture was stirred at RT for 12 hours, then purified directly by preparative TLC on silica gel (25% EtOAc / PE) to give the title compound. LC / MS = 359 [M+H].

[0661] Intermediate 22: 3-(Cyclopropylmethoxy)-5-fluoro-2-iodopyridine

[0662]

[0663] Step A: 5-Fluoro-2-iodopyridin-3-ol

[0664] Under RT, Na2CO3 (6.56 g, 61.9 mmol) and KI (6.17 g, 37.1 mmol) were added to a stirred solution of 5-fluoropyridin-3-ol (3.50 g, 30.9 mmol) in water (50.0 mL), then a solution of iodine (7.85 g, 30.9 mmol) in water (20.0 mL) was added dropwise. The resulting mixture was stirred at RT for 2 hours, then the pH was adjusted to 5 - 6 using 4M aqueous HCl. The resulting precipitate was collected by filtration and dried in vacuo. The crude material was purified by preparative HPLC to give the title compound. LC / MS = 239 [M+H].

[0665] Step B: 3-(Cyclopropylmethoxy)-5-fluoro-2-iodopyridine

[0666] Under RT, to a stirred solution of 5-fluoro-2-iodopyridin-3-ol (0.800 g, 3.35 mmol) in DMF (3.00 mL) was added K2CO3 (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 Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to give the title compound. LC / MS 294 [M+H].

[0667] Intermediate 23: 2-(2,2,2-trifluoroethoxy)-6-(trifluoromethyl)pyrazine

[0668]

[0669] Under RT, to a stirred solution of 2-chloro-6-(trifluoromethyl)pyrazine (2.00 g, 11.0 mmol) and Cs2CO3 (4.28 g, 13.2 mmol) in DMF (11.0 mL) was added 2,2,2-trifluoroethan-1-ol (860 μL, 12.1 mmol). The resulting solution was stirred at 50 °C for 2 h. Then the mixture was filtered through a pad of Celite and the filtrate was purified directly by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to give the title compound. LC / MS = 247 [M+H].

[0670] Intermediate 24: 3-(1,1,2,2-tetrafluoroethoxy)pyridine 1-oxide

[0671]

[0672] Step A: 3-(2-Bromo-1,1,2,2-tetrafluoroethoxy)pyridine

[0673] Under RT, to a stirred solution of pyridin-3-ol (0.500 g, 5.26 mmol) and Cs2CO3 (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). The resulting mixture was stirred at RT for 18 h. The mixture was diluted with water and the aqueous layer was extracted with Et2O. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. LC / MS = 275 [M+H].

[0674] Step B: 3-(1,1,2,2-Tetrafluoroethoxy)pyridine

[0675] At RT, 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). The resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was diluted with water, neutralized with saturated aqueous NaHCO3, and the aqueous layer was extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. LC / MS = 196 [M+H].

[0676] Step C: 3-(1,1,2,2-Tetrafluoroethoxy)pyridine 1-oxide

[0677] At RT, mCPBA (1.09 g, 6.31 mmol) was added to a stirred solution of 3-(1,1,2,2-tetrafluoroethoxy)pyridine (1.03 g, 5.26 mmol) in DCM (11.1 mL). The resulting mixture was stirred at RT for 18 h. The reaction mixture was diluted with water, neutralized with saturated aqueous NaHCO3, and the aqueous layer was extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 10% MeOH / DCM) to give the title compound. LC / MS = 212 [M+H].

[0678] The following intermediate was synthesized by using a procedure similar to that described for Intermediate 24 and appropriate reagents. The intermediate was characterized by LC / MS.

[0679]

[0680] Intermediate 26: 2-chloro-5-methyl-3-(2,2,2-trifluoroethoxy)pyrazine

[0681]

[0682] At RT, 2,2,2-trifluoroethan-1-ol (0.526 ml, 7.36 mmol) was added to a stirred solution of 2,3-dichloro-5-methylpyrazine (1.00 g, 6.13 mmol) and Cs2CO3 (2.40 g, 7.36 mmol) in DMF (6.13 mL). 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 in vacuo to give the title compound. LC / MS = 227 [M+H].

[0683] The following intermediates were synthesized by using a procedure similar to that described for Intermediate 26 and appropriate reagents. The intermediates were characterized by LC / MS.

[0684]

[0685]

[0686] Intermediate 29: 2,4-Dichloro-3-(2,2,2-trifluoroethoxy)pyridine

[0687] At RT, to a stirred solution of 2,4-dichloropyridin-3-ol (330 mg, 2.01 mmol) and K2CO3 (556 mg, 4.02 mmol) in DMF (2.00 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (350 μl, 2.42 mmol). After 10 minutes, the resulting mixture was stirred at 50 °C for 45 minutes, then filtered through a pad of Celite, washed with EtOAc, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 246 [M+H].

[0688] The following intermediates were synthesized by using procedures similar to those described for Intermediate 29 and appropriate reagents. These intermediates were characterized by LC / MS.

[0689]

[0690] Intermediate 32: 2-Chloro-3-(1,1-difluoropropyl)pyridine

[0691]

[0692] At RT, under a N2 atmosphere, 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). The resulting mixture was stirred at 50 °C for 12 hours, then quenched with MeOH and stirred at RT for an additional 0.5 hour. The reaction mixture was diluted with saturated aqueous NaHCO3 and the aqueous layer was extracted with EtOAc. The combined organic fractions were washed successively with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (5% EtOAc / hexanes) to afford the title compound. LC / MS = 192 [M+H].

[0693] Intermediate 33: (5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate

[0694]

[0695] Step A: 5-Chloro-3-(2,2-difluoroethoxy)-2-iodopyridine

[0696] At room temperature, 2,2-difluoroethyl trifluoromethanesulfonate (1.7 mL, 11.6 mmol) was added 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). After 1 hour, the mixture was filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 320 [M+1].

[0697] Step B: (5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol

[0698] At -78 °C, n-butyllithium solution (2.5 M in hexanes, 1.3 mL, 3.3 mmol) was added to a mixture of 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (0.88 g, 2.8 mmol) in toluene (15.3 mL). After 30 minutes, DMF (0.32 mL, 4.1 mmol) was added at -78 °C. After 1 hour, methanol (3.1 mL) and sodium borohydride (0.21 g, 5.5 mmol) were added successively and the resulting mixture was warmed to RT. After 20 minutes, 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 layer was then dried over MgSO4(s), filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 224 [M+1].

[0699] Step C: (5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methyl methanesulfonate

[0700] At -78 °C, methanesulfonyl chloride (48.8 μL, 0.63 mmol) was added 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). After 5 minutes, the mixture was warmed to RT. After an additional 15 minutes, the mixture was diluted with saturated aqueous NaCl and the aqueous layer was extracted once with DCM. The combined organic layers were dried over MgSO4(s), filtered and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 302 [M+1].

[0701] The following intermediates were synthesized using a procedure similar to that described for Intermediate 33 and appropriate reagents and characterized by LC / MS.

[0702]

[0703] Intermediate 35: (3-Fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

[0704]

[0705] Step A: Methyl 3-fluoro-5-(2,2,2-trifluoroethoxy)picolinate

[0706] At RT, Cs2CO3 (2.5 g, 7.6 mmol) was added to a mixture of methyl 3,5-difluoropicolinate (1.1 g, 6.4 mmol) and 2,2,2-trifluoroethanol (0.51 mL, 7.0 mmol) in DMF (6.4 mL). After 30 minutes, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 254 [M+H].

[0707] Step B: (3-Fluoro-5-(2,2,2-trifluoroethoxy)pyridin-2-yl)methanol

[0708] At 0 °C, a solution of LiAlH4 (2 M in THF, 2.6 mL, 5.2 mmol) was added to a mixture of methyl 3-fluoro-5-(2,2,2-trifluoroethoxy)picolinate (870 mg, 3.4 mmol) in THF (17 mL). After 30 minutes, the mixture was diluted with Et2O, H2O and 1 M aqueous NaOH, then warmed to RT. After 15 minutes, MgSO4 was added, the mixture was filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 226 [M+H].

[0709] The following intermediates were synthesized by using procedures similar to those described for Intermediate 35 and appropriate reagents. These intermediates were characterized by LC / MS.

[0710]

[0711] Intermediate 42: (3-(2,2,2-Trifluoroethoxy)pyridin-2-yl)methyl methanesulfonate

[0712]

[0713] Step A: (3-(2,2,2-Trifluoroethoxy)pyridin-2-yl)methanol

[0714] Under RT, 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.6 mL, 4.0 mmol) was added to a mixture of 2-(hydroxymethyl)pyridin-3-ol hydrochloride (500 mg, 3.1 mmol) and K2CO3 (1.3 g, 9.3 mmol) in DMF (3.1 mL). After 15 h, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 208 [M+1].

[0715] Step B: (3-(2,2,2-Trifluoroethoxy)pyridin-2-yl)methyl methanesulfonate

[0716] At 0 °C, methanesulfonyl chloride (0.15 mL, 1.8 mmol) was added 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). After 5 min, the mixture was warmed to RT. 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 MgSO4, filtered, and concentrated in vacuo to give the title compound. The crude product was used without purification. LC / MS = 286 [M+H].

[0717] The following intermediates were synthesized using a procedure similar to that described for Intermediate 42 and appropriate reagents and characterized by LC / MS.

[0718]

[0719] Intermediate 43: 2-(4-amino-1,1-dioxotetrahydro-2H-thiopyran-4-yl)acetonitrile

[0720]

[0721] Step A: 2-(1,1-Dioxotetrahydro-4H-thiopyran-4-ylidene)acetonitrile

[0722] At 0 °C, diethyl cyanomethylphosphonate (0.98 mL, 6.1 mmol) was added to a mixture of potassium tert-butoxide solution (1 M in THF, 6.1 mL, 6.1 mmol) in THF (15 mL). After 15 minutes, the mixture was warmed to RT. After 30 minutes, 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 hour, the mixture was warmed to RT. After 16 hours, 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 Na2SO4, then filtered and concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 172 [M+1].

[0723] Step B: 2-(4-Amino-1,1-dioxotetrahydro-2H-thiopyran-4-yl)acetonitrile

[0724] At RT, aqueous NH3 solution (29 wt%, 3.0 mL, 46.7 mmol) was added to a mixture of 2-(1,1-dioxotetrahydro-4H-thiopyran-4-ylidene)acetonitrile (0.40 g, 2.3 mmol) in MeOH (1.1 mL). The resulting mixture was heated to 100 °C. After 3 hours, the mixture was cooled to RT and concentrated in vacuo to give the title compound. The crude product was used without purification. LC / MS = 189 [M+1].

[0725] Intermediate 44: 4-Amino-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran-1,1-dioxide

[0726]

[0727] Step A: 4-Nitro-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran 1,1-dioxide

[0728] At RT, divinyl sulfone (0.6 mL, 6.0 mmol) was added 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). After 15 hours, 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 Na2SO4, then filtered and concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 262 [M+1].

[0729] Step B: 4-Amino-4-(2,2,2-trifluoroethyl)tetrahydro-2H-thiopyran 1,1-dioxide

[0730] Under RT, Rh / C (5 wt.%, 378 mg, 0.2 mmol) was added 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). A H2 balloon was placed on the reaction mixture, and H2 was bubbled through the reaction mixture for 5 minutes, and then stirring was continued under a H2 atmosphere. After 72 hours, the mixture was filtered through Celite. The filter cake was washed with methanol and DCM, and the filtrate was concentrated in vacuo to give the title compound. The crude product was used without purification. LC / MS = 232 [M+1].

[0731] The following intermediates were synthesized by using procedures similar to those described for Intermediate Int-44 and appropriate reagents. These intermediates were characterized by LC / MS.

[0732]

[0733] Intermediate 47: 4-Amino-2,2,4-trimethyltetrahydro-2H-thiopyran 1,1-dioxide

[0734]

[0735] Step A: 4-((2,4-Di-tert-butyl-6-hydroxyphenyl)amino)-2,2,4-trimethyltetrahydro-2H-thiopyran 1,1-di oxide

[0736] Under RT, a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (1.9 g, 8.5 mmol) in DCE (40 mL) was added to a mixture of 4-amino-2,2-dimethyltetrahydro-2H-thiopyran 1,1-dioxide (1.5 g, 8.5 mmol) in DCE (40 mL). After 5 minutes, the resulting mixture was warmed to 40 °C. After 15 hours, the mixture was cooled to RT and concentrated in vacuo. 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 in Et2O (100 mL) (3.1 M in DME, 16.4 mL, 50.8 mmol) at -78 °C. After 1 hour, the mixture was warmed to RT. After 3 hours, the mixture was poured into saturated aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 396 [M+1].

[0737] Step B: 4-Amino-2,2,4-trimethyltetrahydro-2H-thiopyran-1,1-dioxide

[0738] At 0 °C, H5IO6 (2.1 g, 9.3 mmol) was added 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). After 30 minutes, the organic solvents were removed in vacuo. The aqueous layer was extracted with Et2O / hexane (1:1), and the resulting aqueous layer was concentrated in vacuo. 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, filtered, and concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 192 [M+1].

[0739] Intermediate 48: 3-Amino-3-ethylthiacyclobutane 1,1-dioxide

[0740]

[0741] Step A: 2-Ethyl-2-nitropropane-1,3-diyl bis(4-methylbenzenesulfonate)

[0742] At 0 °C, p-toluenesulfonyl chloride (32.0 g, 168 mmol) was added 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). After 10 minutes, the mixture was warmed to RT. After 15 hours, 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 Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 458 [M+1].

[0743] Step B: 3-Ethyl-3-nitrothiacyclobutane

[0744] At RT, Na2S was added to a mixture of 2-ethyl-2-nitropropane-1,3-diyl bis(4-methylbenzenesulfonate) (10.5 g, 23.0 mmol) in DMSO (115 mL). After 5 minutes, the resulting mixture was heated to 100 °C. After 16 hours, the mixture was cooled to RT, poured into saturated aqueous NaCl, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4, then filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 148 [M+1].

[0745] Step C: 3-Ethyl-3-nitrothiacyclobutane 1,1-dioxide

[0746] Under RT, to a mixture of 3-ethyl-3-nitrothiacyclobutane (150 mg, 1.0 mmol) in DCM (4 mL) was added m-chloroperbenzoic acid (685 mg, 3.1 mmol). 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. LC / MS = 180 [M+1].

[0747] Step D: 3-Amino-3-ethylthiacyclobutane 1,1-dioxide

[0748] Under RT, to a mixture of 3-ethyl-3-nitrothiacyclobutane 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). After 24 h, the mixture was poured into 1 M aqueous NaOH solution, and the mixture was extracted with DCM / MeOH. The combined organic layers were washed with saturated aqueous NaCl solution, dried over Na2SO4, then filtered and concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 150 [M+1].

[0749] Examples

[0750] The following experimental procedures describe in detail the preparation of specific embodiments of the present disclosure. These examples are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.

[0751] Example 1: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxo-thiacyclobutane-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0752]

[0753] Step A: Ethyl 6-bromoimidazo[1,2-a]pyridine-2-carboxylate

[0754] Under RT, to a mixture of 5-bromopyridin-2-amine (6.00 g, 34.7 mmol) and NaHCO3 (5.83 g, 69.4 mmol) in dioxane (20 mL) was added ethyl 3-bromo-2-oxopropanoate (10.1 g, 52.0 mmol). Then the resulting mixture was heated to 90 °C. After 16 h, the mixture was cooled to RT, filtered through diatomaceous earth, and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 50% EtOAc / hexane) to give the title compound. LC / MS = 268 [M+1].

[0755] Step B: Ethyl 6-hydroxyimidazo[1,2-a]pyridine-2-carboxylate

[0756] Under RT, 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) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (54.4 mg, 0.07 mmol). 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 warmed to RT. After 18 h, MgSO4(s) was added, the mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 207 [M+1].

[0757] Step C: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine- 2-carboxylate

[0758] Under RT, 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). After 5 min, 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 h, the mixture was cooled to RT and then concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 416 [M+1].

[0759] Step D: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine- 2-carboxylic acid

[0760] Under RT, 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). After 30 min, the mixture was concentrated in vacuo to give the title compound. The crude product was used without purification. LC / MS = 388 [M+1].

[0761] Step E: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxothietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0762] Under RT, HATU (49.4 mg, 0.13 mmol) was added 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). After 1 hour, the reaction mixture was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 505 [M+1]. 1 HNMR (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, 1H), 7.33 (dd, J = 9.8, 2.2 Hz, 1H), 4.77 (q, J = 8.4 Hz, 2H), 4.70–4.62 (m, 2H), 4.31–4.21 (m, 2H), 1.88 (s, 3H). Human DGAT2 IC 50 = 5.0 nM.

[0763] Using a procedure similar to that described in Example 1 and appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772] Example 59: 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0773]

[0774] Step A: 5-bromo-4-chloro-N,N-bis(4-methoxybenzyl)pyridin-2-amine

[0775] At 0 °C, NaH (60 wt.%, 1.74 g, 43.4 mmol) was added to a mixture of 5-bromo-4-chloropyridin-2-amine (3 g, 14.5 mmol) in DMF (40 ml). After 30 minutes, 1-(chloromethyl)-4-methoxybenzene (6.79 g, 43.4 mmol) was added and the resulting mixture was warmed to RT. 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 layer was then dried over Na2SO4(s), filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 447 [M+1].

[0776] Step B: (6-(bis(4-methoxybenzyl)amino)-4-chloropyridin-3-yl)boronic acid

[0777] 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 PdCl2(dppf) (0.62 g, 0.85 mmol). The resulting mixture was then heated to 80 °C. After 3 h, the mixture was cooled to RT, filtered through Celite and the filtrate was concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 413 [M+1].

[0778] Step C: 6-(bis(4-methoxybenzyl)amino)-4-chloropyridin-3-ol

[0779] At RT, sodium perborate tetrahydrate (2.24 g, 14.54 mmol) was added 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). After 2 h, the mixture was filtered through Celite and the filtrate was concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 385 [M+1].

[0780] Step D: 6-(bis(4-methoxybenzyl)amino)-4-vinylpyridin-3-ol

[0781] Under RT, 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) were added Na2CO3 (0.99 g, 9.35 mmol), potassium vinyltrifluoroborate (2.09 g, 15.59 mmol) and PdCl2(dppf) (0.23 g, 0.31 mmol). Then the resulting mixture was heated to 100 °C. After 12 h, the mixture was cooled to RT, poured into water, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4(s), filtered and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 377 [M+1].

[0782] Step E: 6-(bis(4-methoxybenzyl)amino)-4-ethylpyridin-3-ol

[0783] 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 backfilled with H2, and then stirring was continued under a H2 atmosphere. After 2 h, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 379 [M+1].

[0784] Step F: 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-ethyl-N,N-bis(4-meth oxybenzyl)pyridin-2-amine

[0785] Under RT, to a mixture of 6-(bis(4-methoxybenzyl)amino)-4-ethylpyridin-3-ol (410 mg, 1.08 mmol) in DMF (3 mL) were added Cs2CO3 (529 mg, 1.63 mmol) and 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (298 mg, 1.30 mmol). After 2 h, the mixture was poured into water, and the mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4(s), filtered, and concentrated in vacuo. The crude product was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 589 [M+1].

[0786] Step G: 5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-4-ethylpyridin-2-amine

[0787] At RT, TFA (2 mL) was added 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). After 5 h, the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc and then washed with saturated aqueous NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 348 [M+1].

[0788] Step H: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethylimidazo[1,2- a]pyridine-2-carboxylic acid ethyl ester

[0789] At RT, ethyl 3-bromo-2-oxopropanoate (112 mg, 0.575 mmol) was added 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). The resulting mixture was then heated to 100 °C. After 12 h, the mixture was cooled to RT and then concentrated in vacuo. The crude product was purified by RP HPLC (ACN / water, containing 0.1% FA modifier) to give the title compound as the TFA salt. LC / MS = 444 [M+1].

[0790] Step I: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethylimidazo[1,2- a]pyridine-2-carboxylic acid

[0791] At RT, lithium hydroxide hydrate (8.51 mg, 0.203 mmol) was added 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). After 2 h, the mixture was concentrated under reduced pressure and then dissolved in water. 1 M aqueous 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 Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. The crude product was used without purification. LC / MS = 416 [M+1].

[0792] Step J: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-ethyl-N-(4-methyl- 1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0793] Under RT, HATU (48.0 mg, 0.126 mmol) was added 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). After 1 hour, the reaction mixture was filtered and the filtrate was purified by RP HPLC (ACN / water, 0.1% TFA modifier) to give the title compound as the TFA salt. 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.

[0794] Example 60: 6-[(3-Hydroxy-2-pyridinyl)oxy]-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0795]

[0796] At 0 °C, BCl3 solution (1 M in DCM, 30.0 μL, 0.03 mmol) was added to a mixture of 6-((3-(benzyloxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (7.0 mg, 0.01 mmol) in DCM (0.5 mL). Then the resulting mixture was warmed to RT. After 3 hours, DCM / MeOH (9:1) was added and the resulting mixture was concentrated. The crude product was purified by mass-triggered RP HPLC (ACN / water, containing 0.1% FA modifier) to give the title compound. LC / MS = 417 [M+1]. 1HNMR (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.

[0797] Example 61: 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0798]

[0799] Step A: Ethyl 6-(benzyloxy)-3-methylimidazo[1,2-a]pyridine-2-carboxylate

[0800] At RT, 3-bromo-2-oxobutyric acid methyl ester (7.16 g, 36.7 mmol) was added to a stirred solution of 5-(benzyloxy)pyridin-2-amine (4.90 g, 24.5 mmol) in 1,4-dioxane (100.0 mL). 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 in vacuo. The crude material was purified by flash column chromatography on silica gel (100% EtOAc / hexanes) to afford the title compound. LC / MS = 311 [M+H].

[0801] Step B: Ethyl 6-hydroxy-3-methylimidazo[1,2-a]pyridine-2-carboxylate

[0802] Under RT, 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) were 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). The resulting mixture was stirred at RT 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 in vacuo. The crude material was purified by mass-triggered RP HPLC (C18, 100% ACN, 0.1% FA modifier) to afford the title compound. LC / MS = 221 [M+H].

[0803] Step C: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2- a]pyridine-2-carboxylate

[0804] At room temperature, 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) was added sodium hydride (16.5 mg, 0.413 mmol, 60 wt%). The resulting mixture was stirred at RT for 5 min, 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 h, then cooled to RT and purified directly by flash column chromatography on silica gel (0-100% EtOAc / hexanes) to afford the title compound. LC / MS = 430 [M+H].

[0805] Step D: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2- a]pyridine-2-carboxylic acid

[0806] Under RT, lithium hydroxide monohydrate (40.1 mg, 0.956 mmol) was added 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). The resulting mixture was stirred at RT for 1.5 h and then lyophilized to afford the title compound. LC / MS = 402 [M+H].

[0807] Step E: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl- 1,1-dioxothiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0808] Under RT, 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), and then 4 - methyltetrahydro - 2H - thiopyran - 4 - ammonium 1,1 - dioxide chloride (21.9 mg, 0.110 mmol) was added. The resulting mixture was stirred at RT 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 flash column chromatography on silica gel (0 - 100% EtOAc / hexane) to afford the title compound. 1 1H 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.

[0809] The following compounds were synthesized by using a procedure similar to that described in Example 61 and appropriate reagents. These compounds were characterized by LC / MS.

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818] Example 123: 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]methoxy]imidazo[1,2-a]pyridine-2-carboxamide

[0819]

[0820] At RT, 2-(Chloromethyl)-3-(2,2,2-trifluoroethoxy)pyridine (30.1 mg, 0.133 mmol) was added to a stirred solution of 6-hydroxy-3-methyl-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (30.0 mg, 0.0890 mmol) and K2CO3 (24.6 mg, 0.178 mmol) in DMF (445 μL). The resulting mixture was heated to 50 °C for 2 h. The reaction was cooled to RT and the mixture was purified directly by mass-triggered RPHPLC (C18, 20 to 60% ACN in water, 0.1% FA modifier) to afford the title compound. 1 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.

[0821] The following compounds were synthesized by using procedures similar to those described in Example 123 and appropriate reagents. These compounds were characterized by LC / MS.

[0822]

[0823] Example 128: 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-(3,3,3-trifluoropropoxy)imidazo[1,2-a]pyridine-2-carboxamide

[0824]

[0825] Step A: 6-bromo-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0826] Under RT, lithium hydroxide monohydrate (101 mg, 2.40 mmol) was added 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). The resulting mixture was stirred at RT for 5 h and then lyophilized to give the title compound. LC / MS = 255 / 257 [M+H].

[0827] Step B: 6-bromo-3-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a] pyridine-2-carboxamide

[0828] Under RT, DIPEA (1.33 mL, 7.64 mmol) was added 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), and then 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (611 mg, 3.06 mmol) was added. The resulting mixture was stirred at RT for 1 h, then 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 in vacuo. The crude material was purified by flash column chromatography on silica gel (60% EtOAc / hexane) to give the title compound. LC / MS = 400 / 402 [M+H].

[0829] Step C: 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-(3,3,3-trifluoropropoxy imidazo[1,2-a]pyridine-2-carboxamide

[0830] Under RT, under N2 atmosphere, to a stirred solution of 6-bromo-3-methyl-N-(4-methyl-1,1-dioxotetrahydro-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)oxamide (11.9 mg, 0.040 mmol), 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). The resulting mixture was heated to 80 °C and maintained for 18 h. The reaction mixture was cooled to RT, 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 in vacuo. The crude material was purified directly by mass-triggered RP HPLC (C18, 30 to 50% ACN in water, 0.1% FA modifier) to afford the title compound. 1 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.

[0831] The following compounds were synthesized by using a procedure similar to that described in Example 128 and appropriate reagents. These compounds were characterized by LC / MS.

[0832]

[0833] Example 130: 3-Chloro-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide

[0834]

[0835] Step A: Ethyl 3-chloro-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine- 2-carboxylate

[0836] At RT, NCS (70.0 mg, 0.525 mmol) was added to a stirred 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). The resulting mixture was stirred at room temperature for 15 h, then 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 in vacuo. The crude material was purified by silica gel preparative TLC (50% EtOAc / PE) to afford the title compound. LC / MS = 416 [M+H].

[0837] Step B: 3-Chloro-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine- 2-carboxylic acid

[0838] At RT, lithium hydroxide monohydrate (20.2 mg, 0.481 mmol) was added 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), 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 in vacuo to afford the title compound. LC / MS = 388 [M+H].

[0839] Step C: 3-Chloro-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroeth oxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 2,2,2-trifluoroacetate

[0840] At RT, DIPEA (95.0 μL, 0.542 mmol) and HATU (103 mg, 0.271 mmol) were added to a stirred 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), then 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (45.0 mg, 0.225 mmol) was added. The resulting mixture was stirred at RT for 0.5 h and then purified directly by mass-triggered reversed-phase HPLC (C18, 40 to 60% ACN in water, 0.1% FA modifier) to afford the title compound. 11H 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.

[0841] Example 131: 3-Hydroxy-N-(4-methyl-1,1-dioxothiolan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide

[0842]

[0843] Step A: N-(4-Methyl-1,1-dioxido-tetrahydro-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

[0844] At RT, copper(I) iodide (1.65 mg, 8.66 μmol) in 1,4-dioxane (4.00 mL) was added to a stirred mixture of 2-(trimethylsilyl)ethanol (10.2 mg, 0.0870 mmol), 3-bromo-N-(4-methyl-1,1-dioxotetrahydro-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). The resulting mixture was stirred at 50 °C for 16 h and then concentrated in vacuo. The crude material was purified by silica gel preparative TLC (17% EtOAc / PE) to afford the title compound. LC / MS = 615 [M+H].

[0845] Step B: 3-Hydroxy-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoro ethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide; 2,2,2-trifluoroacetate

[0846] Under RT, TBAF (1 M in THF, 0.390 mL, 0.390 mmol) was added dropwise to a stirred mixture of N-(4-methyl-1,1-dioxotetrahydro-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). The resulting mixture was stirred at RT for 1 h, then 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 in vacuo. The crude material was purified directly by mass-triggered RP HPLC (C18, 20 to 60% ACN in water, 0.1% FA modifier) to give the title compound. 1 1H 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.

[0847] Examples 132 and 133:

[0848] (Example 132): 2-((4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)carbamoyl)-6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid

[0849] (Example 133): N2-(4-Methyl-1,1-dioxothiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2,3-dicarboxamide

[0850]

[0851] Step A: 3-(Furan-2-yl)-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)-6-((3-(2, 2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide

[0852] At RT, PdCl2(dppf) (6.00 mg, 8.20 μmol) was added to a stirred solution of 3-bromo-N-(4-methyl-1,1-dioxotetrahydro-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), K2CO3 (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). The resulting mixture was stirred at 150 °C under microwave for 20 minutes. 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 in vacuo. The crude material was purified by silica gel preparative TLC (100% EtOAc) to afford the title compound. LC / MS = 565 [M+H].

[0853] Step B (Example 132): 2-((4-Methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)carbamoyl)- 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-3-carboxylic acid

[0854] At RT, KMnO4 (69.0 mg, 0.434 mmol) was added to a stirred solution of 3-(furan-2-yl)-N-(4-methyl-1,1-dioxotetrahydro-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). The resulting mixture was stirred at 60 °C for 5 hours. The mixture was filtered through a Celite pad, washed with MeOH, and the filtrate was concentrated in vacuo to afford the title compound. LC / MS = 543 [M+H]. Human DGAT2 IC 50 >9990 nM.

[0855] Step C (Example 133): N2-(4-Methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2- trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2,3-dicarboxamide

[0856] Under RT, to a stirred solution of 2-((4-methyl-1,1-dioxotetrahydro-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 NH4Cl (9.00 mg, 0.166 mmol), 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisourea hexafluorophosphate (V) (42.0 mg, 0.111 mmol) and N-ethyl-N-isopropylpropan-2-amine (36.0 mg, 0.277 mmol). The resulting mixture was stirred at RT for 1 h and then purified directly by mass-triggered RP HPLC (C18, 30 to 60% ACN in water, 0.1% FA modifier) to afford the title compound. 1 1H 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.

[0857] Example 134: 3-Methoxy-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide

[0858]

[0859] Under RT, under N2 atmosphere, to a stirred solution of 3-bromo-N-(4-methyl-1,1-dioxotetrahydro-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-diphenylethyl oxamide (1.03 mg, 3.46 μmol) in 1,4-dioxane (1.00 mL) was added MeOH (69.4 μg, 1.73 mmol). The resulting mixture was stirred at 60 °C for 16 h. The reaction mixture was concentrated in vacuo and the crude material was purified by mass-triggered RP HPLC (C18, 10 mM aqueous NH4HCO3 in ACN) to give the title compound. 1 1H 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.

[0860] Using a method similar to that in Example 134 and appropriate reagents, the following compounds were synthesized and characterized by LC / MS.

[0861]

[0862] Example 136: N-(4-Methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide

[0863]

[0864] Step A: Ethyl 6-hydroxy-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylate

[0865] Under RT, TFAA (83.0 μL, 0.600 mmol) was added 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'-bipyridine)ruthenium(II) hexahydrate (1.50 mg, 2.000 μmol) in ACN (412 μL). The resulting mixture was irradiated with blue LEDs (800 rpm light, 50%) for 16 h. The reaction mixture was concentrated in vacuo and purified by flash column chromatography on silica gel (0 - 90% EtOAc / hexane) to afford the title compound. LC / MS = 275 [M+H].

[0866] Step B: Ethyl 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)imidazo[1,2- a]pyridine-2-carboxylate

[0867] Under RT, DIPEA (42.0 μL, 0.241 mmol) and PyBrop (48.6 mg, 0.104 mmol) were added 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). The resulting solution was stirred at RT for 18 h. The mixture was diluted with DCM and washed with 1 M aqueous NaOH, water, and then brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexane) to afford the title compound. LC / MS = 450 [M+H].

[0868] Step C: 6-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-(trifluoromethyl)imidazo[1,2- a]pyridine-2-carboxylic acid

[0869] Under RT, lithium hydroxide monohydrate (2.06 mg, 0.0490 mmol) was added 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). The resulting mixture was stirred at RT for 1.5 h and then lyophilized to afford the title compound. LC / MS = 422 [M+H].

[0870] Step D: N-(4-Methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)- 2-pyridinyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide

[0871] Under RT, DIPEA (26.0 μL, 0.147 mmol) was added 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), and then 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (10.8 mg, 0.0540 mmol) was added. The resulting mixture was stirred at RT for 2 hours and then purified directly by mass-triggered RP HPLC (C18, 50 to 98% ACN in water, 0.1% FA modifier) to give the title compound. 1 1H 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.

[0872] Example 137: 3-(Hydroxymethyl)-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide

[0873]

[0874] Step A: N-(4-Methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-trifluoroethoxy) pyridin-2-yl)oxy)-3-vinylimidazo[1,2-a]pyridine-2-carboxamide

[0875] Under RT, in an N2 atmosphere, PdCl2(dppf) (5.07 mg, 6.93 μmol) was added to a stirred solution of 3-bromo-N-(4-methyl-1,1-dioxotetrahydro-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). The resulting solution was stirred at 100 °C for 4 hours. The reaction mixture 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 in vacuo. The crude material was purified by silica gel preparative TLC (100% EtOAc) to afford the title compound. LC / MS = 525 [M+H].

[0876] Step B: 3-Formyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)-6-((3-(2,2,2-tri fluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyridine-2-carboxamide

[0877] Under RT, 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) were added to a stirred solution of N-(4-methyl-1,1-dioxotetrahydro-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). The resulting mixture was stirred at 30 °C for 2 hours. The reaction mixture 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 in vacuo to afford the title compound. LC / MS = 527 [M+H].

[0878] Step C: 3-(Hydroxymethyl)-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide

[0879] Under RT, NaBH4 (2.10 mg, 0.0570 mmol) was added to a stirred solution of 3-formyl-N-(4-methyl-1,1-dioxotetrahydro-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). The resulting mixture was stirred at RT 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 Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by mass-triggered RP HPLC (C18, ACN in water, 0.1% FA modifier) to afford the title compound. 1 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.

[0880] Example 138: 6-[5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-7-cyano-3-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0881]

[0882] Step A: 2-Amino-5-bromoisonicotinonitrile

[0883] Under RT, NBS (3.29 g, 18.5 mmol) was added to a stirred solution of 2-aminoisonicotinonitrile (2.00 g, 16.8 mmol) in THF (60.0 mL). The resulting solution was stirred at RT for 2 h. The reaction mixture was quenched with saturated aqueous Na2SO3 and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0-100% EtOAc / hexane) to afford the title compound. LC / MS = 198 and 200 [M+H].

[0884] Step B: 2-(Bis(4-methoxybenzyl)amino)-5-bromoisonicotinonitrile

[0885] At 0 °C, under a N2 atmosphere, 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). The resulting solution was stirred at 0 °C for 0.5 h, 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 in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 438 and 440 [M+H].

[0886] Step C: (6-(Bis(4-methoxybenzyl)amino)-4-cyanopyridin-3-yl)boronic ester

[0887] At RT, under a N2 atmosphere, PdCl2(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'-bis(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). The resulting mixture was stirred at 95 °C for 12 h. The reaction mixture was filtered through a Celite pad, washed with EtOAc, and the filtrate was concentrated in vacuo to afford the title compound. LC / MS = 404 and 486 [M+H].

[0888] Step D: 2-(Bis(4-methoxybenzyl)amino)-5-hydroxyisonicotinonitrile

[0889] At RT, under a N2 atmosphere, 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)boronic acid ester (4.00 g, 4.50 mmol) in THF (80.0 mL). The resulting solution was stirred at 80 °C for 3 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 in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to afford the title compound. LC / MS = 376 [M+H].

[0890] Step E: 2-(Bis(4-methoxybenzyl)amino)-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2- yl)oxy)isonicotinonitrile

[0891] Under RT, Cs2CO3 (911 mg, 2.80 mmol) was added to a stirred solution of 2-(bis(4-methoxybenzyl)amino)-5-hydroxyisonicotinonitrile (700.0 mg, 1.87 mmol) in DMF (7.00 mL). The resulting mixture was stirred at 20 °C for 10 minutes, then 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 hours. 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 in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexane) to give the title compound. LC / MS = 585 [M+H].

[0892] Step F: 2-Amino-5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)isonicotinamide

[0893] Under RT, TFA (1.00 mL) was added 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). The resulting mixture was stirred at RT for 18 hours. The solution was concentrated in vacuo to give the title compound. LC / MS = 345 [M+H].

[0894] Step G: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-cyano-3-methylimid azo[1,2-a]pyridine-2-carboxylic acid methyl ester

[0895] Under RT and under a N2 atmosphere, methyl 3-bromo-2-oxobutyrate (200 mg, 1.026 mmol) was added to a stirred 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). The resulting mixture was stirred at 90 °C for 13 hours. 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 in vacuo. The crude material was purified by preparative TLC on silica gel (33% EtOAc / PE) to give the title compound. LC / MS = 441 [M+H].

[0896] Step H: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-7-cyano-3-methylimid azo[1,2-a]pyridine-2-carboxylic acid

[0897] Under RT, lithium hydroxide monohydrate (4.00 mg, 0.0950 mmol) was added 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). The resulting mixture was stirred at RT for 3 h, then the mixture was concentrated in vacuo to give the title compound. LC / MS = 427 [M+H].

[0898] Step I: 6-[5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl]oxy-7-cyano-3-methyl-N-(4- methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0899] Under RT, DIPEA (24.0 μL, 0.136 mmol) was added 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), then 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (21.9 mg, 0.110 mmol) was added. The resulting mixture was stirred at RT for 1 h, then diluted with EtOAc, filtered through diatomaceous earth, and washed with EtOAc. The filtrate was concentrated in vacuo and the crude material was purified by mass-triggered RP HPLC (C18, ACN in water, 0.1% FA modifier) to give the title compound. 1 1H 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 (brd, 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 IC 50 = 25 nM.

[0900] Example 139: 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0901]

[0902] Step A: Ethyl 3,5-dichloro-6-((5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl)oxy)imid azo[1,2-a]pyridine-2-carboxylate

[0903] Under RT, to a stirred 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) was added NCS (647 mg, 4.85 mmol). The resulting solution was stirred at RT for 72 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to give the title compound. LC / MS = 468 [M + H].

[0904] 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

[0905] Under RT, 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) was added lithium hydroxide monohydrate (0.0240 g, 0.563 mmol). The resulting mixture was stirred at RT for 3 h and then the mixture was concentrated in vacuo to give the title compound. LC / MS = 441 [M + H].

[0906] Step C: 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-meth yl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0907] Under RT, 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) was added HATU (16.0 mg, 0.0420 mmol). The resulting solution was stirred at RT for 1.5 h and then the mixture was directly purified by mass - triggered RP HPLC (C18, 20 to 60% ACN in water, 0.1% FA modifier) to give the title compound. 11H 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.

[0908] Using a procedure similar to that described in Example 139 and appropriate reagents, the following compound was synthesized. The compound was characterized by LC / MS.

[0909]

[0910] Example 141: 3-Chloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0911]

[0912] At RT, under light protection, 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-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (100.0 mg, 0.183 mmol) in THF (914 μL). The resulting solution was stirred at 80 °C for 18 h under light protection and then purified directly by mass-triggered RP HPLC (C18, 55 to 98% ACN in water, 0.1% FA modifier) to give the title compound. 1 1H NMR (400 MHz, methanol-d4) δ 7. LC / MS = 582 [M+H]. Human DGAT2 IC 50 = 2.6 nM.

[0913] Using a procedure similar to that described in Example 141 and appropriate reagents, the following compounds were synthesized. These compounds were characterized by LC / MS.

[0914]

[0915] Example 144: 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide

[0916]

[0917] Step A: Ethyl 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimid azo[1,2-a]pyridine-2-carboxylate

[0918] At RT, 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). The resulting mixture was stirred at RT for 5 minutes, then 5-bromo-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (299 mg, 1.09 mmol) was added. The resulting reaction mixture was heated to 80 °C and maintained for 18 hours, then cooled to RT and diluted with brine. The aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. LC / MS = 474 [M+H].

[0919] Step B: 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2- a]pyridine-2-carboxylic acid

[0920] At RT, lithium hydroxide monohydrate (76.0 mg, 1.82 mmol) was added 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). The resulting mixture was stirred at RT for 1 hour, then concentrated in vacuo to give the title compound. LC / MS = 446 [M+H].

[0921] Step C: 6-[[5-bromo-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl- (1,1-Dioxothiolan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0922] Under RT, 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), and then 4-methyltetrahydro-2H-thiopyran-4-ammonium 1,1-dioxide chloride (182 mg, 0.910 mmol) was added. The resulting mixture was stirred at RT for 18 h, then diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give the title compound. The crude material was purified by flash column chromatography on silica gel (0-100% EtOAc / hexanes then 0-10% MeOH / DCM) to give the title compound. LC / MS = 593 [M+H].

[0923] (1,1-Dioxothiolan-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxothiolan-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0924] Under RT, under a N2 atmosphere, to a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (40.0 mg, 0.0680 mmol), K2CO3 (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) was added PdCl2(dppf) (7.42 mg, 10.2 μmol). The resulting mixture was stirred at 100 °C for 1 h, then cooled to RT and purified directly by flash column chromatography on silica gel (0-100% EtOAc / hexanes) to afford the title compound. 1 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。

[0925] Using a procedure similar to that described in Example 144 and appropriate reagents, the following compound was synthesized. The compound was characterized by LC / MS.

[0926]

[0927] Example 146: 6-[[5-(1-Hydroxy-1-methyl-ethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0928]

[0929] (1,1-Dioxotetrahydro-2H-thiopyran-4-yl)-6-((5-acetyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxotetrahydro-2H-thiopyran-4-yl)-6-((5-acetyl-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0930] At RT, tributyl(1-ethoxyvinyl)tin (300.0 μL, 0.888 mmol) and (PPh3)4Pd (68.4 mg, 0.0590 mmol) were 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-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (350.0 mg, 0.592 mmol) in toluene (1.97 mL). The resulting mixture was stirred at 100 °C for 7 h, 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 NaHCO3 and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0-100% EtOAc / hexane, then 0-10% MeOH / DCM) to give the title compound. LC / MS = 555 [M+H].

[0931] (1,1-Dioxothiolan-4-yl)-6-[[5-(1-hydroxy-1-methylethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxothiolan-4-yl)-6-[[5-(1-hydroxy-1-methylethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0932] At 0 °C, 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-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (300.0 mg, 0.541 mmol) in THF (5.00 mL). The resulting mixture was stirred at 0 °C for 10 minutes, then quenched with saturated aqueous NaHCO3 and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by mass-triggered RP HPLC (C18, 40 to 80% ACN in water, 0.1% FA modifier) to afford the title compound. 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.

[0933] Example 147: 6-[[5-(1-Fluoro-1-methylethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0934]

[0935] At -78 °C, 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-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (45.0 mg, 0.0790 mmol) in DCM (526 μL). The resulting mixture was stirred at RT for 20 minutes, then cooled to 0 °C and quenched with MeOH and water. The resulting solution was concentrated in vacuo and purified directly by mass-triggered RP HPLC (C18, 20 to 60% ACN in water, 0.1% FA modifier) to afford the title compound. 1 H 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.

[0936] Example 148: 6-[[5-Hydroxy-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0937]

[0938] Under RT, bis(pinacolato)diboron (67.6 mg, 0.266 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-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (70.0 mg, 0.118 mmol), PdCl2(dppf) (13.0 mg, 0.0180 mmol) and KOAc (34.8 mg, 0.355 mmol) in 1,4-dioxane (395 μL). The resulting mixture was stirred at 100 °C for 1 h, then cooled to RT and quenched with water (0.100 mL) and HOAc (20.3 μL, 0.355 mmol). The mixture was stirred at RT for an additional 1 h, then H2O (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 MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes, then 0 - 10% MeOH / DCM) to afford the title compound. 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.

[0939] Example 149: 6-[[5-Cyano-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide

[0940]

[0941] Under RT, to a stirred solution of 6-((5-bromo-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide (60.0 mg, 0.101 mmol), PdCl2(dppf) (7.42 mg, 0.0102 mmol) and zinc (1.33 mg, 0.0200 mmol) in DMF (338 μL) was added zinc cyanide (35.7 mg, 0.304 mmol). The resulting mixture was stirred in a microwave at 120 °C for 1 hour, then filtered and purified directly by mass-triggered RP HPLC (C18, 20 to 60% ACN in water, 0.1% FA modifier) to afford the title compound. 1 H 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.

[0942] Example 150: 3-Methyl-N-(4-methyl-1,1-dioxo-thiacyclohexan-4-yl)-6-[[5-methylsulfonyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide

[0943]

[0944] Under RT, to a stirred solution of 6 - ((5 - bromo - 3 - (2,2,2 - trifluoroethoxy)pyridin - 2 - yl)oxy) - 3 - methyl - N - (4 - methyl - 1,1 - dioxotetrahydro - 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) was added sodium methanesulfinate (57.0 mg, 0.558 mmol). The resulting mixture was stirred at 110 °C for 18 h, then saturated aqueous NaHCO3 was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes, then 0 - 10% MeOH / DCM) to give the title compound. 1 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.

[0945] Example 151: 6 - [3 - methyl - 2 - [(4 - methyl - 1,1 - dioxo - thiacyclohexan - 4 - yl)carbamoyl]imidazo[1,2 - a]pyridin - 6 - yl]oxy - 5 - (2,2,2 - trifluoroethoxy)pyridine - 3 - carboxylic acid

[0946]

[0947] Under RT, CO (15 psi) was added to a solution of 6 - ((5 - chloro - 3 - (2,2,2 - trifluoroethoxy)pyridin - 2 - yl)oxy) - 3 - methyl - N - (4 - methyl - 1,1 - dioxotetrahydro - 2H - thiopyran - 4 - yl)imidazo[1,2 - a]pyridine - 2 - carboxamide (30.0 mg, 0.0550 mmol), K2CO3 (15.2 mg, 0.110 mmol), Pd(OAc)2 (1.23 mg, 5.49 μmol) and DCPP (3.35 mg, 5.49 μmol) in DMSO (2.00 mL) and water (0.200 mL). The resulting mixture was stirred at 110 °C for 12 hours and then purified directly by mass - triggered RP HPLC (C18, 31 to 51% ACN in water, 0.1% FA modifier) to give the title compound. 1 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.

[0948] Example 152: 6 - [5 - (dimethylamino) - 3 - (2,2,2 - trifluoroethoxy)pyridin - 2 - yl]oxy - 3 - methyl - N - (3 - methyl - 1,1 - dioxothietan - 3 - yl)imidazo[1,2 - a]pyridin - 1 - ium - 2 - carboxamide

[0949]

[0950] (1,1-Dioxothietan-3-yl)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxothietan-3-yl)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxothietan-3-yl)-6-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0951] Under RT, under N2 atmosphere, PdCl2(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-dioxothiolan-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). The resulting mixture was stirred at 100 °C for 3 hours, then cooled to RT, 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 in vacuo. The crude material was purified by flash column chromatography on silica gel (0 - 100% EtOAc / hexanes) to give the title compound. LC / MS = 611 [M+H].

[0952] (1,1-Dioxothietan-3-yl)-6-((5-((4-methoxybenzyl)amino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxothietan-3-yl)-6-((5-((4-methoxybenzyl)amino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0953] Under RT, copper(II) acetate (26.8 mg, 0.147 mmol), boric acid (91.0 mg, 1.47 mmol) and molecular sieve were added to a stirred solution of 3-methyl-N-(3-methyl-1,1-dioxothiolan-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), (4-methoxyphenyl)methanamine (303 mg, 2.21 mmol) in ACN (5.00 mL). The resulting mixture was stirred at 80 °C under O2 atmosphere for 16 hours, then concentrated in vacuo. The residue was dissolved in water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC on silica gel (33% EtOAc / hexanes) to give the title compound. LC / MS = 620 [M+H].

[0954] (1,1-Dioxothietan-3-yl)-6-((5-amino-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxothietan-3-yl)-6-((5-amino-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0955] At RT, 6-((5-((4-methoxybenzyl)amino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxothietan-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 RT for 1 h and then concentrated in vacuo. The crude material was purified by silica gel preparative TLC (100% EtOAc) to afford the title compound. LC / MS = 500 [M+H].

[0956] (1,1-Dioxothietan-3-yl)-6-((5-(dimethylamino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide (1,1-Dioxothietan-3-yl)-6-((5-(dimethylamino)-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-a]pyridine-2-carboxamide

[0957] At RT, formaldehyde (6.62 mg, 0.220 mmol) and sodium triacetoxyborohydride (53.0 mg, 0.250 mmol) were added to a stirred solution of 6-((5-amino-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(3-methyl-1,1-dioxothietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide (25.0 mg, 0.0500 mmol) in MeOH (0.500 mL). The resulting mixture was stirred at RT for 2 h, then diluted with water and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by mass-triggered RP HPLC (C18, 31 to 51% ACN in water, 0.1% FA modifier) to afford the title compound. 1 1H 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 = 2.35 Hz, 1H), 4.69 (m, 2H), 4.61 (m, 2H), 4.25 (m, 2H), 2.98 (s, 6H), 2.75 (s, 3H), 1.86 (s, 3H). LC / MS = 528 [M+H]. Human DGAT2 IC 50 = 63 nM.

[0958] Example 153: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide

[0959]

[0960] (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester

[0961] To a stirred 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 K2CO3 (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 in vacuo to give the desired product. LC / MS = 208 [M+1].

[0962] (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester

[0963] 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)oxamide (127 mg, 386 μmol), CuI (46.0 mg, 241 μmol) and K3PO4 (512 mg, 2.41 mmol) in DMSO (4.8 mL) was added 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (648 mg, 2.03 mmol), and the reaction mixture was heated to 80 °C. After 16 h, the reaction mixture was diluted with ethyl acetate and filtered through a SiO2 plug. The filtrate was diluted with water and extracted with ethyl acetate. The combined organic fractions were washed with LiCl (1 M aqueous solution) and NaCl (saturated aqueous solution), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was subjected to flash column chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in hexane to give the title compound. LC / MS = 399 [M+1].

[0964] (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-b]pyridazine-2-carboxylic acid lithium salt

[0965] To a stirred 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 min, the reaction mixture was concentrated in vacuo to give the title compound. LC / MS = 371 [M-5].

[0966] (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide

[0967] 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, containing 0.1% FA modifier) to afford the title compound. LC / MS analysis indicated a high conversion of the desired product. LC / MS = 516 [M+1]. 1 1H 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.

[0968] The following compounds were synthesized by using a procedure similar to that described in Example 153 and appropriate reagents. These compounds were characterized by LC / MS.

[0969]

[0970]

[0971]

[0972] Example 166: 6 - ((5 - chloro - 3 - (2,2 - difluoroethoxy)pyridin - 2 - yl)oxy) - 3 - methyl - N - (4 - methyl - 1,1 - dioxotetrahydro - 2H - thiopyran - 4 - yl)imidazo[1,2 - b]pyridazine - 2 - carboxamide

[0973]

[0974] (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide (1,1-Dioxothiolan-4-yl)-6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide

[0975] At 20 °C, 1-bromopyrrolidine-2,5-dione (230 mg, 1.29 mmol) was added in one portion to a stirred 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). After 1 h, the reaction mixture was warmed to 40 °C. After 16 h, the crude residue was cooled to RT and subjected to silica gel flash column chromatography using a 0 - 90% ethyl acetate gradient in hexanes to afford the title compound. LC / MS = 478 [M+1].

[0976] Step B: Ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-b] pyridazine-2-carboxylate

[0977] At 20 °C, 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 PdG2 (77 mg, 115 μmol) was charged with tetrahydrofuran (11.5 mL) and trimethylaluminum (1 M in toluene, 1.15 mL, 2.30 mmol). The reaction mixture was heated to 60 °C. After 16 h, the reaction mixture was diluted with EtOAc and quenched successively with MeOH and water. The reaction mixture was filtered through celite and extracted with EtOAc. The combined organic fractions were washed with NaCl (saturated aqueous solution), dried over MgSO4, filtered and concentrated in vacuo. The crude residue was subjected to SiO2 flash column chromatography eluting with a 0 - 100% ethyl acetate gradient in hexanes to afford the title compound. LC / MS = 413 [M+1].

[0978] Step C: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methylimidazo[1,2-b] pyridazine-2-carboxylic acid

[0979] At 20 °C, lithium hydroxide (10.50 mg, 0.44 mmol) was added to a stirred 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). After 16 h, the reaction mixture was acidified with HCl (1 M, aqueous solution), diluted with water and extracted with EtOAc. The combined organic fractions were washed with NaCl (saturated aqueous solution), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound. LC / MS = 385 [M+1].

[0980] Step D: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-3-methyl-N-(4-methyl-1, 1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide

[0981] To a stirred 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 SiO2 flash column chromatography, eluting with 0-10% MeOH / hexanes in DCM, to afford the title compound. LC / MS = 530 [M+1]. 1 1H 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.

[0982] The following compounds were synthesized using a procedure similar to that described in Example 166 and the appropriate reagents and characterized by LC / MS.

[0983]

[0984]

[0985] Example 168: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide

[0986]

[0987] Step A: Ethyl 5-((3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrazolo[1,5-a]pyridine-2-carboxylate Step B: Ethyl 6-hydroxy-7-methylimidazo[1,2-b]pyridazine-2-carboxylate

[0988] 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 hours, the solvent was removed in vacuo, and the crude residue was dissolved in ethyl acetate. The organic phase was washed with LiCl (1 M aqueous solution), NaCl (saturated aqueous solution), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was subjected to SiO2 flash column chromatography, eluting with a gradient of 0 - 100% ethyl acetate in hexanes to afford the title compound. LC / MS = 240 [M+1].

[0989] Step C: Ethyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methylimidazo[1,2-b]

[0990] To a stirred 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 K2CO3 (7.79 g, 56.3 mmol) was added DMSO (94 ml), and the reaction mixture was heated to 80 °C and maintained for 16 hours. LC / MS indicated a high conversion of 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 in vacuo to afford the title compound. LC / MS = 222 [M+1].

[0991] pyridazine-2-carboxylate Step D: Lithium 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methylimidazo[1,2-b]

[0992] 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)oxamide (238 mg, 723 μmol), CuI (86 mg, 452 μmol), and K3PO4 (960 mg, 4.52 mmol) in DMSO (9.04 ml) was added 5-chloro-3-(2,2-difluoroethoxy)-2-iodopyridine (1.21 g, 3.80 mmol), and the reaction mixture was heated to 80 °C. After 16 hours, 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 aqueous solution) and NaCl (saturated aqueous solution), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was subjected to silica gel flash column chromatography, eluting with a gradient of 0 - 100% ethyl acetate in hexanes to afford the title compound. LC / MS = 413 [M+1].

[0993] pyridazine-2-carboxylate Step E: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)oxy)-7-methyl-N-(4-methyl-1,

[0994] At 20 °C, lithium hydroxide (4.47 mg, 187 μmol) was added 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). After 30 minutes, the reaction mixture was concentrated in vacuo to give the crude title compound. LC / MS = 385 [M - 5].

[0995] 1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide Step A: Methyl 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)imidazo[1,2-b]

[0996] HATU (36.8 mg, 97 μmol) was added to a stirred 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). After 18 hours, the solvent was removed in vacuo and the crude residue was subjected to flash column chromatography on silica gel using a gradient of 0 - 100% ethyl acetate in hexanes to give the title compound. 1 1H 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.

[0997] The following compounds were synthesized by using a procedure similar to that described in Example 168 and appropriate reagents. These compounds were characterized by LC / MS.

[0998]

[0999] Example 175: 3,7-Dichloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide

[1000]

[1001] 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 and the solvent was removed in vacuo after 6 h. The crude residue was dissolved in ethyl acetate. The organic phase was washed with LiCl (1 M aqueous solution), NaCl (saturated aqueous solution), dried over MgSO4, filtered and concentrated in vacuo. The crude material was subjected to SiO2 flash column chromatography, eluting with a gradient of 0–100% ethyl acetate in hexanes to afford the title compound. 1 1H 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.

[1002] The following compounds were synthesized by using procedures similar to those described in Example 175 and appropriate reagents. These compounds were characterized by LC / MS.

[1003]

[1004]

[1005] Example 180: 6-((5-Chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide

[1006]

[1007] pyridazine-2-carboxylate Step B: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)imidazo[1,2-b]

[1008] Under RT, a solution of (5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methanol (174 mg, 780 μmol) in DMF (2.4 mL) was successively treated with NaH (34.0 mg, 851 μmol) and methyl 6-chloroimidazo[1,2-b]pyridazine-2-carboxylate (150 mg, 709 μmol). After 15 minutes, the mixture was subjected to silica gel flash column chromatography using a 0 to 100% EtOAc / hexane gradient to afford the title compound. LC / MS = 399 [M+1].

[1009] pyridazine-2-carboxylic acid Step C: 6-((5-chloro-3-(2,2-difluoroethoxy)pyridin-2-yl)methoxy)-N-(4-methyl-1,1-dioxo

[1010] 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·H₂O (37.3 mg, 888 μmol) in water (1.5 mL) and acetonitrile (1.5 mL) was stirred at 40 °C. After 15 minutes, the solvent was removed in vacuo to afford the title compound. LC / MS = 385 [M+1].

[1011] tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide Step A: Ethyl 6-(2-ethoxyphenoxy)imidazo[1,2-a]pyridine-2-carboxylate

[1012] Under RT, 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). After 30 minutes, the mixture was subjected to silica gel flash column chromatography using a 0 to 100% EtOAc / hexane gradient and then 0 to 10% methanol in DCM to afford the title compound. 1HNMR (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.

[1013] The following compounds were synthesized by using a procedure similar to that described in Example 180 and appropriate reagents. These compounds were characterized by LC / MS.

[1014]

[1015] Example 184: (S)-6-(2-Ethoxyphenoxy)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

[1016]

[1017] Step B: 6-(2-ethoxyphenoxy)imidazo[1,2-a]pyridine-2-carboxylic acid

[1018] A mixture of 2-ethoxyphenol (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, then the mixture was cooled to RT and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (0-10% MeOH / DCM) to give the title compound. LC / MS = 327 [M+H].

[1019] Step C:

[1020] At RT, lithium hydroxide monohydrate (16.0 mg, 0.372 mmol) was added 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). After 18 h, the mixture was concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 299 [M+1].

[1021] Step A: Ethyl 6-bromoimidazo[1,2-a]pyrazine-2-carboxylate (S)-6-(2-Ethoxyphenoxy)-N-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridine-2-carboxamide

[1022] At RT, HATU (184 mg, 0.484 mmol) was added to a mixture of 6-(2-ethoxyphenoxy)imidazo[1,2-a]pyridine-2-carboxylic acid (111 mg, 0.372 mmol), (S)-tetrahydrofuran-3-ammonium chloride (55.2 mg, 0.446 mmol), and DIPEA (195 μL, 1.12 mmol) in DMF (1.5 mL). After 2 h, the reaction mixture was concentrated in vacuo. The crude material was purified by mass-triggered RP HPLC (C18, 30 to 60% ACN in water, 0.1% FA modifier) to afford the title compound. LC / MS = 368 [M+1]. 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.

[1023] Example 185: 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrazine-2-carboxamide

[1024]

[1025] Step B: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]

[1026] Ethyl 3-bromo-2-oxopropionate (3.36 g, 17.2 mmol) was added to a mixture of 5-bromopyrazin-2-amine (2.00 g, 11.5 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100 °C for 12 h, then the mixture was cooled to RT and filtered. The filtrate was diluted with saturated aqueous NaHCO3 to pH = 8, and the solution was extracted with EtOAc. The combined organic layers were washed successively with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (20% EtOAc / hexanes) to afford the title compound. LC / MS = 270 and 272 [M+H].

[1027] pyrazine-2-carboxylate Step C: 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]

[1028] 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), K2CO3 (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 N2 atmosphere for 12 h. The reaction mixture was purified directly by RP HPLC (C18, ACN in water, 0.1% FA modifier) to afford the title compound. LC / MS = 417 [M+H].

[1029] pyrazine-2-carboxylic acid Step D

[1030] Lithium hydroxide monohydrate (2.7 mg, 0.11 mmol) was added 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) at RT. After 1 h, the mixture was dissolved in water, acidified to pH = 4 with 1 M HCl, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. The crude product was used without purification. LC / MS = 389 [M+1].

[1031] Step A: tert-Butyl (5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamate: 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrazine-2-carboxamide

[1032] At 30 °C, HATU (25 mg, 0.067 mmol) was added 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 mmol) and DIPEA (29 μL, 0.17 mmol) in DMF (1.0 mL). After 2 h, the reaction mixture was concentrated in vacuo. The crude material was purified by RP HPLC (C18, ACN in aqueous solution, 0.1% FA modifier) to afford the title compound. LC / MS = 534 [M+1]. 1 1H 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.

[1033] Example 186: 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide

[1034]

[1035] Step B: tert-Butyl (5-hydroxypyrimidin-2-yl)carbamate ​

[1036] To a suspension of (5-bromopyrimidin-2-yl)(tert-butoxycarbonyl)carbamic acid tert-butyl ester (500 mg, 1.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(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)2 (150 mg, 0.668 mmol). The mixture was stirred at 85 °C for 16 h, then the mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. The crude product was used without purification. LCMS - B(OH)2 = 184.0 [M + H - 156].

[1037] ​

[1038] At RT, to a suspension of (tert-butoxycarbonyl)(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl)carbamic acid tert-butyl ester (560 mg, 1.33 mmol) in THF (4.0 mL) and water (4 mL) was added NaBO3·4H2O (422 mg, 3.99 mmol). The mixture was stirred at RT for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound. The crude product was used without purification. LC / MS = 312 [M + H].

[1039] Step C: tert-Butyl ((5-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-yl)carbamate Step D: 5-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)pyrimidin-2-amine

[1040] A mixture of (tert-butoxycarbonyl)(5-hydroxypyrimidin-2-yl)carbamic acid tert-butyl ester (180 mg, 0.578 mmol), 5-chloro-2-fluoro-3-(2,2,2-trifluoroethoxy)pyridine (159 mg, 0.694 mmol), and Cs2CO3 (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 Na2SO4, filtered, and concentrated in vacuo to give the title compound. The crude product was purified by preparative TLC (25% EtOAc / PE) to give the title compound. LC / MS = 321 [M + H - 200].

[1041] Step E: Ethyl 6-((5-chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrimidine-

[1042] 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 the mixture was stirred at RT for 1 h, then the reaction mixture was concentrated in vacuo. The mixture was diluted with water and EtOAc, and then the pH was adjusted to 7 with saturated aqueous Na2CO3. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. The crude product was used without purification. LC / MS = 321 [M+H].

[1043] 2-carboxylate Step F: 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)imidazo[1,2-a]pyrimidine-

[1044] 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-oxopropionate (73.0 mg, 0.374 mmol). The mixture was stirred at 80 °C for 12 h, then the mixture was concentrated in vacuo. The residue was purified directly by preparative TLC (20% EtOAc / PE) to give the title compound LC / MS = 417 [M+H].

[1045] 2-carboxylic acid Step G: 6-((5-Chloro-3-(2,2,2-trifluoroethoxy)pyridin-2-yl)oxy)-N-(4-methyl-1,1-dioxido

[1046] 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.H2O (4.03 mg, 0.096 mmol). The reaction was stirred at RT for 1 h, then the mixture was diluted with water and acidified to pH = 4 with 1M HCl. The mixture was extracted with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. The crude product was used without purification. LC / MS = 389 [M+H].

[1047] tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide Determination

[1048] Under RT, HATU (56 mg, 0.15 mmol) was added 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 mmol) and DIPEA (34 μL, 0.20 mmol) in DMF (3.0 mL). After 1 h, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative TLC (20% EtOAc / PE) to give the title compound. LC / MS = 534 [M+1]. 1 1H 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.

[1049] ​

[1050] Insect cell expression and membrane preparation

[1051] 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 in a shaker incubator at 27 °C. Cells were harvested 48 h after infection with an unlabeled baculovirus expressing human DGAT2 (hDGAT2) at a multiplicity of infection (MOI) of 3. The cell pellet was suspended in a buffer containing 10 mM Tris-HCl pH 7.5, 1 mM EDTA, 250 mM sucrose and Complete Protease Inhibitor Cocktail (Sigma Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2000 x g for 15 min. The membrane fraction was isolated by ultracentrifugation (100,000 x g), resuspended in the same buffer and frozen (-80 °C) for later use. Using Pierce TMThe protein concentration was determined using a BCA Protein Assay Kit (Thermo Fisher Scientific). Protein levels were analyzed by immunoblotting with rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa Fluor 647 (Abcam, ab150075), and then detected using a Typhoon FLA9000 (GE Healthcare).

[1052] LC / MS / MS analysis method

[1053] LC / MS / MS analysis was performed using a Thermal Fisher LX4-TSQ Vantage system. The system consists of an Agilent binary high-performance liquid chromatography (HPLC) pump and a TSQ Vantage triple quadrupole MS / MS instrument. For each sample, 2 μL of the sample from the top organic layer of the in-plate liquid-liquid extraction was injected into a Thermo Betabasic C4 column (2.1 mm x 20 mm, 5 μm particle size). The sample was then eluted using the following conditions: mobile phase: isopropanol: acetonitrile / 10 mM ammonium formate = 50 / 35 / 15 (v / v / v), flow rate: 0.8 mL / min, temperature: 25 °C. Data were acquired in positive ion mode using a heated electrospray ionization (HESI) interface. The operating parameters of the TSQ Vantage MS / MS instrument were spray voltage 3000 V, capillary temperature 280 °C, vaporizer temperature 400 °C, sheath gas 45 arbitrary units, auxiliary gas 10 arbitrary units, S-lens 165, and collision gas 1.0 mTorr. Chromatograms of standard reference materials (SRMs) of 13 C 18 -triolein (Q1: 920.8 > Q3: 621.3) and internal standard 13 C 21 -triolein (Q1: 923.8 > Q3: 617.3) were collected. Peak areas were integrated using Xcalibur Quan software. The 13 C 18 triolein produced in the reaction was compared to the internal standard 13 C 21 -triolein ratio was used to generate inhibition percentages and IC 50 values. The percent inhibition of a compound was calculated using the following formula: Inhibition % = 1 - [(Compound reaction - Low control) / (High control - Low control)] x 100%. Effective compounds were titrated, and the IC 50 was calculated by fitting a four-parameter sigmoidal curve to the formula.

[1054] DGAT2 Enzyme Activity Assay

[1055] Measure the enzyme product using the above membrane preparation 13 C 18 -triolein ([[]] 13 C-1,2,3-tris(cis-9-octadecenoyl)glycerol) amount to determine DGAT2 activity. This assay is carried out in an ABgene 384-well assay plate at rt with a final volume of 25 μL. The assay mixture contains the following: assay buffer (100 mM Tris●Cl, pH 7.0, 20 mM MgCl2, 5% ethanol), 25 μM diolein, 5 μM[[[]] 13 C oleoyl-CoA and 8 ng / μL DGAT2 membrane.

Claims

1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: X, Y, and Z are independently selected from N and C(R 4 ); R 1 For (1) A 6-membered aryl group which is unsubstituted or substituted by 1, 2 or 3 R 5 substituted, (2) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents, (3)-(C 1-6 )alkyl-aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 R 5 substituents (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 substituted with 1, 2 or 3 R 5 substituents (5)-(C 1-3 ) haloalkyl, or (6) optionally substituted by 1, 2 or 3 Rs 5 -substituted -(C 1-6 )alkyl - O -(C 1-6 )alkyl; R 2 For (1) a 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2) phenyl, (3) a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (4)-(C 1-6 )-alkyl - heterocyclic group, wherein the heterocyclic group is a 4-, 5- or 6-membered heterocyclic group 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 ) cycloamine, (8)-(C 3-6 )cycloalkyl-(C 1-6 )alkyl-SO2(C 1-6 )alkyl, or (9) an 8- to 10-membered fused bicyclic heterocycle containing 1 or 2 heteroatoms independently selected from N, O and S, and wherein optionally the bicyclic is independently substituted by one, two or three halogens, Each of the alkyl, aryl, cycloalkyl, heteroaryl, cycloamine, and heterocyclic group is unsubstituted or substituted with 1, 2, 3, 4, or 5 R 6 substituents; R 3 For (1) hydrogen, (2) halogen, (3) hydroxy, (4)(C 1-6 )alkyl (5)(C 1-6 ) haloalkyl, (6)(C 1-6 ) alkyl hydroxy (7)(C 1-6 )alkoxy-, (8) C(=O)NH2, (9) C(=O)OH, or (10)O-(C 1-6 )alkyl; When present, each R 4 is independently (1) hydrogen, (2) halogen, (3)(C 1-3 )alkyl (4)C 1-3 haloalkyl, or (5) cyano; When present, each R 5 is independently: (1) hydrogen, (2) halogen, (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 -OC optionally substituted by halogen 1-6 alkyl - oxetanyl, or (16) O-C optionally substituted by halogen 1-6 alkyl-(C 3-7 ) cycloalkyl; When present, each R 6 is independently: (1) halogen, (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 Halogenated alkyl group.

2. The compound according to claim 1, which has formula Ib: wherein: R 1 is: (1) A 6-membered aryl group which is unsubstituted or substituted by 1, 2 or 3 R 5 substituents, (2) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents, (3)-(C 1-6 )alkyl-aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 R 5 substituents (4)-(C 1-6 )-alkyl - heteroaryl, wherein said heteroaryl is a 5 - or 6 - membered heteroaryl containing 1 nitrogen atom, and wherein said heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents (5)-(C 1-3 ) haloalkyl, or (6) Optionally substituted by 1, 2 or 3 R 5 -substituted -(C 1-6 )alkyl - O -(C 1-6 )alkyl; R 2 is: (1) a 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2) phenyl, (3) a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, (4)-(C 1-6 )alkyl - heterocyclic group, wherein the heterocyclic group is a 4-, 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms independently selected from S (5)-(C 1-6 )alkyl-aryl, (6)-(C 3-6 ) cycloalkyl (7)-(C 3-6 ) cycloamine, (8)-(C 3-6 )cycloalkyl-(C 1-6 )alkyl-SO2(C 1-6 )alkyl, or (9) a 10-membered fused bicyclic heterocycle containing 1 heteroatom independently selected from N, O and S, and wherein optionally the bicyclic is independently substituted by one, two or three halogens, Each of the alkyl, aryl, cycloalkyl, heteroaryl, cycloamine, and heterocyclic group is unsubstituted or substituted with 1, 2, 3, 4, or 5 R 6 substituents; R 3 is: (1) hydrogen, (2) halogen, (3) hydroxy, (4)(C 1-6 ) alkyl (5)(C 1-6 ) haloalkyl, (6)(C 1-6 ) alkyl hydroxy, (7)(C 1-6 ) alkoxy-, (8) C(=O)NH2, (9) C(=O)OH, or (10)O-(C 1-6 )alkyl; When present, each R 4 is independently: (1) hydrogen, (2) halogen, (3)(C 1-3 ) alkyl (4)C 1-3 haloalkyl, or (5) cyano; When present, each R 5 is independently: (1) hydrogen, (2) halogen, (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 by halogen 1-6 alkyl - oxetanyl, or (16) Optionally halogen-substituted O-C 1-6 alkyl-(C 3-7 ) cycloalkyl; When present, each R 6 is independently: (1) halogen, (2) oxo, (3) OH, (4)C 1-3 alkyl (5)C 1-3 Halogenated alkyl (6)C 1-3 alkyl-CN, (7) OC 1-3 alkyl, or (8)C(O)C 1-3 Halogenated alkyl group.

3. The compound according to any one of claims 1-2 or a pharmaceutically acceptable salt thereof, wherein R 1 is: (1) A 6-membered aryl group which is unsubstituted or substituted by 1, 2 or 3 R 5 groups, (2) A 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 R 5 substituents, (3)-CH2-aryl, wherein said aryl is unsubstituted or substituted with 1, 2 or 3 R 5 substituents (4)-CH2-Heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 nitrogen atom, and the heteroaryl is unsubstituted or substituted with 1, 2 or 3 Rs 5 substituted (5)-(C 1-3 ) haloalkyl, or (6) Optionally substituted by 1, 2 or 3 R 5 -substituted -(C 1-6 )alkyl - O -(C 1-6 )alkyl.

4. The compound according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof, wherein R 1 is: (1) An unsubstituted or -OC 1-6 alkyl or O-(C 1-6 ) haloalkyl-substituted 6-membered aryl, (2) A 6-membered heteroaryl containing one or two nitrogen atoms, wherein said heteroaryl is unsubstituted or substituted by one, two or three substituents independently selected from the following: 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, O-C 1-6 alkyl-(C 3-7 )cycloalkyl optionally substituted by halogen, and -OC 1-6 alkyl-oxetanyl optionally substituted by halogen, (3)-CH2-aryl, wherein said aryl is substituted by one or two substituents independently selected from halogen, -OC 1-3 alkyl or -OC 1-3 haloalkyl, (4)-CH2 - heteroaryl, wherein said heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, and wherein said heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents selected from 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.

5. The compound according to any one of claims 1-4 or a pharmaceutically acceptable salt thereof, wherein R 1 is: (1) a 6-membered aryl which is unsubstituted or substituted by OCH2CH3 or OCH2CF3, (2) a 6-membered heteroaryl containing one or two nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 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) -CH2-aryl, wherein the aryl is substituted by one or two substituents independently selected from F, OCH2CH3 and OCHF2, (4) -CH2-heteroaryl, wherein the heteroaryl is a 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, wherein the heteroaryl is unsubstituted or substituted by 1, 2 or 3 substituents selected from: OCH2CHF2, F, Cl, OCH2CF3, CH3, CF3 and OCH2CH3, (5) CH2CH2CF3, or (6)CH2(CH3)2CH2OCH2CH3。 6. The compound according to any one of claims 1-5 or a pharmaceutically acceptable salt thereof, wherein R 2 is: (1) A 4- to 7-membered heterocyclic group containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2) Phenyl, (3) A 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms, (4) -CH2-heterocyclic group, wherein the heterocyclic group is a 4-, 5- or 6-membered heterocyclic group 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 ) cycloamine, (8)-(C 3-6 ) cycloalkyl-CH3-SO2CH3, or (9) A 10-membered fused bicyclic heterocycle containing 1 oxygen atom, wherein optionally the bicyclic is independently substituted by one, two or three halogens, Each of the alkyl, aryl, cycloalkyl, heteroaryl, cycloamine, and heterocyclic group is unsubstituted or substituted by 1, 2, 3, 4, or 5 Rs 6 substituents.

7. The compound according to any one of claims 1-6 or a pharmaceutically acceptable salt thereof, wherein R 2 is: (1) containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted by one, two or three substituents independently selected from 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 heterocyclic group substituted by haloalkyl, (2) Phenyl, (3) Optionally C-substituted 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms 1-3 substituted by alkyl (4)-CH2 - heterocyclic group, wherein the heterocyclic group is a 4- or 6-membered heterocyclic group containing 1, 2 or 3 sulfur atoms, optionally substituted by one, two, three, four or five substituents independently selected from oxo and C 1-3 alkyl, (5) -CH2-aryl, wherein the aryl is a 6-membered aryl, (6) Optionally substituted by one, two or three groups independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, OC 1-3 alkyl and OH substituents substituted -(C 3-6 ) cycloalkyl, (7) - (C 3-6 ) cycloamine optionally substituted with one, two or three substituents independently selected from oxo, (8) -(C4) cycloalkyl-CH3-SO2CH3, or (9) A chromane optionally substituted by one, two or three halogens, Each of the alkyl, aryl, cycloalkyl, heteroaryl, cycloamine, and heterocyclic group is unsubstituted or substituted by 1, 2, 3, 4, or 5 Rs 6 substituents.

8. The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R 2 is: (1) Containing 1, 2 or 3 heteroatoms independently selected from N, O and S, optionally substituted by one, two, three, four or five substituents independently selected from halogen, oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN, C(O)CF3 and (CH3)2 of a 4- to 7-membered heterocyclic group, (2) Phenyl, (3) A 5- or 6-membered heteroaryl containing 1 or 2 nitrogen atoms optionally substituted by CH3, (4) -CH2-heterocyclic group, wherein the heterocyclic group is a 4- or 6-membered heterocyclic group containing 1 sulfur atom optionally substituted by one, two or three substituents independently selected from oxo and CH3, (5) -CH2-aryl, wherein the aryl is a 6-membered aryl, -(C 3-6 ) cycloalkyl optionally substituted with one, two or three substituents independently selected from F, CH3, CF3, OH, F2 and OCH3 (7) Optionally oxo-substituted -(C 3-6 ) cycloamine, (8) -(C4) cycloalkyl-CH3-SO2CH3, or (9) A chromane independently substituted by halogen.

9. The compound according to any one of claims 1-8 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1 heteroatom selected from sulfur, nitrogen and oxygen and optionally substituted by one, two, three, four or five substituents independently selected from halogen, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkyl-CN and C(O)C 1-3 haloalkyl.

10. The compound according to any one of claims 1-9 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1 heteroatom selected from sulfur, nitrogen, and oxygen and optionally substituted with one, two, three, four, or five substituents independently selected from halogen, oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN, C(O)CF3, and (CH3)2.

11. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1 sulfur atom and optionally substituted with one, two, three, four or five substituents independently selected from oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN and (CH3)2.

12. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1 nitrogen atom and optionally substituted with one, two or three substituents independently selected from CH3, CH2CN and C(O)CF3.

13. The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, wherein R 2 is a 4- to 7-membered heterocyclic group containing 1 oxygen atom and optionally substituted by one, two, three, four or five substituents independently selected from CH3, (CH3)2 and CH2CF3.

14. The compound according to any one of claims 1-7 or a pharmaceutically acceptable salt thereof, wherein R 2 is an optionally one, two or three substituents independently selected from halogen, C 1-3 alkyl, C 1-3 haloalkyl, OC 1-3 alkyl and OH substituted -(C 3-6 ) cycloalkyl.

15. A compound according to any one of claims 1 - 8 and 14, or a pharmaceutically acceptable salt thereof, wherein R 2 is a -(C 3-6 ) cycloalkyl optionally substituted with one, two or three substituents independently selected from halogen, oxo, CH3, CH2CF3, CH(CH3)2, CH2CH3, CH2CN, C(O)CF3 and (CH3)2.

16. The compound according to any one of claims 1-15 or a pharmaceutically acceptable salt thereof, 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 alkyl-OH.

17. A compound according to any one of claims 1-16 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, halogen, C 1-3 alkyl, OH, C(O)OH, C(O)NH2, OC 1-3 alkyl, C 1-3 haloalkyl or C 1-3 alkyl-OH.

18. The compound according to any one of claims 1-17 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, Cl, F, CH3, CH(CH3)2, CH2CH3, OH, C(O)OH, C(O)NH2, OCH3, CF3 or CH2OH.

19. A compound according to any one of claims 1-18 or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen or CH3.

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

21. The compound according to any one of claims 1-19 or a pharmaceutically acceptable salt thereof, wherein R 3 is CH3.

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

23. The compound according to any one of claims 1-22 or a pharmaceutically acceptable salt thereof, wherein when present, each R 4 is independently selected from hydrogen, CH3, F, Cl, CH(CH3)2, CF3, CH2CH3 and CN.

24. The compound according to any one of claims 1-21 or a pharmaceutically acceptable salt thereof, wherein when present, each R 4 is independently selected from hydrogen, Cl, F and CH3.

25. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-3, 6-24, wherein each R, when present, 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, -OC 1-6 alkyl-oxetanyl optionally substituted with halogen and O-C 1-6 alkyl-(C 3-7 )cycloalkyl optionally substituted with halogen.

26. A compound according to any one of claims 1-3, 6-25 or a pharmaceutically acceptable salt thereof, wherein when present, each R 5 is R 5 is 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.

27. A compound according to any one of claims 1 - 7, 16 - 26 or a pharmaceutically acceptable salt thereof, wherein each R, when present, 6 is independently selected from 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.

28. A compound according to any one of claims 1-7, 16-27 or a pharmaceutically acceptable salt thereof, wherein each R, when present, 6 is independently selected from halogen, oxo, CH3, CF3, OH, CH2CF3, CH(CH3)2, CH2CH3, OCH3, CH2CN, C(O)CF3 and (CH3)2.

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

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

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

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

33. The compound according to any one of claims 1-32 or a pharmaceutically acceptable salt thereof, wherein R 1 is 34. A compound according to any one of claims 1-32 or a pharmaceutically acceptable salt thereof, wherein R 1 is 35. A compound according to any one of claims 1 - 32 or a pharmaceutically acceptable salt thereof, wherein R 1 is 36. The compound according to any one of claims 1-32 or a pharmaceutically acceptable salt thereof, wherein R 1 is 37. A compound according to any one of claims 1-32 or a pharmaceutically acceptable salt thereof, wherein R 1 is 38. A compound according to any one of claims 1-11, 16-32 or a pharmaceutically acceptable salt thereof, wherein R 2 is 39. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-11, 16-32, wherein R 2 is 40. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is:

41. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is: 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-pyridinyl]oxy]-N-(2,2,4-trimethyl-1,1-dioxo-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, N-(4,4-difluoro-1-methyl-cyclohexyl)-6-[(3-ethoxy-2-pyridinyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxo-thiane-4-yl)imidazo[l,2-a]pyridine-2-carboxamide, 6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[1,1-dioxo-4-(2,2,2-trifluoroethyl)thiane-4-yl]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 8-Fluoro-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(5-Chloro-3-ethoxy-2-pyridinyl)oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[1,1-dioxido-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-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-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-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 7-Methyl-N-(4-methyl-1,1-dioxido-tetrahydro-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-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide, N-(3,3-Difluoro-1-methyl-cyclobutyl)-6-[(3-ethoxy-2-pyridinyl)oxy]imidazo[1,2-a]pyridine-2-carboxamide, 8-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(3,3-difluoro-1-methyl-cyclobutyl)-7-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-[4-methoxy-4-(trifluoromethyl)cyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-8-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]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-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-[(3S)-3-methyl-1,1-dioxido-thiolan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide, 5-Methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-[(1R,2S)-2-hydroxycyclohexyl]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-(2,2,6,6-tetramethyltetrahydropyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 5-Fluoro-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-5,7-dimethyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-[(3-fluoroxet-3-yl)methoxy]-2-pyridinyl]oxy]-7-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[(3-methyl-1,1-dioxido-thietan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-isopropyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 8-Fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxypyridin-2-yl)oxy]-N-phenylimidazo[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-dioxido-thiacyclohexan-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-dioxido-tetrahydro-2H-thiopyran-4-yl]imidazo[1,2-a]pyridine-2-carboxamide, 7-Isopropyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-isopropyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide, N-(6,8-Difluorochroman-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxypyridin-2-yl)oxy]-N-[(3S)-tetrahydrofuran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide, N-Benzyl-6-[(3-ethoxypyridin-2-yl)oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxypyridin-2-yl)oxy]-N-(pyridin-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-isopropyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, N-(4-Methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-8-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-N-(6-methylpyridazin-3-yl)imidazo[1,2-a]pyridine-2-carboxamide 6-[[3-(1,1-Difluoropropyl)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-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-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Hydroxy-2-pyridinyl)oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-[1,1-dioxido-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-pyridinyl]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-pyridinyl]oxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-isopropyl-1,1-dioxido-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-ethyl-1,1-dioxido-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(5-Chloro-3-ethoxy-2-pyridinyl)oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(3-ethyl-1,1-dioxido-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(5-Chloro-3-ethoxy-2-pyridinyl)oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Isopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-Difluoroethoxy)-2-pyridinyl]oxy]-N-[4-(cyanomethyl)-1,1-dioxido-thiacyclohexan-4-yl]-3-methyl-imidazo[1,2-a]-pyridine-2-carboxamide, N-(4-Ethyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-thiacyclohexan-4-yl)-6-[5-methyl-3-(2,2,2-trifluoroethoxy)pyrazin-2-yl]oxy-imidazo[1,2-α]pyridine-2-carboxamide, 6-[[5-Ethyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(2,2-dimethyl-1,1-dioxido-thietan-3-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-3-methyl]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]-pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-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-pyridinyl]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-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]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-pyridinyl]oxy]-N-(4,4-difluoro-1-methylcyclohexyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]-pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]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-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-isopropyl-1,1-dioxido-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(2,2-dimethyl-1,1-dioxido-thian-4-yl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-Ethoxy-5-(trifluoromethyl)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(3-methyl-1,1-dioxido-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-pyridinyl]oxy]-3-methyl-N-[3-(trifluoromethyl)cyclobutyl]imidazo[l,2-a]pyridine-2-carboxamide, N-[3-(Cyanomethyl)-1-(2,2,2-trifluoroacetyl)azetidin-3-yl]-6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(3-fluoro-1-bicyclo[1.1.1]pentyl)-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(2,2,4-trimethyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-[(3R)-3-methyl-1,1-dioxido-thiolan-3-yl]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-[4-methyl-1-(2,2,2-trifluoroacetyl)-4-piperidinyl]imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(3-methyl-1,1-dioxido-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-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, N-(2,2-Dimethyl-1,1-dioxido-thiane-4-yl)-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-imidazo[1,2-a]pyridine-2-carboxamide, N-(4-Ethyl-1,1-dioxido-thiane-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-dioxido-thiane-4-yl)-6-[[4-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-thiane-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-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-[(3-methyl-1,1-dioxido-thietan-3-yl)methyl]imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)-6-[[6-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-[3-(2,2,2-trifluoroethyl)tetrahydropyran-3-yl]imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-[(3S)-6-oxido-piperidin-3-yl]-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)oxy]-3-ethyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3-Ethyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 3-Isopropyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 8-Fluoro-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-fluoro-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-7-fluoro-3-methyl]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 7-Fluoro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 7-Fluoro-3-methyl-N-(4-methyl-1,1-dioxido-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-dioxido-thian-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]methoxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[(2-Ethoxyphenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(3-Ethoxy-2-pyridinyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[(4-Fluorophenyl)methoxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[2-(Difluoromethoxy)phenyl]methoxy]-3-methyl-N-(4-methyl-1,1-dioxothiolan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxothiolan-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-dioxothiolan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3-Chloro-N-(4-methyl-1,1-dioxothiolan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 3-Hydroxy-N-(4-methyl-1,1-dioxothiolan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 2-((4-Methyl-1,1-dioxotetrahydro-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-dioxothiolan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2,3-dicarboxamide, 3-Methoxy-N-(4-methyl-1,1-dioxothiolan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methoxy-N-(3-methyl-1,1-dioxothietan-3-yl)imidazo[1,2-a]pyridin-1-ium-2-carboxamide; 2,2,2-trifluoroacetate, N-(4-Methyl-1,1-dioxothiolan-4-yl)-6-[[3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxamide, 3-(Hydroxymethyl)-N-(4-methyl-1,1-dioxothiolan-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-dioxothiolan-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3,5-Dichloro-6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3-Chloro-6-[[5-chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-5-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-3-fluoro-5-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[5-methyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Cyclopropyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-(1-Hydroxy-1-methylethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-(1-Fluoro-1-methylethyl)-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Hydroxy-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 6-[[5-Cyano-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3-methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-a]pyridine-2-carboxamide, 3-Methyl-N-(4-methyl-1,1-dioxido-thian-4-yl)-6-[[5-methylsulfonyl-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]imidazo[1,2-a]pyridine-2-carboxamide, 6-[3-Methyl-2-[(4-methyl-1,1-dioxido-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-dioxido-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-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoropropoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Fluoro-3-[(1-fluorocyclopropyl)methoxy]-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[3-(2,2-Difluoropropoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[3-(Cyclopropylmethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[3-(Cyclobutoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Chloro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thian-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[3-(2,2-Difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-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-pyridinyl]oxy]-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-[1-(methylsulfonylmethyl)cyclobutyl]imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, N-(4-Methyl-1,1-dioxido-thiane-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-dioxido-tetrahydro-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-dioxido-thietan-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-dioxido-tetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-7-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[3-(2,2-difluoroethoxy)-5-fluoro-2-pyridinyl]oxy]-3,7-dimethyl-N-(4-methyl-1,1-dioxido-thiane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-8-methyl-N-(3-methyl-1,1-dioxido-thietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-Chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-8-methyl-N-(4-methyl-1,1-dioxido-thiane-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-pyridinyl]oxy]-N-(3-methyl-1,1-dioxothietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 3-chloro-6-[[5-chloro-3-(2,2-difluoroethoxy)-2-pyridinyl]oxy]-N-(3-methyl-1,1-dioxothietan-3-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 3,7-dichloro-N-(4-methyl-1,1-dioxothiane-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-dioxothiane-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-pyridinyl]oxy]-N-(3-methyl-1,1-dioxothietan-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-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[2-(difluoromethoxy)-6-fluorophenyl]methoxy]-N-(4-methyl-1,1-dioxothiane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-[[5-fluoro-3-(2,2,2-trifluoroethoxy)-2-pyridinyl]methoxy]-N-(4-methyl-1,1-dioxothiane-4-yl)imidazo[1,2-b]pyridazine-2-carboxamide, 6-((1,4-dimethyl-1H-pyrazol-3-yl)methoxy)-N-(4-methyl-1,1-dioxotetrahydro-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-dioxotetrahydro-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-dioxotetrahydro-2H-thiopyran-4-yl)imidazo[1,2-a]pyrimidine-2-carboxamide.

42. The compound or a pharmaceutically acceptable salt thereof according to claim 41, which is selected from one of the following:

43. The compound or a pharmaceutically acceptable salt thereof according to claim 41, which is:

44. A composition for treating a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases, and heart failure, which comprises the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 41, and a pharmaceutically acceptable carrier.

45. A composition which comprises a pharmaceutically acceptable carrier and the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 41.

46. A method for treating a disorder selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardio-renal diseases, and heart failure, which comprises administering to a patient in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 41.

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

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