Preparation of indolinone derivatives as novel diacylglycerol o-acyltransferase 2 inhibitors

Abstract

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

Description

[0001] This invention is a divisional application of the invention patent application filed on October 6, 2021, with application number 202180076390.9 and titled "Preparation of indoleone derivatives as novel diacylglycerol O-acyltransferase 2 inhibitors". Technical Field

[0002] This invention relates to novel pharmaceutical compounds and methods for preparing such compounds and pharmaceutical compositions comprising such compounds and pharmaceutical carriers, wherein the novel pharmaceutical compounds inhibit 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, cardiorenal diseases such as chronic kidney disease and heart failure, and related diseases and conditions, or as reversals of such diseases. Background Technology

[0003] Triacylglycerol (“TG”) provides a variety of functions in living organisms. One such function of TG is energy storage. TG also plays a role in the synthesis of membrane lipids. TG synthesis in cells protects them from the potential toxic effects of excess fatty acids (“FA”). In intestinal epithelial cells and hepatocytes, TG is synthesized for the assembly and secretion of lipoproteins that transport FA between tissues. TG functions in the water barrier at the skin surface, and TG in adipose tissue provides insulation for the organism.

[0004] The glycerol phosphate and monoacylglycerol pathways are the main pathways for TG biosynthesis. However, the final step in TG synthesis involves the reaction of fatty acyl-CoA and diacylglycerol (“DAG”) to form TG. This reaction is catalyzed by acyl-CoA:diacylglycerol acyltransferases (“DGAT”). Two DGAT enzymes, DGAT1 and DGAT2, have been identified. Although DGAT1 and DGAT2 catalyze the same reaction, they differ significantly at the DNA and protein sequence levels. In in vitro assays, DGAT2 is able to synthesize TG from endogenous fatty acids, while DGAT1 appears to be more dependent on exogenous fatty acids (Yen et al., J. Lipid Research (Li et al., 2008, 49, 2283). Inactivation of DGAT2 weakens cytoplasmic lipid droplet growth, while inactivation of DGAT1 has the opposite effect (Li et al., 2008, 49, 2283). Arterioscler. Thromb. Vasc. Biol 2015, 35, 1080).

[0005] DGAT2 is an integrated membrane protein of the endoplasmic reticulum and is strongly expressed in adipose tissue and liver. DGAT2 appears to be the major DGAT enzyme controlling triglyceride (TG) homeostasis in vivo. Mice lacking DGAT2 survive only a few hours after birth. Mice lacking DGAT1, on the other hand, can survive (Yen et al., J. Lipid Research , 2008, 49, 2283).

[0006] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been largely understood from work exploring antisense oligonucleotides (ASOs) in rodents. In this case, in the presence of DGAT2 gene-specific ASOs... ob / ob In mice, DGAT2 knockdown resulted in a dose-dependent decrease in very low-density lipoprotein (“VLDL”) as well as decreases in plasma TG, total cholesterol, and ApoB (Liu et al., Biochim. Biophys Acta 2008, 1781, 97). In the same study, ob / ob Treatment of mice with DGAT2 antisense oligonucleotides showed increased body weight, decreased fat mass, and decreased liver TG content. (Ibid.) In another study, ob / ob Antisense treatment in mice improved hepatic steatosis and hyperlipidemia (Yu et al., Hepatology (2005, 42, 362). Another study showed that diet-induced hepatic steatosis and insulin resistance in rats were improved by knocking down DGAT2. These effects appear to be specific to DGAT2 inhibition, as ASO targeting DGAT1 did not produce similar beneficial effects. Although the molecular mechanisms behind these observations are still uncertain, the collected data suggest that DGAT2 inhibition is associated with decreased expression of adipogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative / thermogenic genes (CPT1, UCP2) (Choi et al., 2005, 42, 362). J. Bio. Chem ., 2007, 282, 22678).

[0007] In summary, DGAT2 inhibitors are indicated for the treatment of diseases associated with a range of metabolic syndromes, such as hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney disease and heart failure, as well as related diseases and conditions.

[0008] The DGAT2 inhibitor compounds are described in WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, WO2013150416, US20150259323, WO2015077299, WO2017011276, WO2018033832, US201801628, and WO2003053363. Summary of the Invention

[0009] This invention relates to compounds represented by Formula I: It also includes pharmaceutically acceptable salts, esters, and prodrugs, which are DGAT2 inhibitors. Methods for preparing compounds of formula I, pharmaceutical compositions comprising compounds of formula I, and methods for using these compounds to treat hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney disease and heart failure, and related diseases and conditions, comprising administering compounds of formula I to patients in need of treatment. Detailed Implementation

[0010] This disclosure relates to compounds having structural formula I: Or its pharmaceutically acceptable salt, wherein: X, Y, and Z are independently selected from N or C(R). 5 ); R 1 yes (1) Unsubstituted or by 1, 2 or 3 R 6 Substituted phenyl, or (2) A 5- or 6-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the heteroaryl group is unsubstituted or surrounded by 1, 2 or 3 R atoms. 6 Replace, or (3) An 8- to 10-membered fused heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is unsubstituted or surrounded by 1, 2, or 3 R atoms. 6 replace; R 2a and R 2b Selected independently (1) Hydrogen, (2) Halogen, (3) Hydroxyl group, (4) (C) 1-6)alkyl, (5) (C) 1-6 ) Haloalkyl, (6) R 2a and R 2b Combining to form a spiral (C 3-8 )cycloalkyl, which is unsubstituted or optionally C 1-3 Alkyl, halogen, OH mono- or di-substituted, or (7) R 2a and R 2b These combine to form a spirocyclic 4- to 8-membered heterocyclic group, which contains one or two independent heteroatoms selected from N, O, and S, wherein the heterocyclic group is unsubstituted or surrounded by one, two, or three R atoms. 7 replace; R 3 yes (1) A 4- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2) A 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (3)-(C 1-6 )alkyl-heteroaryl, wherein the heteroaryl group is a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, (4)-(C 1-6 alkyl-aryl, (5)-(C 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 3- to 6-membered ring containing one or two heteroatoms independently selected from N, O, and S, (6)-(C 1-6 )alkyl, (7)-(C 3-6 )cycloalkyl, (8)-(C 1-6 )hydroxyalkyl, (9)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b ,or (10)-(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl, Each cycloalkyl or heterocyclic group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl, aryl, or heteroaryl group is unsubstituted or surrounded by 1, 2, or 3 R groups. 10 replace; R 4 yes (1) Hydrogen, or (2) (C)1-3 )alkyl, Or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a monocyclic or bicyclic heterocyclic base ring, which contains one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclic base ring is unsubstituted or surrounded by one, two, or three R atoms. 11 replace, When it exists, each R 5 Selected from (1) Hydrogen, (2) (C) 1-3 )alkyl, (3) (C) 1-3 ) Haloalkyl, (4) Cyano group (5) Halogen, When it exists, each R 6 Selected independently (1) Cyano group (2) Halogen, (3)-OC 1-6 alkyl (4) (C) 3-6 )cycloalkyl groups, which are optionally substituted with halogens or OH, (5)-(C=O)NH2, (6) (C) 3-6 )cycloalkyloxy group, wherein the cycloalkyl group is optionally substituted with a halogen or OH, (7) Hydroxyl group (8)-N(R) 11 )2, (9)-NH(C=O)(C 1-6 )alkyl, (10) (C) 2-6 Cyclic amines, optionally substituted with one or two halogen substituents, (11) (C) 1-6 )haloalkyl- (12) O(C) 1-6 ) Haloalkyl-, optionally substituted with OH, (13)-O(C) 0-3 )alkyl-(C 3-6 )cycloalkyl groups, optionally substituted with one or two halogen substituents, (14)-SO2(C 1-6 )alkyl, (15)-SO2NH(C 1-6 )alkyl, (16)-SC 1-6 alkyl, (17)-SC1-6 Halogenated alkyl, or (18) (C) 1-6 )alkyl, When it exists, each R 7 Selected independently (1) (C) 1-3 )alkyl, (2) Halogen, (3) (C) 1-3 )alkoxy, (4) (C) 1-3 ) Haloalkyl-, or (5) Hydroxyl group, When it exists, R 8a and R 8b Selected independently (1) Hydrogen, (2) (C) 1-3 )alkyl, or (3) (C) 3-7 )cycloalkyl; When it exists, each R 9 Selected independently (1) (C) 1-3 )alkyl, (2) (C) 1-3 ) Haloalkyl-, (3) Oxygenation, (4) (C) 3-6 )cycloalkyl, (5) -N(R) 11 )2, (6) Hydroxyl group (7) (C) 1-3 )alkoxy-, (8) Cyano group (9) Halogen, (10)-SO2(C 1-6 )alkyl, (11)-(C 1-6 )alkylSO2(C 1-6 )alkyl, (12)-C(O)(C 1-3 )alkyl, or (13) O(C) 1-3 )alkyl, When it exists, R 10 Selected independently (1) Hydrogen, (2) (C) 1-3 )alkyl, (3) (C) 1-3 )alkoxy-, (4) Hydroxyl group (5) Halogen, (6) (C) 1-3 )alkyl-S-, (7) (C) 1-3 ) Haloalkyl-, or (8) N(R) 11 )2, When it exists, R 11 Independently (1) Hydrogen, or (2) (C) 1-3 )alkyl.

[0011] Embodiment 1a of this disclosure is a compound of formula I or a pharmaceutically acceptable salt of any of the preceding claims, wherein R 1 yes a) A phenyl group optionally substituted with one to three independent substituents selected from the following: halogen, hydroxyl, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, C groups optionally substituted with halogens or OH groups 3-6 cycloalkyl, -OC 1-3 Alkyl groups, optionally substituted with OH, -OC 1-3 Halogenated alkyl groups, -OC 3-6 cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-3 Alkyl group, -NH(C=O)C 1-3 Alkyl group, C(O)NH2, S(O)2NHC 1-3 Alkyl, N(R) 11 )2 or optionally substituted with one or two halogen substituents; b) A 6-membered heteroaryl group containing one or two nitrogen atoms, which is substituted by one or two substituents independently selected from the following: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 OCs with haloalkyl groups, optionally substituted with 1-2 halogen substituents 0-3 Alkyl-C 3-6 Cycloalkyl, optionally substituted with 1-2 halogens, nitrogen-containing heterocyclic butyl, CN, -SC 1-3 Alkyl or -SC 1-3 Halogenated alkyl groups; c) A 5-membered heteroaryl group containing one to four nitrogen atoms or heteroatoms independently selected from N, O, and S, optionally substituted by one or two substituents independently selected from: halogens, (C... 1-3)alkyl, (C 3-6 )cycloalkyl, (C 1-3 ) Haloalkyl-, -OH or OC 1-3 Alkyl groups, optionally substituted with one or two halogens, OC 0-3 Alkyl-C 3-6 cycloalkyl, O(C) 1-3 ) Haloalkyl-, O(C 1-3 ) Haloalkyl-OH, or a nitrogen-containing heterocyclic butyl group optionally substituted with one or two halogens; or d) An 8- to 10-membered fused heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is unsubstituted or halogenated, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 ) Haloalkyl-, OH or OC 1-3 Alkyl substitution.

[0012] Embodiment 1b of this disclosure is a compound of formula I or a pharmaceutically acceptable salt of any of the preceding claims, wherein R 1 yes a) A phenyl group optionally substituted with one to three independent substituents selected from the following: halogen, hydroxyl, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, C groups optionally substituted with halogens or OH groups 3-6 cycloalkyl, -OC 1-3 Alkyl groups, optionally substituted with OH, -OC 1-3 Halogenated alkyl, OC 3-6 cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-3 Alkyl group, -NH(C=O)C 1-3 alkyl; b) A 6-membered heteroaryl group containing one or two nitrogen atoms, which is substituted by one or two substituents independently selected from the following: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl groups, -OC 3-6 cycloalkyl, CN, -SC 1-3 Alkyl or -SC 1-3 Halogenated alkyl groups; c) A 5-membered heteroaryl group containing one to four nitrogen atoms or heteroatoms independently selected from N, O, and S, optionally substituted by one or two substituents independently selected from: halogens, (C... 1-3 )alkyl, (C 3-6)cycloalkyl, (C 1-3 ) Haloalkyl-, OH or OC 1-3 Alkyl; or d) An 8- to 10-membered fused heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is unsubstituted or halogenated, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 ) Haloalkyl-, OH or OC 1-3 Alkyl substitution.

[0013] Embodiment 2 of this disclosure is a compound of Formula I, or a compound as in Embodiment 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It is not an alkyl group.

[0014] Embodiment 3a of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-2 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes a) A phenyl group substituted with one to three independent substituents selected from the following: halogen, hydroxyl, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, C groups optionally substituted with halogens or OH groups 3-6 cycloalkyl, -OC 1-3 Alkyl groups, optionally substituted with OH, -OC 1-3 Halogenated alkyl groups, -OC 3-6 cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-6 Alkyl or -NH(C=O)C 1-3 Alkyl group, C(O)NH2, S(O)2NHC 1-3 Alkyl, N(R) 11 2. A nitrogen-containing heterocyclic butyl group optionally substituted with one or two halogen substituents; b) A 6-membered heteroaryl group containing one or two nitrogen atoms, which is substituted by one or two substituents selected from: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl groups, optionally substituted with 1-2 halogens, OC 0-3 Alkyl-C 3-6 Cycloalkyl, optionally substituted with 1-2 halogens, nitrogen-containing heterocyclic butyl, CN, -SC 1-3 Alkyl, -SC 1-3 Halogenated alkyl groups; c) A 5-membered heteroaryl group containing one to four nitrogen atoms or heteroatoms independently selected from N, O, and S, optionally substituted by one or two substituents independently selected from: halogens, (C... 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 ) Haloalkyl-, -OH, OC 1-3 Alkyl groups, optionally substituted with one or two halogens, OC 0-3 Alkyl-C 3-6 cycloalkyl, O(C) 1-3 ) Haloalkyl-, O(C 1-3 ) Haloalkyl-OH, or a nitrogen-containing heterocyclic butyl group optionally substituted with one or two halogens; or d) An 8- to 10-membered fused heteroaryl group containing at least one nitrogen and optionally one oxygen.

[0015] Embodiment 3b of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-2 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes a) A phenyl group substituted with one to three independent substituents selected from the following: halogen, hydroxyl, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, C groups optionally substituted with halogens or OH groups 3-6 cycloalkyl, -OC 1-3 Alkyl groups, optionally substituted with OH, -OC 1-3 Halogenated alkyl groups, -OC 3-6 cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-6 Alkyl or -NH(C=O)C 1-3 Alkyl group, wherein the cycloalkyl group is optionally substituted with a halogen or OH; b) A 6-membered heteroaryl group containing one or two nitrogen atoms, which is substituted by one or two substituents selected from: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 Halogenated alkyl groups, -OC 3-6 cycloalkyl, CN, -SC 1-3 Alkyl, -SC 1-3 Halogenated alkyl groups; c) A 5-membered heteroaryl group containing one to four nitrogen atoms or heteroatoms independently selected from N, O, and S, optionally substituted by one or two substituents independently selected from: halogens, (C... 1-3 )alkyl, (C 3-6)cycloalkyl, (C 1-3 ) Haloalkyl-, -OH or OC 1-3 alkyl, or d) An 8- to 10-membered fused heteroaryl group containing at least one nitrogen and optionally one oxygen.

[0016] Embodiment 4 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-3 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes a) Phenyl groups substituted with the following substituents: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -O-cyclopropyl, optionally substituted with halogen or hydroxyl, -SC 1-3 Alkyl, -SC 1-3 Halogenated alkyl groups, S(O)₂NHCH₃, S(O)₂C 1-3 Alkyl group, -NH(C=O)C 1-3 Alkyl, CN, a nitrogen-containing heterocyclic butyl group optionally substituted with one or two fluorine substituents, C(O)NH2, N(CH3)2, wherein the phenyl group is optionally further substituted with one or two fluorine atoms; b) A 6-membered heteroaryl group containing one or two nitrogen atoms, which is substituted by one or two substituents selected from the following: C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3 Alkyl groups, optionally substituted with hydroxyl groups - OC 1-3 Haloalkyl, -O-cyclopropyl, optionally substituted with halogen or hydroxyl, -OC 1-3 Alkyl-C 3-6 cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Halogenated alkyl groups, nitrogen-containing heterocyclic butyl groups optionally substituted with one or two fluorine groups, halogens, -OC 1-3 Alkyl-OH, -OC 1-3 Halogenated alkyl-OH, wherein the 6-membered heteroaryl group is optionally further substituted with 1 or 2 fluorine atoms or CH3; c) A 5-membered heteroaryl group containing one to four nitrogen atoms or heteroatoms independently selected from N, O, and S, optionally substituted by one or two substituents independently selected from: halogens, (C... 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 ) Haloalkyl-, -OH, OC 1-6 Alkyl groups, optionally substituted with one or two halogens, OC 0-3 Alkyl-C3-6 cycloalkyl, O(C) 1-3 ) Haloalkyl-, O(C 1-3 ) Haloalkyl-OH, or a nitrogen-containing heterocyclic butyl group optionally substituted with 1 to 2 fluorine substituents; or d) Contains one or two independent heteroatoms selected from nitrogen or oxygen, which are 9 or 10 fused heteroaryl groups, optionally substituted with methyl groups.

[0017] Embodiment 5 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-4 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0018] Embodiment 6a of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-4 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It is a phenyl group substituted with one or two of the following substituents: -OH, -CH3, -CF2CH3, -OCHF2, -OCH2CH3, -OCH(CH3)2, -OCF2CH3, -OCF2CHF2, -OCH2CHF2, -OCF3, O-cyclopropyl, cyclopropyl, -SCHF2, CN, F, S(O)2NHCH3, C(O)NH2, S(O)2CH3, N(CH3)2, -NH(C=O)CH3, aziridine, or 3,3-difluoroaziridine, wherein the phenyl group is optionally further substituted with one or two fluorine atoms.

[0019] Embodiment 6b of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-4 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It is a phenyl group substituted with one or two of the following substituents: -OH, -CH3, -CF2CH3, -OCHF2, -OCH2CH3, -OCF2CHF2, -OCH2CHF2, -OCF3, O-cyclopropyl, -SCHF2, -NH(C=O)CH3 or 3,3-difluoroazacyclobutyl, wherein the phenyl group is optionally further substituted with one or two fluorine atoms.

[0020] Embodiment 7a of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-4 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It is a pyridyl group substituted with one or two independent substituents selected from the following: F, OH, -CH3, -CF2CH3, -OCH(CH3)2, OCHF2, -OCH2CH3, -OCF2CH3, -OCF2CHF2, -OCH2CH(CH3)2, -OCH2CHF2, -OCH2CF3, -OCF3, cyclopropyl, O-cyclopropyl, O-CH2-cyclopropyl optionally substituted with 1 or 2 F, O-CH2-cyclobutyl optionally substituted with 2 F, OCH2CF2CH3, OCH2CF2CHF2, OCF2CH2OH or -SCHF2.

[0021] Embodiment 7b of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-4 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It is a pyridinyl group that is substituted by one or two independent substituents selected from the following: F, OH, -CH3, -CF2CH3, -OCHF2, -OCH2CH3, -OCF2CH3, -OCF2CHF2, -OCH2CHF2, -OCF3, cyclopropyl or -SCHF2.

[0022] Embodiment 8 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-4 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It is a pyrimidinyl group that is substituted by one or two substituents independently selected from the following: F, OCH2CHF2, OCH2CF3.

[0023] Embodiment 9 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-4 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 It is a 9- or 10-membered fused heteroaryl group containing one nitrogen atom.

[0024] Embodiment 10 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-6 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0025] Embodiment 11 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-6 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0026] Embodiment 12 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0027] Embodiment 13 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-6 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0028] Embodiment 14 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0029] Embodiment 15 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0030] Embodiment 16 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0031] Embodiment 17 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-6 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0032] Embodiment 18 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-6 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0033] Embodiment 19 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0034] Embodiment 20 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0035] Embodiment 21 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0036] Embodiment 22 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-5 or 7, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 1 yes .

[0037] Embodiment 23 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-22 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b It is selected from one of the following: (1) R 2a and R 2b It's hydrogen. (2) R 2a It is hydrogen and R 2b Yes (C) 1-6 )alkyl, or R 2a Yes (C) 1-6 )alkyl and R 2b It's hydrogen. (3) R 2a It is halogen and R 2b Yes (C) 1-6 )alkyl, or R 2a Yes (C) 1-6 )alkyl and R 2b It's halogen. (4) R 2a It is hydroxyl and R 2b Yes (C) 1-6 )alkyl, or R 2a Yes (C) 1-6 )alkyl and R 2b It is a hydroxyl group. (5) R 2a It is hydroxyl and R 2b Yes (C) 1-6 ) Haloalkyl, or R 2a Yes (C) 1-6 ) Haloalkyl and R 2b It is a hydroxyl group. (6) R 2a and R 2b Each is independently selected from (C) 1-6 )alkyl, (7) R 2a and R 2b These combine to form a spirocyclic 4- to 8-membered heterocyclic group, which contains one or two independent heteroatoms selected from N, O, and S, wherein the heterocyclic group is unsubstituted or surrounded by one, two, or three R atoms. 7 Replace, or (8) R 2a and R 2b Combining to form a spiral (C 3-8 )cycloalkyl, which is unsubstituted or optionally C 1-6 Alkyl, halogen, or OH mono- or di-substituted.

[0038] Embodiment 24 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-23 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Independently selected from H and C 1-3 Alkyl groups, or together forming spiro compounds 1-6 Cycloalkyl.

[0039] Embodiment 25a of this disclosure is a compound of formula I, or a compound of the same type as embodiments 1-23, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2a and R 2b It is independently selected from hydrogen, CH3, OH, CF3, CH(CH3)2 or CH2CH3.

[0040] Embodiment 25b of this disclosure is a compound of formula I or a compound of the class of embodiments 1-23 or thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 2a and R 2b It is independently selected from hydrogen, CH3, CH(CH3)2 or CH2CH3.

[0041] Embodiment 26 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-23 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b It combines with the carbon to form cyclobutyl, cyclopropyl, or cyclopentyl.

[0042] Embodiment 27a of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-22 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes (1) A 4- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2) A 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (3)-(C 1-6 )alkyl-heteroaryl, wherein the heteroaryl group is a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, (4)-(C 1-6 alkyl-aryl, (5)-(C 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 3- to 6-membered ring containing one or two heteroatoms independently selected from N, O, and S, (6)-(C 1-6 )alkyl, (7)-(C 3-6 )cycloalkyl, (8)-(C 1-6 )hydroxyalkyl, (9)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b ,or (10)-(C 1-6 )alkyl-S(O)2-(C1-3 )alkyl, Each aryl, heteroaryl, cycloalkyl, or heterocyclic group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl, aryl, or heteroaryl group is unsubstituted or substituted by 1, 2, or 3 R groups. 10 replace.

[0043] Embodiment 27b of this disclosure is a compound of formula I or a compound as described in any of embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes (1) A 4- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2) A 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (3)-(C 1-6 )alkyl-heteroaryl, wherein the heteroaryl group is a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, (4)-(C 1-6 alkyl-aryl, (5)-(C 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 3- to 6-membered ring containing one or two heteroatoms independently selected from N, O, and S, (6)-(C 1-6 )alkyl, (7)-(C 3-6 )cycloalkyl, (8)-(C 1-6 )hydroxyalkyl, (9)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b ,or (10)-(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl, Each aryl, heteroaryl, cycloalkyl, or heterocyclic group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl, aryl, or heteroaryl group is unsubstituted or surrounded by 1, 2, or 3 R groups. 10 replace.

[0044] Embodiment 28 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes (1) A 4- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2)-(C 3-6 )cycloalkyl, (3)-(C 1-6 )hydroxyalkyl, (4)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b ,or (5)-(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl, Each cycloalkyl or heterocyclic group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 R groups. 10 replace.

[0045] Embodiment 29 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes (1) A 4- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2)-(C 3-6 )cycloalkyl, (3)-(C 1-6 )hydroxyalkyl, (4)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b , (5)-(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl, (6) (C) 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 5-membered heterocyclic group containing 1 O heteroatom, (7) A 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (8) (C) 1-6 )alkyl-heteroaryl, wherein the heteroaryl group is a 5-membered heteroaryl group containing 2 N heteroatoms, Each aryl, heteroaryl, cycloalkyl, or heterocyclic group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 R groups. 10 replace.

[0046] Embodiment 30 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R3 yes (1) Optionally covered by halogens, hydroxyl groups, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-3 Haloalkyl, S(O)2C 1-3 Alkyl, C 1-3 Alkyl S(O)2C 1-3 Alkyl, OC 1-3 Alkyl or C 1-6 Alkoxy-substituted 4- to 6-membered cycloalkyl groups, (2) A 4, 5, or 6-membered heterocyclic group containing one sulfur atom or one oxygen atom, optionally bonded by C 1-6 Alkyl, C 1-3 Alkyl (OH), OH, C 1-3 Halogenated or oxo-substituted mono-, di-, or tri-substituted compounds (3) C 1-6 Alkyl group, wherein the alkyl group is optionally coated with a halogen, OH, CF3, S(O)2CH3, S(O)2NH-cyclohexyl or C 1-3 Alkyl mono-substituted, di-substituted, or tri-substituted, (4) A six-membered heterocyclic group containing one nitrogen atom, which is optionally bonded by C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)C 1-3 Alkyl, S(O)2C 1-3 Alkyl mono-substituted, di-substituted, or tri-substituted, (5) (C) 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 5-membered heterocyclic group containing one O heteroatom, which is optionally mono-, di-, or tri-substituted with OH. (6) A 5-membered heteroaryl group containing 1 S atom and 2 N heteroatoms, which is optionally bonded by C 1-6 Alkyl monosubstituted, disubstituted, trisubstituted, or (7) (C) 1-6 )alkyl-heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl containing 2 N heteroatoms, which is optionally C 1-6 Alkyl monosubstituted, disubstituted, and trisubstituted.

[0047] Embodiment 31 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes (1) 4- to 6-membered cycloalkyl groups optionally substituted with F, OH, S(O)2CH3, CH2S(O)2CH3, CF3, OCH3, or CH3. (2) A 4- to 6-membered heterocyclic group containing one sulfur atom, which is optionally monosubstituted, disubstituted, or trisubstituted by oxo, CHF2, CH2CH3, or CH3. (3) A 5- or 6-membered heterocyclic group containing one oxygen atom, which may be monosubstituted, disubstituted, or trisubstituted by CH3, OH, or CH2OH. (4) C 1-6 Alkyl group, wherein the alkyl group is optionally monosubstituted, disubstituted, or trisubstituted by halogen, OH, CF3, S(O)2CH3, S(O)2NH-cyclohexyl or CH3. (5) A six-membered heterocyclic group containing one nitrogen atom, which is optionally substituted, disubstituted, or trisubstituted with CH3, C(O)CH3, CH2CHF2, S(O)2CH3N-, (6) (C) 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 5-membered heterocyclic group containing one O heteroatom, which is optionally mono-, di-, or tri-substituted with OH. (7) A 5-membered heteroaryl group containing 1 S atom and 2 N heteroatoms, which may be monosubstituted, disubstituted, trisubstituted, or substituted with CH2CH3. (8) CH3-heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl containing 2 N heteroatoms, which is optionally monosubstituted, disubstituted or trisubstituted by CH3.

[0048] Embodiment 32 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes (1) A 4- to 6-membered cycloalkyl group, optionally coated with a halogen, a hydroxyl group, or a C-membered cycloalkyl group. 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy substitution, (2) A 4, 5, or 6-membered heterocyclic group containing one sulfur atom or one oxygen atom, optionally bonded by C 1-6 Alkyl, C 1-3 Alkyl (OH), OH or oxo-substituted mono-, di-, or tri-substituted, (3) C 1-6 Alkyl (OH), wherein the alkyl group is optionally coated with a halogen, CF3 or C 1-3 Alkyl monosubstituted, disubstituted, or trisubstituted.

[0049] Embodiment 33 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes (1) 4 to 6-membered cycloalkyl groups, optionally substituted with F, OH, S(O)2CH3, CH2S(O)2CH3, CF3, or OCH3. (2) A 4- to 6-membered heterocyclic group containing one sulfur atom, which is optionally oxidized or monosubstituted, disubstituted or trisubstituted by CH3; (3) A 5- or 6-membered heterocyclic group containing one oxygen atom, which is optionally monosubstituted, disubstituted, or trisubstituted by CH3 or CH2OH; or (4) C 1-6 Alkyl groups, wherein the alkyl group is optionally coated with a halogen, OH, CF3, S(O)2CH3, or S(O)2NR. 8a R 8b It can be monosubstituted, disubstituted, or trisubstituted with CH3.

[0050] Embodiment 34 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0051] Embodiment 35 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0052] Embodiment 36 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes .

[0053] Embodiment 37 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes .

[0054] Embodiment 38 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes .

[0055] Embodiment 39 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-26 or a pharmaceutically acceptable salt of any of the foregoing, wherein R 3 yes .

[0056] Embodiment 40 of this disclosure is a compound of Formula I or a compound of the class of Embodiments 1-39 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 4 It's H.

[0057] Embodiment 41 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-40 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, halogen, or CN.

[0058] Embodiment 42 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-41 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, F, Cl, or CN.

[0059] Embodiment 43 of this disclosure is a compound of Formula I or a compound of the class of Embodiments 23-42 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 6 It is cyano, halogen, -OC 1-6 Alkyl groups, optionally substituted with halogens or OH groups (C 3-6 )cycloalkyl, -(C=O)NH2, wherein the cycloalkyl group is optionally substituted with a halogen or OH. 3-6 )cycloalkyloxy, hydroxyl, -N(R 11 )2、-NH(C=O)(C 1-6 )alkyl, optionally substituted with one or two halogen substituents (C 2-6 )cyclic amines, (C 1-6 ) Haloalkyl-, optionally substituted with OH- -O(C 1-6 ) Haloalkyl, optionally substituted with one or two halogens -O(C 0-3 )alkyl-(C 3-6 )cycloalkyl, -SO2(C 1-6 )alkyl, -SO2NH(C 1-6 )alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl or (C 1-6 )alkyl.

[0060] Embodiment 44 of this disclosure is a compound of Formula I or a compound of the class of Embodiments 23-43 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 6 It is cyano, halogen, -OC 1-6 Alkyl groups, optionally substituted with halogens or OH groups (C 3-6 )cycloalkyl, -(C=O)NH2, wherein the cycloalkyl group is optionally substituted with a halogen or OH. 3-6 )cycloalkyloxy, hydroxyl, -N(R 11 )2、-NH(C=O)(C 1-6 )alkyl, optionally substituted with one or two halogen substituents (C 2-6 )cyclic amines, (C 1-6 ) Haloalkyl-, -O(C 1-6 ) Haloalkyl, -SO2(C 1-6 )alkyl, -SO2NH(C 1-6 )alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups.

[0061] Embodiment 45 of this disclosure is a compound of Formula I, or a compound of the same type as Embodiments 23-43, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 6 It contains halogens, hydroxyl groups, CN, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C optionally substituted with halogen or OH 3-6 cycloalkyl, -OC 1-6 Alkyl groups, optionally substituted with OH, -OC 1-6 Haloalkyl groups, optionally substituted with one or two halogens, -O(C) 1-3 )alkyl-(C 3-6 )cycloalkyl, -OC 3-6 cycloalkyl, -SO2NH(C 1-6 )alkyl, -S(O)2C 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups or NH(C=O)C 1-3 Alkyl groups, optionally substituted with OH (C 2-6 )cyclic amines, N(C 1-3 )alkyl, -O(C 3-6 )cycloalkyl.

[0062] Embodiment 46 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 23-43 and 44 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 6 It contains halogens, hydroxyl groups, CN, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C optionally substituted with halogen or OH 3-6 cycloalkyl, -OC 1-6 Alkyl, -OC 1-6 Halogenated alkyl groups, -OC 3-6 cycloalkyl, -S(O)2C 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups or NH(C=O)C 1-3 Alkyl groups, wherein the cycloalkyl groups are optionally substituted with halogens, CN or OH.

[0063] Embodiment 47 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 23-43 and 44 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -F, OH, C 1-6 Alkyl, -C 1-6 Halogenated alkyl, OC 1-6 cycloalkyl, -OC 1-6Alkyl, -OC 1-6 Halogenated alkyl groups, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups or -NH(C=O)C 1-3 Alkyl groups, wherein the cycloalkyl groups are optionally substituted with 1-3 F groups.

[0064] Embodiment 48 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 23-43 and 45 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -F, CN, OH, -CH3, -CF2CH3, -OCF2CH3, -OCHF2, -OCF3, OCH2CF3, -OCH2CH3, OCH(CH3)2, -OCF2CHF2, -OCH2CHF2, -OCHF2CH3, OCH2CF2CH3, OCH2CH(CH3)2, OCH2CF2CHF2, -cyclopropyl, -O-cyclopropyl, OCH2-cyclopropyl optionally substituted with 1 or 2 F, OCH2-cyclobutyl optionally substituted with 1 or 2 F, azacyclobutyl optionally substituted with 1 or 2 F, -SCHF2, S(O)2CH3, S(O)2NHCH3, C(O)NH2, N(CH3)2, OCF2CH2OH or -NH(C=O)CH3.

[0065] Embodiment 49 of this disclosure is a compound of Formula I or a compound of the class of Embodiments 23-48 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -F, OH, -CH3, -CF2CH3, -OCHF2, -OCF3, -OCH2CH3, OCH(CH3)2, -OCF2CHF2, -OCH2CHF2, -OCHF2CH3, -cyclopropyl, -O-cyclopropyl, -SCHF2 or -NH(C=O)CH3.

[0066] Embodiment 50 of this disclosure is a compound of Formula I or a compound of the class of Embodiments 1-49 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 7 It is halogen, C 1-6 Halogenated alkyl groups or OH groups.

[0067] Embodiment 51 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-50 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 7 It is F, CF3, or OH.

[0068] Embodiment 52 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-51 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 8aIt is H.

[0069] Embodiment 53 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-52 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 8b It is H.

[0070] Embodiment 54 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-51 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b It is independently selected from hydrogen and cyclohexyl.

[0071] Embodiment 55a of this disclosure is a compound of formula I or a compound of the class of embodiments 1-54 or the like, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 9 =O, -OH, halogen, OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl OH, -SO2(C 1-3 )alkyl or -C( 1-3 )alkylSO2(C 1-3 alkyl, C(O)C 1-3 alkyl.

[0072] Embodiment 55b of this disclosure is a compound of formula I or a compound of the class of embodiments 1-55 or the like, or a pharmaceutically acceptable salt of any of the foregoing, wherein R 9 =O, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl OH, -SO2(C 1-3 )alkyl or -C( 1-3 )alkylSO2(C 1-3 )alkyl.

[0073] Embodiment 56 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-56 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 9 =O, -OH, CH3, CH2CH3, F, CF3, CH2OH, OCH3, SO2CH3 or CH2SO2CH3.

[0074] Embodiment 57 of this disclosure is a compound of Formula I or a compound of the same type as Embodiments 1-56 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 10 It is hydrogen, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl OH or -C(1-6 )alkylSO2(C 1-6 )alkyl.

[0075] Embodiment 58 of this disclosure is a compound of Formula I or a compound of the class of Embodiments 1-57 or any of the foregoing, or a pharmaceutically acceptable salt thereof, wherein R 10 It is hydrogen, OH, CH3, CH2CH3, F, CF3, CH2OH, or CH2SO2CH3.

[0076] Embodiment 59 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-58 or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N and Y is C(R) 5 Z and C(R) are C(R) 5 ).

[0077] Embodiment 60 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-58 or a pharmaceutically acceptable salt of any of the foregoing, wherein X is a C(R) compound. 5 Y is N and Z is C(R) 5 ).

[0078] Embodiment 61 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-58 or a pharmaceutically acceptable salt of any of the foregoing, wherein X, Y, and Z are C(R) compounds. 5 ).

[0079] Embodiment 62 of this disclosure is a compound of Formula I or a compound as described in any of Embodiments 1-58 or a pharmaceutically acceptable salt of any of the foregoing, wherein X is N, Y is N and Z is C(R) 5 ).

[0080] In Embodiment 63 of the present invention, a compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples 1-159 below, is provided.

[0081] In embodiment 64, the present invention is selected from the following compounds: , , , , , , , Or its pharmaceutically acceptable salt.

[0082] In embodiment 65, the present invention comprises compounds selected from the following: , , , Or, or a pharmaceutically acceptable salt thereof.

[0083] In embodiment 66, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0084] In embodiment 67, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0085] In embodiment 68, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0086] In embodiment 69, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0087] In embodiment 70, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is In embodiment 71, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0088] In embodiment 72, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0089] In embodiment 73, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0090] In embodiment 74, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0091] In embodiment 75, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0092] In embodiment 76, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0093] In embodiment 77, the present invention is a compound, or a pharmaceutically acceptable salt thereof, which is .

[0094] In embodiment 78 of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof is: , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , or .

[0095] In embodiment 79 of the present invention, the compound of formula I or a pharmaceutically acceptable salt thereof is: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3-isopropyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1'-(3-(difluoromethoxy)phenyl)- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2'-oxospiro[cyclobutane-1,3'-indoline]-5'-formamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(( S )-3-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, ( S)-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl -N -(( S )-3-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-(3-methyl-1,1-dioxo-thiacyclopentan-3-yl)-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -[(1 S ,2 R )-2-hydroxycyclopentyl]-3,3-dimethyl-2-oxo-indoline-5-carboxamide, 3,3-Dimethyl- N -[(3 S [3-Methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide, 3,3-Dimethyl- N -[(3 R [3-Methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide, 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]- N -[4-(hydroxymethyl)tetrahydropyran-4-yl]-3,3-dimethyl-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 S)-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide 3,3-Dimethyl- N -[(3 R [5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide, 3,3-Dimethyl- N -[(3 S [5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide, 3,3-Dimethyl- N -(4-methyl-1,1-dioxo-thiacyclohexyl-4-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)- N -(4-hydroxy-2-methylpentan-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)- N -(4-hydroxy-2-methylpentan-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[2-(2,2-difluoroethoxy)pyrimidin-4-yl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-(3-quinolinyl)indoline-5-carboxamide N -[2-(cyclohexylaminosulfonyl)ethyl]-1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[1-(methylsulfonylmethyl)cyclohexyl]-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -(3-ethyl-1,1-dioxo-thiocyclobut-3-yl)-3,3-dimethyl-2-oxo-indoline-5-carboxamide 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -[(3 R)-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexane-4-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-(3-methyl-1,1-dioxo-thiacyclopentan-3-yl)-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -(3,3-difluoro-1-methyl-cyclobutyl)-3,3-dimethyl-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide 1-[5-(difluoromethoxy)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(5-ethoxy-3-pyridyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(2,2-difluoroethoxy)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethylthio)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[2-(2,2-difluoroethoxy)-5-fluoro-4-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(2,2-difluoroethoxy)-2,3-difluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(2,2-difluoroethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[6-(2,2-difluoroethoxy)pyrazin-2-yl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethylthio)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(1,1-difluoroethyl)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(1,1-difluoroethoxy)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(2,2-difluoroethoxy)-2-methyl-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide ( R)-1'-(3-(difluoromethoxy)phenyl)- N -(3-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-formamide 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1'-[3-(difluoromethoxy)phenyl]- N -[(3 R [3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-formamide, 1'-[3-(difluoromethoxy)phenyl]- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-formamide 1'-[3-(difluoromethoxy)phenyl]- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-formamide 1'-[3-(difluoromethoxy)phenyl]- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2'-oxo-spiro[cyclopropane-1,3'-indoline]-5'-formamide 1'-[3-(difluoromethoxy)phenyl]- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2'-oxo-spiro[cyclopropane-1,3'-indoline]-5'-formamide 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 4 R)-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 4 R )-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 4 S )-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 4 S )-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 5 R 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 5 R 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 5 S 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 5 S 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 S ,2 R )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 R ,2 R )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 S ,2 S )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 R ,2 S )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -(1,1-Dimethyl-2-methylsulfonyl-ethyl)-3,3-dimethyl-2-oxo-indoline-5-carboxamide 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 7-Fluoro-3,3-Dimethyl- N -(4-methyl-1,1-dioxo-thiacyclohexyl-4-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N-(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thionecyclobut-3-yl)-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 R)-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohex-4-yl)-2-oxo-pyrrolo[2,3-] b ]Pyridine-5-carboxamide, 7-Fluoro-3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide 7-Fluoro-3,3-Dimethyl- N -[(3 R [3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide, 7-Fluoro-3,3-Dimethyl- N -[(3 S [3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohex-4-yl)-2-oxo-pyrrolo[2,3-] b ]Pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thionecyclobut-3-yl)-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 3,3-Dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-1-(2-methylbenzo[d]oxazol-6-yl)-2-oxoindoline-5-carboxamide 1-[6-(2,2-difluoroethoxy)pyridazin-4-yl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(2-(3,3-difluoroazacyclobut-1-yl)-3-fluoropyridin-4-yl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(4-acetamido-3-hydroxyphenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( R )- N -(1-(2,2-difluoroethyl)-3-methylpiperidin-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1-(methylsulfonyl)piperidin-3-yl)-2-oxoindoline-5-carboxamide, ( R )- N -(1-acetyl-3-methylpiperidin-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)- N -(4-methoxy-4-(trifluoromethyl)cyclohexyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 7-Cyano-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiam-4-yl)-2-oxo-2,3-dihydro-1 H -Pyrrolo[2,3-c]pyridine-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 7-(3-(difluoromethoxy)phenyl)-5,5-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine-3-carboxamide 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)indoline-5-carboxamide, 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-ethoxy-5-fluoropyridin-4-yl)-3,3-dimethyl- N-(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)indoline-5-carboxamide, 1-(4-(2,2-difluoropropoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)indoline-5-carboxamide, 1-(4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-((3,3-difluorocyclobutyl)methoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-Cyclopropoxypyridin-2-yl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(difluoromethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2-H -thiaran-4-yl)-2-oxo-1-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)indoline-5-carboxamide, 1-(5-(difluoromethoxy)pyridin-3-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(5-(trifluoromethoxy)pyridin-3-yl)indoline-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(1-((methylsulfonyl)methyl)cyclobutyl)-2-oxoindoline-5-carboxamide, 1-(4-(2,2-difluoroethoxy)-3-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(2,2-difluoropropoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-(2,2-difluoroethoxy)pyridazine-3-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)pyrimidin-2-yl)-3,3-dimethyl- N-(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-(azacyclobut-1-yl)-2-fluorophenyl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-Isopropoxypyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-((1-fluorocyclopropyl)methoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(cyclopropylmethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-Isobutoxypyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-fluoro-4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-(1,1-difluoro-2-hydroxyethoxy)pyridin-3-yl)-3,3-dimethyl-N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(3,3-difluoroazacyclobut-1-yl)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoropropoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(difluoromethoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoropropoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide N -(4-(difluoromethyl)-1,1-dioxatetrahydro-2 H (-thiaran-4-yl)-1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(5-fluoro-2-isopropoxypyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)- N -((3-hydroxytetrahydrofuran-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)- N -((1-ethyl-1 H 3,3-Dimethyl-2-oxoindoline-5-carboxamide (-pyrazol-4-yl)methyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(3-Cyclopropylphenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-Isopropoxyphenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-Fluorophenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-Cyanophyn)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxo-3-(trifluoromethyl)indoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxo-3-(trifluoromethyl)indoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiam-4-yl)-1-(3-( N (-Methylaminosulfonyl)phenyl)-2-oxoindoline-5-carboxamide 1-(3-Carbamoylphenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-1-(3-(methylsulfonyl)phenyl)-2-oxoindoline-5-carboxamide, or 1-(3-(dimethylamino)phenyl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide.

[0096] This invention includes pharmaceutically acceptable salts of the compounds defined therein.

[0097] In one embodiment, the present invention is a composition comprising an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

[0098] The present invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0099] The present invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent).

[0100] The present invention also provides a pharmaceutical composition comprising an effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof, and an effective amount of at least one other pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent), and a pharmaceutically acceptable carrier.

[0101] In one embodiment, the present invention provides a composition for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, and cardiorenal diseases such as chronic kidney disease or heart failure, comprising a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt thereof.

[0102] In one embodiment, the present invention provides a composition for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, and cardiorenal diseases such as chronic kidney disease or heart failure, comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0103] In one embodiment, the present invention provides a composition for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, and cardiorenal diseases such as chronic kidney disease or heart failure, comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0104] In one embodiment, the present invention provides a method for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney disease, or heart failure in subjects with such treatment needs, comprising administering to the subject a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof.

[0105] In one embodiment, the present invention provides a method for treating hepatic steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases such as chronic kidney disease, or heart failure in patients in need, comprising administering to the patient a therapeutically effective amount of at least one compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0106] The method of the present invention includes administering a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0107] In another embodiment, the present invention includes a method for treating NASH and / or fibrosis, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need.

[0108] In another embodiment, the invention includes a method for treating NASH and / or fibrosis, comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, to a patient in need.

[0109] In another embodiment, the present invention includes a method for treating NASH and / or fibrosis comprising administering to a patient in need a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0110] In another embodiment, the invention includes a method for treating NASH and / or fibrosis comprising administering to a patient in need a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0111] In another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH and / or fibrosis.

[0112] In another embodiment, the invention includes the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH and / or fibrosis.

[0113] When referred to, "alkyl" means a saturated aliphatic hydrocarbon group with a specified number of carbon atoms, whether branched or straight. If no number is specified, it is intended to refer to 1-6 carbon atoms as straight-chain alkyl and 3-7 carbon atoms as branched alkyl. Examples of alkyl groups 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" as defined below. 1-4"alkyl", followed by a straight-chain or branched alkyl group having 5 or 6 carbon atoms, including all possible isomers. "C 1-6 "Alkyl" refers to a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms, including all possible isomers, and includes C14. 1-6 Each alkyl group includes hexyl and pentyl isomers, and each of the following: n-butyl, isobutyl, sec-butyl, and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively referred to as "C4 alkyl", Bu = butyl), n-propyl and isopropyl (propyl, isopropyl, collectively referred to as "C3 alkyl"; Pr = propyl), ethyl (Et), and methyl (Me). Common abbreviations for alkyl groups are used throughout the specification; for example, methyl may be represented by the conventional abbreviation including "Me" or CH3, or as a symbol for an extended bond of the terminal group, e.g., This indicates that ethyl can be represented by "Et" or CH2CH3, propyl by "Pr" or CH2CH2CH3, butyl by "Bu" or CH2CH2CH2CH3, and so on. For example, the structure... and It has an equivalent meaning. C 1-6 Alkyl groups include n-butyl, isobutyl, sec-butyl and tert-butyl, n-propyl and isopropyl, ethyl and methyl. If no number is specified, 1-6 carbon atoms are intended for straight-chain or branched alkyl groups.

[0114] A "cyclic amine" is a cyclic ring containing one nitrogen atom.

[0115] "Alkoxy" refers to an alkyl group bonded to an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, and propoxy.

[0116] "Aryl" refers to an aromatic monocyclic or polycyclic moiety containing 6 to 14 ring carbon atoms. In one embodiment, the aryl group contains about 6 to 10 ring carbon atoms. Monocyclic aromatic rings include, but are not limited to, phenyl. Polycyclic rings include, but are not limited to, naphthalene rings and bicyclic rings, wherein the phenyl group is fused to C14. 5-7 cycloalkyl or C 5-7 Cycloalkenyl ring. The aryl group may optionally be substituted by one or more substituents as defined herein. Bonding can occur through any of the carbon atoms in any ring.

[0117] "Fused aryl" refers to an aromatic ring fused with a heterocyclic group or cycloalkyl group.

[0118] "Halogen" or "halogen group" includes fluorine, chlorine, bromine and iodine.

[0119] "Cycloalkyl" refers to a non-aromatic monocyclic or polycyclic system containing about 3 to 10 carbon atoms in a ring. If the number of atoms is not specified, 3-10 carbon atoms are intended. Cycloalkyl groups can also fused to form 1-3 carbon rings. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C" is used in conjunction with the meaning of the cycloalkyl group. 1-6 "Cycloalkyl" refers to a cycloalkyl group having 1 to 6 ring carbon atoms. The term "C" is also used in this context. 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms in its ring. Therefore, for example, "C 3-6 "Cycloalkyl" includes each of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. A cycloalkyl group is unsubstituted or substituted with one or more cyclic substituents, which may be the same or different and are as defined herein. When a cycloalkyl group is a substituent on an alkyl group, the cycloalkyl substituent can be bonded to any available carbon on the alkyl group. The following describes the C on the alkyl group. 3-6 Cycloalkyl substituents, wherein the substituent is a crude cyclopropyl group: .

[0120] "Halogenated alkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group have been replaced by a halogen. In one embodiment, the halogenated alkyl group has 1 to 6 carbon atoms. Non-limiting examples of halogenated alkyl groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2Cl, and CCl3. The term "C" is used in conjunction with the meaning of the halogenated alkyl group. 1-6 "Halogenated alkyl" or "halogenated C" 1-6 "Alkyl" refers to a haloalkyl group having 1 to 6 carbon atoms.

[0121] "Haloalkoxy", "haloalkyl-O", and, for example, "halogen (C)" 1-6 The terms "alkoxy" and "alkyl" are used interchangeably and refer to alkyl groups substituted with halogens linked by an oxygen atom. Haloalkoxy groups include monosubstituted and polyhalogenated alkoxy groups. Examples include trifluoromethoxy, chloromethoxy, and bromomethoxy, as well as OCH2CF3, OCH2CHF2, OCF2CF3, and OCF2CHF2.

[0122] "Heterocyclic group," "heterocyclic," or "heterocyclic" refers to a monocyclic structure in which one or more atoms (one or more heteroatoms) in the ring are elements other than carbon. Heteroatoms are typically O, S, or N atoms. Heterocyclic rings containing more than one heteroatom can contain different heteroatoms. Bicyclic portions include fused, spirocyclic, and bridged bicyclic rings, and each ring may contain one or more heteroatoms. The rings attached to the remainder of the molecule may or may not contain heteroatoms. Either ring in a bicyclic heterocyclic ring can be saturated, partially unsaturated, or unsaturated. Heterocyclic rings can be attached to the remainder of the molecule via a ring carbon atom, an epoxy atom, or a ring nitrogen atom. Examples of heterocyclic groups include piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azacyclic butane, ethylene oxide, aziridine, etc.

[0123] "Bicyclic heterocyclic group", "bicyclic heterocycle", or "bicyclic heterocyclic" refers to a heterocycle fused with another ring system. Fusing can be bridging or non-bridging.

[0124] Unless otherwise specified, as used herein, the term "heteroaryl" refers to a stable monocyclic, bicyclic, or tricyclic ring having up to 10 atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from O, N, and S. Heteroaryl groups within this definition include, but are not limited to: benzimidazolyl, benzofuranyl, benzofuranyl, benzopyrazolyl, benzotriazolyl, benzothiophene, benzooxazolyl, carbazoyl, carbaolinyl, arolinyl, furanyl, imidazoyl, indololinyl, indolyl, indolazinyl, indolazolyl, isobenzofuranyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthiapyridyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazolyl Azinyl, pyrazolyl, pyridazinyl, pyridopyridyl, pyridyl, pyrimidinyl, pyrroleyl, quinazolinyl, quinolinyl, quinoxolinyl, tetrazolyl, tetrazolpyridyl, thiadiazolyl, thiazolyl, thiophene, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophene, dihydrobenzooxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothiophene, quinolinyl, isoquinolinyl, oxazolyl, and tetrahydroquinolinyl.

[0125] "Fused heteroaryl" is a heteroaryl group fused with aryl or heteroaryl groups.

[0126] "Oxide" refers to oxygen atom bonded to an atom via a double bond. Examples of oxo groups are the double-bonded oxygen atoms in ketones, sulfoxides, sulfones, and sulfate esters.

[0127] "Hydroxyalkyl" or "-hydroxy(C)" 1-3 "alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl (-OH) group.

[0128] "Cyanalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a cyano (-CN) group.

[0129] "Hydroxyhaloalkyl" means an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl (-OH) group, or in which one or more hydrogen atoms are replaced by a halogen.

[0130] "Hydroxycycloalkyl" refers to a cycloalkyl group in which one or more hydrogen atoms are replaced by hydroxyl (-OH) groups.

[0131] The term "composition" is intended to cover products containing specified amounts of specified ingredients, as well as any products directly or indirectly produced by combining specified amounts of specified ingredients.

[0132] The term "at least one" means one or more. The meaning of "at least one" in relation to the number of compounds of the present invention is unrelated to the meaning in relation to the number of chemotherapeutic agents.

[0133] The term "chemotherapy agent" refers to drugs (medications or active pharmaceutical ingredients) used to treat cancer (i.e., anti-tumor agents).

[0134] The term "effective amount" means "therapeutic effective amount." It refers to the amount of an active compound or drug that elicits a biological or pharmaceutical response sought by researchers, veterinarians, physicians, or other clinicians in a tissue, system, animal, or human.

[0135] The term “cancer treatment” or “cancer therapy” refers to the application of the treatment to mammals with a cancerous condition and refers to the effect of alleviating the cancerous condition by killing cancer cells, as well as the effect of inhibiting cancer growth and / or metastasis.

[0136] Unless otherwise specified herein, as used herein, the term "carbocyclic" (and its variations, such as "carbocyclic" or "carbocyclic group") refers to a C3 to C6 monocyclic ring, for example, C3... 3-6 Monocyclic carbocyclic rings. A carbocyclic ring can be attached to the rest of the molecule at any carbon atom, resulting in a stable compound. Saturated carbocyclic rings include, for example, "cycloalkyl" rings, such as cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings include, for example... .

[0137] Unless otherwise specified, the term "saturated heterocycle" refers to a stable 4- to 7-membered monocyclic heteroatom-containing ring system, consisting of a carbon atom and one to four heteroatoms independently selected from N, O, and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Particularly applicable are rings containing one oxygen or sulfur atom, one to four nitrogen atoms, or a combination of one oxygen or sulfur atom and one or two nitrogen atoms. Heterocycles can be attached to any heteroatom or carbon atom to form a stable structure. Representative examples include azacyclic butanes, oxacyclic butanes, thiocyclic butanes, diazacyclic butanes, dioxacyclic butanes, dithiocyclic butanes, pyrrolidines, tetrahydrofurans, thiocyclic pentanes, imidazolides, pyrazolidines, oxazolidines, isoxazolidines, thiazolides, dioxacyclic pentanes, piperidines, oxanes, thiazolides, piperazines, morpholine, thiomorpholine, dioxanes, dithiazolides, trioxanes, trithiazolides, azacyclic heptanes, oxacyclic heptanes, thiocyclic heptanes, and high-piperazines. For example, a "saturated 6-membered heterocycle" is a stable 6-membered monocyclic ring system containing heteroatoms. An example of a saturated 6-membered heterocycle is piperidine. Similarly, but not limited to, a "saturated 4-membered heterocycle" is a stable 4-membered monocyclic ring system containing heteroatoms.

[0138] Unless otherwise specified herein, the term "unsaturated heterocycle" refers to a monocyclic unsaturated heterocycle having a specified number of atomic members (e.g., 5-membered), including a specified number of heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S). Examples include a 5-membered ring containing one nitrogen (pyrrole), one oxygen (furan), or one sulfur (thiophene) atom; a 5-membered ring containing one nitrogen and one sulfur (thiazole) atom; a 5-membered ring containing one nitrogen and one oxygen (oxazole or isoxazole) atom; a 5-membered ring containing two nitrogen (imidazolium or pyrazole) atoms; a 5-membered aromatic ring containing three nitrogen (triazole) atoms; a 5-membered aromatic ring containing one oxygen, one nitrogen, or one sulfur atom; and a 5-membered aromatic ring containing two heteroatoms independently selected from oxygen, nitrogen, and sulfur (e.g., oxazole). Other examples are thiophene, imidazolium, isothiazole, oxadiazole, and isoxazole. For example, an "unsaturated 6-membered heterocycle" is a 6-membered ring containing 6 atomic members, including at least one heteroatom. Similarly, an "unsaturated 5-membered heterocycle" is a 5-membered ring containing 5 atomic members, including at least one heteroatom.

[0139] A “stable” compound is a compound that can be prepared and isolated, and whose structure and properties remain or can be substantially unchanged for a period of time sufficient to allow the compound to be used for the purposes described herein (e.g., for treatment or prophylactic administration to a subject).

[0140] The compounds disclosed herein are limited to the stable compounds covered by Formula I and its embodiments. For example, certain portions defined in Formula I may be unsubstituted or substituted, and the latter is intended to cover substitution patterns (i.e., the number and type of substituents) that are chemically possible for that portion and produce stable compounds.

[0141] The term "substituted" means that one or more hydrogen atoms on a specified atom are replaced by a group selected from those shown, provided that the substitution does not exceed the normal valence of the specified atom under the existing conditions, and that the substitution produces a stable compound. In cases where multiple substituent moieties are disclosed or claimed, the substituted compound may be independently monosubstituted or polysubstituted by one or more of the disclosed or claimed substituent moieties. Independent substitution means that the (two or more) substituents may be the same or different. Combinations of substituents and / or variants are permitted only if such combinations produce a stable compound. If a substituent is itself substituted by more than one group, it should be understood that these multiple groups may be on the same carbon or different carbons, as long as a stable structure is produced. Optionally substituted means compounds containing specified optional substituents as well as compounds not containing optional substituents.

[0142] As used in this article, wavy lines Indicates the connection point with the rest of the compound.

[0143] When the ring atom is represented by a variable such as "X", for example, Variables are defined by indicating the atom located at a position in the variable ring without describing the ring bonds associated with that atom. For example, when X in the above ring is nitrogen, the definition would show "N" and would not describe the associated bonds; for example, it would not show "=N-". Similarly, when X is a carbon atom substituted with bromine, the definition would show "C-Br" and would not describe the associated bonds; for example, it would not show... .

[0144] This invention also includes derivatives of Formula I compounds as prodrugs and solvates. Compounds of this invention with any pharmaceutically acceptable prodrug modifications that result in in vivo conversion into compounds within the scope of this invention are also within the scope of this invention. After administration to a patient, the prodrug is converted in vivo into a Formula I compound through normal metabolism or chemical processes, such as hydrolysis in the blood. Such prodrugs include those exhibiting enhanced bioavailability, tissue specificity, and / or cellular delivery to improve drug absorption of Formula I compounds. The effects of such prodrugs can be caused by modifications to physicochemical properties, such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine drug permeability.

[0145] For example, esters may optionally be prepared by esterifying a available carboxylic acid group or by forming an ester on a available hydroxyl group in the compound. Similarly, unstable amides may be prepared. Pharmaceutically acceptable esters or amides of the compounds of the present invention may be prepared as prodrugs that can be hydrolyzed, particularly in vivo, back to an acid (or -COO-, depending on the pH of the fluid or tissue in which the transformation occurs) or hydroxyl form, and are therefore covered within the scope of the present invention. This includes those esters and acyl groups known in the art for altering solubility or hydrolytic properties for use as sustained-release formulations or prodrug formulations. Examples of pharmaceutically acceptable prodrug modifications include, but are not limited to, -C 1-6 Alkyl esters and -C substituted with phenyl esters 1-6 alkyl.

[0146] "Celite®" (Fluka) diatomite is diatomaceous earth and can also be called "celite".

[0147] When any variable (e.g., R) 1 When a substituent (e.g., R) appears more than once in any component or in Formula I or other general formulas herein, its definition for each occurrence is independent of its definition for each other occurrence. Such combinations are permitted only when the combination of substituents and / or variables produces a stable compound. In selecting the compounds of this invention, those skilled in the art will recognize that various substituents are selected in accordance with well-known principles of chemical structural connectivity and stability, i.e., R... 1 Unless explicitly stated otherwise, substitution of any atom in the ring (e.g., aryl, heteroaryl, or saturated heterocycle) by a specified substituent is permitted, provided that such ring substitution is chemically permissible and produces a stable compound.

[0148] It should be noted that if there is a difference between the chemical name and the structure, it should be understood that the structure is dominant.

[0149] Compounds of Formula I may contain one or more asymmetric centers and thus may exist as racemic mixtures and racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers. The asymmetric centers present in Formula I compounds may each independently have an S-configuration or an R-configuration. When the bond with a chiral carbon is described as a straight line in the structural formula of this invention, it should be understood that the (R) and (S) configurations of the chiral carbon, and therefore the enantiomers and mixtures thereof, are all encompassed in the formula. Similarly, when the chiral designation of a chiral carbon is not used to enumerate the names of compounds, it should be understood that the (R) and (S) configurations of the chiral carbon, and therefore the single enantiomers and mixtures thereof, are all encompassed within that name. The generation of specific stereoisomers or mixtures thereof may be identified in instances of obtaining such stereoisomers or mixtures, but this does not in any way limit all stereoisomers and mixtures thereof to exclude them from the scope of this invention.

[0150] The compounds of this invention comprise all possible enantiomers and diastereomers, as well as mixtures of two or more stereoisomers, such as mixtures of enantiomers and / or diastereomers in all proportions. Therefore, enantiomers are the subject of this invention, existing as pure enantiomeric forms of levorotatory and dextrorotatory enantiomers, as racemic forms, and as mixtures of two enantiomers in all proportions. In the case of cis / trans isomers, this invention includes cis and trans isomers, as well as mixtures of these forms in all proportions. This invention is intended to cover all such stereoisomeric forms of compounds of formula I.

[0151] Compounds of Formula I can be separated into their respective diastereomers, for example, by fractional crystallization from a suitable solvent (e.g., MeOH or EtOAc or mixtures thereof), or by chiral chromatography using an optically active stationary phase. Optionally, derivatization can be performed prior to the separation of stereoisomers. The separation of mixtures of stereoisomers can be carried out as an intermediate step in the synthesis of the Formula I compound, or from the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography, if necessary, using crystalline products or intermediates derived from reagents containing asymmetric centers of known absolute configuration. Alternatively, any stereoisomer or isomer of Formula I compound can be obtained via stereospecific synthesis using optically pure starting materials or reagents of known absolute configuration. This invention includes all such isomers, as well as salts, solvates (including hydrates), and solvated salts of such racemates, enantiomers, diastereomers, and tautomers, and mixtures thereof.

[0152] If desired, racemic mixtures of compounds can be separated, thereby isolating individual enantiomers. Separation can be performed using methods well-known in the art, such as coupling the racemic mixture of compounds with a pure enantiomeric compound to form a diastereomer mixture, followed by separation of the individual diastereomers using standard methods, such as fractional crystallization or chromatography. The coupling reaction typically uses a salt formed from an enantiomerically pure acid or base. The diastereomeric derivatives can then be converted to pure enantiomers by cleaving the added chiral residues. Racemic mixtures of compounds can also be directly separated by chromatography using a chiral stationary phase, methods well-known in the art.

[0153] For compounds of formula I containing olefinic double bonds described herein, unless otherwise stated, the meaning includes both the E and Z geometric isomers.

[0154] Some of the compounds described herein can exist as tautomers with different hydrogen bond sites, accompanied by one or more double bond shifts. For example, ketones and their enol forms are keto-enol tautomers. The compounds of Formula I of this invention cover single tautomers and mixtures thereof.

[0155] In compounds of Formula I, atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with specific isotopes having the same number of atoms but different atomic masses or mass numbers from those predominantly found in nature. The present invention, as described and claimed herein, encompasses all suitable isotopic variants of compounds of Formula I and embodiments thereof. For example, different isotopic forms of hydrogen (H) include protons (… 1 H) and deuterium ( 2 H (also referred to as D in this document). Protium is the main hydrogen isotope found in nature. Enrichment of deuterium can provide certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or can provide compounds as standards for characterizing biological samples. Isotope-enriched compounds of Formula I can be prepared without excessive experimentation using conventional techniques well known to those skilled in the art or using methods similar to those described in the schemes and examples herein, using appropriate isotope enrichment reagents and / or intermediates.

[0156] It should be understood that compounds of Formula I may be prepared in pharmaceutically acceptable salt form, or in non-pharmaceutically acceptable salt form when used as a precursor of a free compound or a pharmaceutically acceptable salt thereof, or in other synthetic operations. The compounds of the present invention, including the examples, may also include compounds of Formula I that are unsuitable for direct use as pharmaceuticals due to low physiological compatibility, but may be used, for example, as a chemical reaction or for the preparation of physiologically acceptable salts.

[0157] The compounds of this invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid, including inorganic or organic bases and inorganic or organic acids.

[0158] The term "pharmaceutically acceptable salt" refers to the non-toxic salts of the basic compounds of this invention, which are typically prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of this invention include, but are not limited to, the following: acetates, ascorbic acid salts, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, camphorates, camphorsulfonates, camsylates, carbonates, chlorides, clavate salts, citrates, dihydrochlorides, edetate salts, ethanedisulfonates, estolates, esylates, fumarates, gluconate, gluconate, glutamate, glycolyllarsanilate, hexylresorcinate, and hydatidamine. (ydrabamine), hydrobromide, hydrochloride, hydroxynaphthoate, iodide, hydroxyethyl sulfonate, lactate, lactobionate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucilage, naphthalene sulfonate, nitrate, N-methylglucosamine ammonium salt, oleate, oxalate, bis(hydroxynaphthoate) (emborate), palmitate, pantothenate, phosphate / bisphosphonate, polygalacturonic acid ester, propionate, salicylate, stearate, sulfate, acetite, succinate, tannic acid ester, tartrate, teoclate, thiocyanate, toluenesulfonate, triethyl iodide, valerate, etc. Furthermore, when the compounds of the present invention contain an acidic moiety, suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases, such as aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, trivalent manganese, divalent manganese, potassium, sodium, zinc, etc. In one embodiment, the salts of the acidic compounds are as follows: ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts.

[0159] Compounds of Formula I can form stable alkali metal, alkaline earth metal, or optionally substituted ammonium salts by using basic reagents such as hydroxides, carbonates, bicarbonates, alkoxides, and ammonia, organic bases, or alternatively basic amino acids.

[0160] Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamine, and salts from basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-diphenylmethylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, aminoglucose, histidine, hydatidamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. It also includes the quaternization of basic nitrogen-containing groups by reagents such as: low-carbon alkyl halides, such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl; and dipentyl sulfate; long-chain halides, such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; aralkyl halides, such as benzyl and phenethyl bromides, etc.

[0161] The preparation of pharmaceutically acceptable salts, including their stereoisomers, from compounds of Formula I capable of forming salts is carried out by known methods, for example, mixing the compounds of the present invention with an equal volume of a solution containing the desired acid, base, etc., and then collecting the desired salt by filtering the salt or removing the solvent by distillation. The compounds of the present invention 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 the present invention can form acid addition salts and simultaneously form salts with bases.

[0162] If a compound of formula I contains both acidic and basic groups in its molecule, the present invention also includes, in addition to the salt forms described above, an inner salt or betaine (zwitterion). The salt can be obtained from a compound of formula I by conventional methods known to those skilled in the art, such as by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion or cation exchange with other salts.

[0163] The present invention includes compounds of structural formula I and their salts, particularly pharmaceutically acceptable salts, solvates of such compounds and their solvated salt forms, wherein such forms are possible unless otherwise specified.

[0164] Furthermore, the compounds of the present invention can exist in amorphous and / or one or more crystalline forms; therefore, all amorphous and crystalline forms and mixtures thereof, including the examples of Formula I compounds, are intended to be included within the scope of the present invention. Additionally, some compounds of the present invention 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 invention, particularly pharmaceutically acceptable solvates and hydrates, as well as unsolvated and anhydrous forms, are also covered within the scope of the present invention.

[0165] Therefore, the compounds, embodiments, and specific compounds described in the examples and claimed herein encompass their salts, all possible stereoisomers and tautomers, physical forms (e.g., amorphous and crystalline forms), solvates and hydrates, and any combination of these forms, as well as salts, their prodrug forms, and salts of their prodrug forms, unless otherwise specified.

[0166] The present invention also relates to pharmaceuticals comprising at least one compound of formula I and / or a pharmaceutically acceptable salt of a compound of formula I and / or optionally a stereoisomer of a compound of formula I or a pharmaceutically acceptable salt of a stereoisomer of a compound of formula I, as well as pharmaceutically acceptable mediators, carriers, additives and / or other active substances and excipients.

[0167] The medicament according to the invention can be administered orally, by inhalation, rectally, or transdermally, or by subcutaneous, intra-articular, intraperitoneal, or intravenous injection. Oral administration is preferred. Compounds of Formula I can be used to coat stents and other surfaces that come into direct contact with blood in the body.

[0168] The present invention also relates to a method for preparing a medicament comprising introducing at least one compound of formula I into a suitable form of administration using a pharmaceutically acceptable carrier and optionally additional suitable active substances, additives or adjuvants.

[0169] The present invention also relates to a method for preparing compounds of formula I, which is described below and can be used to obtain the compounds of the present invention.

[0170] The term "therapeutic effective (or effective) dose" and similar descriptions, such as "therapeutic effective dose," are intended to mean an amount of medicine that will reduce the symptoms of a condition, illness, or disease being treated in an animal or human (i.e., a condition, illness, or disease related to DGAT2 activity). The term "preventive effective (or effective) dose" and similar descriptions, such as "preventive effective dose," are intended to mean an amount of medicine that will prevent or reduce the symptoms or occurrence of a condition, illness, or disease being treated in an animal or human (i.e., a condition, illness, or disease related to DGAT2 activity). Dosing regimens using the compounds of the present invention are selected based on a variety of factors, including patient type, race, age, weight, sex, and medical condition; the severity of the condition to be treated; the potency of the compound chosen for administration; the route of administration; and the patient's renal and hepatic function. These factors are taken into account entirely within the scope of a general clinician in order to determine the therapeutically effective or preventive effective dose required to prevent, counteract, or halt the progression of the condition. It should be understood that a specific daily dose can be both a therapeutically effective dose for treating conditions such as hepatic steatosis, diabetes, obesity, hyperlipidemia, and hypercholesterolemia, and a preventatively effective dose for treating conditions such as NASH.

[0171] For example, conditions, illnesses, and diseases that can be treated or prevented by inhibiting DGAT2 using compounds of formula I include, for example, the following: nonalcoholic steatohepatitis (NASH), fibrosis, hyperlipidemia, type 1 diabetes, type 2 diabetes, cognitive decline, dementia, coronary artery disease, ischemic stroke, restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial hyperlipidemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral artery disease, diabetic retinopathy, and diabetes. Diseased nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina pectoris, embolism, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypertriglyceridemia, insulin resistance, glucose intolerance, erectile dysfunction, skin and connective tissue disorders, hyperapolipoprotein B lipoproteinemia, non-alcoholic hepatic steatosis, cardiorenal diseases such as chronic kidney disease and heart failure, and related diseases and conditions.

[0172] Compounds of Formula I and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, and especially to humans, as medicines, mixed with each other, or in the form of pharmaceutical preparations. The term "patient" includes animals, preferably mammals, and especially humans, that use the active agents of the present invention to prevent or treat a medical condition. Administration of a medicine to a patient includes self-administration and administration by another person to the patient. A patient may need or expect treatment for an existing disease or medical condition, or may need or expect preventative treatment to prevent or reduce the risk of developing such a disease or medical condition. As used herein, a patient's "need" treatment for an existing condition or preventative treatment encompasses both the need for determination by a medical professional and the patient's expectation of such treatment.

[0173] Furthermore, the subject of this invention is a pharmaceutical formulation (or pharmaceutical composition) comprising at least one compound of formula I in a therapeutically effective dose in the form of an active ingredient and / or a pharmaceutically acceptable salt thereof and a conventionally pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier substances and / or additives.

[0174] Therefore, the subject matter of the present invention is, for example: the compound and its pharmaceutically acceptable salt used as a medicament, a pharmaceutical preparation comprising a therapeutically effective dose of the compound and / or its pharmaceutically acceptable salt in the form of an active ingredient, and a conventionally pharmaceutically acceptable carrier, and the use of the compound and / or its pharmaceutically acceptable salt in the treatment or prevention of the aforementioned syndromes, and its use in the preparation of medicaments for these purposes.

[0175] The medicament according to the invention can be administered orally, for example, in the form of pills, tablets, enamel-coated tablets, sugar-coated tablets, granules, hard gelatin capsules and soft gelatin capsules, aqueous solutions, alcoholic solutions or oil solutions, syrups, emulsions or suspensions, or, for example, rectally in the form of suppositories. Administration can also be performed non-rectally (e.g., subcutaneously, intramuscularly or intravenously) in the form of injection or infusion of solutions. Other suitable forms of administration are, for example, percutaneous or topical application, such as in the form of ointments, tinctures, sprays or percutaneous treatment systems, or inhalation as nasal sprays or aerosol mixtures, or, for example, in the form of microcapsules, implants or sticks. For example, preferred forms of administration depend on the disease to be treated and its severity.

[0176] For the production of pills, tablets, sugar-coated tablets, and hard gelatin capsules, carriers such as lactose, starch (e.g., corn starch, or starch derivatives), talc, stearic acid, or salts thereof can be used. Carriers for soft gelatin capsules and suppositories include, for example, fats, waxes, semi-solid and liquid polyols, natural oils, or hardened oils. Suitable carriers for preparing solutions (e.g., solutions for injection), or emulsions or syrups include, for example, water, physiological saline solution, alcohols (e.g., ethanol, glycerol, polyols), sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. Compounds of formula I and their pharmaceutically acceptable salts can also be lyophilized, and the resulting lyophilized products can be used, for example, for the preparation of injectable or infusion formulations. Suitable carriers for microcapsules, implants, or rods include, for example, copolymers of glycolic acid and lactic acid.

[0177] Suitable solid or galenal formulations include, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops, or injectable solutions and formulations that prolong the release of the active substance, and which use conventional excipients such as mediators, disintegrants, binders, coating agents, swelling agents, flow aids or lubricants, flavoring agents, sweeteners, and solubilizers in their preparation. Frequently used excipients that may be mentioned include magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, gelatin, starch, cellulose and their derivatives, animal and vegetable oils such as cod liver oil, sunflower oil, peanut oil or sesame oil, polyethylene glycol, and solvents such as sterile water, as well as monools or polyols such as glycerol.

[0178] In addition to active compounds and carriers, pharmaceutical formulations may also contain conventional additives such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffers, solvents, solubilizers, reagents for achieving reservoir function, salts for changing osmotic pressure, coating agents, or antioxidants.

[0179] The dosage of the Formula I active compound and / or its pharmaceutically acceptable salt to be applied depends on the individual case and, by convention, is adapted to the individual case to achieve the best effect. Therefore, it depends on the nature and severity of the condition, illness, or disease to be treated, as well as the sex, age, weight, and individual responsiveness of the person or animal to be treated, the efficacy and duration of action of the compound used, whether the treatment is acute, chronic, or prophylactic, or whether other active compounds besides the Formula I compound are administered.

[0180] Combination drugs The compounds of the present invention can be administered alone or in combination with one or more other therapeutic agents or other suitable agents disclosed herein, depending on the condition being treated. Therefore, in some embodiments, one or more compounds of the present invention will be administered co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously with or alone with a second agent. This combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in different dosage forms, and single administration. That is, the compound of formula (I) and any of the aforementioned agents may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of formula (I) and any of the aforementioned agents may be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compound of formula (I) may be administered immediately after any of the aforementioned agents, or vice versa. In some embodiments of the single administration regimen, the compound of formula (I) and any of the aforementioned agents are administered at intervals of minutes, hours, or days.

[0181] Since one aspect of the invention contemplates the treatment of diseases / conditions with combinations of individually administerable pharmaceutically active compounds, the invention further relates to the combination of individual pharmaceutical compositions in the form of a kit. The kit contains two separate pharmaceutical compositions: a compound of formula (I) and a second pharmaceutical compound. The kit includes a container for containing the individual compositions, such as a separator bottle or separator foil packaging. Other examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for using the individual components. The kit format is particularly advantageous when the individual components are preferably administered in different dosage forms (e.g., oral, non-rectal; IV, transdermal, and subcutaneous), at different dose intervals, or when the prescribing healthcare professional requires titration of the combined individual components.

[0182] One or more additional pharmacologically active agents may be administered in combination with a compound of Formula I. One or more additional active agents are intended to be one or more pharmaceutically active agents that are active in vivo, including prodrugs that are converted to a pharmaceutically active form after administration, which are different from the compound of Formula I, and also include the free acid, free base, and pharmaceutically acceptable salt of said additional active agent. Generally, any suitable one or more additional active agents, including but not limited to antihypertensive agents, antiobesity agents, anti-inflammatory agents, antifibrotic agents, and antiatherosclerotic agents, such as lipid-modifying compounds, antidiabetic agents, and / or antiobesity agents, may be used in any combination of a single-dose formulation with a compound of Formula I (fixed-dose drug combination), or may be administered to a patient in one or more individual-dose formulations that allow for simultaneous or sequential administration of the active agents (co-administration of individual active agents).

[0183] Examples of other active agents that may be used include, but are not limited to, angiotensin-converting enzyme inhibitors (e.g., alapril, benazepril, captopril, siropril, cilazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, muvipril, perindopril, quinapril, ramipril, spiropril, temopril, or quindopril), angiotensin II receptor antagonists (e.g., losartan, i.e., COZAAR®, valsartan, candesartan, olmesartan, telmisartan, and any of these drugs used in combination with hydrochlorothiazide, such as HYZAAR®); neutral peptidase inhibitors (e.g., COZAAR®, valsartan, candesartan, olmesartan, telmisartan, and any of these drugs used in combination with hydrochlorothiazide, such as HYZAAR®); and neutral peptidase inhibitors (e.g., COZAAR®, valsartan, candesartan, olmesartan, telmisartan, and any of these drugs used in combination with hydrochlorothiazide, such as HYZAAR®). Examples include thiorphan and phosphoramidon, aldosterone antagonists, aldosterone synthase inhibitors, and renin inhibitors (e.g., urea derivatives of dipeptides and tripeptides, amino acids and their derivatives, amino acid chains linked by non-peptide bonds, dipeptide and tripeptide derivatives, peptidyl amino glycols and peptidyl β-aminoacyl amino glycol carbamates; and small molecule renin inhibitors, including diol sulfonamides and N-morpholino derivatives, N-heterocyclic alcohols and pyrolimidazolones; and pepsin derivatives and fluorine and chlorine derivatives containing statone peptides, enalkrein, RO 42-5892, A 65317, CP80794, ES 1005, ES 8891, SQ 34017, and alikran (2(S), 4(S), 5(S), 7(S)- N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)-phenyl]octamido hemifumarate (SPP600, SPP630, and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, and vardenafil), vasodilators, and calcium channel blockers (e.g., amlodipine, nifedipine, verapamil, diltiazem, galopamil, niludipine, nimodipine, nicardipine). Potassium channel activators (e.g., nicorandil, pinacidil, clocarline, minoxidil, apralicarlin, cloprazolam), diuretics (e.g., hydrochlorothiazide), sympatholytic agents, β-adrenergic blockers (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartrate), α-adrenergic blockers (e.g., doxazosin, prazosin, or α-methyldopa), central α-adrenergic agonists, peripheral vasodilators (e.g., hydralazine); lipid-lowering agents, such as HMG-CoA reducers. Enzyme inhibitors, such as simvastatin and lovastatin, marketed as lactone prodrugs and as post-administration inhibitors in ZOCOR® and MEVACOR®, and pharmaceutically acceptable salts of dihydroxysecanoic acid HMG-CoA reductase inhibitors, such as atorvastatin (especially the calcium salt marketed by LIPITOR®), rosuvastatin (especially the calcium salt marketed by CRESTOR®), pravastatin (especially the sodium salt marketed by PRAVACHOL®), fluvastatin (especially the sodium salt marketed by LESCOL®), sivastatin, and pitavastatin. Statins; cholesterol absorption inhibitors, such as ezetimibe (ZETIA®) and ezetimibe in combination with any other lipid-lowering agents, such as the aforementioned HMG-CoA reductase inhibitors, especially in combination with simvastatin (VYTORIN®) or atorvastatin calcium; immediate-release or controlled-release forms of niacin and / or HMG-CoA reductase inhibitors; niacin receptor agonists, such as acipimox and acyclovir, and partial niacin receptor agonists; anticholesterol agents such as PCSK9 inhibitors (aliculumab, evolocumab), Nexletol TM (Bepaediatric acid, an ACL inhibitor) and Vascepa ®(Eicosapentaenoic acid ethyl ester); metabolic modifiers, including insulin and insulin mimics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, ocglitazone, linagliptin, vildagliptin); insulin sensitizers, including (i) β-clogoxetine / FGFR1-activating monoclonal antibodies (e.g., MK-3655), pan FGFR1-4 / KLB modulators, FGF19 analogs (e.g., Aldafermin), and (ii) PPARγ agonists, such as glitazone (e.g., pioglitazone, AMG 131, CHS). 131, MBX2044, mitoglione, lobeglitazone, IDR-105, rosiglitazone and baglitazone), and other PPAR ligands, including (1) dual PPARα / γ agonists (e.g., ZYH2, ZYH1, GFT505, sitagliptina, mogrieza, agrieza, sogrieza and nagrieza); (2) PPARα agonists such as fenofibrate acid derivatives (e.g. gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate); (3) selective PPARγ modulators (SPPARγM) (e.g., such as those in WO 02 / 060388, WO 02 / 08188, WO 2004 / 019869, WO 2004 / 020409, WO2004 / 020408 and WO (iii) those disclosed in 2004 / 066963); (iv) PPARγ partial agonists; (v) PPARα / δ dual agonists (e.g., Elafibranor); (iii) biguanides, such as metformin and pharmaceutically acceptable salts thereof, particularly metformin hydrochloride and its extended-release formulations, such as Glumetza™, Fortamet™ and GlucophageXR™; and (iv) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin lisgludec, insulin degludec, insulin glargine, insulin lispro and their respective inhaled formulations). Leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylureas and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glibenclamide, glipizide, glimepiride, miglinide, meglitinide, 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 mimics, such as GLP-1, GLP-1 analogs, derivatives, and mimics;And GLP-1 receptor agonists (e.g., duraglutide, smegglutide, abiglutide, exenatide, liraglutide, lixinatide, tasglutide, CJC-1131, and BIM-51077, including their intranasal, transdermal, and once-weekly formulations), bile acid sequestrants (e.g., colestilan, colestistimide, colesvelam hydrochloride, colestipol, colestrenylamine, and dialkylaminoalkyl derivatives of cross-linked dextran), acyl-CoA: cholesterol acyltransferase inhibitors (e.g., avamabib); anti-obesity compounds; agents intended for inflammatory conditions, such as aspirin, nonsteroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase agonists (GKA) (e.g., AZD6370); type 1 11β-hydroxysteroid dehydrogenase inhibitors (e.g., such as those found in...). Those disclosed in U.S. Patent Nos. 6,730,690 and LY-2523199; CETP inhibitors (e.g., acetyltropib, torcetrapib, and evacetrapib); fructose 1,6-bisphosphatase inhibitors (e.g., those disclosed in U.S. Patent Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782; and 6,489,476); acetyl-CoA carboxylase-1 or 2 (ACC1 or ACC2) inhibitors; AMP-activated protein kinase (AMPK) activators; other G protein-coupled receptor agonists: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., those disclosed in WO Those disclosed in WO 2009 / 001836); neuromodulatory peptide U receptor agonists (e.g., such as those disclosed in WO 2009 / 042053, including but not limited to neuromodulatory S (NMS)); SCD modulators (e.g., Aramchol); GPR-105 antagonists (e.g., such as those disclosed in WO 2009 / 001836). Those disclosed in 2009 / 000087); SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2, such as empagliflozin, dapagliflozin, canagliflozin and eogliflozin, BI-10773, repaggliflozin, TS-071, topagliflozin, eogliflozin and LX-4211); acyl-CoA carboxylase inhibitors (ACC, MK-4074); diacylglycerol acyltransferase 1 and 2 inhibitors (DGAT-1 and DGAT-2); fatty acid synthase inhibitors; acyl-CoA: monoacylglycerol acyltransferase 1 and 2 inhibitors (MGAT-1 and MGAT-2).TGR5 receptor agonists (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimics, and PACAP receptor 3 agonists; IL-1β antibodies (e.g., XOMA052 and kanamycin); antifibrotic and / or anti-inflammatory agents (CCR2 / CCR5 dual receptor antagonists (e.g., cenicriviroc)); galactoglobulin 3 inhibitors (e.g., belapectin, GB-1107, GB-1211), siRNAs targeting HSP 47 (e.g., BMS-986263); NSAIDs derived from pirfenidone (e.g., hydroxynidone), A3AR agonists (e.g., namodsen, FM101); TGFTX4 (e.g., nitrozonide).5-Lipoxygenase inhibitors (e.g., tyrosine), bifunctional urate inhibitors (e.g., ACQT1127), adiponectin receptor agonists (e.g., ALY688), TNF receptor antagonists (e.g., atrosimab), autotaxin inhibitors (e.g., BLD-0409, TJC 0265, TJC 0316), CCL24 blocking monoclonal antibodies (e.g., CM101), IL-11 inhibitors (e.g., ENx 108A), LPA1 receptor antagonists (e.g., EPGN 696), dual JAK1 / 2 inhibitors (e.g., EX 76545), GPR antagonists (e.g., GPR91 antagonists), integrin avβ1, avβ3, and avβ6 inhibitors (e.g., IDL). 2965), NLRP3 antagonists (e.g., IFM-514), inflammasome inhibitors (e.g., JT194, JT349), cell membrane permeation inhibitors (e.g., Larazotide), CCR5 antagonists (e.g., Ieronlimab), TNF inhibitors (e.g., LIVNate), integrin avβ6 inhibitors (e.g., MORF β6), NLRP inflammasome antagonists, siRNA (e.g., OLX 701), dual TFGβ / hedgehog inhibitors (e.g., Oxy 200), GPR40 agonists / GPR84 antagonists (e.g., PBI-4547), neutrophil elastase inhibitors (e.g., PHP-303), integrin inhibitors (e.g., PLN-1474), TGFβ1 modulators (e.g., PRM-151), CCK receptor antagonists (e.g., proglutamine), LOXL2 inhibitors (e.g., PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitors (e.g., cGAS / STING antagonists), kinase inhibitors RNases, membrane protein mAbs, tumor necrosis factor inhibitors, NRF2 activators (e.g., SCO 116), SSAO inhibitors (e.g., TERN 201), TRAIL2 agonists (e.g., TLY012), IL-6 receptor antagonists (e.g., TZLS) 501), AOC3 inhibitors (e.g., UD-014), SSAO / VAP-1 inhibitors, TREM2); antioxidants (e.g., vitamin E); anti-inflammatory agents (e.g., norfloxacin, ciprofloxacin, ceftriaxone); coagulation modifiers (e.g., anticoagulants, antiplatelet agents, pentoxifylline, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonists (e.g., tesipatide); dual GLP-1 / GRA (e.g., cotadutide, ALT-801, DD 01, G49, PB-718);Dual GLP-1 inhibitors (e.g., CT 868); GLP-1 / GRA / GIP triple agonists (e.g., HM15211); GRP120 stimulators / inflammasome modulators PPARγ dual agonists (e.g., KDT501); GLP-1 / FGF21 inhibitors (e.g., YH25724); GLP-1 agonists (e.g., semaglutide (semaglutide sc), XW 003); selective thyroid hormone receptor-β agonists (e.g., resmetiro); apoptosis regulators (JNK-1 inhibitors (e.g., CC-90001), peroxidase inhibitors (e.g., AZM198), ASK-1 inhibitors (e.g., CS-17919, SRT)). 015); erythropoietin stimulants (erythropoietin receptor agonists (e.g., cinbinetide)); glucose pathway modulators (SGLT-2 inhibitors (e.g., Forxiga, Forxiga (dapagliflozin)); dual SGLT-1 / 2 inhibitors (e.g., linaggliflozin), glucose-6-phosphate dehydrogenase inhibitors (e.g., fluasterone), LAPS glucagon combination (e.g., HM14320), SGLT-1 inhibitors (e.g., SGL5213)); immunomodulators (TLR4 inhibitors (e.g., GBK-233), immunomodulatory polyclonal antibodies (e.g., IMM-124E), TLR4 antagonists (e.g., JKB-122), CD3 monoclonal antibodies (e.g., foralumab), TLR4 antagonists (e.g., JKB)). 133), TLR4 inhibitors (e.g., mosmomod), 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., semaglutide (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., otepra), THR-β agonists (e.g., resmetirom, 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, and HSD17β13 inhibitors.Metabolic modulators (FXR agonists (e.g., Ocaliva (obeticholic acid), IOT022), recombinant variants of FGF19 (e.g., aldafermin), bispecific FGFR1 / KLB antibodies (e.g., BFKB8488A), mTOT modulators (e.g., MSDC-0602K), pegylated analogs of FGF21 (e.g., pegbelfermin, BMS-986171), non-biliary FXR agonists (e.g., cilofexor), EDP-305, EYP 001, tropifexor, MET409, AGN-242256, AGN-242266, EDP 297, HPG 1860, MET642, RDX023, TERN) 101), ACC inhibitors (e.g., firsocostat, PF-05221304), ketohexokinase inhibitors (e.g., PF-06835919), AMPK activators (e.g., PXL770, MSTM 101, O304), bile acid modulators (e.g., Albiero), FGF21 analogs (e.g., BIO89-100), MOTSc analogs (e.g., CB4211), cyclin inhibitors (e.g., CRV431), FGF19 (e.g., DEL 30), mitochondrial uncoupling agents (e.g., GEN 3026), FXR / GPCR dual agonists (e.g., INT-767), cysteine ​​derivatives (e.g., KB-GE-001), dual amyloid and calcitonin receptor agonists (e.g., KBP-089), transient FXR agonists (e.g., M... 1217), anti-β-clogrene (KLB)-FGFR1c receptor complex mAbs (e.g., MK3655), GDF15 analogs (e.g., NGM395), cyclin inhibitors (e.g., NV556), LXR modulators (e.g., PX329, PX655, PX788), LXR inverse agonists (e.g., PX016), deuterated obeticholic acid (e.g., ZG 5216)); PPAR modulators (dual PPARα / γ agonists (e.g., elafibranor), PPAR pan agonists (e.g., lanylano), PPARα agonists (e.g., Parmodia), PPARγ agonists (e.g., CHS 131), MPC inhibitors (e.g., PXL065), PPARδ / γ agonists (e.g., T3D 959)); RAAS mIM modulators (mineralocorticoid receptor antagonists (e.g., aparene, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium)).Neurotransmitter modulators (cannabinoid receptor modulators, CB1 receptor antagonists (e.g., CRB-4001, IM-102, nimesimab), TPH1 inhibitors (e.g., CU 02), GPR120 agonists (e.g., KBR2001), combinations of cannabinoids and phytoinflammatory 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 their bromocriptine mesylate and rapid-release formulations; or used in combination with other medicines beneficial for the prevention or treatment of the aforementioned diseases, including sodium nitroprusside and diazoxide, and chemically feasible free acid, free base, and pharmaceutically acceptable salt forms of the aforementioned active agents.

[0184] This invention includes pharmaceutically acceptable salts of compounds as defined herein, including pharmaceutically acceptable salts of all structural formulas, embodiments, and categories defined herein. Compounds relating to structural formula (I) include compounds of other general structural formulas, such as those falling within the scope of formula (I).

[0185] Dosage of compound (I) If the patient responds or stabilizes after the treatment cycle, the treatment cycle can be repeated based on the judgment of a skilled clinician. After completing the treatment cycle, the patient can continue taking the compound of the invention at the same dose as administered in the treatment regimen. This maintenance dose can be maintained until the patient progresses or no longer tolerates the dose (in which case the dose can be reduced and the patient can continue at a reduced dose).

[0186] Those skilled in the art will recognize that the actual dosage and administration regimen used in the method of the present invention can vary according to the judgment of a skilled clinician. The actual dosage used can vary depending on the patient's needs and the severity of the condition being treated. Determining an appropriate dosage for a specific situation is within the scope of the art. A skilled clinician can make a decision to change the dosage and administration regimen after considering factors such as the patient's age, condition and body type, the severity of the condition being treated, and the patient's response to treatment.

[0187] The dosing regimen using the compounds of this invention is selected based on a variety of factors, including patient type, race, age, weight, sex, and medical condition; the severity of the condition to be treated; the potency of the compound chosen for administration; the route of administration; and the patient's renal and hepatic function. These factors are taken into consideration to determine the therapeutically effective or preventatively effective dose required to prevent, counteract, or halt disease progression; it is entirely within the scope of a reasonably skilled clinician. It should be understood that a specific daily dose can be both a therapeutically effective dose, e.g., for treating an oncological condition, and a preventatively effective dose, e.g., for preventing an oncological condition.

[0188] Although individual needs vary, the determination of the optimal range of effective amounts of the compounds of the present invention is within the scope of the art. For human administration in the therapeutic or preventative treatment of the conditions and ailments identified herein, for example, the usual dose of the compounds of the present invention may be from about 0.05 mg / kg / day to about 50 mg / kg / day, for example, at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, for example, it may be from about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). The dosage of the compound can be about 0.1 mg / kg / day to about 50 mg / kg / day, about 0.05 mg / kg / day to about 10 mg / kg / day, about 0.05 mg / kg / day to about 5 mg / kg / day, about 0.05 mg / kg / day to about 3 mg / kg / day, about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / kg / day, about 0.05 mg / kg / day to about 0.1 mg / kg / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 100 mg / day. mg / day or approximately 100 mg / day to approximately 250 mg / day. Such doses can be administered as a single dose or divided into multiple doses.

[0189] Pharmaceutical Composition The compounds of Formula I and their pharmaceutically acceptable salts can be administered to animals, preferably to mammals, and particularly to humans, as drugs, mixed with each other, or in the form of pharmaceutical compositions. The terms "subject" or "patient" include animals, preferably mammals, and particularly humans, that use the active agents of the present invention to prevent or treat a medical condition.

[0190] Administration of Formula I compounds to a subject includes self-administration and administration by another person to a patient. A subject may need or expect treatment for an existing disease or medical condition, or may need or expect preventative treatment to prevent or reduce the risk of said disease or medical condition occurring. As used herein, a subject's "need" treatment for an existing condition or preventative treatment encompasses situations requiring determination by a medical professional, and situations where the subject expects such treatment.

[0191] Most of the methods for the safe and effective administration of these agents are known to those skilled in the art. Furthermore, their administration is described in standard literature.

[0192] If the patient responds or stabilizes after the treatment cycle, the treatment cycle can be repeated based on the judgment of a skilled clinician. After completing the treatment cycle, the patient can continue taking the compound of the invention at the same dose as administered in the treatment regimen. This maintenance dose can be maintained until the patient progresses or no longer tolerates the dose (in which case the dose can be reduced and the patient can continue at a reduced dose).

[0193] Those skilled in the art will recognize that the actual dosage and administration regimen used in the method of the present invention can vary according to the judgment of a skilled clinician. The actual dosage used can vary depending on the patient's needs and the severity of the condition being treated. Determining an appropriate dosage for a specific situation is within the scope of the art. A skilled clinician can make a decision to change the dosage and administration regimen after considering factors such as the patient's age, condition and body type, the severity of the condition being treated, and the patient's response to treatment.

[0194] The dosage and frequency of administration of Formula I compounds and any other agents will be adjusted according to the judgment of the attending clinician (physician), taking into account factors such as the patient's age, condition and body type, and the severity of the condition being treated.

[0195] The compounds of this invention can also be used to prepare drugs for the treatment of NASH and fibrosis.

[0196] The compounds of this invention can also be combined with therapeutic, chemotherapeutic, and anticancer agents for the treatment of hepatocellular carcinoma. Combinations of currently disclosed compounds with therapeutic agents, chemotherapeutic agents, and anticancer agents are within the scope of this invention. Examples of such agents can be found in *Cancer Principles and Practice of Oncology*, VT Devita and S. Hellman (eds.), 9th edition (May 16, 2011), Lippincott Williams & Wilkins Publishers. Those skilled in the art will be able to identify suitable combinations of agents based on the drugs and the specific characteristics of 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 inhibitors, antiproliferative agents, isoprenoid 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 therapeutics, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinase (RTK), and agents that interfere with cell cycle checkpoints.

[0197] Chemotherapy agents 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 chemotherapy agents can vary depending on the cancer being treated and the known effects of the chemotherapy agent on the disease. Furthermore, treatment regimens (e.g., dosage and timing of administration) can vary based on the knowledge of a skilled clinician, taking into account the observed effects of the administered agent on the patient and the observed response of the cancer to the administered agent. The specific selection of a chemotherapy agent will depend on the attending physician's diagnosis, their assessment of the patient's condition, and the appropriate treatment regimen.

[0198] Initial administration can be performed according to established protocols known in the art, and then, based on observed effects, skilled clinicians can modify the dosage, administration method, and administration time.

[0199] After assessing the condition being treated and the patient's condition, the determination of the order of administration and the number of repetitions of chemotherapy during the treatment regimen is entirely within the knowledge of a skilled physician.

[0200] Therefore, based on experience and knowledge, as treatment progresses, practicing physicians can modify each regimen for administering chemotherapy agents according to the individual patient's needs. All such modifications are within the scope of this invention.

[0201] 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 anticancer agent can be modified based on the cancer being treated and the known effects of the anticancer agent on the disease.

[0202] Initial administration can be performed according to established protocols known in the art, and then, based on observed effects, skilled clinicians can modify the dosage, administration method, and administration time.

[0203] The specific choice of medication will depend on the attending physician's diagnosis, their assessment of the patient's condition, and the appropriate treatment plan.

[0204] After assessing the cancer being treated and the patient's condition, determining the order of administration and the number of repetitions of medications during the treatment regimen is entirely within the knowledge of a skilled physician.

[0205] Therefore, based on experience and knowledge, as treatment progresses, practicing physicians can modify each regimen for administering anticancer agents according to the individual patient's needs. All such modifications are within the scope of this invention.

[0206] When assessing the effectiveness of administered treatment, the attending clinician will consider the patient's overall health status and more specific physical signs, such as relief of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual tumor shrinkage, or suppression of metastasis. Tumor size can be measured using standard methods, such as radiological studies, like CAT or MRI scans, and continuous measurements can be used to determine whether tumor growth has been slowed or even reversed. Reduction of disease-related symptoms such as pain and improvement in the overall condition can also help determine the effectiveness of treatment.

[0207] The compounds, compositions, and methods disclosed herein are for the treatment of cancer. Cancers that can be treated by the compounds, compositions, and methods disclosed herein include, but are not limited to: liver cancer: hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0208] PD-1 inhibitors include pembrolizumab, nivolumab, and MPDL3280A. PDL inhibitors include atezolizumab, avelumab, and durvalumab.

[0209] The present invention also relates to a method of treating hepatocellular carcinoma in a human patient, comprising administering to the patient a compound of the present invention (i.e., compound of formula I) and a PD-1 antagonist. The compound of the present invention and the PD-1 antagonist may be administered simultaneously or sequentially.

[0210] 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™, Merck & Co., Inc., Kenilworth, NJ, USA), nivolumab (OPDIVO™, Bristol-Myers Squibb Company, Princeton, NJ, USA), cimiprimab (LIBTAYO™, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA), atezolizumab (TECENTRIQ™, Genentech, San Francisco, CA, USA), durvalumab (IMFINZI™, AstraZeneca Pharmaceuticals LP, Wilmington, DE), or avelumab (BAVENCIO™, Merck KGaA, Darmstadt, Germany).

[0211] In some embodiments, the PD-1 antagonist is pembrolizumab. In a particular sub-implementation, the method includes administering 200 mg of pembrolizumab to a patient approximately every three weeks. In other sub-implementations, the method includes administering 400 mg of pembrolizumab to a patient approximately every six weeks.

[0212] In another sub-implementation, the method involves administering 2 mg / kg pembrolizumab to the patient approximately every three weeks. In a particular sub-implementation, the patient is a pediatric patient.

[0213] In some embodiments, the PD-1 antagonist is nivolumab. In a particular sub-implementation, the method includes administering 240 mg of nivolumab to the patient approximately every two weeks. In other sub-implementations, the method includes administering 480 mg of nivolumab to the patient approximately every four weeks.

[0214] In some embodiments, the PD-1 antagonist is cimiprimab. In a particular embodiment, the method includes administering 350 mg of cimiprimab to the patient approximately every 3 weeks.

[0215] In some embodiments, the PD-1 antagonist is atezolizumab. In a particular sub-implementation, the method includes administering 1200 mg of atezolizumab to the patient approximately every three weeks.

[0216] In some embodiments, the PD-1 antagonist is durvalumab. In a particular sub-implementation, the method includes administering 10 mg / kg durvalumab to the patient approximately every two weeks.

[0217] In some embodiments, the PD-1 antagonist is avirumab. In a particular sub-implementation, the method includes administering 800 mg of avirumab to the patient approximately every two weeks.

[0218] The compounds of the present invention or pharmaceutically acceptable salts thereof can also be used in combination with the following therapeutic agents for the treatment of cancer: pembrolizumab (Keytruda) ® Plenaxis depot ® ); Prokine ® ); Proleukin ® ); Alenzab (Campath) ® Panretin (alvitamin A acid) ® ); Allopurinol (Zyloprim) ® Hexamethylmelamine (HME) ® ); Ethyol ® Anastrozole (Arimidex) ® Arsenic trioxide (Trisenox) ® ); asparaginase (Elspar) ® Azacitidine (Vidaza) ® ); Bevacizumab (Avastin) ® Targretin capsules ® Targretin gel; ® ); Bleoxane ® ); Bortezomib (Velcade) ® Busulfex Intravenous Injection ® Oral myleran ® ); Calotestosterone (Methosarb) ® ); capecitabine (Xeloda) ® Paraplatin ® ); Camustin (BCNU) ® BiCNU ® ); Camustin (Gliadel) ® ); Carmustine and Polifeprosan 20 implant (Gliadel Wafer) ®Celebrex ® ); Cetuximab (Erbitux) ® ); Leukeran chlorate ® ); cisplatin ® Leustatin ® ,2-CdA ® ); Clolar ® ); Cytoxamide ® Neosar ® ); Cytoxan Injection ® ); Cytoxan Tablet ® ); Cytosar-U ® ); Cytarabine liposomes (DepoCyt) ® ); Dacarbazine (DTIC-Dome) ® Actinomycin D (Cosmegen) ® Aranesp; ® ); DanuoXome liposomes ® ); Daunorubicin ® ); daunomycin, cerubidine ® ); Ontak (a type of interleukin) ® ); Right Lei Zuosheng (Zinecard) ® ); Taxotere ® Doxorubicin (Adriamycin PFS) ® Doxorubicin ® Rubex ® Doxorubicin (Adriamycin PFSInjection) ® Doxorubicin liposomes ® ); Dromostanolone propionate ® Masterone injection (drolidine propionate) ® Elliott's B Solution ® ); Ellence ® ); epogen ® ); Erlotinib (Tarceva) ®); Emcytine ® ); Etoposide phosphate ® ); Etoposide, VP-16 (Vepesid) ® Aromasin ® ); Neupogen ® ); Fluorouracil (intra-arterial) (FUDR) ® Fludara () ® ); fluorouracil, 5-FU (Adrucil ® ); Faslodex ® Gefitinib (Iressa) ® Gemzathibrine ® ); Gelatinumab ozomicin (Mylotarg) ® ); Goserelin acetate (Zoladex Implant) ® ); Goserelin acetate (Zoladex) ® Histrelin implant ® ); Hydroxyurea ® ); Zevalin ® Idamycin ® ); ifosfamide (IFEX) ® ); Imatinib mesylate (Gleevec) ® Interferon α-2a (Roferon A) ® ); Interferon α-2b (Intron A) ® ); Irinotecan (Camptosar) ® ); Lenalidomide (Revlimid) ® Letrozole (Femara) ® ); Wellcovorin ® Leucovorin ® ); Leuprolide acetate (Eligard) ® ); Levamisole (Ergamisol ® Lomustine, CCNU (CeeBU) ® ); dichloromethyldiethylamine, nitrogen mustard (Mustargen) ® ); Megestrol acetate (Megace) ® ); Alkeran, L-PAM ® ); 6-MP (Purinethol) ®Mesnex ® Mesnex tabs ® Methotrexate ® ); Methoxam (Uvadex) ® Mitomycin C ® ); Lysodren ® Novantrone ® ); Nandrolone phenylpropionate (Durabolin-50) ® ); Arranon ® ); Nofetaclopramide (Verluma) ® ); Neumega-1 interleukin ® ); Eloxatin ® ); Paxene ® ); Taxol ® ); Paclitaxel protein-binding particles (Abraxane) ® ); Kepivance ® ); pamidronate (Aredia) ® ); Adagen (Pegademase Bovine) ® Oncasparase ® ); Neulasta ® ); Pemetrexed disodium (Alimta) ® Nipent (a type of acetaminophen) ® ); piperobromide (Vercyte) ® ); Prucalomycin, Mithracin ® ); Photofrin ® Matulane (procarbazine) ® ); Atabrine ® ); Elitek ® ); Rituxan ® Rapamycin; Leukine ® Prokine ® Sorafenib (Nexavar) ® ); Streptozotocin (Zanosar) ® Sunitinib maleate ® ); Talc (Sclerosol)® ); Nolvadex ® Temozolomide ® ); teniposide, VM-26 (Vumon ® ); testosterone (Teslac) ® Thioguanine, 6-TG ® Thioplex ® Topotecan (Hycamtin) ® Toremifene (Fareston®); Tosimomab (Bexxar) ® Tosimomab / I- 131 Tosimomab (Bexxar®); Trastuzumab (Herceptin) ® ); Retinoic acid, ATRA (Vesanoid ® ); Uracil Mustard Capsules ® Valstar ® ); Vincristine (Velban) ® Oncovin ® ); Changchun Navelbine ® ); Zolinota ® ) and zoledronic acid (Zometa) ® (or its pharmaceutically acceptable salt). Method for preparing the compounds of the present invention The following examples are provided to provide a more complete understanding of the invention. Starting materials are commercially available unless otherwise stated. They should not be construed as limiting the invention in any way.

[0219] Several methods for preparing the compounds of the present invention are described in the following schemes and examples. Starting materials and intermediates are purchased, prepared by known procedures, or otherwise described. Some common routes for compounds of Formula I are also described in the following schemes. In some cases, the order of steps in the reaction scheme can be changed to promote the reaction or avoid unwanted reaction products. For stereoisomers, enantiomer A refers to the enantiomer that elutes faster / earlier at the separation point, enantiomer B refers to the enantiomer that elutes slower / later, and this nomenclature is maintained until the remainder of the synthetic sequence of a given enantiomer series, regardless of whether subsequent intermediates and the final compound may have the same or opposite elution order.

[0220] Throughout the synthesis scheme and examples, unless otherwise stated, abbreviations and acronyms may have the following meanings: ACN = Acetonitrile AcOH = Acetic acid CDI = 1,1'-carbonyldiimidazole Cu(OAc)₂ = Copper acetate DAST = diethylaminosulfur trifluoride DIEA = diisopropylethylamine DMF = dimethylformamide DMS = dimethyl sulfide DMSO = dimethyl sulfoxide DCE = 1,2-dichloroethane DCM = dichloromethane DIPEA = N,N-Diisopropylethylamine DPPA = Biphenyl azidophosphate dppf = 1,1'-bis(biphenylphosphino)ferrocene Et = Ethyl EtOAc = Ethyl acetate EDC = N-(3-Dimethylaminopropyl)-N′-Ethylcarbodiimide hydrochloride RP HPLC = Reversed-phase high-performance liquid chromatography h or hr = hours HATU = 1-[bis(dimethylamino)methylene]-1 H -1,2,3-Triazolo[4,5-b]pyridinium 3-oxy-hexafluorophosphate Hex = hexane HOAc = Acetic acid HOBT = Hydroxybenzotriazole IPA = Isopropanol Me = methyl mCPBA = m-chloroperoxybenzoic acid MgSO4 = Magnesium sulfate MP-cyanoborohydride = Macroporous polymer-supported cyanoborohydride rt or RT = room temperature nBu4LI = Tetra-n-butylammonium iodide NBS = N - Bromosuccinimide NCS = N -Chlorosuccinimide NIS = N -Iodosuccinimide PdCl2(dppf) = [bis(biphenylphosphino)ferrocene]palladium(II) dichloride SFC = Supercritical Fluid Chromatography SM = Starting material t-Bu-OH = tert-butanol tBuBrettPhos = 2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-3,6-dimethoxy-1,1′-biphenyl THF = Tetrahydrofuran TFA = Trifluoroacetic acid Xphos = 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl XPhos Pd G2 = Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) In addition, aq is an aqueous solution, TLC is thin-layer chromatography; Ts is toluenesulfonyl; UV is ultraviolet; W is watt; wt.% is weight percentage; xg is gravity multiple; [α]D is the specific rotation of polarized light at 589 nm; ℃ is degree Celsius; % w / v is the percentage of the weight of the former reagent relative to the volume of the latter reagent.

[0221] LCMS conditions: Column: SUPELCO Ascentis Express C18 3 x 100 mm, 2.7 μm. Solvent system: A - water containing 0.05% TFA and B - acetonitrile containing 0.05% TFA.

[0222] Gradient condition: 10 - 99% B within 3.5 min.

[0223] General synthesis scheme While the invention has been described in conjunction with the specific embodiments described above, many alternatives, modifications, and variations will be apparent to those skilled in the art. In some cases, the order of steps in the reaction process may be altered to promote the reaction or avoid unwanted reaction products. All such alternatives, modifications, and variations are intended to fall within the spirit and scope of the invention.

[0224] [General Solution] Using Chan-Lam or Goldberg type systems via copper-mediated... N- The functionalization reaction prepares compound I from 1-1 and R1-X, yielding 1-2. 1-2 is coupled with an amide of a suitable amine, as described in the general formula scheme, to obtain compound (I). The order of steps in some embodiments can be changed to facilitate synthesis.

[0225] intermediate Intermediate-1: 3-Bromo-5-(1,1,2,2-tetrafluoroethoxy)pyridine Step A: 3-Bromo-5-(2-Bromo-1,1,2,2-Tetrafluoroethoxy)pyridine 1,2-Dibromo-1,1,2,2-Tetrafluoroethane (0.58 ml, 4.90 mmol) was added to a stirred solution of 5-bromopyridin-3-ol (0.85 g, 4.90 mmol) and Cs₂CO₃ (3.19 g, 9.79 mmol) in DMF (9.8 ml) using a syringe, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with Et₂O. The combined organic fractions were washed with water and NaCl (saturated aqueous solution), dried over MgSO₄, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–30% EtOAc / hexane gradient to give the title compound. LC / MS = 351 [M+1].

[0226] Step B: 3-Bromo-5-(1,1,2,2-Tetrafluoroethoxy)pyridine Zinc powder (0.79 g, 12.04 mmol) was added in portions to a stirred solution of 3-bromo-5-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridine (1.42 g, 4.01 mmol) in acetic acid (4.0 ml) at 50 °C. The reaction mixture was stirred at 50 °C for 1 hour. The reaction mixture was diluted with water, neutralized with NaHCO3 (saturated aqueous solution), and extracted with DCM. The combined organic fractions were dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was purified by rapid silica gel column chromatography using a 0–40% EtOAc / hexane gradient to give the title compound. LC / MS = 275 [M+1].

[0227] Intermediate-2: 3-Bromo-5-(1,1-Difluoroethoxy)pyridine HF-pyridine (14.86 g, 150 mmol) was added to a solution of xenon dichloride (1.69 g, 10.00 mmol) and 1-(5-bromopyridin-3-yl)ethyl-1-one (1.00 g, 5.00 mmol) in DCM (16.66 ml), and the mixture was stirred at RT for 18 h. The reaction mixture was slowly poured into a stirred mixture of NaHCO3 (saturated aqueous solution) and ice. The aqueous phase was extracted with DCM. The combined organic fractions were washed with NaCl (saturated aqueous solution), dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–40% EtOAc / hexane gradient to give the title compound. LC / MS = 238 [M+1].

[0228] Intermediate-3: 3-Bromo-5-(2,2-Difluoroethoxy)pyridine 2,2-difluoroethyl trifluoromethanesulfonate (380 µl, 2.87 mmol) was added to a stirred solution of 5-bromopyridin-3-ol (0.50 g, 2.87 mmol) and Cs₂CO₃ (1.87 g, 5.75 mmol) in DMF (14.4 mL) using a syringe, and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with water and extracted with Et₂O. The combined organic fractions were washed with water and NaCl (saturated aqueous solution), dried over MgSO₄, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–40% EtOAc / hexane gradient to give the title compound. LCMS = 238 [M+1].

[0229] Intermediate-4: (3-bromo-4-fluorophenyl)(difluoromethyl)thion Diethyl (bromodifluoromethyl)phosphonate (1.72 ml, 9.66 mmol) was added dropwise to a stirred solution of 3-bromo-4-fluorobenzenethiol (1.00 g, 4.83 mmol) and KOH (5.42 g, 97 mmol) in a mixture of acetonitrile (24.2 ml) and water (24.2 ml) using a syringe at 0 °C. The reaction mixture was allowed to warm naturally to 20 °C over 16 hours. The reaction mixture was diluted with Et₂O, washed with water and NaCl (saturated aqueous solution), dried over MgSO₄, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using 100% hexane to give the title compound.

[0230] Intermediate-5: 3-Iodo-5-(2,2-difluoroethoxy)-2-methylpyridine Add 3-bromo-5-(2,2-difluoroethoxy)-2-methylpyridine (1.18 g, 4.67 mmol) and (1R,2R)- as a solution in dioxane (9.3 ml) to a stirred mixture of sodium iodide (1.40 g, 9.33 mmol) and CuI (0.044 g, 0.23 mmol). N1,N2 -Dimethylcyclohexane-1,2-diamine (0.066 g, 0.47 mmol). The reaction mixture was heated to 110 °C and maintained for 16 hours. The reaction mixture was diluted with EtOAc, filtered through a SiO2 stopper, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0-30% EtOAc hexane gradient to obtain the title compound.

[0231] Example The following experimental procedures detail the preparation of specific embodiments of this disclosure. These embodiments are for illustrative purposes only and are not intended to limit the scope of this disclosure in any way.

[0232] Example 1: 1'-(3-(difluoromethoxy)phenyl)- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2'-oxospiro[cyclobutane-1,3'-indoline]-5'-formamide Step A: 5'-Bromospiro[cyclobutane-1,3'-indoline]-2'-one To a solution of 5-bromoindolin-2-one (400 mg, 1.89 mmol) in THF (40 mL), n-butyllithium (2.5 M in hexane, 2.57 mL, 6.41 mmol) was added, and the reaction mixture was stirred at -10 °C under N2 for 0.5 h. Then, the mixture was further stirred at -10 °C under N2. N,N,N',N' 1,3-Tetramethylethylenediamine (745 mg, 6.41 mmol) and 11,3-diiodopropane (0.214 mL, 1.868 mmol) were added to the mixture. The reaction mixture was slowly heated to 25 °C and stirred under N2 for 3 h. The reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 252 and 254 [M+1].

[0233] Step B: 5'-Bromo-1'-(3-(difluoromethoxy)phenyl)spiro[cyclobutane-1,3'-indoline]-2'-one In a glove box, K₂CO₃ (132 mg, 0.952 mmol) was added to a solution of 5'-bromospiro[cyclobutane-1,3'-indoline]-2'-one (120 mg, 0.476 mmol) in acetonitrile (2.5 mL). N,N' -Dimethylethylenediamine (16.78 mg, 0.190 mmol), 1-bromo-3-(difluoromethoxy)benzene (0.401 mL, 2.86 mmol), and iodide ketone (I) (18.13 mg, 0.095 mmol). The reaction mixture was stirred at 90 °C for 14 h, then quenched with water and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residues were purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 394 and 396 [M+1].

[0234] Step C: Ethyl 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclobutane-1,3'-indoline]-5'-carboxylic acid Potassium acetate (93 mg, 0.951 mmol) and PdCl2 (dppf) (23.20 mg, 0.032 mmol) were added to a solution of 5'-bromo-1'-(3-(difluoromethoxy)phenyl)spiro[cyclobutane-1,3'-indoline]-2'-one (125 mg, 0.317 mmol) in EtOH (5 mL). The mixture was stirred at 80 °C for 14 h under a CO2 balloon. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 388 [M+1].

[0235] Step D: 3-(1-Carboxycyclobutyl)-4-((3-(difluoromethoxy)phenyl)amino)benzoic acid Ethyl 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclobutane-1,3'-indoline]-5'-carboxylate (80 mg, 0.207 mmol) in a solution of MeOH (4 mL) was added to a solution of lithium hydroxide monohydrate (17.33 mg, 0.413 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure and dissolved in H2O. HCl (1N in water) was added to the mixture until pH = 4. The mixture was then extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. LC / MS = 378 [M+1].

[0236] Step E: 1'-(3-(difluoromethoxy)phenyl)- N -(3-Methyl-1,1-dioxathionecyclobut-3-yl)-2'- oxospiro[cyclobutane-1,3'-indoline]-5'-formamide DIEA (0.046 mL, 0.265 mmol) and HATU (30.2 mg, 0.080 mmol) were added to a solution of 3-(1-carboxycyclobutyl)-4-((3-(difluoromethoxy)phenyl)amino)benzoic acid (20 mg, 0.053 mmol) in DMF (2 mL). The mixture was stirred at 25 °C for 0.5 h. Then, 1,1-dioxide of 3-amino-3-methylthiocyclobutane (9.31 mg, 0.069 mmol) was added to the mixture. The mixture was stirred at 25 °C for 1 h. The crude mixture was purified by mass-triggered reversed-phase HPLC (acetonitrile / water, containing 0.1% TFA modifier) ​​to give the title compound. LC / MS = 477 [M+1]. 1 H NMR (400 MHz, CDCl3-d1) δ 8.05 (d, J = 1.6 Hz, 1H), 7.49-7.62 (m, 2H), 7.26-7.31 (m, 1H), 7.20 (dd, J = 1.6, 4.0 Hz, 2H), 6.36-6.91 (m, 3H), 4.62(d, J = 14.4 Hz, 2H), 4.12-4.29 (m, 2H), 2.73-2.85 (m, 2H), 2.32-2.52 (m,4H), 1.94 (s, 3H). Human DGAT2 IC 50 = 65.4 nM.

[0237] Example 2: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide Step A: 1-(3-(difluoromethoxy)phenyl)-1 H Methyl indole-5-carboxylate In a nitrogen atmosphere at 28 °C, 1 mmol of 1-bromo-3-(difluoromethoxy)benzene (50 mg, 0.224 mmol) was added to a solution of toluene (1.5 mL). H Methyl indole-5-carboxylate (47.1 mg, 0.269 mmol), tripotassium phosphate (143 mg, 0.673 mmol), cuprous iodide(I) (4.27 mg, 0.022 mmol), and N,N'-Dimethylethylenediamine (3.95 mg, 0.045 mmol). The mixture was stirred at 100 °C for 12 h, then poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 318 [M+1].

[0238] Step B: 3-Bromo-1-(3-(difluoromethoxy)phenyl)-1 H Methyl indole-5-carboxylate At 28 °C, 1-(3-(difluoromethoxy)phenyl)-1 H Methyl indole-5-carboxylate (70 mg, 0.221 mmol) was mixed with NBS (43.2 mg, 0.243 mmol) in 1.5 mL of DMF. The mixture was stirred at 28 °C for 1 h, then poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 396 [M+1].

[0239] Step C: 1-(3-(difluoromethoxy)phenyl)-3-(prop-1-en-2-yl)-1 H Methyl indole-5-carboxylate In a N2 atmosphere at 28 °C, 3-bromo-1-(3-(difluoromethoxy)phenyl)-1 H- Methyl indole-5-carboxylate (70 mg, 0.177 mmol) was prepared in a solution of dioxane (1.5 mL) and water (0.3 mL) with added K₂CO₃ (73.3 mg, 0.530 mmol), potassium isopropenyltrifluoroborate (39.2 mg, 0.265 mmol), and PdCl₂(dppf) (12.93 mg, 0.018 mmol). The mixture was stirred at 80 °C for 1 h. The mixture was poured into H₂O, the precipitate was filtered off, and then the precipitate was dissolved in ethyl acetate and concentrated under reduced pressure to give the title compound. LC / MS = 358 [M+1].

[0240] Step D: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1 H Methyl indole-5-carboxylate 1-(3-(difluoromethoxy)phenyl)-3-(prop-1-en-2-yl)-1- HA mixture of methyl indole-5-carboxylate (53 mg, 0.148 mmol) and moistened Pd / C (15.78 mg, 0.148 mmol, 10%) in MeOH (5 mL) was stirred for 1 h. The mixture was filtered through a CELITE filter, and the solvent was evaporated under reduced pressure to give the crude product. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 360 [M+1].

[0241] Step E: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1 H -Indole-5-carboxylic acid At 28 °C, 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1 H Methyl indole-5-carboxylate (35 mg, 0.097 mmol) was added to a solution of potassium trimethylsilyl alcohol (37.5 mg, 0.292 mmol) in THF (1.5 mL). The mixture was stirred at 60 °C for 5 h and then concentrated under reduced pressure to give the title compound. LC / MS = 346 [M+1].

[0242] Step F: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl- N -(3-methyl-1,1-dioxathione-3- (base)-1 H -Indole-5-carboxamide At 28 °C, 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1 H Indole-5-carboxylic acid (20 mg, 0.058 mmol) was added to a solution of DMF (1 mL) with DIEA (0.030 mL, 0.174 mmol) and HATU (26.4 mg, 0.069 mmol). The mixture was stirred at 28 °C for 5 min, and then 1,1-dioxide of 3-amino-3-methylthiocyclobutane (9.39 mg, 0.069 mmol) was added. The mixture was stirred at 28 °C for another 10 min, then poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 463 [M+1].

[0243] Step G: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl- N -(3-methyl-1,1-dioxathione-3- 2-oxoindoline-5-carboxamide At 26 °C, the 1-(3-(difluoromethoxy)phenyl)-3-isopropyl- N -(3-Methyl-1,1-dioxathionecyclobut-3-yl)-1 H-Indole-5-carboxamide (15 mg, 0.032 mmol) was added to a mixture of CH2Cl2 (1 mL) with NCS (4.76 mg, 0.036 mmol). The mixture was stirred at 26 °C for 1 h. The mixture was concentrated, and the residue was dissolved in HOAc (1 mL) and H3PO4 (0.25 mL). The mixture was stirred at 100 °C for 1.5 h and then concentrated to give the crude product. The crude mixture was purified by mass-triggered reversed-phase HPLC (ACN / water, containing 0.1% TFA modifier) ​​to give the title compound. LC / MS = 479 [M+1]. 1 H NMR (500MHz, chloroform-d1) δ 7.89 (s, 1H), 7.78 (dd, J1 = 8.3Hz, J2 = 1.0 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 7.26 (dd, J1 = 8.2 Hz, J2=2.1Hz, 2H), 7.18 (s, 1H), 6.70 - 7.12 (m, 2H), 4.56 (br d, J = 14.4 Hz, 2H), 4.20 (br d, J = 14.9 Hz, 2H), 3.70 (d, J = 3.2 Hz, 1H), 2.46 - 2.65 (m, 1H),1.81 (s, 3H), 1.11 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H). Human DGAT2 IC 50 =1093 nM.

[0244] Example 3: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide Step A: Methyl 3,3-dimethyl-2-oxoindoline-5-carboxylate TEA (1.219 mL, 8.75 mmol) and PdCl2 (dppf) (320 mg, 0.437 mmol) were added to a solution of 5-bromo-3,3-dimethylindolin-2-one (700 mg, 2.92 mmol) in MeOH (30 mL) at 25 °C under an argon atmosphere. The mixture was stirred for 15 h at 80 °C under a CO atmosphere (50 psi). LC-MS showed the formation of the desired product. The mixture was poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 220 [M+1].

[0245] Step B: Methyl 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylate Methyl 3,3-dimethyl-2-oxoindoline-5-carboxylate (40 mg, 0.182 mmol) was added to a solution of dioxane (1 mL) under a N2 atmosphere. 1R, 2R )- N1 N2-Dimethylcyclohexane-1,2-diamine (5.19 mg, 0.036 mmol), potassium carbonate (76 mg, 0.547 mmol), cuprous iodide(I) (3.47 mg, 0.018 mmol), and 1-bromo-3-(difluoromethoxy)benzene (40.7 mg, 0.182 mmol). The mixture was stirred at 100 °C for 15 h, then poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 362 [M+1].

[0246] Step C: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid Methyl 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylate (90 mg, 0.249 mmol) was added to a solution of MeOH (2 mL) / water (0.5 mL) with LiOH·H₂O (23.86 mg, 0.996 mmol). The mixture was stirred at 30 °C for 2 h. Then, it was concentrated under reduced pressure. HCl (1 N in water) was added until pH = 4. The mixture was then extracted with DCM. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LC / MS = 348 [M+1].

[0247] Step D: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathione- 3-yl)-2-oxoindoline-5-carboxamide HATU (52.5 mg, 0.138 mmol) and DIEA (0.060 mL, 0.346 mmol) were added to a solution of 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid (40 mg, 0.115 mmol) in DCM (1 mL). The mixture was stirred at 50 °C for 10 min, and then 1,1-dioxide of 3-amino-3-methylthiocyclobutane (18.68 mg, 0.138 mmol) was added at 50 °C under N2 atmosphere. The mixture was stirred at 50 °C for 3 h, then poured into H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude substance was purified by rapid silica gel chromatography using a 0-100% EtOAc / hexane gradient to give the title compound. LC / MS = 465 [M+1]. 1 ¹H NMR (500 MHz, methanol-d⁴) δ 7.94 (d, J = 1.53 Hz, 1H), 7.82 (dd, J1 = 8.32 Hz, J2 = 1.75 Hz, 1H), 7.65 (t, J = 8.01 Hz, 1H), 7.26 - 7.40 (m, 3H), 6.76 - 7.13 (m, 2H), 4.61 (br d, J = 14.50 Hz, 2H), 4.21 - 4.29 (m, 2H), 1.86 (s, 3H), 1.54 (s, 6H). Human DGAT2 IC 50 = 29.3 nM.

[0248] Examples 4a and 4b: 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide and 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide Step A: 3-Ethyl-3-methylindoline-2-one At -78 °C, 3-methylindolin-2-one (300 mg, 2.038 mmol) and N,N,N',N'-Tetramethylethylenediamine (711 mg, 6.12 mmol) was added to a mixture of 2.5 M butyllithium (1.794 mL, 4.48 mmol in hexane) in THF (9 mL), and the reaction mixture was stirred at -78 °C under N2 for 0.5 h. Then, a solution of iodoethane (477 mg, 3.06 mmol) in THF (3 mL) was added to the mixture at -78 °C under N2. The reaction mixture was slowly heated to -20 °C and stirred for 1 h. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 176 [M+1].

[0249] Step B: 5-Bromo-3-ethyl-3-methylindoline-2-one Br2 (0.035 mL, 0.685 mmol) was added to a solution of 3-ethyl-3-methylindolin-2-one (100 mg, 0.571 mmol) in HOAc (10 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h under an N2 balloon. The reaction mixture was quenched with a saturated aqueous solution of Na2SO3, diluted with water, and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–100% EtOAc / hexane) to give the title compound. LC / MS = 254 and 256 [M+1].

[0250] Step C: 5-Bromo-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methylindoline-2-one In a glove box, K₂CO₃ (54.4 mg, 0.394 mmol) was added to a solution of 5-bromo-3-ethyl-3-methylindololin-2-one (50 mg, 0.197 mmol) in acetonitrile (1 mL). N,N' -Dimethylethylenediamine (6.94 mg, 0.079 mmol), 1-bromo-3-(difluoromethoxy)benzene (0.193 mL, 1.377 mmol), and cuprous iodide(I) (7.49 mg, 0.039 mmol). The reaction mixture was stirred at 90 °C for 13 h, then poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 396 and 398 [M+1].

[0251] Step D: Ethyl 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-2-oxoindoline-5-carboxylate Potassium acetate (37.2 mg, 0.379 mmol) and PdCl2 (dppf) (9.23 mg, 0.013 mmol) were added to a solution of 5-bromo-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methylindoline-2-one (50 mg, 0.126 mmol) in EtOH (5 mL). The mixture was stirred at 80 °C for 13 h under a CO2 balloon. LC-MS showed complete consumption of the starting material. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 390 [M+1].

[0252] Step E: 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-2-oxoindoline-5-carboxylic acid Lithium hydroxide monohydrate (8.62 mg, 0.205 mmol) was added to a solution of ethyl 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-2-oxoindoline-5-carboxylate (40 mg, 0.103 mmol) in MeOH (2 mL) and water (0.2 mL). The mixture was stirred at 25 °C for 24 h, concentrated under reduced pressure, and dissolved in H₂O. Hydrochloric acid (1 N in water) was added to the mixture until pH = 4. The mixture was then extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the title compound. LC / MS = 362 [M+1].

[0253] Step F: 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl N -(3-methyl-1,1-dioxane heterocyclic ring) But-3-yl)-2-oxoindoline-5-carboxamide DIEA (0.089 mL, 0.512 mmol) and HATU (58.4 mg, 0.154 mmol) were added to a solution of 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-2-oxoindoline-5-carboxylic acid (37 mg, 0.102 mmol) in DMF (2 mL). The mixture was stirred at 25 °C for 0.5 h. Then, 1,1-dioxide of 3-amino-3-methylthiocyclobutane (18.00 mg, 0.133 mmol) was added, and the mixture was stirred at 25 °C for 1 h. The crude mixture was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% TFA modifier) ​​to give the title compound. LC / MS = 479 [M+1].

[0254] Step G: 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl N -(3-methyl-1,1-dioxane heterocyclic ring) butan-3-yl)-2-oxoindoline-5-carboxamide and 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(3-methyl 1,1-dioxathionylbutan-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N A mixture of two stereoisomers of -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide (50 mg, 0.104 mmol) was given to isomer EX-4a (fast elution). LC / MS = 479 [M+1]. 1 HNMR (400 MHz, chloroform-d1) δ 7.71 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 1.6, 8.0 Hz,1H), 7.50-7.57 (m, 1H), 7.25 - 7.28 (m, 1H), 7.16 - 7.22 (m, 2H), 6.89 (d, J= 8.4 Hz, 1H), 6.37 - 6.78 (m, 2H), 4.60 (d, J = 14.8 Hz, 2H), 4.20 (d, J =14.8 Hz, 2H), 2.00-2.16 (m, 1H), 1.83 - 1.94 (m, 4H), 1.49 (s, 3H), 0.69 (t, J = 7.2 Hz, 3H). Human DGAT2 IC 50 = 1103 nM. Isomer EX-4b (slower elution). LC / MS = 479 [M+1]. 1 H NMR (400 MHz, chloroform-d1) δ 7.71 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 1.6, 8.4Hz, 1H), 7.50-7.57 (m, 1H), 7.25-7.28 (m, 1H), 7.17-7.23 (m, 2H), 6.89 (d, J= 8.4 Hz, 1H), 6.38-6.77 (m, 2H), 4.60 (br d, J = 14.8 Hz, 2H), 4.20 (d, J =14.8 Hz, 2H), 2.01-2.13 (m, 1H), 1.84-1.96 (m, 4H), 1.50 (s, 3H), 0.69 (t, J = 7.2 Hz, 3H). Human DGAT2 IC 50 =104 nM.

[0255] The following compounds were synthesized using a procedure similar to that described in Example 4 and with appropriate reagents. These compounds were characterized by LC / MS.

[0256] Examples 6a and 6b: 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide Step A: 1-(3-(difluoromethoxy)phenyl)-1 H Methyl indole-5-carboxylate In a glove box, methyl 1H-indole-5-carboxylate (500 mg, 2.85 mmol) was added to a solution of DMSO (5 mL) with 1-bromo-3-(difluoromethoxy)benzene (1910 mg, 8.56 mmol), cuprous iodide (I) (54.4 mg, 0.285 mmol), K₂CO₃ (789 mg, 5.71 mmol), and ( 1R, 2R )- N,N' -Dimethyl-1,2-cyclohexanediamine (81 mg, 0.571 mmol). The reaction mixture was stirred at 110 °C for 12 h. TLC showed the formation of the desired product. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by rapid column chromatography on silica gel (0-100% EtOAc / hexane) to give the title compound. LC / MS = 318 [M+1].

[0257] Step B: 1-(3-(difluoromethoxy)phenyl)-1 H -Indole-5-carboxylic acid Lithium hydroxide monohydrate (800 mg, 19.06 mmol) was added to 1-(3-(difluoromethoxy)phenyl)-1 H Methyl indole-5-carboxylate (1 g, 3.15 mmol) was prepared in a mixture of MeOH (10 mL), THF (3.00 mL), and water (1 mL). The mixture was stirred at 25 °C for 13 h. LCMS showed the formation of the desired product. HCl (1 N in water) was added to the mixture until pH = 4, followed by extraction with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound.

[0258] Step C: 1-(3-(difluoromethoxy)phenyl)- N -(3-Methyl-1,1-dioxathionecyclobut-3-yl)-1 H -in dole-5-carboxamide 3-Amino-3-methylthiocyclobutane 1,1-dioxide dihydrochloride (0.91 g, 4.37 mmol) was added to 1-(3-(difluoromethoxy)phenyl)-1 H -Indole-5-carboxylic acid (0.95 g, 3.13 mmol), HATU (1.78 g, 4.68 mmol), and DIEA (2.2 mL, 12.60 mmol) were in a mixture of DCM (20 mL). The mixture was stirred at 25 °C for 0.5 h. LC-MS showed the formation of the desired product. The mixture was poured into H2O and then extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel by rapid column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 421 [M+1].

[0259] Step D: 1-(3-(difluoromethoxy)phenyl)- N -(3-Methyl-1,1-dioxathionecyclobut-3-yl)-2,3- Dioxoindololin-5-formamide At 25 °C, 1-(3-(difluoromethoxy)phenyl)- N -(3-Methyl-1,1-dioxathionecyclobut-3-yl)-1 H -Indole-5-carboxamide (900 mg, 2.141 mmol) was reacted with chromium oxide (VI) (856 mg, 8.56 mmol) in a solution of acetone (8 mL) / acetic acid (6 mL) / water (3 mL). The mixture was stirred at room temperature for 3 h. LC-MS showed the formation of the desired product. The reactants were poured into saturated NH4Cl and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 451 [M+1].

[0260] Step E: 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl N -(3-methyl-1,1-dioxane heterocyclic ring) But-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)- NA mixture of 3-methyl-1,1-dioxathionecyclobut-3-yl)-2,3-dioxoindoline-5-carboxamide (0.8 g, 1.776 mmol) and lithium bromide (0.31 g, 3.57 mmol) in THF (15 mL) was cooled to -70 °C, treated with methylmagnesium bromide (1.8 mL, 3.60 mmol), and stirred at -70 °C for 2 h under N2. LC-MS showed the formation of the desired product. The reactants were poured into saturated NH4Cl and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% TFA modifier) ​​to give the title compound in TFA salt form. LC / MS = 467 [M+1]. A mixture of two stereoisomers was purified by chiral SFC (column DAICL CHIRALCEL OD (250 mm × 30 mm × 10 μm), conditions 0.1% NH3H2O ​​EtOH). EX-6a (faster elution): LC / MS = 467 [M+1]. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.00 (d, J=1.47 Hz, 1H), 7.84 (dd, J=1.47, 8.31 Hz, 1H), 7.58–7.67 (m, 1H), 7.25–7.36 (m, 3H), 6.72–7.13 (m, 2H), 4.57–4.98 (m, 2H), 4.22–4.65 (m, 2H), 1.82 (s, 3H), 1.66 (s, 3H). Human DGAT₂ IC 50 = 3933 nM. EX-6b (slower elution): LC / MS = 467 [M+1]. 1 ¹H NMR (400 MHz, methanol-d⁴) δ 8.00 (d, J=1.96 Hz, 1H), 7.84 (dd, J=1.71, 8.56 Hz, 1H), 7.58–7.66 (m, 1H), 7.24–7.36 (m, 3H), 6.72–7.13 (m, 2H), 4.57–4.86 (m, 2H), 4.22–4.53 (m, 2H), 1.82 (s, 3H), 1.66 (s, 3H). Human DGAT₂ IC 50 = 290 nM.

[0261] The following compounds were synthesized using a procedure similar to that described in Example 6 and with appropriate reagents. These compounds were characterized by LC / MS.

[0262] Example 8: 1-(3-(difluoromethoxy)phenyl)-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide Step A: 1-(3-(difluoromethoxy)phenyl)-3-methyl- N -(3-methyl-1,1-dioxathione-3- 2-oxoindoline-5-carboxamide Triethylsilane (1.3 g, 11.18 mmol) was added to 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl- under a nitrogen atmosphere. N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide (130 mg, 0.279 mmol) in a solution of TFA (3 mL). The resulting mixture was heated at 80 °C. o Stirred at C for 13 h. LC-MS showed the formation of the desired product. The reactants were poured into saturated NH4Cl and extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% TFA modifier) ​​to give the title compound in TFA salt form. LC / MS = 451 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 7.92 (s, 1H), 7.81 (br d, J=8.24 Hz, 1H), 7.64 (t, J=8.09 Hz, 1H), 7.35 (br d, J=7.93 Hz, 1H), 7.26-7.32 (m, 2H), 6.78-7.11 (m,2H), 4.58-4.60 (m, 2H), 4.23-4.27 (m, 2H), 4.12 (q, J=7.12 Hz, 1H), 3.80 (q,J=7.58 Hz, 1H), 1.85 (s, 3H), 1.61 (d, J=7.63 Hz, 3H). DGAT2 IC 50 = 2730 nM.

[0263] Examples 9a and 9b: 1-(3-(difluoromethoxy)phenyl)-3-fluoro-3-methyl- N-(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide Step A: 1-(3-(difluoromethoxy)phenyl)-3-fluoro-3-methyl- N -(3-methyl-1,1-dioxane heterocyclic ring) But-3-yl)-2-oxoindoline-5-carboxamide At 0 °C, 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide (100 mg, 0.214 mmol) was added to a solution of DCM (7 mL) with DAST (0.115 mL, 0.870 mmol), and the reaction mixture was stirred at 0 °C for 1 h under N2. LC-MS showed the formation of the desired product. The reaction mixture was poured into saturated NaHCO3 and then extracted with DCM (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexane) to give the title compound. LC / MS = 469 [M+1]. The racemic mixture was purified by chiral SFC (IC-H column, 40% / 60% ethanol / CO2). EX-9a (faster elution): LC / MS = 469 [M+1]. 1 H NMR (400 MHz, methanol-d4) δ8.11 (t, J=1.76 Hz, 1H), 7.93 (td, J=1.71, 8.31 Hz, 1H), 7.58-7.72 (m, 1H),7.33-7.38 (m, 1H), 7.27-7.32 (m, 2H), 6.73-7.14 (m, 2H), 4.58 (br d, J=14.48Hz, 2H), 4.17-4.27 (m, 2H), 1.85-1.93 (m, 3H), 1.83 (s, 3H). Hu DGAT2 IC 50 = 339nM. EX-9b (slower elution): LC / MS = 469 [M+1]. 1H NMR (400 MHz, methanol-d4) δ 8.11 (t, J=1.76 Hz, 1H), 7.93 (td, J=1.76, 8.22 Hz, 1H), 7.60-7.68 (m, 1H), 7.35 (dd, J=0.98, 8.80 Hz, 1H), 7.27-7.32 (m, 2H), 6.73-7.14 (m, 2H), 4.58 (br d, J=14.48Hz, 2H), 4.18-4.26 (m, 2H), 1.85-1.93 (m, 3H), 1.83 (s, 3H). Hu DGAT2 IC 50 = 169nM.

[0264] Example 10: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohex-4-yl)-2-oxo-indoline-5-carboxamide Step A: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid 3,3-Dimethyl-2-oxoindoline-5-carboxylic acid (5.0 g, 24.4 mmol), 1-(difluoromethoxy)-3-iodobenzene (9.9 g, 36.5 mmol), and ( 1R, 2R )- N1,N2 1,2-Dimethylcyclohexane-1,2-diamine (0.69 g, 4.9 mmol) and potassium carbonate (10.1 g, 73.1 mmol) were added to a stirred solution of acetonitrile (48.7 mL) with CuI (0.46 g, 2.44 mmol). The thick-walled pressure vessel was sealed and heated to 95 °C for 18 hours. The reactants were diluted with water, acidified with HCl (1 M aqueous solution), and stirred for 45 minutes. The resulting brown solution was extracted with DCM. The combined organic fractions were dried over Na2SO4 and adsorbed onto SiO2. The crude material was purified by rapid silica gel chromatography using a 0-100% EtOAc / hexane gradient to give the title compound. LC / MS = 348 [M+1].

[0265] Step B: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thioheterocyclic ring) (hexyl-4-yl)-2-oxo-indoline-5-carboxamide To 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid (50 mg, 0.14 mmol), 4-amino-4-methyltetrahydro-2-carboxylic acid... H1,1-thiaran dioxide (23.5 mg, 0.14 mmol) and Hunig base (75 µl, 0.43 mmol) were added to a stirred solution of DMF (1440 µl) with HATU (57.5 mg, 0.15 mmol). The reaction mixture was stirred at RT for 16 h, diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 493 [M+1]. 1 H NMR (500 MHz, chloroform-d) δ 7.75 (d, J = 1.7 Hz, 1H), 7.60 – 7.54 (m, 2H),7.34 – 7.31 (m, 1H), 7.24 (d, J = 8.0 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.60(t, J = 73.2 Hz, 1H), 5.70 (s, 1H), 3.23 – 3.15 (m, 2H), 3.03 (d, J = 14.2Hz, 2H), 2.82 (d, J = 15.0 Hz, 2H), 2.42 – 2.33 (m, 2H), 1.62 (s, 3H), 1.55 (s, 6H). Human DGAT2 IC 50 =39 nM.

[0266] The following compounds were synthesized using a procedure similar to that described in Example 10 and with appropriate reagents. These compounds were characterized by LC / MS.

[0267] Example 62: 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide Step A1: 1-(4-(benzyloxy)pyridin-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid Under nitrogen atmosphere, the following substances were added: 3,3-dimethyl-2-oxoindoline-5-carboxylic acid (1000 mg, 4.87 mmol), CuI (464 mg, 2.436 mmol), potassium carbonate (2020 mg, 14.62 mmol), 4-(benzoxy)-2-bromopyridine (3861 mg, 14.62 mmol), and (… 1R, 2R )- N1,N2 Acetonitrile (9.7 mL) was added to a stirred mixture of 1,2-dimethylcyclohexane-1,2-diamine (693 mg, 4.87 mmol), and the resulting solution was heated to 90 °C for 16 hr. The reactants were diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered through a silica stopper, and concentrated under vacuum. The crude residue was purified by rapid column chromatography on silica gel (0-100% EtOAc / hexane) to give the title compound. LC / MS = 389 [M+1].

[0268] Step B: 1-(4-(benzyloxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro- 2 H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide 1-(4-(benzyloxy)pyridin-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid (932 mg, 2.4 mmol), DIEA (1.0 mL, 6.00 mmol), and 4-amino-4-methyltetrahydro-2-carboxylic acid were administered. H 1,1-thiaran dioxide hydrochloride (503 mg, 2.52 mmol) was added to a stirred solution of DMF (24 mL) with HATU (958 mg, 2.52 mmol). The reaction mixture was stirred for 18 hours. The reaction mixture was diluted with water, and the precipitate was collected by filtration. The recovered solid was purified by rapid column chromatography on silica gel (0-70% EtOAc / hexane) to give the title compound. LC / MS = 534 [M+1].

[0269] Step C: 1-(4-hydroxypyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thia (4-yl)-2-oxoindoline-5-carboxamide Using a syringe under nitrogen atmosphere, 1-(4-(benzooxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H(-thiaran-4-yl)-2-oxoindoline-5-carboxamide (0.96 g, 1.80 mmol) was reacted with triethylsilane (2.88 mL, 18.03 mmol) dropwise in a stirred solution of ethanol (18.03 mL). The reaction mixture was stirred for 3 hours and purged with argon for 5 minutes, diluted with dichloromethane, and filtered through diatomaceous earth. The solvent was removed under vacuum to give the crude title compound, which was ready for use without further purification. LC / MS = 444 [M+1].

[0270] Step D: 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxane) Tetrahydro-2 H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide To 1-(4-hydroxypyridin-2-yl)-3,3-dimethyl -N -(4-methyl-1,1-dioxatetrahydro-2- H 155 mg (0.35 mmol)-2-oxoindoline-5-carboxamide and cesium carbonate (228 mg, 0.70 mmol) were added to a stirred solution of 1.7 mL DMF containing 2,2-difluoroethyl trifluoromethanesulfonate (46.0 µl, 0.35 mmol). The reaction mixture was stirred at 20 °C for 3 hr. The solvent was removed under vacuum, and the crude reaction mixture was purified by rapid column chromatography on silica gel (0-100% EtOAc / hexane) to give the title compound. LC / MS = 508 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ8.49 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.82 (dd, J = 8.4, 1.6Hz, 1H), 7.76 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 5.8, 2.3 Hz, 1H), 6.62 – 6.32 (m, 1H), 4.53 (td, J = 14.7, 3.2Hz, 2H), 3.18 (t, J = 12.0 Hz, 2H), 3.06 (d, J = 13.8 Hz, 2H), 2.80 (d, J =14.5 Hz, 2H), 2.02 (t, J = 12.2 Hz, 2H), 1.52 – 1.37 (m, 9H). Human DGAT2 IC 50 = 61nM.

[0271] Example 63: 3,3-Dimethyl- N-(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)indololin-5-carboxamide Step A: 1-(4-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl- 1,1-Dioxatetrahydro-2 H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide To 1-(4-hydroxypyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2H-thiaran-4-yl)-2-oxoindoline-5-carboxamide (919 mg, 2.07 mmol) and cesium carbonate (1.35 g, 4.14 mmol) were added to a stirred solution of DMSO (10.4 mL) with 1,2-dibromo-1,1,2,2-tetrafluoroethane (808 mg, 3.11 mmol). The reaction mixture was heated to 60 °C for 16 hr. After cooling, the solvent was removed under vacuum to give the crude title compound. LC / MS = 624 [M+2].

[0272] Step B: 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4- (1,1,2,2-Tetrafluoroethoxy)pyridin-2-yl)indololin-5-carboxamide The crude 1-(4-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide was dissolved in AcOH (10 mL). Zinc (677 mg, 10.36 mmol) was added, and the reaction mixture was heated to 60 °C for 10 min. The reaction mixture was cooled, diluted with water, and extracted with 6:1 Et2O / DCM. The combined organic fractions were washed with NaCl (saturated aqueous solution), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel (0-100% EtOAc / hexane) to give the title compound (EX-63). LC / MS = 544 [M=1]. 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J = 5.7 Hz,1H), 7.96 (d, J = 1.4 Hz, 1H), 7.89 – 7.81 (m, 2H), 7.81 – 7.72 (m, 2H), 7.43(d, J = 4.4 Hz, 1H), 7.06 – 6.80 (m, 1H), 3.19 (t, J = 12.1 Hz, 2H), 3.06 (d,J = 13.9 Hz, 2H), 2.80 (d, J = 14.5 Hz, 2H), 2.03 (t, J = 12.2 Hz, 2H), 1.51–1.41 (m, 9H). DGAT2 IC 50 = 0.8 nM.

[0273] The following compounds were synthesized using a procedure similar to that described in Example 63 and with appropriate reagents. These compounds were characterized by LC / MS.

[0274] Example 88: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide Step A: 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxoindoline- 5-Formamide To 3,3-dimethyl-2-oxoindoline-5-carboxylic acid (2.5 g, 12.2 mmol), 4-amino-4-methyltetrahydro-2-carboxylic acid... H 1,1-thiaran dioxide hydrochloride (2.4 g, 12.2 mmol) and DIEA (4.24 ml, 24.4 mmol) were added to a stirred solution of DMF (122 ml) with 2,4,6-trioxy-2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane (11.6 g, 18.3 mmol) and the reaction mixture was stirred at 20 °C for 48 hr. The reaction mixture was concentrated under vacuum and purified by rapid column chromatography on silica gel (0-100% EtOAc / hexane) to give the title compound. LC / MS = 350 [M+1].

[0275] Step B: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1- Dioxatetrahydro-2 H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide Under nitrogen atmosphere, towards 3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2H-thiaran-4-yl)-2-oxoindoline-5-carboxamide (50 mg, 0.14 mmol), CuI (13.59 mg, 0.071 mmol), potassium carbonate (59.2 mg, 0.43 mmol), 4-bromo-2-(2,2-difluoroethoxy)-5-fluoropyridine (73.1 mg, 0.29 mmol) and ( 1R, 2R )- N1, N2 Acetonitrile (285 µl) was added to a stirred mixture of 1,2-dimethylcyclohexane-1,2-diamine (20.30 mg, 0.14 mmol). The solution was heated to 95 °C for 48 hr. The reaction mixture was cooled, diluted with EtOAc, filtered through a silica stopper, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel (0–100% EtOAc / hexane) to give the title compound (EX-88). LC / MS = 526 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.49 (d, J = 1.2 Hz,1H), 7.97 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 8.3, 1.6 Hz, 1H), 7.78 (s, 1H),7.31 (d, J = 4.8 Hz, 1H), 6.90 (dd, J = 8.2, 1.6 Hz, 1H), 6.43 (tt, J = 54.6,3.4 Hz, 1H), 4.63 (t, J = 14.6 Hz, 2H), 3.17 (t, J = 11.8 Hz, 2H), 3.05 (d, J= 14.1 Hz, 2H), 2.79 (d, J = 14.6 Hz, 2H), 2.02 (t, J = 11.0 Hz, 2H), 1.52 –1.37 (m, 9H). Human DGAT2 IC 50 = 3.4 nM.

[0276] The following compounds were synthesized using a procedure similar to that described in Example 88 and with appropriate reagents. These compounds were characterized by LC / MS.

[0277] Example 94: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide Step A: 6-Fluoro-3,3-Dimethyl-5-vinylindoline-2-one Add 5-bromo-6-fluoro-3,3-dimethylindololin-2-one (2.50 g, 9.69 mmol), potassium vinyltrifluoroborate CH2CHBF3K (2.60 g, 19.37 mmol), PdCl2(dppf) (0.71 g, 0.97 mmol), and triethylamine (4.05 ml, 29.1 mmol) to a vial. Evaporate the vial and backfill with nitrogen three times. Add ethanol (64.6 ml) and water (6.5 mL) sequentially, and heat the reaction mixture to 90 °C for 6 hr. Cool the reaction mixture, dilute with DCM, dry over MgSO4, filter, and concentrate under vacuum. Purify the crude residue by rapid column chromatography on silica gel (0–50% EtOAc in hexane) to give the title compound. LC / MS = 206 [M+1].

[0278] Step B: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-5-vinylin Dolin-2-one Under nitrogen atmosphere, 6-fluoro-3,3-dimethyl-5-vinylindoline-2-one (200 mg, 0.98 mmol), CuI (93 mg, 0.49 mmol), potassium carbonate (404 mg, 2.92 mmol), 4-bromo-2-(2,2-difluoroethoxy)-5-fluoropyridine (499 mg, 1.95 mmol) and ( 1R, 2R )- N1,N2 Acetonitrile (1.9 ml) was added to a stirred mixture of 1,2-dimethylcyclohexane-1,2-diamine (139 mg, 0.98 mmol). The reaction mixture was heated to 95 °C for 48 hr, then diluted with EtOAc, filtered through a silica stopper, and concentrated under vacuum. The crude residue was purified by rapid column chromatography on silica gel (0–100% EtOAc in hexane) to give the title compound. LC / MS = 381 [M+1].

[0279] Step C: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindole 5-Phosporin-5-carbaldehyde NaIO4 (112 mg, 0.526 mmol) was added to a stirred solution of 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-5-vinylindololin-2-one (50 mg, 0.131 mmol), 2,6-dimethylpyridine (30.5 µl, 0.263 mmol), and H4K2O6Os (1.21 mg, 3.29 µmol) in 1,4-dioxane (657 µl) and water (657 µl) at 0 °C. The reaction mixture was stirred at 20 °C for 3 hr. The reaction mixture was diluted with NaCl (saturated aqueous solution) and extracted with ethyl acetate. The combined organic fractions were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel (0-50% EtOAc in hexane) to give the title compound. LC / MS = 382 [M+1].

[0280] Step D: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindole 5-Lin-carboxylic acid Sodium chlorite (0.034 g, 0.38 mmol) was added to a stirred solution of 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindoline-5-carboxaldehyde (0.049 g, 0.127 mmol), 2-methylbut-2-ene (0.14 ml, 1.27 mmol), and disodium hydrogen phosphate (0.10 g, 0.83 mmol) in a mixture of t-BuOH (0.85 ml), acetone (0.85 ml), and water (0.85 ml) at 0 °C. The reaction mixture was stirred for 2 hr. The crude mixture was extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered, and evaporated under vacuum. The crude material was used directly in subsequent reactions. LC / MS = 399 [M+1].

[0281] Step E: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl- 1,1-Dioxatetrahydro-2 H (-thiaran-4-yl)-2-oxoindololin-5-carboxamide HATU (44.1 mg, 0.110 mmol) was added to 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindoline-5-carboxylic acid (44 mg, 0.110 mmol), 4-amino-4-methyltetrahydro-2H-thiaran 1,1-dioxide hydrochloride (22.06 mg, 0.110 mmol), and DIEA (57.9 µl, 0.33 mmol) in a stirred solution of DCM (1.1 mL). The reaction mixture was stirred at RT for 16 hr, diluted with EtOAc, filtered through a SiO2 stopper, and concentrated under vacuum. The crude material was purified by rapid column chromatography on silica gel (0-100% EtOAc / hexane) to give the title compound (EX-94). LC / MS = 544 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.48 (d, J = 1.2 Hz, 1H), 8.10 (s, 1H), 7.73 (d, J = 6.7 Hz, 1H), 7.30 (d, J = 4.8 Hz, 1H), 6.90 (d, J = 9.0 Hz, 1H), 6.43 (tt, J = 54.5, 3.4 Hz, 1H), 4.63 (s, 2H), 3.19–3.01 (m, 4H), 1.99 (t, J = 11.9 Hz, 2H), 1.44 (s, 9H). Signal masking at 2H. Human GAT2IC 50 = 0.6 nM.

[0282] The following compounds were synthesized using a procedure similar to that described in Example 94 and with appropriate reagents. These compounds were characterized by LC / MS.

[0283] Example 100: 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide Step A: 3,3-Dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-methyl amide Propanephosphonic anhydride (3.10 g, 4.87 mmol) was added to a stirred solution of 3,3-dimethyl-2-oxoindoline-5-carboxylic acid (1.00 g, 4.87 mmol) and 3-amino-3-methylthiocyclobutane 1,1-dioxide hydrochloride (1.26 g, 7.31 mmol) in DMF (48 mL). The reaction mixture was stirred at 20 °C for 48 h, then diluted with HCl (1 M aqueous solution) and extracted with DCM. The combined organic fractions were dried over HCl (1 M aqueous solution) and NaCl (saturated aqueous solution) and MgSO4, filtered, and concentrated under vacuum to give the title compound. LC / MS = 323 [M+1].

[0284] Step B: 3,3-Dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxo-1-(5-(trifluoro) (Methoxy)pyridin-3-yl)indoline-5-carboxamide To 3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide (50 mg, 0.16 mmol), (5-(trifluoromethoxy)pyridin-3-yl)boronic acid (64.2 mg, 0.31 mmol), and Cu(OAc)₂ (56.3 mg, 0.31 mmol) were added to a solution of DMF (310 µl) with pyridine (125 µl, 1.55 mmol). The vials were heated to 90 °C in air overnight. The reaction mixture was diluted with EtOAc, filtered through a SiO₂ stopper, and concentrated under vacuum. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 484 [M+1]. 1 H NMR (500 MHz, methanol-d4) δ 8.77 (d, J = 1.8 Hz, 1H), 8.68 (s, 1H), 8.07 (s, 1H), 7.93 (d, J = 1.5 Hz, 1H), 7.82 (dd, J = 8.3, 1.7Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 4.58 (d, J = 14.5 Hz, 2H), 4.23 (d, J =14.7 Hz, 2H), 1.83 (s, 3H), 1.54 (s, 6H). Human DGAT2 IC 50 = 372 nM.

[0285] The following compounds were synthesized using a procedure similar to that described in Example 100 and with appropriate reagents. These compounds were characterized by LC / MS.

[0286] Example 103: 1-[5-(2,2-difluoroethoxy)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thionecyclobut-3-yl)-2-oxo-indoline-5-carboxamide Under nitrogen atmosphere, 3,3-dimethyl- N A stirred mixture of (3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide (50 mg, 0.16 mmol), CuI (2.95 mg, 0.016 mmol), and potassium carbonate (42.9 mg, 0.310 mmol) was added as a solution of 3-bromo-5-(2,2-difluoroethoxy)pyridine (73.8 mg, 0.310 mmol) in acetonitrile (310 µl). 1R, 2R )- N1,N2 -Dimethylcyclohexane-1,2-diamine (4.41 mg, 0.031 mmol). The resulting solution was heated to 95 °C for 16 h, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 480 [M+1]. 1 H NMR (500 MHz, chloroform-d) δ 8.44 (s, 2H), 7.80 (d, J = 1.7 Hz, 1H), 7.64 (dd, J = 8.3, 1.8 Hz, 1H), 7.41 (t, J = 2.3Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 6.39 (s, 1H), 6.16 (tt, J = 54.7, 3.9 Hz, 1H), 4.61 (d, J = 14.5 Hz, 2H), 4.33 (td, J = 12.8, 4.0 Hz, 2H), 4.24 (d, J =14.7 Hz, 2H), 1.95 (s, 3H), 1.56 (s, 6H). Human DGAT2 IC 50 = 50 nM.

[0287] The following compounds were synthesized using a procedure similar to that described in Example 103 and with appropriate reagents. These compounds were characterized by LC / MS.

[0288] Example 119: ( R )-1'-(3-(difluoromethoxy)phenyl)- N -(3-methyl-1,1-dioxatetrahydrothiophene-3- 2'-oxospiro[cyclopropane-1,3'-indoline]-5'-formamide Step A: 5'-Bromo-1'-(3-(difluoromethoxy)phenyl)spiro[cyclopropane-1,3'-indoline]-2'-one Pyridine (0.85 mL, 10.5 mmol) was added to a stirred solution of 5'-bromospiro[cyclopropane-1,3'-indoline]-2'-one (0.50 g, 2.100 mmol), (3-(difluoromethoxy)phenyl)boronic acid (0.79 g, 4.20 mmol), and Cu(OAc)₂ (0.38 g, 2.10 mmol) in DMF (4.2 mL). The reaction mixture was stirred at 75 °C for 60 h under air, then poured into water and acidified with HCl (1 M aqueous solution). The mixture was extracted with DCM, washed with NaHCO₃ (saturated aqueous solution) and NaCl (saturated aqueous solution), dried over MgSO₄, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–40% EtOAc / hexane gradient to give the title compound. LC / MS = 381 [M+1].

[0289] Step B: 1'-(3-(difluoromethoxy)phenyl)-5'-vinylspiro[cyclopropane-1,3'-indoline]-2'-one At 20 °C, 5'-bromo-1'-(3-(difluoromethoxy)phenyl)spiro[cyclopropane-1,3'-indoline]-2'-one (0.22 g, 0.58 mmol), potassium trifluoro(vinyl)-l4-borane (0.078 g, 0.581 mmol), PdCl2(dppf) (0.043 g, 0.058 mmol), and Na2CO3 (0.19 g, 1.74 mmol) were added to a 40 mL screw-cap vial equipped with a magnetic stir bar. The vial was evacuated and backfilled three times with nitrogen. Dioxane (4.8 mL) and water (1.0 mL) were added sequentially, and the reaction mixture was heated to 90 °C for 6 hours. LCMS analysis showed a high degree of conversion to the desired product. The reactants were diluted with DCM, dried over MgSO4, filtered, and concentrated under vacuum. The title compound was obtained by rapid silica gel column chromatography of the crude residue using a 0-50% EtOAc / hexane gradient. LC / MS = 330 [M+1].

[0290] Step C: 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-formaldehyde Sodium periodate (332 mg, 1.55 mmol) was added to a stirred solution of 1'-(3-(difluoromethoxy)phenyl)-5'-vinylspiro[cyclopropane-1,3'-indoline]-2'-one (127 mg, 0.39 mmol), 2,6-dimethylpyridine (90 µl, 0.78 mmol), and K2[OsO2(OH)4] (3.57 mg, 9.70 µmol) in dioxane (1.9 mL) and water (1.9 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h. LCMS analysis showed a high degree of conversion to the desired product. The reaction mixture was diluted with NaCl (saturated aqueous solution) and extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered, and concentrated under vacuum. The crude material was subjected to rapid silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 330 [M+1].

[0291] Step D: 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid NaClO2 (0.04 g, 0.44 mmol) was added to a stirred solution of 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxaldehyde (97 mg, 0.30 mmol), 2-methylbut-2-ene (0.31 mL, 2.95 mmol), and NaH2PO4 (0.12 g, 0.96 mmol) in a mixture of t-BuOH (2.0 mL) and water (2.0 mL) at 0 °C. The reaction mixture was stirred for 16 h. The crude mixture was extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered, and evaporated under vacuum to give the title compound. LC / MS = 346 [M+1].

[0292] Step E: ( R )-1'-(3-(difluoromethoxy)phenyl)- N -(3-Methyl-1,1-dioxatetrahydrothiophene-3-yl)- 2'-Oxospiro[cyclopropane-1,3'-indoline]-5'-formamide To 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid (33.8 mg, 0.098 mmol), ( R1,1-dioxide hydrochloride (18.20 mg, 0.098 mmol) of 1,1-amino-3-methyltetrahydrothiophene (51.3 µl, 0.29 mmol) and Hunig base (51.3 µl, 0.29 mmol) were added to a stirred solution of DMF (980 µl) with HATU (39.1 mg, 0.10 mmol). The reaction mixture was stirred at RT for 16 h, diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 477 [M+1]. 1 H NMR (500 MHz, chloroform-d) δ 7.60 – 7.54 (m, 2H),7.41 (d, J = 1.6 Hz, 1H), 7.38 – 7.33 (m, 1H), 7.28 (m, 1H), 7.23 (d, J = 8.3Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.60 (t, J = 73.3 Hz, 1H), 6.28 (s, 1H), 3.65 (d, J = 13.5 Hz, 1H), 3.50 – 3.39 (m, 1H), 3.35 – 3.25 (m, 1H), 3.17 (d,J = 13.8 Hz, 1H), 3.15 – 3.06 (m, 1H), 2.27 (ddd, J = 13.8, 10.3, 8.3 Hz, 1H), 1.94 (q, J = 4.0 Hz, 2H), 1.79 (s, 3H), 1.75 (q, J = 4.1 Hz, 2H). (DGAT2IC) 50 = 118 nM.

[0293] The following compounds were synthesized using a procedure similar to that described in Example 119 and with appropriate reagents. These compounds were characterized by LC / MS.

[0294] Example 128: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(5-methyl-1,1-dioxo-thiacyclopentan-3-yl)-2-oxo-indoline-5-carboxamide Step A: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid Add 1-(difluoromethoxy)-3-iodobenzene (1.97 g, 7.31 mmol) as a solution in acetonitrile (9.8 mL) to a stirred mixture of 3,3-dimethyl-2-oxoindoline-5-carboxylic acid (1.00 g, 4.87 mmol), CuI (0.093 g, 0.49 mmol), and K₂CO₃ (2.02 g, 14.62 mmol). 1R, 2R )- N1,N2 -Dimethylcyclohexane-1,2-diamine (0.14 g, 0.98 mmol) was heated to 90 °C for 16 h. The reaction mixture was diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered through a SiO2 stopper, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0-80% EtOAc / hexane gradient to give the title compound. LC / MS = 348 [M+1].

[0295] Step B: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(5-Methyltetrahydrothiophene-3-yl)-2-oxo 5-carboxylidene indoline-5-carboxamide HATU (0.115 g, 0.30 mmol) was added to a stirred solution of 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid (0.10 g, 0.29 mmol), 5-methyltetrahydrothiophene-3-amine (0.034 g, 0.29 mmol), and Hunig base (0.15 mL, 0.86 mmol) in DCM (2.9 mL). The reaction mixture was stirred at RT for 16 h, diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum to give the crude title compound. LC / MS = 447 [M+1].

[0296] Step C: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(5-methyl-1,1-dioxatetrahydrothiophene- 3-yl)-2-oxoindoline-5-carboxamide To 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(5-methyltetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide (129 mg, 0.29 mmol) was added to a stirred solution of m-CPBA (177 mg, 0.72 mmol) in DCM (2.9 mL). The reaction mixture was stirred at RT for 0.5 h, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 479 [M+1].

[0297] Step D: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(5-methyl-1,1-dioxo-thioheterocyclic ring) pentyl-3-yl)-2-oxo-indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N A mixture of four stereoisomers of 5-methyl-1,1-dioxo-thiacyclopentan-3-yl)-2-oxo-indoline-5-carboxamide was obtained as singlet isomers EX-128a and EX-128b (rapid elution). The mixture of EX-128a and EX-128b was then purified by chiral SFC (AD-H column, 15% ethanol / CO2) to give isomer EX-128a (rapid elution). LC / MS = 479 [M+1]. 1 H NMR (500 MHz, chloroform-d) δ 7.78 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 8.3,1.7 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 7.23 (d, J =8.2 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.75 (s, 1H), 6.60 (t, J = 73.2 Hz,1H). 4.98 (s, 1H), 3.47 – 3.34 (m, 2H), 3.23 (d, J = 13.7 Hz, 1H), 2.78 –2.67 (m, 1H), 2.18 (ddd, J = 14.5, 9.1, 5.9 Hz, 1H), 1.55 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H). Human DGAT2 IC 50 = 90 nM. EX-128b (slow elution). LC / MS = 479 [M+1]. 1H NMR (500 MHz, chloroform-d) δ 7.77 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.3, 1.7 Hz, 1H), 7.57 (t, J = 8.3 Hz, 1H), 7.34 – 7.30 (m, 1H), 7.23 (d, J = 7.7 Hz, 2H), 6.94(d, J = 8.3 Hz, 1H), 6.77 – 6.43 (m, 2H), 4.94 (dt, J = 16.0, 7.9 Hz, 1H), 3.64 (dd, J = 13.9, 8.4 Hz, 1H), 3.33 – 3.20 (m, 1H), 3.07 (dd, J = 13.9, 5.6Hz, 1H), 2.82 (dt, J = 14.4, 7.5 Hz, 1H), 1.91 (ddd, J = 13.4, 11.3, 8.3 Hz, 1H), 1.54 (s, 6H), 1.47 (d, J = 6.7 Hz, 3H). Human DGAT2 IC 50 = 404.2 nM. Ex-128c (medium-speed elution). LC / MS = 479 [M+1]. 1 H NMR (500 MHz, chloroform-d) δ 7.78 (d, J = 1.6 Hz, 1H), 7.63 (dd, J = 8.3, 1.8 Hz, 1H), 7.57 (t, J = 8.2 Hz, 1H), 7.31 (d, J =8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 6.94 (d, J = 8.2 Hz, 1H), 6.79 – 6.44(m, 2H), 5.00 – 4.95 (m, 1H), 3.47 – 3.33 (m, 2H), 3.23 (d, J = 14.0 Hz, 1H),2.78 – 2.67 (m, 1H), 2.18 (ddd, J = 14.5, 9.1, 5.9 Hz, 1H), 1.55 (s, 6H), 1.45 (d, J = 7.0 Hz, 3H). Human DGAT2 IC 50 = 1935 nM. EX-128d (slow elution). LC / MS = 479 [M+1]. 1H NMR (500 MHz, chloroform-d) δ 7.77 (d, J = 1.5 Hz, 1H), 7.62 (dd, J = 8.3,1.8 Hz, 1H), 7.57 (t, J = 8.3 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.23 (d, J =7.7 Hz, 2H), 6.94 (d, J = 8.3 Hz, 1H), 6.80 – 6.43 (m, 2H), 4.95 (dq, J =15.8, 7.9 Hz, 1H), 3.64 (dd, J = 13.9, 8.4 Hz, 1H), 3.32 – 3.17 (m, 1H), 3.07(dd, J = 13.9, 5.7 Hz, 1H), 2.83 (dt, J = 14.5, 7.5 Hz, 1H), 1.91 (ddd, J =13.5, 11.3, 8.4 Hz, 1H), 1.54 (s, 6H), 1.48 (d, J = 6.7 Hz, 3H). Human DGAT2 IC 50 >10000 nM.

[0298] The following compounds were synthesized using a procedure similar to that described in Example 128 and with appropriate reagents. These compounds were characterized by LC / MS.

[0299] Example 132: 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thionecyclobut-3-yl)-2-oxo-indoline-5-carboxamide Step A: 2-(2,5-dibromophenyl)- N -(2-Fluoro-5-(trifluoromethoxy)phenyl)acetamide HATU (1.36 g, 3.57 mmol) was added to a stirred solution of 2-(2,5-dibromophenyl)acetic acid (1.00 g, 3.40 mmol) in pyridine (34.0 mL), and the reaction mixture was stirred at 50 °C for 30 min. 2-fluoro-5-(trifluoromethoxy)aniline (0.66 g, 3.40 mmol) was added by injection, and the reaction mixture was stirred at 50 °C for 16 h. The solvent was removed under vacuum. The residue was dissolved in toluene, and the solvent was removed again under vacuum. The crude material was dried and absorbed on SiO2, and rapid silica gel column chromatography using a 0–40% EtOAc / hexane gradient was performed to give the title compound. LC / MS = 470 [M+1].

[0300] Step B: 5-Bromo-1-(2-fluoro-5-(trifluoromethoxy)phenyl)indoline-2-one To 2-(2,5-dibromophenyl)- N A mixture of 1.55 g (3.29 mmol) of 2-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide, CuI (0.063 g, 0.33 mmol), and K₂CO₃ (0.91 g, 6.58 mmol) was added as a solution in acetonitrile (6.6 mL). (1R,2R)-N1,N2 -Dimethylcyclohexane-1,2-diamine (0.094 g, 0.66 mmol). The resulting reaction mixture was heated to 50 °C for 16 h, then diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered through a SiO2 stopper, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0-50% EtOAc / hexane gradient to give the title compound. LC / MS = 390 [M+1].

[0301] Step C: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-5-vinylindoline-2-one Water (4.5 mL) was added to a stirred solution of 5-bromo-1-(2-fluoro-5-(trifluoromethoxy)phenyl)indoline-2-one (1.05 g, 2.69 mmol), potassium vinyltrifluoroborate (0.43 g, 3.23 mmol), PdCl2(dppf) (0.20 g, 0.27 mmol), and K2CO3 (1.12 g, 8.08 mmol) in dioxane (22.5 mL) under nitrogen atmosphere. The reaction mixture was heated to 90 °C for 16 h, diluted with DCM, dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–50% EtOAc / hexane gradient to give the title compound. LC / MS = 338 [M+1].

[0302] Step D: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-5-vinylindoline-2-one MeI (359 µl, 5.76 mmol) was added dropwise to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-5-vinylindoline-2-one (648 mg, 1.92 mmol) and Cs₂CO₃ (1.88 g, 5.76 mmol) in DMF (7.7 mL) using a syringe. The reaction mixture was stirred at 20 °C for 1 h, then quenched with water and extracted with DCM. The combined organic fractions were washed with NaCl (saturated aqueous solution), dried over MgSO₄, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–30% EtOAc / hexane gradient to give the title compound. LC / MS = 366 [M+1].

[0303] Step E: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxaldehyde NaIO4 (1.51 g, 7.10 mmol) was added to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-5-vinylindololin-2-one (648 mg, 1.77 mmol), 2,6-dimethylpyridine (411 µl, 3.55 mmol), and K2[OsO2(OH)4] (16.34 mg, 0.044 mmol) in dioxane (8.9 mL) and water (8.9 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h, then diluted with NaCl (saturated aqueous solution) and extracted with EtOAc. The combined organic fractions were dried over MgSO4, filtered, and concentrated under vacuum. The crude substance was subjected to rapid silica gel column chromatography using a 0–50% EtOAc / hexane gradient to give the title compound. LC / MS = 368 [M+1].

[0304] Step F: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid NaClO2 (0.32 g, 3.50 mmol) was added to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxaldehyde (0.43 g, 1.17 mmol), 2-methylbut-2-ene (1.237 mL, 11.68 mmol), and NaH2PO4 (0.91 g, 7.59 mmol) in a mixture of t-BuOH (7.8 mL), acetone (7.8 mL), and water (7.8 mL) at 0 °C. The reaction mixture was then stirred at 20 °C for 16 h. The crude mixture was extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered, and evaporated under vacuum to give the crude title compound. LC / MS = 384 [M+1].

[0305] Step G: 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thio) Heterocyclic butyl-3-yl)-2-oxo-indoline-5-carboxamide HATU (20.83 mg, 0.055 mmol) was added to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid (20.0 mg, 0.052 mmol), 3-amino-3-methylthiocyclobutane 1,1-dioxide hydrochloride (8.96 mg, 0.052 mmol), and Hunig base (27.3 µl, 0.16 mmol) in DMF (522 µl), and the reaction mixture was stirred at RT for 16 h. The reaction mixture was diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, containing 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 501 [M+1]. 1 ¹H NMR (500 MHz, chloroform-d) δ 7.78 (d, J = 1.6 Hz, 1H), 7.64 (dd, J = 8.2, 1.7 Hz, 1H), 7.37 (d, J = 5.3 Hz, 3H), 6.77–6.70 (m, 1H), 6.37 (s, 1H), 4.61 (d, J = 14.3 Hz, 2H), 4.23 (d, J = 14.5 Hz, 2H), 1.95 (s, 3H), 1.57 (s, 6H). Human DGAT2 IC 50 = 51 nM.

[0306] The following compounds were synthesized using a procedure similar to that described in Example 132 and with appropriate reagents. These compounds were characterized by LC / MS.

[0307] Example 136: 7-Fluoro-3,3-Dimethyl- N -(4-methyl-1,1-dioxo-thiacyclohex-4-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indololin-5-carboxamide Step A: 7-Fluoro-3,3-Dimethyl-5-vinylindoline-2-one Water (13.0 mL) was added to a stirred solution of 5-bromo-7-fluoro-3,3-dimethylindolin-2-one (2.02 g, 7.83 mmol), potassium trifluoro(vinyl)-14-borane (1.26 g, 9.39 mmol), PdCl2(dppf) (0.57 g, 0.78 mmol), and Na2CO3 (2.49 g, 23.48 mmol) in dioxane (65.2 mL) under a nitrogen atmosphere. The reaction mixture was heated to 90 °C for 6 hours, then diluted with DCM, dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–50% EtOAc / hexane gradient to give the title compound. LC / MS = 206 [M+1].

[0308] Step B: 7-Fluoro-3,3-Dimethyl-1-(5-(trifluoromethoxy)pyridin-3-yl)-5-vinylindololin-2-one Add 3-bromo-5-(trifluoromethoxy)pyridine (590 mg, 2.44 mmol) as a solution in acetonitrile (2.4 mL) to a stirred mixture of 7-fluoro-3,3-dimethyl-5-vinylindoline-2-one (250 mg, 1.22 mmol), CuI (23.20 mg, 0.12 mmol), and K₂CO₃ (337 mg, 2.44 mmol). (1R,2R)-N1,N2 -Dimethylcyclohexane-1,2-diamine (34.7 mg, 0.24 mmol). The reaction mixture was heated to 95 °C for 16 h, then diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered through a SiO2 stopper, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using an EtOAc / hexane gradient to give the title compound. LC / MS = 367 [M+1].

[0309] Step C: 7-Fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridin-3-yl)indoline-5-carboxaldehyde Sodium periodate (803 mg, 3.76 mmol) was added to a stirred solution of 7-fluoro-3,3-dimethyl-1-(5-(trifluoromethoxy)pyridin-3-yl)-5-vinylindololin-2-one (344 mg, 0.94 mmol), 2,6-dimethylpyridine (218 µl, 1.88 mmol), and K₂[OsO₂(OH)₄] (8.65 mg, 0.023 mmol) in dioxane (4.7 mL) and water (4.7 mL) at 0 °C. The reaction mixture was stirred at 20 °C for 3 h, then diluted with NaCl (saturated aqueous solution) and extracted with EtOAc. The combined organic fractions were dried over MgSO₄, filtered, and concentrated under vacuum. The crude material was subjected to rapid silica gel column chromatography using a 0–50% EtOAc / hexane gradient to give the title compound. LC / MS = 369 [M+1].

[0310] Step D: 7-Fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridin-3-yl)indoline-5-carboxylic acid NaClO2 (0.23 g, 2.57 mmol) was added to a stirred solution of 7-fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridin-3-yl)indoline-5-carboxaldehyde (0.32 g, 0.86 mmol), 2-methylbut-2-ene (0.91 mL, 8.58 mmol), and NaH2PO4 (0.67 g, 5.58 mmol) in a mixture of t-BuOH (5.72 mL), acetone (5.7 mL), and water (5.7 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 16 h. The crude mixture was extracted with DCM. The combined organic fractions were dried over Na2SO4, filtered, and evaporated under vacuum to provide the title compound. LCMS = 385 [M+1].

[0311] Step E: 7-Fluoro-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo- 1-(5-(trifluoromethoxy)pyridin-3-yl)indoline-5-carboxamide HATU (31.2 mg, 0.082 mmol) was added to a stirred solution of 7-fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridin-3-yl)indoline-5-carboxylic acid (30 mg, 0.078 mmol), 4-amino-4-methyltetrahydro-2H-thiaran 1,1-dioxide hydrochloride (15.59 mg, 0.078 mmol), and Hunig base (40.9 µl, 0.23 mmol) in DMF (781 µl). The reaction mixture was stirred at 20 °C for 16 h. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 530 [M+1]. 1¹H NMR (500 MHz, chloroform-d) δ 8.70 – 8.60 (m, 2H), 7.68 (s, 1H), 7.56 (d, J = 1.5 Hz, 1H), 7.40 (dd, J = 11.4, 1.4 Hz, 1H), 5.68 (s, 1H), 3.23 – 3.13 (m, 2H), 3.05 (d, J = 14.5 Hz, 2H), 2.81 (d, J = 14.8 Hz, 2H), 2.46 – 2.34 (m, 2H), 1.59 (s, 6H). Human DGAT2 IC 50 = 40 nM.

[0312] The following compounds were synthesized using a procedure similar to that described in Example 136 and with appropriate reagents. These compounds were characterized by LC / MS.

[0313] Example 154: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohex-4-yl)-2-oxo-pyrrolo[2,3-] b ]Pyridine-5-carboxamide Step A: 1-(3-(difluoromethoxy)phenyl)-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate To 1 H -pyrrolo[2,3- b A stirred mixture of methyl pyridine-5-carboxylate (1.00 g, 5.68 mmol), CuI (0.11 g, 0.57 mmol), and K3PO4 (2.53 g, 11.92 mmol) was added as a solution of 1-(difluoromethoxy)-3-iodobenzene (2.30 g, 8.51 mmol) in toluene (5.7 mL). (1R,2R)-N1,N2 -Dimethylcyclohexane-1,2-diamine (0.161 g, 1.14 mmol). The resulting reaction mixture was heated to 95 °C for 16 h, then diluted with EtOAc, filtered through a SiO2 stopper, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–30% EtOAc / hexane gradient to give the title compound. LC / MS = 319 [M+1].

[0314] Step B: 3,3-Dibromo-1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate At 20 °C for 30 min, 1-(3-(difluoromethoxy)phenyl)-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (1.60 g, 5.03 mmol) in t Tribromopyridine (5.14 g, 16.09 mmol) was added in portions to a stirred solution of BuOH (40.2 mL) and dioxane (10.05 mL). After 5 hours, the reaction mixture was diluted with water and extracted with DCM. The combined organic fractions were washed with NaHCO3 (saturated aqueous solution) and NaCl (saturated aqueous solution), dried over MgSO4, filtered, and concentrated under vacuum to give the crude title compound. LC / MS = 491 [M+1].

[0315] Step C: 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1 H -pyrrolo[2,3- b ]Pyridine-5- Methyl formate Within 30 min, 3,3-dibromo-1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (2.46 g, 5.00 mmol) was added in portions to a stirred suspension of acetic acid (25 mL) with zinc (3.27 g, 50.0 mmol). The suspension became solid, and the mixture was sonicated for 3 h. A second portion of zinc (3.27 g, 50.0 mmol) was added, and the reaction mixture was sonicated again for 1 h. The reaction mixture was diluted with DCM, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–50% EtOAc / hexane gradient to give the title compound. LC / MS = 335 [M+1].

[0316] Step D: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1 H -pyrrolo[2, 3- b Methyl pyridine-5-carboxylate 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1- H -pyrrolo[2,3- bMethyl pyridine-5-carboxylate (300 mg, 0.90 mmol) and Cs₂CO₃ (877 mg, 2.69 mmol) were added dropwise to a stirred solution of DMF (3.6 mL) with MeI (168 µl, 2.69 mmol). The reaction mixture was stirred at 20 °C for 1 h, then quenched with water and extracted with DCM. The combined organic fractions were washed with NaCl (saturated water-soluble), dried over MgSO₄, filtered, and concentrated under vacuum. The crude residue was subjected to rapid silica gel column chromatography using a 0–40% EtOAc / hexane gradient to give the title compound. LC / MS = 363 [M+1].

[0317] Step E: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1 H -pyrrolo[2, 3- b ]Pyridine-5-carboxylic acid To 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1 H -pyrrolo[2,3- b Methyl pyridine-5-carboxylate (0.33 g, 0.90 mmol) and LiOH (0.22 g, 9.00 mmol) were reacted with water (1.5 mL) in a stirred solution of THF (6.1 mL) and methanol (3.0 mL). The reaction mixture was stirred at 20 °C for 3 h, then acidified with 1 M HCl, diluted with water, and extracted with DCM. The combined organic fractions were dried over MgSO4, filtered, and concentrated under vacuum to give the title compound. LC / MS = 349 [M+1].

[0318] Step F: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thioheterocyclic ring) (hexyl-4-yl)-2-oxo-pyrrolo[2,3-) b ]Pyridine-5-carboxamide To 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1 H -pyrrolo[2,3- b Pyridine-5-carboxylic acid (25 mg, 0.072 mmol), 4-amino-4-methyltetrahydro-2-carboxylic acid H 1,1-thiaran dioxide (11.72 mg, 0.072 mmol) and Hunig base (37.6 µl, 0.22 mmol) were added to a stirred solution of DMF (718 µl) with HATU (28.7 mg, 0.075 mmol). The reaction mixture was stirred at RT for 16 h, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-triggered reversed-phase HPLC (ACN / water, with 0.1% formic acid modifier) ​​to give the title compound. LC / MS = 494 [M+1]. 1H NMR (500 MHz, chloroform-d) δ 8.51 (d, J =2.1 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.51 – 7.46(m, 1H), 7.42 (s, 1H), 7.21 (d, J = 8.3 Hz, 1H), 6.60 (t, J = 73.5 Hz, 1H), 5.71 (s, 1H), 3.22 – 3.12 (m, 2H), 3.04 (d, J = 14.5 Hz, 2H), 2.80 (d, J =15.1 Hz, 2H), 2.45 – 2.32 (m, 2H), 1.62 (s, 3H), 1.57 (d, J = 3.6 Hz, 6H). ΔGAT2 IC50 = 161 nM.

[0319] The following compounds were synthesized using a procedure similar to that described in Example 154 and with appropriate reagents. These compounds were characterized by LC / MS.

[0320] Measurement Insect cell expression and membrane preparation Sf-9 insect cells were maintained at 27°C in a shaking incubator in Grace insect cell culture medium containing 10% heat-inactivated fetal bovine serum, 1% Pluronic F-68, and 0.14 µg / ml kanamycin sulfate. Cells were harvested 48 hours after infection with unlabeled baculovirus expressing human DGAT2 (hDGAT2) at an infection ratio (MOI) of 3. Cell aggregates were resuspended in buffer containing 10 mM Tris-HCl pH 7.5, 1 mM EDTA, 250 mM sucrose, and a complete protease inhibitor mixture (Sigma-Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2000 xg for 15 min. Membrane fractions were separated by ultracentrifugation (100,000 xg), resuspended in the same buffer, and frozen (-80°C) for later use. Protein concentrations were determined using the Pierce™ BCA Protein Assay Kit (Thermo Fisher Scientific). Immunoblotting was performed using rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa Fluor. ®647 (Abcam, ab150075) was then analyzed for protein expression levels using a Typhoon FLA9000 (GE Healthcare) assay.

[0321] LC / MS / MS analysis methods LC / MS / MS analysis was performed using a Thermal Fisher LX4-TSQ Vantage system. This system consisted of an Agilent binary high-performance liquid chromatography (HPLC) pump and a TSQ Vantage triple quadrupole MS / MS instrument. For each sample, 2 µL of sample from the top organic layer of 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 under the following conditions: mobile phase: isopropanol: acetonitrile / 10 mM ammonium formate = 50 / 35 / 15 (v / v / v), flow rate: 0.8 mL / min, temperature: 25 °C. Data were acquired in positive mode using a heated electrospray ionization (HESI) interface. The operating parameters of the TSQ Vantage MS / MS instrument were: spray voltage 3000 V, capillary temperature 280 °C, evaporator temperature 400 °C, sheath gas 45 units (any), auxiliary gas 10 units (any), lens 165 S, and collision gas 1.0 mTorr. Collected in 33 seconds 13 C 18 - Trioleic acid glycerides (Q1: 922.8 > Q3: 621.3) and internal standard 13 C 21 Chromatogram of standard reference material (SRM) for triolein (Q1: 923.8 > Q3: 117.3). Peak areas were integrated using Xcalibur Quan software. The peak areas generated in the reactants... 13 C 18 - Trioleic acid glycerides and internal standards were added 13 C 21 The ratio between trioleic acid glycerides is used to generate the inhibition percentage and IC50. 50 Value. The percentage of inhibition by the compound is calculated using the following formula: Inhibition % = 1 - [(Compound response - Low control) / (High control - Low control)] x 100%. The effective compound is titrated and the IC50 is calculated using a 4-parameter S-curve fitting formula. 50 .

[0322] DGAT2 enzyme activity assay DGAT2 activity was measured by preparing the enzyme product using the above-mentioned membrane. 13 C 18 -trioleylglycerol ( 13The assay was performed using C-1,2,3-tris(cis-9-octadecenoyl)glycerol. The assay was conducted at rt in ABgene 384-well plates with a final volume of 25 µL. The assay mixture contained the following: assay buffer (100 mM Tris-Cl, pH 7.0, 20 mM MgCl2, 5% ethanol), 25 µM dioleylglycerol, 5 µM... 13 C-oleoyl-CoA and 8 ng / µL DGAT2 membrane.

Claims

1. A compound of formula I: or its pharmaceutically acceptable salt, wherein: X, Y, and Z are independently selected from N or C(R). 5 ); R 1 yes (1) Unsubstituted or by 1, 2 or 3 R 6 Substituted phenyl, (2) A 5- or 6-membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, wherein the heteroaryl group is unsubstituted or surrounded by 1, 2 or 3 R atoms. 6 Replace, or (3) An 8- to 10-membered fused heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is unsubstituted or substituted by 1, 2, or 3 R atoms. 6 replace; R 2a and R 2b Selected independently (1) Hydrogen, (2) Halogen, (3) Hydroxyl group (4) (C) 1-6 )alkyl, (5) (C) 1-6 ) Haloalkyl, (6) R 2a and R 2b Combining to form a spiral (C 3-8 )cycloalkyl, which is unsubstituted or optionally C 1-3 Alkyl, halogen, OH mono- or di-substituted, or (7) R 2a and R 2b These combine to form a spirocyclic 4- to 8-membered heterocyclic group containing one or two independent heteroatoms selected from N, O, and S, wherein the heterocyclic group is unsubstituted or surrounded by one, two, or three R atoms. 7 replace; R 3 yes (1) A 4- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2) A 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (3)-(C 1-6 ) alkyl-heteroaryl, wherein the heteroaryl group is a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, (4)-(C 1-6 alkyl-aryl, (5)-(C 1-6 ) alkyl-heterocyclic group, wherein the heterocyclic group is a 3- to 6-membered ring containing one or two heteroatoms independently selected from N, O, and S, (6)-(C 1-6 )alkyl, (7)-(C 3-6 )cycloalkyl, (8)-(C 1-6 )hydroxyalkyl, (9)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b ,or (10)-(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl, Each cycloalkyl or heterocyclic group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl, aryl, or heteroaryl group is unsubstituted or surrounded by 1, 2, or 3 R groups. 10 replace; R 4 yes (1) Hydrogen, (2) (C) 1-3 )alkyl, Or R 3 and R 4 Together with the nitrogen atom to which it is attached, it forms a monocyclic or bicyclic heterocyclic base ring containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclic base ring is unsubstituted or surrounded by one, two, or three R atoms. 11 replace, When it exists, each R 5 Selected from (1) Hydrogen, (2) (C) 1-3 )alkyl, (3) (C) 1-3 ) Haloalkyl, (4) Cyano group, or (5) Halogen, When it exists, each R 6 Selected independently (1) Cyano group (2) Halogen, (3)-OC 1-6 alkyl (4) (C) 3-6 )cycloalkyl groups, which are optionally substituted with halogens or OH, (5)-(C=O)NH2, (6) (C) 3-6 )cycloalkyloxy group, wherein the cycloalkyl group is optionally substituted with a halogen or OH, (7) Hydroxyl group (8)-NR 11 R 11 , (9)-NH(C=O)(C 1-6 )alkyl, (10) (C) 2-6 Cyclic amines, optionally substituted with one or two halogen substituents, (11) (C) 1-6 )haloalkyl- (12) O(C) 1-6 ) Haloalkyl-, optionally substituted with OH, (13)-O(C) 0-3 )alkyl-(C 3-6 )cycloalkyl groups, optionally substituted with one or two halogens, (14)-SO2(C 1-6 )alkyl, (15)-SO2NH(C 1-6 )alkyl, (16)-SC 1-6 alkyl, (17)-SC 1-6 Halogenated alkyl, or (18) (C) 1-6 )alkyl, When it exists, each R 7 Selected independently (1) (C) 1-3 )alkyl, (2) Halogen, (3) (C) 1-3 )alkoxy, (4) (C) 1-3 ) Haloalkyl-, or (5) Hydroxyl group, When it exists, R 8a and R 8b Selected independently (1) Hydrogen, (2) (C) 1-3 )alkyl, or (3) (C) 3-7 )cycloalkyl; When it exists, each R 9 Selected independently (1) (C) 1-3 )alkyl, (2) (C) 1-3 ) Haloalkyl-, (3) Oxygenation, (4) (C) 3-6 )cycloalkyl, (5)-N(R 11 )2, (6) Hydroxyl group (7) (C) 1-3 )alkoxy-, (8) Cyano group (9) Halogen, (10)-SO2(C 1-6 )alkyl, (11)-(C 1-6 )alkylSO2(C 1-6 )alkyl, (12)-C(O)(C 1-3 )alkyl, or (13) O(C) 1-3 )alkyl, When it exists, R 10 Selected independently (1) Hydrogen, (2) (C) 1-3 )alkyl, (3) (C) 1-3 )alkoxy-, (4) Hydroxyl group (5) Halogen, (6) (C) 1-3 )alkyl-S-, (7) (C) 1-3 ) Haloalkyl-, or (8)N(R 11 )2, R 11 When it exists, it is independent. (1) Hydrogen, or (2) (C) 1-3 )alkyl.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 yes a. A phenyl group optionally substituted with one to three independent substituents selected from the following: halogen, hydroxyl, CN, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, C groups optionally substituted with halogens or OH groups 3-6 cycloalkyl, -OC 1-3 Alkyl groups, optionally substituted with OH, -OC 1-3 Halogenated alkyl groups, -OC 3-6 cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-3 Alkyl group, -NH(C=O)C 1-3 Alkyl group, C(O)NH2, S(O)2NHC 1-3 Alkyl, N(R) 11 )2 or optionally substituted with one or two halogen substituents; b. A 6-membered heteroaryl group containing one or two nitrogen atoms, which is substituted by one or two substituents independently selected from: halogen, hydroxyl, C. 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl groups, optionally substituted with 1-2 halogens, OC 0-3 Alkyl-C 3-6 Cycloalkyl, optionally substituted with 1-2 halogens, nitrogen-containing heterocyclic butyl, CN, -SC 1-3 Alkyl or -SC 1-3 Halogenated alkyl groups; c. A 5-membered heteroaryl group containing one to four nitrogen atoms or heteroatoms independently selected from N, O, and S, optionally substituted by one or two substituents independently selected from: halogens, (C... 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 ) Haloalkyl-, -OH, OC 1-3 Alkyl groups, optionally substituted with one or two halogens, OC 0-3 Alkyl-C 3-6 cycloalkyl, O(C) 1-3 ) Haloalkyl-, O(C 1-3 ) Haloalkyl-OH, or a nitrogen-containing heterocyclic butyl group optionally substituted with one or two halogens; or d. An 8- to 10-membered fused heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is unsubstituted or halogenated, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 ) Haloalkyl-, OH or OC 1-3 Alkyl substitution.

3. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, wherein R 1 yes a. Phenyl groups substituted with the following substituents: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -O-cyclopropyl, optionally substituted with halogen or hydroxyl, -SC 1-3 Alkyl, -SC 1-3 Halogenated alkyl groups, S(O)₂NHCH₃, S(O)₂C 1-3 Alkyl group, -NH(C=O)C 1-3 Alkyl, CN, azahexacyclobutyl, C(O)NH2, N(CH3)2, optionally substituted with one or two fluorine substituents, and wherein the phenyl group is optionally further substituted with one or two fluorine atoms; b. A 6-membered heteroaryl group containing one or two nitrogen atoms, which is substituted by one or two substituents selected from the following: C 1-3 Alkyl, C 1-3 Halogenated alkyl groups, -OC 1-3 Alkyl groups, optionally substituted with hydroxyl groups -OC 1-3 Haloalkyl, -O-cyclopropyl, optionally substituted with halogen or hydroxyl, -OC 1-3 Alkyl-C 3-6 cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, nitrogen-containing heterocyclic butyl groups optionally substituted with one or two fluorine groups, halogen, -OC 1-3 Alkyl-OH, -OC 1-3 Halogenated alkyl-OH, wherein the 6-membered heteroaryl group is optionally further substituted with 1 or 2 fluorine atoms or CH3; c. A 5-membered heteroaryl group containing one to four nitrogen atoms or heteroatoms independently selected from N, O, and S, optionally substituted by one or two substituents independently selected from: halogens, (C... 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 ) Haloalkyl-, -OH, OC 1-6 Alkyl groups, optionally substituted with one or two halogens, OC 0-3 Alkyl-C 3-6 cycloalkyl, O(C) 1-3 ) Haloalkyl-, O(C 1-3 ) Haloalkyl-OH, or a nitrogen-containing heterocyclic butyl group optionally substituted with 1 to 2 fluorine substituents; or d. Containing one or two independent heteroatoms selected from nitrogen or oxygen, of a 9- or 10-membered fused heteroaryl group, optionally substituted with a methyl group.

4. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a phenyl group substituted with a substituent selected from the following: -OH, -CH3, -CF2CH3, -OCHF2, -OCH2CH3, -OCH(CH3)2, -OCF2CH3, -OCF2CHF2, -OCH2CHF2, -OCF3, O-cyclopropyl, cyclopropyl, -SCHF2, CN, F, S(O)2NHCH3, C(O)NH2, S(O)2CH3, N(CH3)2, -NH(C=O)CH3, aziridine, or 3,3-difluoroaziridine, wherein the phenyl group is optionally further substituted with one or two fluorine atoms.

5. The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is a pyridinyl group substituted with one or two independent substituents selected from the following: F, OH, -CH3, -CF2CH3, -OCH(CH3)2, OCHF2, -OCH2CH3, -OCF2CH3, -OCF2CHF2, -OCH2CH(CH3)2, -OCH2CHF2, -OCH2CF3, -OCF3, cyclopropyl, O-cyclopropyl, O-CH2-cyclopropyl optionally substituted with 1 or 2 F, O-CH2-cyclobutyl optionally substituted with 2 F, OCH2CF2CH3, OCH2CF2CHF2, OCF2CH2OH, aziridine, 3,3-difluoroaziridine, or -SCHF2.

6. The compound according to any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b It is selected from one of the following: a. R 2a and R 2b It's hydrogen. b. R 2a It is hydrogen and R 2b Yes (C) 1-6 )alkyl, or R 2a Yes (C) 1-6 )alkyl and R 2b It's hydrogen. c. R 2a It is halogen and R 2b Yes (C) 1-6 )alkyl, or R 2a Yes (C) 1-6 )alkyl and R 2b It's halogen. d. R 2a It is hydroxyl and R 2b Yes (C) 1-6 )alkyl, or R 2a Yes (C) 1-6 )alkyl and R 2b It is a hydroxyl group. e. R 2a It is hydroxyl and R 2b Yes (C) 1-6 ) Haloalkyl, or R 2a Yes (C) 1-6 ) Haloalkyl and R 2b It is a hydroxyl group. f. R 2a and R 2b Each is independently selected from (C) 1-6 )alkyl, g. R 2a and R 2b These combine to form a spirocyclic 4- to 8-membered heterocyclic group containing one or two independent heteroatoms selected from N, O, and S, wherein the heterocyclic group is unsubstituted or surrounded by one, two, or three R atoms. 7 Replace, or h. R 2a and R 2b Combining to form a spiral (C 3-8 )cycloalkyl, which is unsubstituted or optionally C 1-6 Alkyl, halogen, or OH mono- or di-substituted.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b Independently selected from H and C 1-3 Alkyl groups, or together forming spirochetes 1-6 Cycloalkyl.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from (1) A 4- to 7-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2) A 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (3)-(C 1-6 ) alkyl-heteroaryl, wherein the heteroaryl group is a 5- or 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, (4)-(C 1-6 alkyl-aryl, (5)-(C 1-6 )-Heterocyclic group, wherein the heterocyclic group is a 3- to 6-membered ring containing one or two heteroatoms independently selected from N, O, and S, (6)-(C 1-6 )alkyl, (7)-(C 3-6 )cycloalkyl, (8)-(C 1-6 )hydroxyalkyl, (9)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b ,or (10)-(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl, (11)-(C 1-6 Alkyl-heterocyclic group, wherein the heterocyclic group is a 5-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. Each aryl, heteroaryl, cycloalkyl, or heterocyclic group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl, aryl, or heteroaryl group is unsubstituted or surrounded by 1, 2, or 3 R groups. 10 replace.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R 3 yes (1) A 4- to 6-membered heterocyclic group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S. (2)-(C 3-6 )cycloalkyl, (3)-(C 1-6 )hydroxyalkyl, (4)-(C 1-6 )alkyl-S(O)2-NR 8a R 8b , (5)-(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl, (6) (C) 1-6 )alkyl-heterocyclic group, wherein the heterocyclic group is a 5-membered heterocyclic group containing one O heteroatom, (7) A 5- to 6-membered heteroaryl group containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or (8) (C) 1-6 )alkyl-heteroaryl, wherein the heteroaryl is a 5-membered heteroaryl containing 2 N heteroatoms, Each cycloalkyl or heteroaryl group is unsubstituted or surrounded by 1, 2, or 3 R groups. 9 Substitution, wherein each alkyl group is unsubstituted or substituted with 1, 2 or 3 R groups. 10 replace.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 3 yes .

11. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 3 yes .

12. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 3 yes .

13. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R 3 yes .

14. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein R 4 It's H.

15. The compound according to any one of claims 1-14, or a pharmaceutically acceptable salt thereof, wherein R 5 It is H, F, Cl, or CN.

16. The compound according to any one of claims 1-15, or a pharmaceutically acceptable salt thereof, wherein R 6 It contains halogens, hydroxyl groups, CN, and -C. 1-6 Alkyl, -C 1-6 Haloalkyl, -C optionally substituted with halogen or OH 3-6 cycloalkyl, -OC 1-6 Alkyl groups, optionally substituted with OH, -OC 1-6 Haloalkyl groups, optionally substituted with one or two halogen substituents, -O(C 1-3 )alkyl-(C 3-6 )cycloalkyl, -OC 3-6 cycloalkyl, -SO2NH(C 1-6 )alkyl, -S(O)2C 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 Halogenated alkyl groups or NH(C=O)C 1-3 Alkyl groups, optionally substituted with one or two halogen substituents (C 2-6 )cyclic amines, N(C 1-3 )alkyl, -O(C 3-6 )cycloalkyl.

17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-16, wherein R 6 It is F, CN, OH, -CH3, -CF2CH3, -OCF2CH3, -OCHF2, -OCF3, OCH2CF3, -OCH2CH3, OCH(CH3)2, -OCF2CHF2, -OCH2CHF2, -OCHF2CH3, OCH2CF2CH3, OCH2CH(CH3)2, OCH2CF2CHF2, -cyclopropyl, -O-cyclopropyl, OCH2-cyclopropyl optionally substituted with 1 or 2 F, OCH2-cyclobutyl optionally substituted with 1 or 2 F, azacyclobutyl optionally substituted with 1 or 2 F, -SCHF2, S(O)2CH3, S(O)2NHCH3, C(O)NH2, N(CH3)2, OCF2CH2OH or -NH(C=O)C 1-3 alkyl.

18. The compound according to any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b It is independently selected from hydrogen and cyclohexyl.

19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, wherein R 9 =O, -OH, halogen, OC 1-3 Alkyl, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl OH, -SO2(C 1-3 )alkyl or -C( 1-3 )alkylSO2(C 1-3 alkyl, C(O)C 1-3 alkyl.

20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, wherein R 10 It is hydrogen, OH, CH3, CH2CH3, F, CF3, CH2OH, or CH2SO2CH3.

21. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein X is N and Y is C(R) 5 Z and C(R) are C(R) 5 ).

22. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein X is a C(R) compound. 5 Y is N and Z is C(R) 5 ).

23. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein X, Y, and Z are each C(R) 5 ).

24. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-20, wherein X is N, Y is N and Z is C(R) 5 ).

25. A compound selected from: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , or , Or its pharmaceutically acceptable salt.

26. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3-isopropyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1'-(3-(difluoromethoxy)phenyl)- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2'-oxospiro[cyclobutane-1,3'-indoline]-5'-formamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl- N -(( S )-3-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, ( S )-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl -N -(( S )-3-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-(3-methyl-1,1-dioxo-thiacyclopentan-3-yl)-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -[(1 S ,2 R )-2-hydroxycyclopentyl]-3,3-dimethyl-2-oxo-indoline-5-carboxamide, 3,3-Dimethyl- N -[(3 S [3-Methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide, 3,3-Dimethyl- N -[(3 R [3-Methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide, 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]- N -[4-(hydroxymethyl)tetrahydropyran-4-yl]-3,3-dimethyl-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide 3,3-Dimethyl- N -[(3 R [5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide, 3,3-Dimethyl- N -[(3 S [5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide, 3,3-Dimethyl- N -(4-methyl-1,1-dioxo-thiacyclohexyl-4-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)- N -(4-hydroxy-2-methylpentan-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)- N -(4-hydroxy-2-methylpentan-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[2-(2,2-difluoroethoxy)pyrimidin-4-yl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-(3-quinolinyl)indoline-5-carboxamide N -[2-(cyclohexylaminosulfonyl)ethyl]-1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[1-(methylsulfonylmethyl)cyclohexyl]-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -(3-ethyl-1,1-dioxo-thiocyclobut-3-yl)-3,3-dimethyl-2-oxo-indoline-5-carboxamide 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexane-4-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-(3-methyl-1,1-dioxo-thiacyclopentan-3-yl)-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -(3,3-difluoro-1-methyl-cyclobutyl)-3,3-dimethyl-2-oxo-indoline-5-carboxamide 3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide 1-[5-(difluoromethoxy)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(5-ethoxy-3-pyridyl)-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide, 1-[5-(2,2-difluoroethoxy)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethylthio)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[2-(2,2-difluoroethoxy)-5-fluoro-4-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(2,2-difluoroethoxy)-2,3-difluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(2,2-difluoroethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[6-(2,2-difluoroethoxy)pyrazin-2-yl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethylthio)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(1,1-difluoroethyl)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(1,1-difluoroethoxy)-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(2,2-difluoroethoxy)-2-methyl-3-pyridyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide ( R )-1'-(3-(difluoromethoxy)phenyl)- N -(3-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-formamide 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1'-[3-(difluoromethoxy)phenyl]- N -[(3 R [3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-formamide, 1'-[3-(difluoromethoxy)phenyl]- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-formamide 1'-[3-(difluoromethoxy)phenyl]- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-formamide 1'-[3-(difluoromethoxy)phenyl]- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2'-oxo-spiro[cyclopropane-1,3'-indoline]-5'-formamide 1'-[3-(difluoromethoxy)phenyl]- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2'-oxo-spiro[cyclopropane-1,3'-indoline]-5'-formamide 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 4 R )-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 4 R )-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 4 S )-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 4 S )-4-methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 5 R 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 5 R 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 S 5 S 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((3 R 5 S 5-Methyl-1,1-dioxatetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 S ,2 R )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 R ,2 R )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 S ,2 S )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -((1 R ,2 S )-2-(methylsulfonyl)cyclopentyl)-2-oxoindoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]- N -(1,1-Dimethyl-2-methylsulfonyl-ethyl)-3,3-dimethyl-2-oxo-indoline-5-carboxamide 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 7-Fluoro-3,3-Dimethyl- N -(4-methyl-1,1-dioxo-thiacyclohexyl-4-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-indoline-5-carboxamide, 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohexyl-4-yl)-2-oxo-indoline-5-carboxamide 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thionecyclobut-3-yl)-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohex-4-yl)-2-oxo-pyrrolo[2,3-] b ]Pyridine-5-carboxamide, 7-Fluoro-3,3-Dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide 7-Fluoro-3,3-Dimethyl- N -[(3 R [3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide, 7-Fluoro-3,3-Dimethyl- N -[(3 S [3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indoline-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(4-methyl-1,1-dioxo-thiocyclohex-4-yl)-2-oxo-pyrrolo[2,3-] b ]Pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thionecyclobut-3-yl)-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 R )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl- N -[(3 S )-3-methyl-1,1-dioxo-thiacyclopentan-3-yl]-2-oxo-pyrrolo[2,3- b ]Pyridine-5-carboxamide, 3,3-Dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-1-(2-methylbenzo[d]oxazol-6-yl)-2-oxoindoline-5-carboxamide, 1-[6-(2,2-difluoroethoxy)pyridazin-4-yl]-3,3-dimethyl- N -(3-methyl-1,1-dioxo-thiocyclobut-3-yl)-2-oxo-indoline-5-carboxamide 1-(2-(3,3-difluoroazacyclobut-1-yl)-3-fluoropyridin-4-yl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(4-acetamido-3-hydroxyphenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( R )- N -(1-(2,2-difluoroethyl)-3-methylpiperidin-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1-(methylsulfonyl)piperidin-3-yl)-2-oxoindoline-5-carboxamide, ( R )- N -(1-acetyl-3-methylpiperidin-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)- N -(4-methoxy-4-(trifluoromethyl)cyclohexyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 7-Cyano-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiam-4-yl)-2-oxo-2,3-dihydro-1 H -Pyrrolo[2,3-c]pyridine-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 7-(3-(difluoromethoxy)phenyl)-5,5-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine-3-carboxamide 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)indoline-5-carboxamide, 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-ethoxy-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4-(2,2,2-trifluoroethoxy)pyridin-2-yl)indoline-5-carboxamide, 1-(4-(2,2-difluoropropoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(4-(2,2,3,3-tetrafluoropropoxy)pyridin-2-yl)indoline-5-carboxamide, 1-(4-((2,2-difluorocyclopropyl)methoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-((3,3-difluorocyclobutyl)methoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-Cyclopropoxypyridin-2-yl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(difluoromethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(6-(2,2,2-trifluoroethoxy)pyrimidin-4-yl)indoline-5-carboxamide, 1-(5-(difluoromethoxy)pyridin-3-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-2-oxo-1-(5-(trifluoromethoxy)pyridin-3-yl)indoline-5-carboxamide, 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(difluoromethoxy)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(2-(2,2-difluoroethoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(1-((methylsulfonyl)methyl)cyclobutyl)-2-oxoindoline-5-carboxamide, 1-(4-(2,2-difluoroethoxy)-3-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(2,2-difluoropropoxy)-5-fluoropyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-(2,2-difluoroethoxy)pyridazine-3-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)pyrimidin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(6-(2,2-difluoroethoxy)pyrimidin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-(azacyclobut-1-yl)-2-fluorophenyl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-Isopropoxypyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-((1-fluorocyclopropyl)methoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(cyclopropylmethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-Isobutoxypyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(1,1-difluoroethyl)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-fluoro-4-(1,1,2,2-tetrafluoroethoxy)pyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(5-(1,1-difluoro-2-hydroxyethoxy)pyridin-3-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(2-(3,3-difluoroazacyclobut-1-yl)-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoropropoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(difluoromethoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)pyridin-2-yl)-6-fluoro-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(difluoromethoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoropropoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(4-(2,2-difluoroethoxy)-5-fluoropyridin-2-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide N -(4-(difluoromethyl)-1,1-dioxatetrahydro-2 H (-thiaran-4-yl)-1-(2-ethoxy-5-fluoropyridin-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(5-fluoro-2-isopropoxypyridin-4-yl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)- N -((3-hydroxytetrahydrofuran-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl- N -(5-methyl-1,3,4-thiadiazol-2-yl)-2-oxoindoline-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)- N -((1-ethyl-1 H pyrazol-4-yl)methyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide 1-(3-Cyclopropylphenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-Isopropoxyphenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-Fluorophenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 1-(3-Cyanophyn)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxo-3-(trifluoromethyl)indoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxo-3-(trifluoromethyl)indoline-5-carboxamide ( R )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide ( S )-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 1-(3-(difluoromethoxy)phenyl)-3-methyl- N -(3-methyl-1,1-dioxathionecyclobut-3-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiam-4-yl)-1-(3-( N (-Methylaminosulfonyl)phenyl)-2-oxoindoline-5-carboxamide 1-(3-Carbamoylphenyl)-3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide 3,3-Dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H -thiaran-4-yl)-1-(3-(methylsulfonyl)phenyl)-2-oxoindoline-5-carboxamide, or 1-(3-(dimethylamino)phenyl)-3,3-dimethyl- N -(4-methyl-1,1-dioxatetrahydro-2- H (-thiaran-4-yl)-2-oxoindoline-5-carboxamide.

27. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein: , , , , , , , or .

28. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein: , , , Or, or a pharmaceutically acceptable salt thereof.

29. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

30. The compound of claim 25 or a pharmaceutically acceptable salt thereof, which is .

31. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

32. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

33. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

34. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

35. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

36. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

37. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein... .

38. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

39. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

40. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, which is .

41. A composition for treating conditions selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease, and heart failure, comprising a compound according to any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

42. A composition comprising a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40.

43. A method for treating conditions selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal disease, and heart failure, comprising administering to a patient in need a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40.

44. Use of any compound of any one of claims 1 to 40 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating conditions selected from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, cardiorenal diseases and heart failure.

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