Preparation of oxindole derivatives as novel diacylglyceride o-acyltransferase 2 inhibitors
Patent Information
- Authority / Receiving Office
- KR · KR
- Patent Type
- Applications
- Current Assignee / Owner
- Filing Date
- 2021-10-06
- Publication Date
- 2026-08-12
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Figure PAT00118_ABST
Abstract
Description
Technology Field
[0001] The present invention relates to a novel pharmaceutical compound that inhibits diacylglyceride O-acyltransferase 2 ("DGAT2") and may be useful for preventing, treating, or acting as a reversal agent for hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic diseases such as chronic kidney disease and heart failure, and related diseases and conditions, as well as a method for preparing a pharmaceutical composition comprising such compound and a pharmaceutical carrier. Background Technology
[0002] Triacylglycerols ("TG") perform various functions in living organisms. One of these functions of TG is energy storage. TG also plays a role in the synthesis of membrane lipids. In cells, TG synthesis can protect cells from the potential toxic effects of excess fatty acids ("FA"). In intestinal and hepatocytes, TG is synthesized for the assembly and secretion of lipoproteins that transport FA between tissues. TG acts as the surface moisture barrier of the skin, and in adipose tissue, TG provides insulation within the organism.
[0003] The glycerol phosphate and monoacylglycerol pathways are the major pathways for the biosynthesis of TG. 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 the acyl-CoA:diacylglycerol acyltransferase ("DGAT") enzyme. Two types of DGAT enzymes, DGAT1 and DGAT2, have been identified. Although DGAT1 and DGAT2 catalyze the same reaction, they differ significantly at the level of DNA and protein sequences. DGAT2 can synthesize TG in in vitro assays using endogenous fatty acids, whereas DGAT1 appears to be more dependent on exogenous fatty acids (Yen et al., J. Lipid Research, 2008, 49, 2283). Inactivation of DGAT2 impairs cytosolic lipid droplet growth, whereas inactivation of DGAT1 has the opposite effect. (Li et al., Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1080).
[0004] DGAT2 is an endogenous membrane protein of the endoplasmic reticulum and is strongly expressed in adipose tissue and the liver. DGAT2 appears to be the dominant DGAT enzyme controlling TG homeostasis in vivo. DGAT2-deficient mice survive for only a few hours after birth. On the other hand, DGAT1-deficient mice are viable (Yen et al., J. Lipid Research, 2008, 49, 2283).
[0005] Despite this perinatal lethal phenotype, the metabolic role of DGAT2 has been largely understood through efforts utilizing antisense oligonucleotides (ASOs) in rodents. In this setting, DGAT2 knockdown in ob / ob mice with DGAT2 gene-specific ASOs induced a dose-dependent reduction in very low-density lipoprotein ("VLDL") and a decrease in plasma TG, total cholesterol, and ApoB (Liu, et al., Biochim. Biophys Acta 2008, 1781, 97). In the same study, DGAT2 antisense oligonucleotide treatment in ob / ob mice resulted in reduced body weight gain, fat weight, and liver TG content. In another study, antisense treatment in ob / ob mice improved hepatic steatosis and hyperlipidemia (Yu, et al., Hepatology, 2005, 42, 362). Another study showed that diet-induced hepatic steatosis and insulin resistance were improved by knocking down DGAT2 in rats. These effects appear to be specific to the inhibition of DGAT2, as ASOs did not induce similar beneficial effects for DGAT1. Although the molecular mechanisms supporting these observations remain uncertain, collective data suggest that inhibition of DGAT2 is associated with decreased expression of lipidogenic genes (SREBP1c, ACC1, SCD1, and mtGPAT) and increased expression of oxidative / thermogenic genes (CPT1, UCP2) (Choi et al., J. Bio. Chem., 2007, 282, 22678).
[0006] In light of the above, DGAT2 inhibitors are useful for treating diseases associated with the spectrum of metabolic syndrome, such as hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic diseases, such as chronic kidney disease and heart failure and related diseases and conditions.
[0007] DGAT2 inhibitor compounds are described in WO2021064590, WO2016036633, WO2016036636, WO2016036638, WO2018093696, WO2018093698, WO2013150416, US20150259323, WO2015077299, WO2017011276, WO2018033832, US201801628, and WO2003053363.
[0008] The present invention relates to a compound represented by the following chemical formula I, which is a DGAT2 inhibitor:
[0009]
[0010] In addition, the invention relates to salts, esters, and prodrugs that are pharmaceutically permissible. Furthermore, the invention provides a compound of Formula I, a method for preparing a pharmaceutical composition comprising the compound of Formula I, and a method for treating said diseases and conditions using said compound, comprising administering the compound of Formula I to a patient requiring treatment for hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic diseases, such as chronic kidney disease and heart failure, and related diseases and conditions. Specific details for implementing the invention
[0011] The present disclosure relates to a compound having the following structural formula I or a pharmaceutically acceptable salt thereof:
[0012]
[0013] Here:
[0014] X, Y, and Z are independently N or C(R 5 Selected from );
[0015] R 1 is the following:
[0016] (1) Unsubstituted or 1, 2 or 3 R6 phenyl substituted with, or
[0017] (2) A 5- or 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or has 1, 2, or 3 R atoms 6 Replaced with, or
[0018] (3) 8- to 10-membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or has 1, 2, or 3 R atoms 6 Replaced with;
[0019] R 2a and R 2b is independently selected from doing:
[0020] (1) Hydrogen,
[0021] (2) Halogen,
[0022] (3) Hydroxy,
[0023] (4) (C 1-6 )alkyl,
[0024] (5) (C 1-6 )haloalkyl,
[0025] (6) R 2a and R 2b is connected, unsubstituted, or arbitrarily C 1-3 Spiro(C) monosubstituted or dissubstituted with alkyl, halogen, or OH groups 3-8 )forming a cycloalkyl group, or
[0026] (7) R 2a and R 2b ... are connected to form a spiro 4- to 8-membered heterocyclyl containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or has one, two, or three R atoms 7 Substituted by;
[0027] R 3is the following:
[0028] (1) 4- to 7-membered heterocyclil containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
[0029] (2) A 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
[0030] (3) -(C 1-6 )alkyl-heteroaryl, where the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,
[0031] (4) -(C 1-6 )alkyl-aryl,
[0032] (5) -(C 1-6 )alkyl-heterocyclyl, where heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,
[0033] (6) -(C 1-6 )alkyl,
[0034] (7) -(C 3-6 )cycloalkyl,
[0035] (8) -(C 1-6 )hydroxyalkyl,
[0036] (9) -(C 1-6 )alkyl-S(O)2-NR 8a R 8b , or
[0037] (10) -(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl,
[0038] Here, each cycloalkyl or heterocyclyl is unsubstituted or has 1, 2, or 3 R 9 It is substituted with, where each alkyl, aryl, or heteroaryl is unsubstituted or has 1, 2, or 3 R 10 Replaced with;
[0039] R 4 is the following or:
[0040] (1) Hydrogen, or
[0041] (2) (C 1-3 )alkyl,
[0042] or R 3 and R 4 They combine with the nitrogen atoms to which they are attached to form a mono- or unicyclic heterocyclyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclyl ring is unsubstituted or has one, two, or three R atoms 11 Substituted by,
[0043] In cases where they exist, each R 5 is selected from the following:
[0044] (1) Hydrogen,
[0045] (2) (C 1-3 )alkyl,
[0046] (3) (C 1-3 )haloalkyl,
[0047] (4) Cyano,
[0048] (5) Halogen,
[0049] In cases where they exist, each R 6 is independently selected from doing:
[0050] (1) Cyano,
[0051] (2) Halogen,
[0052] (3) -OC 1-6 alkyl,
[0053] (4) Optionally substituted with halogen or OH (C 3-6 )cycloalkyl,
[0054] (5) -(C=O)NH2,
[0055] (6) (C 3-6 ) cycloalkyloxy, where the cycloalkyl is optionally substituted with a halogen or OH,
[0056] (7) Hydroxy,
[0057] (8) -N(R 11 )2,
[0058] (9) -NH(C=O)(C 1-6 )alkyl,
[0059] (10) Optionally substituted with 1 or 2 halogen substituents (C 2-6 )Cyclic amine,
[0060] (11) (C 1-6 )haloalkyl-,
[0061] (12) -O(C) arbitrarily substituted with OH 1-6 )haloalkyl,
[0062] (13) -O(C optionally substituted with 1 or 2 halogen substituents 0-3 )alkyl-(C 3-6 )cycloalkyl,
[0063] (14) -SO2(C 1-6 )alkyl,
[0064] (15) -SO2NH(C 1-6 )alkyl,
[0065] (16) -SC 1-6 alkyl,
[0066] (17) -SC 1-6 haloalkyl, or
[0067] (18) (C 1-6 )alkyl,
[0068] In cases where they exist, each R 7 is independently selected from doing:
[0069] (1) (C 1-3 )alkyl,
[0070] (2) Halogen,
[0071] (3) (C 1-3 )alkoxy-,
[0072] (4) (C 1-3 )haloalkyl-, or
[0073] (5) Hydroxy,
[0074] In cases where it exists, R 8a and R 8b is independently selected from doing:
[0075] (1) Hydrogen,
[0076] (2) (C 1-3 )alkyl, or
[0077] (3) (C 3-7 )cycloalkyl;
[0078] In cases where they exist, each R 9 is independently selected from doing:
[0079] (1) (C 1-3 )alkyl,
[0080] (2) (C 1-3 )haloalkyl-,
[0081] (3) Oxo,
[0082] (4) (C 3-6 )cycloalkyl,
[0083] (5) N(R 11 )2,
[0084] (6) Hydroxy,
[0085] (7) (C 1-3 )Alkoxyl-,
[0086] (8) Cyano,
[0087] (9) Halogen,
[0088] (10) -SO2(C 1-6 )alkyl,
[0089] (11) -(C 1-6 )alkyl SO2(C 1-6 )alkyl,
[0090] (12) -C(O)(C 1-3 )alkyl, or
[0091] (13) O(C 1-3 )alkyl,
[0092] In cases where it exists, R 10 is independently selected from doing:
[0093] (1) Hydrogen,
[0094] (2) (C 1-3 )alkyl,
[0095] (3) (C 1-3 )alkoxy-,
[0096] (4) Hydroxy,
[0097] (5) Halogen,
[0098] (6) (C 1-3 )alkyl-S-,
[0099] (7) (C 1-3 )haloalkyl-, or
[0100] (8) N(R 11 )2,
[0101] R 11 is to do it independently in the case where it exists:
[0102] (1) Hydrogen, or
[0103] (2) (C 1-3 )alkyl
[0104] Embodiment 1a of the present disclosure is R 1 This is a compound of the following chemical formula I, or a salt of any of the above that is permitted by constraint:
[0105] a) Halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, OC 1-3 -OC optionally substituted with alkyl or OH 1-3 Haloalkyl, -OC 3-6 Cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-3 Alkyl, -(NH(C=O)C 1-3 Alkyl, C(O)NH2, S(O)2NHC 1-3 Alkyl, N(R 11)2, or phenyl optionally substituted with 1 to 3 substituents independently selected from azetidinyl optionally substituted with 1 or 2 halogen substituents;
[0106] b) Containing 1 or 2 nitrogen atoms and halogens, hydroxyl groups, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, OC optionally substituted with 1-2 halogen substituents 0-3 Alkyl-C 3-6 Cycloalkyl, azetidinyl optionally substituted with 1-2 halogens, CN, -SC 1-3 alkyl, or -SC 1-3 A 6-membered heteroaryl substituted with one or two substituents independently selected from haloalkyls;
[0107] c) containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, and a halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 )haloalkyl-, OH or OC 1-3 OC optionally substituted with alkyl or 1-2 halogens O-3 Alkyl-C 3-6 Cycloalkyl, O(C 1-3 )haloalkyl-, O(C 1-3 )a pentagonal heteroaryl optionally substituted with 1 to 2 substituents independently selected from azetidinyl optionally substituted with 1-2 halogens, haloalkyl-OH; or
[0108] d) an 8- to 10-membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or a halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 )haloalkyl-, OH or OC 1-3 Substituted with alkyl.
[0109] Embodiment 1b of the present disclosure is R 1 This is a compound of the following chemical formula I, or a salt of any of the above that is permitted by constraint:
[0110] a) Halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, OC 1-3 -OC optionally substituted with alkyl or OH 1-3 Haloalkyl, -OC 3-6 Cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-3 Alkyl, -(NH(C=O)C 1-3 phenyl optionally substituted with 1 to 3 substituents independently selected from alkyl;
[0111] b) Containing 1 or 2 nitrogen atoms and halogens, hydroxyl groups, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -OC 3-6 Cycloalkyl, CN, -SC 1-3 alkyl, or -SC 1-3 A 6-membered heteroaryl substituted with one or two substituents independently selected from haloalkyls;
[0112] c) containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S and a halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 )haloalkyl-, OH or OC 1-3 5-membered heteroaryl optionally substituted with 1 to 2 substituents independently selected from alkyls; or
[0113] d) an 8- to 10-membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or a halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 )haloalkyl-, OH or OC 1-3 Substituted with alkyl.
[0114] Embodiment 2 of the present disclosure is R 1 This is a non-alkyl compound of Formula I or Embodiment 1, or a salt of any of the above that is permitted by constraint.
[0115] Embodiment 3a of the present disclosure is R 1 This is a compound of Formula I or any one of Embodiments 1-2 below, or a salt of any of the above that is permitted by constraint:
[0116] a) Halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, -OC 1-3 -OC optionally substituted with alkyl or OH 1-3 Haloalkyl, -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, C(O)NH2, S(O)2NHC 1-3 Alkyl, N(R 11 )2, 1, or 2 halogen substituents optionally substituted for phenyl substituted with 1 to 3 substituents independently selected from azetidinyl;
[0117] b) Containing 1 or 2 nitrogen atoms and halogens, hydroxyl groups, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -OC 1-3 Alkyl, -OC 1-3Haloalkyl, OC optionally substituted with 1-2 halogens 0-3 Alkyl-C 3-6 Cycloalkyl, azetidinyl optionally substituted with 1-2 halogens, CN, -SC 1-3 Alkyl, -SC 1-3 A 6-membered heteroaryl substituted with 1 to 2 substituents selected from haloalkyls;
[0118] c) containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, and a halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 )haloalkyl-, OH, OC 1-3 OC optionally substituted with alkyl or 1-2 halogens 0-3 Alkyl-C 3-6 Cycloalkyl, O(C 1-3 )haloalkyl-, O(C 1-3 )a pentagonal heteroaryl optionally substituted with 1 to 2 substituents independently selected from azetidinyl optionally substituted with 1-2 halogens, haloalkyl-OH; or
[0119] d) an 8- to 10-membered fused heteroaryl containing at least one nitrogen and optionally one oxygen.
[0120] Embodiment 3b of the present disclosure is R 1 This is a compound of Formula I or any one of Embodiments 1-2 below, or a salt of any of the above that is permitted by constraint:
[0121] a) Halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, -OC 1-3 -OC optionally substituted with alkyl or OH 1-3 Haloalkyl, -OC 3-6 Cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-6Alkyl or -NH(C=O)C 1-3 phenyl substituted with 1 to 3 substituents independently selected from alkyl, wherein the cycloalkyl is optionally substituted with a halogen or OH;
[0122] b) Containing 1 or 2 nitrogen atoms and halogens, hydroxyl groups, C 1-3 Alkyl, C 1-3 Haloalkyl, C 3-6 Cycloalkyl, -OC 1-3 Alkyl, -OC 1-3 Haloalkyl, -OC 3-6 Cycloalkyl, CN, -SC 1-3 Alkyl, -SC 1-3 A 6-membered heteroaryl substituted with 1 to 2 substituents selected from haloalkyls;
[0123] c) containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, and a halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 )haloalkyl-, OH or OC 1-3 A 5-membered heteroaryl optionally substituted with one or two substituents independently selected from alkyl, or
[0124] d) an 8- to 10-membered fused heteroaryl containing at least one nitrogen and optionally one oxygen.
[0125] Embodiment 4 of the present disclosure is R 1 This is a compound of Formula I or any one of Embodiments 1-3 below, or a salt of any of the above that is permitted by constraint:
[0126] a) Halogen, hydroxy, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 -O-cyclopropyl, -SC optionally substituted with a haloalkyl, halogen, or hydroxyl group 1-3 Alkyl, -SC 1-3Haloalkyl, S(O)2NHCH3, S(O)2C 1-3 Alkyl, -NH(C=O)C 1-3 Azetidinyl optionally substituted with alkyl, CN, 1 or 2 fluorosubstituents, phenyl substituted with a substituent selected from C(O)NH2, N(CH3)2, wherein phenyl is optionally additionally substituted with 1 or 2 fluorine atoms;
[0127] b) Containing 1 or 2 nitrogen atoms and C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 -OC optionally substituted with alkyl or hydroxyl 1-3 -O-cyclopropyl, -OC2 optionally substituted with a haloalkyl, halogen, or hydroxyl group 1-3 Alkyl-C 3-6 Cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, azetidinyl optionally substituted with 1 or 2 fluorosubstituents, halogen, -OC 1-3 Alkyl-OH, -OC 1-3 A 6-membered heteroaryl substituted with one or two substituents selected from haloalkyl-OH, wherein the 6-membered heteroaryl is optionally further substituted with one or two fluorine atoms or CH3;
[0128] c) containing 1 to 4 nitrogen atoms or heteroatoms independently selected from N, O and S, and a halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-6 )haloalkyl-, -OH, OC 1-6 OC optionally substituted with alkyl or 1-2 halogens 0-3 Alkyl-C 3-6 Cycloalkyl, O(C 1-3 )haloalkyl-, O(C 1-3 )haloalkyl-OH, a pentagonal heteroaryl optionally substituted with 1 to 2 substituents independently selected from azetidinyl optionally substituted with 1-2 fluorosubstituents; or
[0129] d) a 9 or 10-membered fused heteroaryl containing one or two heteroatoms independently selected from nitrogen or oxygen and optionally substituted with methyl.
[0130] Embodiment 5 of the present disclosure is R 1 This is a compound of Formula I or any one of Embodiments 1-4, or a salt of any of the above that is permitted by constraint:
[0131] .
[0132] Embodiment 6a of the present disclosure is R 1 This is a compound of any one of Formula I or Embodiments 1-4, or a salt of any of the above that is constrained by the following: a phenyl substituted with a substituent selected from -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, azetidinyl, or 3,3-difluoroazetidinyl, wherein the phenyl is optionally additionally substituted with one or two fluorine atoms.
[0133] Embodiment 6b of the present disclosure is R 1 This is a compound of any one of Formula I or Embodiments 1-4, or a salt of any of the above that is substituted with a substituent selected from -OH, -CH3, -CF2CH3, -OCHF2, -OCH2CH3, -OCF2CHF2, -OCF2CHF2, -OCF3, O-cyclopropyl, -SCHF2, -NH(C=O)CH3, or 3,3-difluoroazetidinyl, wherein the phenyl is optionally additionally substituted with one or two fluorine atoms.
[0134] Embodiment 7a of the present disclosure is R 1It is any one of the compounds of Formula I or Embodiments 1-4, which is 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 Fs, O-CH2-cyclobutyl optionally substituted with 2 Fs, OCH2CF2CH3, OCH2CF2CHF2, OCF2CH2OH, or -SCHF2, or a salt of any of the above that is permitted by the constraints.
[0135] Embodiment 7b of the present disclosure is R 1 This F, OH, -CH3, -CF2CH3, -OCHF2, -OCH2CH3, -OCF2CH3, - It is a compound of Formula I or any one of Embodiments 1-4 which is pyridinyl substituted with one or two substituents independently selected from OCF2CHF2, -OCH2CHF2, -OCF3, cyclopropyl, or -SCHF2, or a salt of any of the above that is permitted by the constraints.
[0136] Embodiment 8 of the present disclosure is R 1 It is a compound of Formula I or any one of Embodiments 1-4 that is substituted with one or two substituents independently selected from F, OCH2CHF2, OCH2CF3, or a salt of any of the above that is permitted under constraint.
[0137] Embodiment 9 of the present disclosure is R 1 It is a compound of Formula I or any one of Embodiments 1-4 that is a 9 or 10-membered fused heteroaryl containing one N atom, or a salt of any of the above that is permitted by constraint.
[0138] Embodiment 10 of the present disclosure is R 1 this It is a compound of formula I or any one of embodiments 1-6, or a salt of any of the above that is permitted by constraint.
[0139] Embodiment 11 of the present disclosure is R 1 this It is a compound of formula I or any one of embodiments 1-6, or a salt of any of the above that is permitted by constraint.
[0140] Embodiment 12 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0141] Embodiment 13 of the present disclosure is R 1 this It is a compound of formula I or any one of embodiments 1-6, or a salt of any of the above that is permitted by constraint.
[0142] Embodiment 14 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0143] Embodiment 15 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0144] Embodiment 16 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0145] Embodiment 17 of the present disclosure is R 1 this It is a compound of formula I or any one of embodiments 1-6, or a salt of any of the above that is permitted by constraint.
[0146] Embodiment 18 of the present disclosure is R 1 this It is a compound of formula I or any one of embodiments 1-6, or a salt of any of the above that is permitted by constraint.
[0147] Embodiment 19 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0148] Embodiment 20 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0149] Embodiment 21 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0150] Embodiment 22 of the present disclosure is R 1 this It is a compound of any one of Formula I or Embodiments 1-5 or 7, or a salt of any of the above that is permitted by constraint.
[0151] Embodiment 23 of the present disclosure is R 2a and R 2b is a compound of Formula I or Embodiments 1-22 or its class selected from one of the following, or a salt of any of the above that is permitted by constraint:
[0152] (1) R 2a and R 2b is hydrogen, or
[0153] (2) R 2a is hydrogen and R 2b is (C 1-6 )alkyl or R 2a is (C 1-6 )alkyl and R 2b is hydrogen, or
[0154] (3) R 2a is a halogen and R 2b is (C 1-6 )alkyl or R 2a is (C 1-6 )alkyl and R 2b is a halogen, or
[0155] (4) R 2a is a hydroxyl and R 2b is (C 1-6 )alkyl or R 2a is (C 1-6 )alkyl and R 2b is a hydroxyl group,
[0156] (5) R 2a is a hydroxyl and R 2b is (C 1-6 )haloalkyl, or R 2a is (C 1-6 )haloalkyl and R 2b is a hydroxyl group,
[0157] (6) R 2a and R 2b are each independently (C 1-6 Selected from )alkyl,
[0158] (7) R 2a and R 2b ... are connected to form a spiro 4- to 8-membered heterocyclyl containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or has one, two, or three R atoms 7 Replaced by, or
[0159] (8) R 2a and R 2b is connected, unsubstituted, or C 1-6Spiro(C) optionally monosubstituted or dissubstituted with alkyl, halogen, or OH. 3-8 ) Forms a cycloalkyl group.
[0160] Embodiment 24 of the present disclosure is R 2a and R 2b independently H, and C 1-3 Selected from alkyls, or together with spiro C 1-6 It is a compound of Formula I or Embodiments 1-23 or of the same class that forms a cycloalkyl group, or a salt of any of the above that is permitted by limitation.
[0161] Embodiment 25a of the present disclosure is R 2a and R 2b is a compound of Formula I or Embodiments 1-23 or their class that is independently selected from hydrogen, CH3, OH, CF3, CH(CH3)2 or CH2CH3, or a salt of any of the above that is permitted by constraint.
[0162] Embodiment 25b of the present disclosure is R 2a and R 2b is a compound of Formula I or of Embodiments 1-23 or of the same class that is independently selected from hydrogen, CH3, CH(CH3)2 or CH2CH3, or a salt of any of the above that is permitted by constraint.
[0163] Embodiment 26 of the present disclosure is R 2a and R 2b It is a compound of Formula I or Embodiments 1-23 or a class thereof, in which both of these are connected to the carbon to which they are attached to form cyclobutyl, cyclopropyl, or cyclopentyl, or a salt of any of the above that is permitted by limitation.
[0164] Embodiment 27a of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-22 below, or a salt of any of the above that is permitted by constraint:
[0165] (1) 4- to 7-membered heterocyclil containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
[0166] (2) A 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
[0167] (3) -(C 1-6 )alkyl-heteroaryl, where the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,
[0168] (4) -(C 1-6 )alkyl-aryl,
[0169] (5) -(C 1-6 )alkyl-heterocyclyl, where heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,
[0170] (6) -(C 1-6 )alkyl,
[0171] (7) -(C 3-6 )cycloalkyl,
[0172] (8) (C 1-6 )hydroxyalkyl,
[0173] (9) -(C 1-6 )alkyl-S(O)2-NR 8a R 8b , or
[0174] (10) -(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl,
[0175] Here, each aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or has 1, 2, or 3 R 9 It is substituted with, where each alkyl, aryl, or heteroaryl is unsubstituted or has 1, 2, or 3 R 10 Replaced with.
[0176] Embodiment 27b of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0177] (1) 4- to 7-membered heterocyclil containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
[0178] (2) A 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,
[0179] (3) -(C 1-6 )alkyl-heteroaryl, where the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,
[0180] (4) -(C 1-6 )alkyl-aryl,
[0181] (5) -(C 1-6 )alkyl-heterocyclyl, where heterocyclyl is a 3- to 6-membered ring containing 1 or 2 heteroatoms independently selected from N, O and S,
[0182] (6) -(C 1-6 )alkyl,
[0183] (7) -(C 3-6 )cycloalkyl,
[0184] (8) (C 1-6 )hydroxyalkyl,
[0185] (9) -(C 1-6 )alkyl-S(O)2-NR 8a R 8b , or
[0186] (10) -(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl,
[0187] Here, each aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or has 1, 2, or 3 R 9 It is substituted with, where each alkyl, aryl, or heteroaryl is unsubstituted or has 1, 2, or 3 R 10 Replaced with.
[0188] Embodiment 28 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0189] (1) 4- to 6-membered heterocyclil containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,
[0190] (2) -(C 3-6 )cycloalkyl,
[0191] (3) -(C 1-6 )hydroxyalkyl,
[0192] (4) -(C 1-6 )alkyl-S(O)2-NR 8a R 8b , or
[0193] (5) -(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl,
[0194] Here, each cycloalkyl or heterocyclyl is unsubstituted or has 1, 2, or 3 R 9 It is substituted with, where each alkyl group is unsubstituted or has 1, 2, or 3 R groups. 10 Replaced with.
[0195] Embodiment 29 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0196] (1) 4- to 6-membered heterocyclil containing 1, 2, or 3 heteroatoms independently selected from N, O, and S,
[0197] (2) -(C 3-6 )cycloalkyl,
[0198] (3) -(C 1-6 )hydroxyalkyl,
[0199] (4) -(C 1-6 )alkyl-S(O)2-NR 8a R 8b ,
[0200] (5) -(C 1-6 )alkyl-S(O)2-(C 1-3 )alkyl,
[0201] (6) (C 1-6 )alkyl-heterocyclyl, where the heterocyclyl is a 5-membered heterocyclyl containing one O heteroatom,
[0202] (7) A 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, or
[0203] (8) (C 1-6 )alkyl-heteroaryl, where the heteroaryl is a 5-membered heteroaryl containing two N heteroatoms,
[0204] Here, each aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or has 1, 2, or 3 R 9 It is substituted with, where each alkyl group is unsubstituted or has 1, 2, or 3 R groups. 10 Replaced with.
[0205] Embodiment 30 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0206] (1) Halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl, OC1-3 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 4 to 6-membered cycloalkyl optionally substituted with an alkoxyl,
[0207] (2) Contains one sulfur atom or one oxygen atom and C 1-6 Alkyl, C 1-3 Alkyl(OH), OH, C 1-3 4, 5, or 6-membered heterocyclils optionally monosubstituted, disubstituted, or trisubstituted with haloalkyl or oxo,
[0208] (3) C 1-6 Alkyl, where alkyl is a halogen, OH, CF3, S(O)2CH3, S(O)2NH-cyclohexyl or C 1-3 Optionally monosubstituted, disubstituted, or trisubstituted with alkyl,
[0209] (4) Contains 1 nitrogen atom and C 1-6 Alkyl, C 1-6 Haloalkyl, C(O)C 1-3 Alkyl, S(O)2C 1-3 6-membered heterocyclils optionally monosubstituted, disubstituted, or trisubstituted with alkyl groups,
[0210] (5) (C 1-6 )alkyl-heterocyclyl, where the heterocyclyl is a 5-membered heterocyclyl containing one O heteroatom and optionally monosubstituted, disubstituted, or trisubstituted with OH,
[0211] (6) Contains 1 S atom and 2 N heteroatoms and C 1-6 5-membered heteroaryls optionally monosubstituted, disubstituted, or trisubstituted with alkyl, or
[0212] (7) (C 1-6 )alkyl-heteroaryl, where the heteroaryl contains two N heteroatoms and C 1-6 It is a 5-membered heteroaryl alkyl arbitrarily monosubstituted, disubstituted, or trisubstituted.
[0213] Embodiment 31 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0214] (1) 4 to 6-membered cycloalkyl optionally substituted with F, OH, S(O)2CH3, CH2S(O)2CH3, CF3, OCH3, CH3,
[0215] (2) 4 to 6-membered heterocyclils containing one sulfur atom and optionally monosubstituted, disubstituted, or trisubstituted with iodine, CHF2, CH2CH3, or CH3,
[0216] (3) A 5- or 6-membered heterocyclyl containing one oxygen atom and optionally monosubstituted, disubstituted, or trisubstituted with CH3, OH, or CH2OH,
[0217] (4) C 1-6 Alkyl, where the alkyl is optionally monosubstituted, disubstituted, or trisubstituted with a halogen, OH, CF3, S(O)2CH3, S(O)2NH-cyclohexyl, or CH3,
[0218] (5) A six-membered heterocyclil containing one nitrogen atom and optionally N-substituted, disubstituted, or trisubstituted with CH3, C(O)CH3, CH2CHF2, or S(O)2CH3,
[0219] (6) (C 1-6 )alkyl-heterocyclyl, where the heterocyclyl is a 5-membered heterocyclyl containing one O heteroatom and optionally monosubstituted, disubstituted, or trisubstituted with OH,
[0220] (7) A 5-membered heteroaryl containing one S atom and two N heteroatoms, optionally monosubstituted, disubstituted, or trisubstituted with CH2CH3, or
[0221] (8) CH3-heteroaryl, where heteroaryl is a 5-membered heteroaryl containing two N heteroatoms and optionally unsubstituted, disubstituted, or trisubstituted with CH3.
[0222] Embodiment 32 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0223] (1) Halogen, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 4 to 6-membered cycloalkyl optionally substituted with an alkoxyl,
[0224] (2) Contains one sulfur atom or one oxygen atom and C 1-6 Alkyl, C 1-3 4, 5, or 6-membered heterocyclils optionally monosubstituted, disubstituted, or trisubstituted with alkyl (OH), OH, or oxo,
[0225] (3) C 1-6 Alkyl(OH), where alkyl is a halogen, CF3, or C 1-3 Optionally monosubstituted, disubstituted, or trisubstituted with alkyl.
[0226] Embodiment 33 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0227] (1) 4 to 6-membered cycloalkyl optionally substituted with F, OH, S(O)2CH3, CH2S(O)2CH3, CF3, OCH3,
[0228] (2) 4 to 6-membered heterocyclils containing one sulfur atom and optionally monosubstituted, disubstituted, or trisubstituted with iodine or CH3;
[0229] (3) 5 or 6-membered heterocyclils containing one oxygen atom and optionally monosubstituted, disubstituted, or trisubstituted with CH3 or CH2OH; or
[0230] (4) C 1-6 Alkyl, where alkyl is a halogen, OH, CF3, S(O)2CH3, S(O)2NR 8a R 8b, or arbitrarily substituted with CH3, bisubstituted, or trisubstituted.
[0231] Embodiment 34 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0232] .
[0233] Embodiment 35 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0234] .
[0235] Embodiment 36 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0236] .
[0237] Embodiment 37 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0238] .
[0239] Embodiment 38 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0240] .
[0241] Embodiment 39 of the present disclosure is R 3 This is a compound of Formula I or any one of Embodiments 1-26, or a salt of any of the above that is permitted by constraint:
[0242] .
[0243] Embodiment 40 of the present disclosure is R 4 It is a compound of the chemical formula I or embodiment 1-39 or of the same class as H, or a salt of any of the above that is permitted by constraint.
[0244] Embodiment 41 of the present disclosure is R 5 It is a compound of Formula I or Embodiment 1-40 or of the class thereof in which is H, a halogen or CN, or a salt of any of the above that is permitted by constraint.
[0245] Embodiment 42 of the present disclosure is R 5 It is a compound of Formula I or Embodiment 1-41 or of the same class in which is H, F, Cl, or CN, or a salt of any of the above that is permitted by constraint.
[0246] Embodiment 43 of the present disclosure is R 6 This cyano, halogen, -OC 1-6 Optionally substituted with alkyl, halogen, or OH (C 3-6 )cycloalkyl, -(C=O)NH2, cycloalkyl optionally substituted with a halogen or OH (C 3-6 ) Cycloalkyloxy, hydroxy, -N(R1 1 )2, -NH(C=O) (C 1-6 )alkyl, optionally substituted with 1 or 2 halogen substituents (C 2-6 )Cyclic amine, (C 1-6 )haloalkyl-, -O(C optionally substituted with OH 1-6 )haloalkyl, -O(C optionally substituted with 1 or 2 halogens 0-3 )alkyl-(C 3-6 )cycloalkyl, -SO2(C 1-6 )alkyl, -SO2NH(C 1-6 )alkyl, -SC 1-6 Alkyl, -SC 1-6 haloalkyl, or (C 1-6) It is an alkyl compound of Formula I or of Embodiments 23-42 or of the same class, or a salt of any of the above that is permitted by constraint.
[0247] Embodiment 44 of the present disclosure is R 6 This cyano, halogen, -OC 1-6 Optionally substituted with alkyl, halogen, or OH (C 3-6 )cycloalkyl, -(C=O)NH2, cycloalkyl optionally substituted with a halogen or OH (C 3-6 ) Cycloalkyloxy, hydroxy, -N(R 11 )2, -NH(C=O)(C 1-6 )alkyl, optionally substituted with 1 or 2 halogen substituents (C 2-6 )Cyclic amine, (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 It is a compound of Formula I or of Embodiments 23-43 or of the same class that is a haloalkyl, or a salt of any of the above that is permitted by limitation.
[0248] Embodiment 45 of the present disclosure is R 6 This halogen, hydroxy, CN, -C 1-6 Alkyl, -C 1-6 -C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, -OC 1-6 -OC optionally substituted with alkyl or OH 1-6 -O(C alkyl, optionally substituted with 1 or 2 halogens) 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 haloalkyl, or NH(C=O)C 1-3alkyl, optionally substituted with OH (C 2-6 )Cyclic amine, N(C 1-3 )alkyl, -O(C 3-6 ) It is a compound of Formula I, which is a cycloalkyl, or of Embodiments 23-43 or of the same class, or a salt of any of the above that is permitted by limitation.
[0249] Embodiment 46 of the present disclosure is R 6 This halogen, hydroxy, CN, -C 1-6 Alkyl, -C 1-6 -C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -OC 3-6 Cycloalkyl, -S(O)2C 1-6 Alkyl, -SC 1-6 Alkyl, -SC 1-6 haloalkyl, or NH(C=O)C 1-3 alkyl, wherein the cycloalkyl is optionally substituted with a halogen, CN, or OH, is a compound of Formula I or embodiments 23-43 and 44 or a class thereof, or a salt of any of the above that is permitted by limitation.
[0250] Embodiment 47 of the present disclosure is R 6 This -F, OH, C 1-6 Alkyl, -C 1-6 Haloalkyl, OC 1-6 Cycloalkyl, -OC 1-6 Alkyl, -OC 1-6 Haloalkyl, -SC 1-6 Alkyl, -SC 1-6 haloalkyl, or -NH(C=O)C 1-3 alkyl, wherein the cycloalkyl is optionally substituted with 1 to 3 additional Fs, is a compound of Formula I or embodiments 23-43 and 44 or a class thereof, or a salt of any of the above that is permitted by constraint.
[0251] Embodiment 48 of the present disclosure is R 6Formula I or Embodiments 23-43, which 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, azetidine 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, and 45 or a compound of its class, or a salt of any of the above that is permitted under restrictions.
[0252] Embodiment 49 of the present disclosure is R 6 This is a compound of Formula I having F, OH, -CH3, -CF2CH3, -OCHF2, -OCF3, -OCH2CH3, OCH(CH3)2, -OCF2CHF2, -OCH2CHF2, -OCHF2CH3, -cyclopropyl, -O-cyclopropyl, -SCHF2 or -NH(C=O)CH3, or of Embodiments 23-48 or a class thereof, or a salt of any of the above that is permitted by the constraints.
[0253] Embodiment 50 of the present disclosure is R 7 This halogen, C 1-6 It is a compound of Formula I or Embodiment 1-49 or its class that is a haloalkyl or OH, or a salt of any of the above that is permitted by the constraints.
[0254] Embodiment 51 of the present disclosure is R 7 This is a compound of Formula I, which is F, CF3, or OH, or of Embodiments 1-50 or of the same class, or a salt of any of the above that is permitted by the constraints.
[0255] Embodiment 52 of the present disclosure is R8a It is a compound of the chemical formula I or embodiment 1-51 or of the same class as H, or a salt of any of the above that is permitted by constraint.
[0256] Embodiment 53 of the present disclosure is R 8b It is a compound of the chemical formula I or embodiment 1-52 or a class thereof in which α is H, or a salt of any of the above that is permitted by constraint.
[0257] Embodiment 54 of the present disclosure is R 8a and R 8b is a compound of Formula I or Embodiments 1-51 or its class that is independently selected from hydrogen and cyclohexyl, or a salt of any of the above that is permitted by constraint.
[0258] Embodiment 55a of the present disclosure is R 9 g =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 )alkyl SO2(C 1-3 )alkyl, C(O)C 1-3 It is an alkyl compound of Formula I or of Embodiments 1-54 or of the same class, or a salt of any of the above that is permitted by limitation.
[0259] Embodiment 55b of the present disclosure is R 9 g =O, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkyl OH, -SO2(C 1-3 )alkyl, or -C( 1-3 )alkyl SO2(C 1-3 ) It is an alkyl compound of Formula I or of Embodiments 1-55 or of the same class, or a salt of any of the above that is permitted by limitation.
[0260] Embodiment 56 of the present disclosure is R 9is a compound of Formula I, in which =O, OH, CH3, CH2CH3, F, CF3, CH2OH, OCH3, SO2CH3 or CH2SO2CH3, or of Embodiments 1-56 or of the class thereof, or any of the above, or a salt that is permitted by the constraints of any of the above.
[0261] Embodiment 57 of the present disclosure is R 10 This hydrogen, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 alkyl OH, or -C( 1-6 )alkyl SO2(C 1-6 ) It is an alkyl compound of formula I or embodiment 1-56 or a compound of its class, or a salt of any of the above that is permitted by constraint.
[0262] Embodiment 58 of the present disclosure is R 10 This is hydrogen, OH, CH3, CH2CH3, F, CF3, CH2OH, or CH2SO2CH3, or a compound of the formula I or embodiment 1-57 or its class, or a salt of any of the above that is permitted by limitation.
[0263] Embodiment 59 of the present disclosure is that X is N and Y is C(R 5 ) and Z is C(R 5 It is a compound of any one of the chemical formula I or embodiments 1-58, or a salt of any of the above that is permitted by constraint.
[0264] Embodiment 60 of the present disclosure is that X is C(R 5 ) and Y is N and Z is C(R 5 It is a compound of any one of the chemical formula I or embodiments 1-58, or a salt of any of the above that is permitted by constraint.
[0265] Embodiment 61 of the present disclosure is that X, Y and Z are C(R 5 It is a compound of any one of the chemical formula I or embodiments 1-58, or a salt of any of the above that is permitted by constraint.
[0266] Embodiment 62 of the present disclosure is that X is N, Y is N, and Z is C(R 5 It is a compound of any one of the chemical formula I or embodiments 1-58, or a salt of any of the above that is permitted by constraint.
[0267] Embodiment 63 of the present invention provides a compound or a pharmaceutically acceptable salt thereof as described in any one of Examples 1-159 as presented below.
[0268] In Embodiment 64, the present invention comprises a compound selected from the following:
[0269] , or is a salt permitted under his constraints.
[0270] In Embodiment 65, the present invention comprises a compound selected from the following:
[0271] , or is a salt permitted under his constraints.
[0272] In Embodiment 66, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0273] In Embodiment 67, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0274] In Embodiment 68, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0275] In Embodiment 69, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0276] In Embodiment 70, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0277] In Embodiment 71, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0278] In Embodiment 72, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0279] In Embodiment 73, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0280] In Embodiment 74, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0281] In Embodiment 75, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0282] In Embodiment 76, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0283] In Embodiment 77, the present invention It is a compound or a salt that is permitted under the pharmaceutical regulations.
[0284] In Embodiment 78 of the present invention, the compound of Formula I or a salt thereof that is pharmaceutically acceptable is as follows:
[0285]
[0286]
[0287]
[0288]
[0289]
[0290] .
[0291] In Embodiment 79 of the present invention, the compound of Formula I or a salt thereof that is pharmaceutically acceptable is as follows:
[0292] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0293] 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0294] 1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-carboxamide,
[0295] (R)-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0296] (S)-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0297] (R)-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-((S)-3-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide,
[0298] (S)-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-((S)-3-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide,
[0299] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indolin-5-carboxamide,
[0300] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[(3R)-(3-methyl-1,1-dioxo-thiolan-3-yl)]-2-oxo-indolin-5-carboxamide,
[0301] 1-[3-(difluoromethoxy)phenyl]-N-[(1S,2R)-2-hydroxycyclopentyl]-3,3-dimethyl-2-oxo-indolin-5-carboxamide,
[0302] 3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[3-(trifluoromethoxy)phenyl]indolin-5-carboxamide,
[0303] 3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[3-(trifluoromethoxy)phenyl]indolin-5-carboxamide,
[0304] 3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]indolin-5-carboxamide,
[0305] 1-[3-(difluoromethoxy)phenyl]-N-[4-(hydroxymethyl)tetrahydropyran-4-yl]-3,3-dimethyl-2-oxo-indolin-5-carboxamide,
[0306] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0307] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0308] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indolin-5-carboxamide,
[0309] 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0310] 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0311] 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,
[0312] 3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indolin-5-carboxamide,
[0313] 3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indolin-5-carboxamide,
[0314] 3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indolin-5-carboxamide,
[0315] 3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indolin-5-carboxamide,
[0316] (R)-1-(3-(difluoromethoxy)phenyl)-N-(4-hydroxy-2-methylpentane-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide,
[0317] (S)-1-(3-(difluoromethoxy)phenyl)-N-(4-hydroxy-2-methylpentane-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide,
[0318] 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0319] 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0320] 1-(2-ethoxy-5-fluoro-4-pyridyl)-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0321] 1-[2-(2,2-difluoroethoxy)pyrimidine-4-yl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0322] 3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-1-(3-quinolyl)indoline-5-carboxamide,
[0323] N-[2-(cyclohexylsulfamoyl)ethyl]-1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-2-oxo-indolin-5-carboxamide,
[0324] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[1-(methylsulfonylmethyl)cyclohexyl]-2-oxo-indolin-5-carboxamide,
[0325] 1-[3-(difluoromethoxy)phenyl]-N-(3-ethyl-1,1-dioxo-tiethane-3-yl)-3,3-dimethyl-2-oxo-indolin-5-carboxamide,
[0326] 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0327] 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0328] 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0329] 1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indolin-5-carboxamide,
[0330] 3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]indolin-5-carboxamide,
[0331] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[(3S)-(3-methyl-1,1-dioxo-thiolan-3-yl)]-2-oxo-indolin-5-carboxamide,
[0332] 1-[3-(difluoromethoxy)phenyl]-N-(3,3-difluoro-1-methyl-cyclobutyl)-3,3-dimethyl-2-oxo-indolin-5-carboxamide,
[0333] 3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indolin-5-carboxamide,
[0334] 1-[5-(difluoromethoxy)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0335] 1-(5-ethoxy-3-pyridyl)-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0336] 1-[5-(2,2-difluoroethoxy)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0337] 1-[5-(difluoromethylsulfanyl)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0338] 1-[2-(2,2-difluoroethoxy)-5-fluoro-4-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0339] 1-[5-(2,2-difluoroethoxy)-2,3-difluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0340] 1-[5-(2,2-difluoroethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0341] 1-[6-(2,2-difluoroethoxy)pyrazine-2-yl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0342] 1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0343] 1-[5-(difluoromethylsulfanyl)-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0344] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0345] 1-[5-(1,1-difluoroethyl)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indoline-5-carboxamide,
[0346] 1-[5-(1,1-difluoroethoxy)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0347] 1-[5-(2,2-difluoroethoxy)-2-methyl-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0348] (R)-1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2'-oxosspiro[cyclopropane-1,3'-indolin]-5'-carboxamide,
[0349] 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0350] 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,
[0351] 1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0352] 1'-[3-(difluoromethoxy)phenyl]-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2'-oxo-spiro[cyclopentane-1,3'-indolin]-5'-carboxamide,
[0353] 1'-[3-(difluoromethoxy)phenyl]-N-(4-methyl-1,1-dioxo-thian-4-yl)-2'-oxo-spiro[cyclopentane-1,3'-indolin]-5'-carboxamide,
[0354] 1'-[3-(difluoromethoxy)phenyl]-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2'-oxo-spiro[cyclopentane-1,3'-indolin]-5'-carboxamide,
[0355] 1'-[3-(difluoromethoxy)phenyl]-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2'-oxo-spiro[cyclopropane-1,3'-indolin]-5'-carboxamide,
[0356] 1'-[3-(difluoromethoxy)phenyl]-N-(4-methyl-1,1-dioxo-thian-4-yl)-2'-oxo-spiro[cyclopropane-1,3'-indolin]-5'-carboxamide,
[0357] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,4R)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0358] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3R,4R)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0359] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,4S)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0360] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3R,4S)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0361] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,5R)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0362] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3R,5R)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0363] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,5S)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0364] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3R,5S)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,
[0365] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((1S,2R)-2-(methylsulfonyl)cyclopentyl)-2-oxoindolin-5-carboxamide,
[0366] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((1R,2R)-2-(methylsulfonyl)cyclopentyl)-2-oxoindolin-5-carboxamide,
[0367] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((1S,2S)-2-(methylsulfonyl)cyclopentyl)-2-oxoindolin-5-carboxamide,
[0368] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((1R,2S)-2-(methylsulfonyl)cyclopentyl)-2-oxoindolin-5-carboxamide,
[0369] 1-[3-(difluoromethoxy)phenyl]-N-(1,1-dimethyl-2-methylsulfonyl-ethyl)-3,3-dimethyl-2-oxo-indolin-5-carboxamide,
[0370] 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0371] 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0372] 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0373] 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indolin-5-carboxamide,
[0374] 7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indolin-5-carboxamide,
[0375] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0376] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0377] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0378] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,
[0379] 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0380] 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0381] 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indolin-5-carboxamide,
[0382] 1-(2-ethoxy-5-fluoro-4-pyridyl)-7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,
[0383] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0384] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0385] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0386] 1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0387] 7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indolin-5-carboxamide,
[0388] 7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indolin-5-carboxamide,
[0389] 7-fluoro-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indolin-5-carboxamide,
[0390] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0391] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0392] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0393] 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,
[0394] 3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-1-(2-methylbenzo[d]oxazole-6-yl)-2-oxoindolin-5-carboxamide,
[0395] 1-[6-(2,2-difluoroethoxy)pyridazine-4-yl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,
[0396] 1-(2-(3,3-difluoroazetidin-1-yl)-3-fluoropyridine-4-yl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0397] 1-(4-acetamido-3-hydroxyphenyl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0398] (R)-N-(1-(2,2-difluoroethyl)-3-methylpiperidine-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,
[0399] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1-(methylsulfonyl)piperidine-3-yl)-2-oxoindolin-5-carboxamide,
[0400] (R)-N-(1-acetyl-3-methylpiperidin-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,
[0401] 1-(3-(difluoromethoxy)phenyl)-N-(4-methoxy-4-(trifluoromethyl)cyclohexyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,
[0402] 7-cyano-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0403] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxamide,
[0404] 1-(3-(difluoromethoxy)phenyl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0405] 7-(3-(difluoromethoxy)phenyl)-5,5-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine-3-carboxamide,
[0406] 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0407] 1-(4-(2,2-difluoroethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0408] 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridine-2-yl)indolin-5-carboxamide,
[0409] 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0410] 1-(2-ethoxy-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0411] 1-(2-ethoxy-5-fluoropyridine-4-yl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0412] 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(2,2,2-trifluoroethoxy)pyridine-2-yl)indoline-5-carboxamide,
[0413] 1-(4-(2,2-difluoropropoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0414] 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(2,2,3,3-tetrafluoropropoxy)pyridine-2-yl)indolin-5-carboxamide,
[0415] 1-(4-((2,2-difluorocyclopropyl)methoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0416] 1-(4-((3,3-difluorocyclobutyl)methoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0417] 1-(4-cyclopropoxypyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0418] 1-(4-(difluoromethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0419] 1-(2-(difluoromethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0420] 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(6-(2,2,2-trifluoroethoxy)pyrimidine-4-yl)indolin-5-carboxamide,
[0421] 1-(5-(difluoromethoxy)pyridine-3-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0422] 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(5-(trifluoromethoxy)pyridine-3-yl)indolin-5-carboxamide,
[0423] 1-(2-(difluoromethoxy)-5-fluoropyridine-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0424] 1-(2-(difluoromethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0425] 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-3,3-dimethyl-N-(1-((methylsulfonyl)methyl)cyclobutyl)-2-oxoindolin-5-carboxamide,
[0426] 1-(4-(2,2-difluoroethoxy)-3-fluoropyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0427] 1-(2-(2,2-difluoropropoxy)-5-fluoropyridine-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0428] 1-(5-(2,2-difluoroethoxy)pyridazine-3-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0429] 1-(4-(2,2-difluoroethoxy)pyrimidine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0430] 1-(6-(2,2-difluoroethoxy)pyrimidine-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0431] 1-(5-(azetidine-1-yl)-2-fluorophenyl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0432] 1-(4-isopropoxypyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0433] 1-(4-((1-fluorocyclopropyl)methoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0434] 1-(4-(cyclopropylmethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0435] 1-(4-isobutoxypyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0436] 1-(4-(1,1-difluoroethyl)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0437] 1-(5-fluoro-4-(1,1,2,2-tetrafluoroethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0438] 1-(5-(1,1-difluoro-2-hydroxyethoxy)pyridine-3-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,
[0439] 1-(2-(3,3-difluoroazetidin-1-yl)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0440] 1-(4-(2,2-difluoropropoxy)pyridine-2-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0441] 1-(4-(difluoromethoxy)pyridine-2-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0442] 1-(4-(2,2-difluoroethoxy)pyridine-2-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0443] 1-(4-(difluoromethoxy)-5-fluoropyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0444] 1-(4-(2,2-difluoropropoxy)-5-fluoropyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0445] 1-(4-(2,2-difluoroethoxy)-5-fluoropyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0446] N-(4-(difluoromethyl)-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-1-(2-ethoxy-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindolin-5-carboxamide,
[0447] 1-(5-fluoro-2-isopropoxypyridine-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0448] 1-(3-(difluoromethoxy)phenyl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,
[0449] 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(5-methyl-1,3,4-thiadiazole-2-yl)-2-oxoindolin-5-carboxamide,
[0450] 1-(3-(difluoromethoxy)phenyl)-N-((1-ethyl-1H-pyrazole-4-yl)methyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,
[0451] 1-(3-cyclopropylphenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0452] 1-(3-isopropoxyphenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0453] 1-(3-fluorophenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0454] 1-(3-cyanophenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0455] (R)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxo-3-(trifluoromethyl)indolin-5-carboxamide,
[0456] (S)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxo-3-(trifluoromethyl)indolin-5-carboxamide,
[0457] (R)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0458] (S)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0459] 1-(3-(difluoromethoxy)phenyl)-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,
[0460] 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-1-(3-(N-methylsulfamoyl)phenyl)-2-oxoindoline-5-carboxamide,
[0461] 1-(3-carbamoylphenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,
[0462] 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-1-(3-(methylsulfonyl)phenyl)-2-oxoindolin-5-carboxamide, or
[0463] 1-(3-(dimethylamino)phenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide.
[0464] The present invention includes a salt that is permitted under the constraints of the compound defined herein.
[0465] In one embodiment, the present invention is a composition comprising an effective amount of at least one compound of formula I or a salt thereof that is pharmaceutically acceptable.
[0466] 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.
[0467] The present invention also provides a pharmaceutical composition comprising an effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts thereof, and an effective amount of one or more other pharmaceutically active ingredients (e.g., chemotherapy agents).
[0468] The present invention also provides a pharmaceutical composition comprising an effective amount of one or more compounds of Formula I or pharmaceutically acceptable salts thereof, an effective amount of one or more other pharmaceutically active ingredients (e.g., chemotherapeutic agents), and a pharmaceutically acceptable carrier.
[0469] In one embodiment, the present invention provides a composition for treating hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic disease, such as chronic kidney disease or heart failure, comprising an acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt thereof.
[0470] In one embodiment, the present invention provides a composition for treating hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic disease, such as chronic kidney disease or heart failure, comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
[0471] In one embodiment, the present invention provides a composition for treating hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic disease, 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.
[0472] In one embodiment, the present invention provides a method for treating hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic disease such as chronic kidney disease or heart failure in a subject requiring treatment for said subject, comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof to said subject requiring treatment for said subject
[0473] In one embodiment, the present invention provides a method for treating hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic disease such as chronic kidney disease or heart failure in a patient requiring treatment for said patient, comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.
[0474] The method of the present invention comprises administering a pharmaceutical composition comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[0475] In another embodiment, the present invention comprises a method for treating NASH and / or fibrosis, comprising administering a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient requiring treatment for NASH and / or fibrosis.
[0476] In another embodiment, the present invention comprises 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 requiring treatment for NASH and / or fibrosis.
[0477] In another embodiment, the present invention comprises a method for treating NASH and / or fibrosis, comprising administering a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient requiring treatment for NASH and / or fibrosis.
[0478] In another embodiment, the present invention comprises a method for treating NASH and / or fibrosis, comprising administering to a patient requiring treatment for NASH and / or fibrosis a composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[0479] In another embodiment, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicine for treating NASH and / or fibrosis.
[0480] In another embodiment, the present invention comprises the use of a compound of Formula I or a pharmaceutically acceptable salt thereof for the manufacture of a medicine for the treatment of NASH and / or fibrosis.
[0481] "Alkyl" refers to branched and straight-chain saturated aliphatic hydrocarbon groups having a specified number of carbon atoms. If no number is specified, 1 to 6 carbon atoms are intended to be linear, and 3 to 7 carbon atoms are intended to be branched alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, octyl, nonyl, etc. For example, the term "C 1-6 "alkyl" refers to all "C" defined as follows 1-4 "Alkyl" + contains a linear or branched-chain alkyl group having 5 or 6 carbon atoms (including all possible isomers). "C 1-6 "Alkyl" refers to a linear or branched-chain alkyl group comprising all possible isomers having 1, 2, 3, 4, 5, or 6 carbon atoms, and includes C-, iso-, sec-, and tert-butyl (butyl, i-butyl, s-butyl, t-butyl, collectively "C4alkyl"; Bu = butyl), n- and i-propyl (propyl, i-propyl, collectively "C3alkyl"; Pr = propyl), ethyl (Et), and methyl (Me), as well as their respective hexyl and pentyl isomers.1-6 It includes each alkyl group within the alkyl group. Abbreviations commonly used for alkyl groups are used throughout the specification, for example, methyl is "Me" or a symbol that is a CH3 or a terminal group extended bond, for example They can be represented by common abbreviations including, ethyl can be represented by "Et" or CH2CH3, propyl can be represented by "Pr" or CH2CH2CH3, butyl can be represented by "Bu" or CH2CH2CH2CH3, etc. For example, structure has an equivalent meaning. C 1-6 Alkyl groups include n-, iso-, sec-, and t-butyl, n- and isopropyl, ethyl, and methyl. Unless a number is specified, 1 to 6 carbon atoms are intended for linear or branched alkyl groups.
[0482] "Cyclical amine" refers to a cyclic ring containing one nitrogen atom.
[0483] "Alkoxy" refers to an alkyl group connected to oxygen. Examples of alkoxy groups include methoxy, ethoxy, propoxy, etc.
[0484] "Aryl" refers to an aromatic monocyclic or multicyclic ring moiety comprising 6 to 14 cyclic carbon atoms. In one embodiment, the aryl group contains about 6 to 10 cyclic carbon atoms. Monocyclic aryl rings include, but are not limited to, phenyl. Multicyclic rings include, but are not limited to, naphthyl and non-cyclic rings, wherein phenyl is C 5-7 Cycloalkyl or C 5-7 It is fused to a cycloalkenyl ring. The aryl group may be optionally substituted with one or more substituents as defined herein. Bonding may be formed through any carbon atom of any ring.
[0485] "Fused aryl" refers to an aryl ring fused with a heterocyclyl or cycloalkyl.
[0486] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine.
[0487] "Cycloalkyl" refers to a non-aromatic mono- or multicyclic ring system comprising about 3 to 10 cyclic carbon atoms. Unless the number of atoms is specified, 3 to 10 carbon atoms are intended. Cycloalkyls may also fuse to form 1 to 3 carbocyclic rings. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The term "C 1-6 "Cycloalkyl" refers to a cycloalkyl group having 1 to 6 cyclic carbon atoms. The term "C 3-6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 cyclic carbon atoms. Thus, for example, "C 3-6 "Cycloalkyl" comprises cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, respectively. The cycloalkyl group is unsubstituted or substituted with one or more cyclic substituents as defined above, which may be the same or different. Where the cycloalkyl is a substituent on the alkyl group, the cycloalkyl substituent may be bonded to any bondable carbon within the alkyl group. The following is -C on the alkyl group. 3-6 This is an example of a cycloalkyl substituent, where the substituent is the cyclopropyl of the bold line:
[0488] "Haloalkyl" refers to an alkyl group as defined above, in which one or more hydrogen atoms of the alkyl group are replaced by a halogen. In one embodiment, the haloalkyl group has 1 to 6 carbon atoms. Non-limiting examples of haloalkyl groups include CH2F, CHF2, CF3, CH2CF3, CH2CHF2, CF2CF3, CF2CHF2, CH2Cl, and CCl3. The term "C 1-6 "haloalkyl" or "haloC" 1-6 "Alkyl" refers to a haloalkyl group having 1 to 6 carbons.
[0489] "haloalkoxy", "haloalkyl-O" and derivatives, e.g., "halo(C 1-6 "Alkoxy" is used interchangeably and refers to a halogenated alkyl group connected via an oxygen atom. Haloalkoxy includes monoiogenated as well as polyiogenated alkoxy groups. Examples include trifluoromethoxy, chloromethoxy, and bromomethoxy, as well as OCH2CF3, OCH2CHF2, OCF2CF3, and OCF2CHF2.
[0490] "Heterocyclil," "heterocycle," or "heterocyclic" refers to a monocyclic ring structure in which one or more atoms within the ring, which are heteroatom(s), are elements other than carbon. The heteroatoms are typically O, S, or N atoms. Heterocycles containing more than one heteroatom may contain different heteroatoms. The cyclic ring moiety comprises fused, spirocyclic, and cross-linked cyclic rings, and may contain one or more heteroatoms in any one of the rings. The ring attached to the remainder of the molecule may or may not contain a heteroatom. The ring of the cyclic heterocycle may be saturated, partially unsaturated, or unsaturated. The heterocycle may be attached to the remainder of the molecule through the cyclic carbon atom, the cyclic oxygen atom, or the cyclic nitrogen atom. Examples of heterocyclyl groups include piperidine, piperazine, morpholine, pyrrolidine, tetrahydrofuran, azetidine, oxiran, or aziridine.
[0491] "Bicyclic heterocyclil," "bicyclic heterocycle," or "bicyclic heterocyclic" refers to a heterocyclic ring fused to another ring system. The fusion may be cross-linked or non-cross-linked.
[0492] Except as mentioned herein, the term “heteroaryl” as used herein refers to a stable monocyclic, noncyclic, or tricyclic ring of 10 or fewer atoms in each ring, wherein at least one ring is aromatic and contains 1 to 4 heteroatoms selected from the group consisting of O, N and S. The heteroaryl groups within this category of definition include benzimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazollyl, indolinyl, indolyl, indolazinyl, indazollyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazollyl, isoxazolyl, naftpyridinyl, oxadiazollyl, oxazolyl, oxazolin, isoxazolin, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazollyl, tetrazolopyridyl, thiadiazolyl, Includes, but not limited to, thiazolyl, thienyl, triazolyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline.
[0493] "Fused heteroaryl" is a heteroaryl fused with an aryl or heteroaryl.
[0494] "Oxo" refers to oxygen connected to an atom by a double bond. Examples of oxo groups are the double-bonded oxygen in ketones, sulfoxides, sulfones, and sulfates.
[0495] "Hydroxyalkyl" or "hydroxy(C 1-3 ")alkyl" refers to an alkyl group having one or more hydrogen atoms replaced by a hydroxyl (-OH) group.
[0496] "Cyanoalkyl" means an alkyl group having one or more hydrogen atoms replaced by a cyano (-CN) group.
[0497] "Hydroxyhaloalkyl" means an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl (-OH) group and one or more hydrogen atoms are replaced by a halogen.
[0498] "Hydroxycycloalkyl" means a cyclic alkyl group having one or more hydrogen atoms replaced by a hydroxyl (-OH) group.
[0499] The term "composition" is intended to encompass a product containing specified amounts of specified components, as well as any product produced directly or indirectly from a combination of specified amounts of specified components.
[0500] The term "at least one" means one or more than one. The meaning of "at least one" in relation to the number of compounds of the present invention is independent of the meaning in relation to the number of chemotherapy agents.
[0501] The term "chemotherapy agent" refers to a drug (medicinal or pharmaceutical active ingredient) used to treat cancer (i.e., an antitumor agent).
[0502] The term "effective dose" means "therapeutic effective dose." The term "therapeutic effective dose" refers to the amount of an active compound or pharmaceutical agent sought by a researcher, veterinarian, physician, or other clinician to elicit a biological or medical response in tissues, systems, animals, or humans.
[0503] The term “treating cancer” or “treating cancer” refers to administration to mammals suffering from a cancerous condition, refers to the effect of alleviating the cancerous condition by killing cancerous cells, and also refers to the effect of inducing inhibition of cancer growth and / or metastasis.
[0504] Except as provided herein, the term “carbocycle” (and variations thereof, e.g., “carbocyclic” or “carbocyclil”) as used herein refers to a C3 to C6 monocyclic ring, e.g., C3, unless otherwise indicated. 3-6It refers to a monocyclic carbocycle. A carbocycle can attach to the rest of a molecule at any carbon atom to form a stable compound. Saturated carbocyclic rings include, for example, "cycloalkyl" rings, such as cyclopropyl, cyclobutyl, etc. Unsaturated carbocyclic rings include, for example, Includes
[0505] Except as mentioned, the term “saturated heterocycle” refers to a stable 4- to 7-membered monocyclic heteroatom-containing ring system consisting of a carbon atom and 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, wherein the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. A ring containing one oxygen or sulfur, 1 to 4 nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms is particularly useful. The heterocyclic ring may be attached to any heteroatom or carbon atom to form a stable structure. Representative examples include azetidine, oxetane, thiethane, diazetidine, dioxetane, dithiethane, pyrrolidine, tetrahydrofuran, thiolan, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolan, piperidine, oxane, thian, piperazine, morpholine, thiomorpholine, dioxane, dithian, trioxane, trithian, azephan, oxephan, thiephan, and homopiperazine. For example, a "saturated six-membered heterocycle" is a stable six-membered monocyclic heteroatom-containing ring system. An example of a saturated six-membered heterocycle is piperidine. Likewise, to a non-limiting extent, a "saturated quaternary heterocycle" is a stable 4-membered monocyclic heteroatom-containing ring system.
[0506] Except as provided herein, the term “unsaturated heterocycle” refers to a monocyclic unsaturated heterocycle having a specified number of atomic members (e.g., pentatonic) including a specified number of heteroatoms (e.g., 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S), e.g., 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 (imidazole or pyrazol) 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; or a group independently selected from oxygen, nitrogen, and sulfur. It refers to a 5-membered aromatic ring containing two heteroatoms (e.g., oxazole), additional examples being thiophene, imidazole, isothiazol, oxadiazole, and isoxazole. For example, an "unsaturated 6-membered heterocycle" is a 6-membered ring containing 6 atomic members containing at least 1 heteroatom. Likewise, an "unsaturated 5-membered heterocycle" is a 5-membered ring containing 5 atomic members containing at least 1 heteroatom.
[0507] A "stable" compound is a compound that can be manufactured and isolated and whose structure and properties remain essentially unchanged or can be maintained for a period sufficient to allow for the use of the compound for the purposes described herein (e.g., therapeutic or prophylactic administration to a subject).
[0508] The compounds of the present disclosure are limited to stable compounds encompassed by Formula I and embodiments thereof. For example, a specific moiety as defined in Formula I may be unsubstituted or substituted, the latter being intended to encompass substitution patterns (i.e., the number and types of substituents) that produce a chemically possible and stable compound for the moiety.
[0509] The term “substituted” means that one or more hydrogens on a specified atom are replaced by a group selected from the group represented therein, provided that the substitution does not exceed the normal valence of the specified atom under existing conditions, and the substitution produces a stable compound. Where multiple substituent moiety is disclosed or claimed, the substituted compound may be independently substituted, either alone or in multiple ways, by one or more of the disclosed or claimed substituent moiety. Being independently substituted means that (two or more) substituents may be identical or different. Combinations of substituents and / or variable groups are permissible only if such combination produces a stable compound. Where a substituent itself is substituted by more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, provided that a stable structure is produced. “Optionally substituted” means a compound containing the specified optional substituent(s) as well as a compound not containing the optional substituent(s).
[0510] The wavy line used in this document It indicates the attachment site for the remainder of the compound.
[0511] In cases where a ring atom is represented by a variable group such as "X", for example In the case of, the variable group is defined by indicating the atom located at the variable ring position without illustrating the ring bond associated with the atom. For example, if X in the ring is nitrogen, the definition will indicate "N" and will not illustrate the bond associated therewith, for example, "=N-". Similarly, if X is a carbon atom substituted with bromide, the definition will indicate "C-Br" and will not illustrate the bond associated therewith, for example, will not indicate the following: .
[0512] The present invention also includes derivatives of the compound of Formula I that act as prodrugs and solvates. Any pharmaceutically permissible prodrug modification of the compound of the present invention that is converted in vivo into a compound within the scope of the present invention is also within the scope of the present invention. After administration to a patient, the prodrug is converted in the body by normal metabolic or chemical processes, for example, through hydrolysis in the blood. Such prodrugs include those exhibiting enhanced bioavailability, tissue specificity, and / or cell delivery to improve the drug absorption of the compound of Formula I. The effects of such prodrugs may be produced from modifications of physicochemical properties, such as lipophilicity, molecular weight, charge, and other physicochemical properties that determine the permeability of the drug.
[0513] For example, esters may be produced by the esterification of optionally available carboxylic acid groups or by the formation of esters on available hydroxyl groups within the compound. Similarly, unstable amides may be produced. Pharmaceutically acceptable esters or amides of the compounds of the present invention may be produced to act as prodrugs that can be rehydrolyzed into acid (or -COO- depending on the pH of the fluid or tissue where conversion occurs) or hydroxyl forms, particularly in vivo, and are themselves encompassed within the scope of the present invention. Esters and acyl groups known in the relevant art are included to modify solubility or hydrolysis characteristics for use as sustained-release or prodrug formulations. Examples of pharmaceutically acceptable prodrug modifications include -C 1-6 -C substituted with alkyl esters and phenyl esters 1-6 It includes, but is not limited to, alkyl groups.
[0514] "Celite®" (Fluka) diatomite is diatomite and can be referred to as "Celite".
[0515] Arbitrary variable (e.g., R 1 Where (etc.) appears more than once in any component or in Formula I or other formulas of the present invention, its definition in each case is independent of its definition in all other cases. Combinations of substituents and / or variable groups are acceptable only if such combinations produce a stable compound. In selecting the compounds of the present invention, a person skilled in the art would recognize various substituents, namely R 1 It will be recognized that the substitutions, etc., should be selected in accordance with the widely known principles of chemical structural connectivity and stability. Unless otherwise explicitly stated, substitution by named substituents is permitted on any atom within a ring (e.g., aryl, heteroaryl ring, or saturated heterocyclic ring), provided that such ring substitution produces a chemically permissible and stable compound.
[0516] It should be noted that in the event of a discrepancy between the chemical name and the structure, the structure is understood to be dominant.
[0517] Compounds of structural formula I may contain one or more asymmetric centers and thus may appear as racemic mixtures, racemic mixtures, single enantiomers, mixtures of diastereomers, and individual diastereomers. All asymmetric centers present in the compounds of formula I may independently have S coordination or R coordination. When the bond to the chiral carbon is depicted as a straight line in the structural formula of the present invention, it is understood that both (R) and (S) coordinations of the chiral carbon, and thus both enantiomers and mixtures thereof, are encompassed within the formula. Similarly, when a compound name is mentioned without a chiral designation for the chiral carbon, it is understood that both (R) and (S) coordinations of the chiral carbon, and thus individual enantiomers and mixtures thereof, are encompassed by the name. The preparation of specific stereoisomers or mixtures thereof may be identified in examples where such stereoisomers or mixtures are obtained, but this does not in any way limit the inclusion of all stereoisomers and mixtures thereof within the scope of the present invention.
[0518] The compounds of the present invention comprise all possible enantiomers and diastereomers, and mixtures of two or more stereoisomers, for example, mixtures of all ratios of enantiomers and / or diastereomers. Accordingly, enantiomers are the subject of the present invention in the form of enantiomerically pure as both levorotatory and levorotatory counterparts, racemic forms, and mixtures of all ratios of two enantiomers. In the case of cis / trans isomerism, the present invention comprises both cis and trans forms, as well as mixtures of all ratios of these forms. The present invention is intended to include all such stereoisomer forms of the compound of structural formula I.
[0519] The compound of structural formula I can be separated into its individual diastereomers, for example, by fractional crystallization from a suitable solvent, e.g., MeOH or EtOAc or a mixture thereof, or by chiral chromatography using an optically active stationary phase. Optionally, derivatization may be performed prior to the separation of the stereoisomers. Separation of a mixture of stereoisomers may be performed at an intermediate stage during the synthesis of the compound of formula I, or on the final racemic product. Absolute stereochemistry may be determined, if necessary, by X-ray crystallography of the derivatized crystalline product or crystalline intermediate using a reagent containing an asymmetric center of known absolute coordination. Alternatively, any stereoisomer or isomer of the compound of formula I may be obtained by stereospecific synthesis using an optically pure starting material or a reagent of known absolute coordination. The present invention comprises all such isomers, as well as salts, solvates (including hydrates), and solvated salts of such racemics, enantiomers, diastereomers, and tautomers, and mixtures thereof.
[0520] If desired, a racemic mixture of compounds can be separated to isolate individual enantiomers. Separation can be carried out by methods widely known in the art, such as coupling the racemic mixture of compounds to an enantiomerically pure compound to form a diastereomer mixture, and then separating the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction often involves the formation of a salt using an enantiomerically pure acid or base. Subsequently, the diastereomer derivative can be converted into a pure enantiomer by cleaving an added chiral residue. A racemic mixture of compounds can also be directly separated by chromatographic methods using a chiral stationary phase, which is widely known in the art.
[0521] For compounds of Formula I described herein containing olefinic double bonds, unless otherwise specified, they are intended to include both E and Z geometric isomers.
[0522] Some of the compounds described herein may exist as tautomers having different attachment sites of hydrogen accompanied by one or more double bond transfers. For example, ketones and their enol forms are keto-enol tautomers. Individual tautomers as well as mixtures thereof are encompassed in the compounds of Formula I of the present invention.
[0523] In a compound of structural formula I, an atom may represent its natural isotopic abundance, or one or more of the atoms may be artificially enriched into a specific isotope having the same atomic number but a different atomic mass or mass number from that which is predominantly found in nature. The present invention, as described and claimed herein, is intended to include all suitable isotopic variations of the compound of structural formula I and its embodiments. For example, different isotopic forms of hydrogen (H) include light hydrogen (1 H) and deuterium ( 2 It includes H (also denoted as D herein). Light hydrogen is the dominant hydrogen isotope found in nature. Concentration to deuterium may provide specific therapeutic benefits, such as an increase in in vivo half-life or a reduction in dosage requirements, or may provide compounds useful as standards for characterizing biological samples. The isotope-enriched compounds within structural formula I can be prepared without excessive experimentation by conventional techniques widely known to those skilled in the art, or by methods similar to those described in the reaction schemes and examples herein using appropriate isotope-enriched reagents and / or intermediates.
[0524] It will be understood that the compound of structural formula I can be prepared as a pharmaceutically acceptable salt, or as a precursor to a free compound or its pharmaceutically acceptable salt, or as a pharmaceutically unacceptable salt when used in other synthetic operations. The compounds of the present invention, including the compounds of the examples, may also include all salts of the compound of formula I that are not directly suitable for pharmaceutical use due to low physiological compatibility, but can be used, for example, as intermediates for chemical reactions or the preparation of physiologically acceptable salts.
[0525] The compounds of the present invention may 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 base or acid, including an inorganic or organic base and an inorganic or organic acid.
[0526] Salts of basic compounds encompassed within the term "pharmaceutical acceptable salts" generally refer to non-toxic salts of the compounds of the present invention prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include, but are not limited to, the following: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edicilate, estolate, esylate, fumarate, gluteptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydrabamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, maleate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, Methyl sulfate, methanesulfonate, mucate, napsylate, nitrate, N-methylglucarmin ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, valerate, etc. Additionally, where the compound of the present invention possesses an acidic moiety, suitable pharmaceutically permissible salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese disodium, manganese iodide, potassium, sodium, zinc, etc. In one embodiment, the salts of the acidic compound are as follows: ammonium, calcium, magnesium, potassium, and sodium salts.
[0527] In combination with basic reagents, such as hydroxide, carbonate, hydrogen carbonate, alkoxide, and ammonia, organic bases, or alternatively basic amino acids, compounds of formula I form stable alkali metals, alkaline earth metals, or optionally substituted ammonium salts.
[0528] Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamines, and basic ion-exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. In addition, the basic nitrogen-containing group can be quaternized with agents such as lower alkyl halides, e.g., methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates, e.g., dimethyl, diethyl, dibutyl; and diamyl sulfate, long-chain halides, e.g., decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, aralkyl halides, e.g., benzyl and phenethyl bromide.
[0529] The preparation of a pharmacologically acceptable salt from a compound of Formula I capable of forming a salt, including in stereoisomer forms, is carried out by known methods, for example, by mixing a solution containing an equivalent amount of the compound of the present invention and a desired acid, base, etc., and then collecting the desired salt by filtering the salt or distilling the solvent. The compound of the present invention and its salt may form solvates with a solvent, such as water, ethanol, or glycerol. Depending on the type of substituent of the side chain, the compound of the present invention may simultaneously form an acid addition salt and a salt with a base.
[0530] In cases where the compound of Formula I contains acidic and basic groups simultaneously within the molecule, the present invention also includes an internal salt or betaine (zwitterion) in addition to the salt forms mentioned. The salt may be obtained from the compound of Formula I by conventional methods known to those skilled in the art, for example by combination with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange from another salt.
[0531] The present invention comprises compounds of structural formula I as well as their salts, in particular pharmaceutically acceptable salts, solvates of such compounds and solvated salt forms thereof, wherein such forms are possible unless otherwise specified.
[0532] Additionally, the compounds of the present invention may exist in an amorphous form and / or one or more crystalline forms, and all amorphous and crystalline forms of the compounds of Formula I, including the examples, and mixtures thereof are intended to be included within the scope of the present invention. Furthermore, some of the compounds of the present invention may form solvates (i.e., hydrates) with water or solvates with conventional 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, are likewise included within the scope of the present invention along with their nonsolved and anhydrous forms.
[0533] Accordingly, the compounds in the general structural formula, 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), solvate and hydrate forms and any combination thereof, as well as their salts, prodrug forms, and salts of their prodrug forms, wherein such forms are possible unless otherwise specified.
[0534] The present invention also relates to a medicine containing one or more compounds of Formula I and / or a pharmaceutically acceptable salt of a compound of Formula I and / or optionally a stereoisomer form of a compound of Formula I or a pharmaceutically acceptable salt of a stereoisomer form of a compound of Formula I together with a pharmaceutically acceptable vehicle, carrier, additive and / or other active substance and adjuvant.
[0535] The medicine according to the present invention may be administered by oral, inhalation, rectal, or transdermal administration, or by subcutaneous, intra-articular, intraperitoneal, or intravenous injection. Oral administration is preferred. Coating with a compound of Formula I is possible on stents and other surfaces in the body that come into contact with blood.
[0536] The present invention also relates to a method for manufacturing a medicine, comprising making at least one compound of Formula I into a suitable dosage form using a pharmaceutically acceptable carrier and optionally additional suitable active substances, additives, or adjuvants.
[0537] The present invention also relates to a method for preparing a compound of Formula I, wherein the compound of the present invention can be obtained by the method described below.
[0538] The terms “therapeutic effective dose (or effective dose)” and similar descriptions, e.g., “therapeutic effective dose” are intended to mean an amount of pharmaceutical drug that alleviates the symptoms of a disorder, condition, or disease to be treated in animals or humans (i.e., a disorder, condition, or disease associated with DGAT2 activity). The terms “preventive effective dose (or effective dose)” and similar descriptions, e.g., “preventive effective dose” are intended to mean an amount of pharmaceutical drug that prevents or reduces the symptoms or occurrence of a disorder, condition, or disease to be treated in animals or humans (i.e., a disorder, condition, or disease associated with DGAT2 activity). The administration regimen using the compounds of the present invention is selected based on various factors including the patient’s type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the efficacy of the selected compound to be administered; the route of administration; and the patient’s renal and hepatic function. Consideration of these factors is within the authority of a clinician of ordinary skill for the purpose of determining the therapeutically effective or preventively effective dose required to prevent, respond to, or halt the progression of the condition. It is understood that the specific daily dose may simultaneously be both a therapeutic effective dose for the treatment of, for example, hepatic steatosis, diabetes, obesity, hyperlipidemia, and hypercholesterolemia, and a prophylactic effective dose for, for example, NASH.
[0539] Disorders, conditions, and diseases that can be treated or prevented by inhibiting DGAT2 using a compound of Formula I are, for example, non-alcoholic fatty liver disease (NASH), fibrosis, hyperlipidemia, type I diabetes mellitus, type II diabetes mellitus, cognitive decline, dementia, coronary heart disease, ischemic stroke, restenosis, peripheral vascular disease, intermittent claudication, myocardial infarction, dyslipidemia, postprandial dyslipidemia, obesity, osteoporosis, hypertension, congestive heart failure, left ventricular hypertrophy, peripheral artery disease, diabetic retinopathy, diabetic nephropathy, glomerulosclerosis, chronic renal failure, diabetic neuropathy, metabolic syndrome, syndrome X, coronary heart disease, angina pectoris, thrombosis, atherosclerosis, myocardial infarction, transient ischemic attack, stroke, hyperglycemia, hyperinsulinemia, hypertriglyceridemia, insulin resistance, glucose intolerance disorders, Erectile dysfunction, skin and connective tissue disorders, hyper-apo-B lipoproteinemia, non-alcoholic fatty liver disease, psychosomatic diseases, such as chronic kidney disease and heart failure, and related diseases and conditions.
[0540] The compound of Formula I and its pharmaceutically acceptable salts may be administered to animals, preferably mammals, and particularly humans, as a pharmaceutical in itself, as a mixture with one another, or in the form of a pharmaceutical formulation. The term “patient” includes animals, preferably mammals, and particularly humans, who use the active agent of the present invention for the prevention or treatment of a medical condition. Administering the drug to a patient includes both self-administration and administration to the patient by another person. A patient may need or desire treatment for an existing disease or medical condition, or may need or desire prophylactic treatment to prevent or reduce the risk of developing said disease or medical condition. As used herein, a patient “needing” treatment or prophylactic treatment for an existing condition encompasses both the determination of need by a medical professional and the patient’s desire for such treatment.
[0541] In addition, the subject of the present invention is a pharmaceutical formulation (or pharmaceutical composition) comprising, as an active ingredient, at least one compound of Formula I in a therapeutically effective dose and / or a pharmaceutically acceptable salt thereof, and a conventional pharmaceutically acceptable carrier, i.e., one or more pharmaceutically acceptable carrier materials and / or additives.
[0542] Accordingly, the subject of the present invention is, for example, said compound and its pharmaceutically acceptable salt for use as a pharmaceutical, pharmaceutical formulations comprising said compound and / or its pharmaceutically acceptable salt in a therapeutically effective dose as an active ingredient and a conventional pharmaceutically acceptable carrier, and the use of said compound and / or its pharmaceutically acceptable salt in the therapy or prevention of said syndrome, as well as the use thereof for manufacturing medicines for these purposes.
[0543] The pharmaceutical according to the present invention may be administered orally, for example in the form of pills, tablets, lacquer tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, aqueous, alcoholic or oily solutions, syrups, emulsions or suspensions, or rectally, for example in the form of suppositories. Administration may also be performed parenterally, for example subcutaneously, intramuscularly, or intravenously in the form of solutions for injection or infusion. Other suitable forms of administration are transdermal or topical administration, for example in the form of ointments, tinctures, sprays or transdermal treatment systems, or inhalation administration in the form of nasal sprays or aerosol mixtures, or for example, microcapsules, implants, or rods. The preferred form of administration depends, for example, on the disease to be treated and its severity.
[0544] For the manufacture of pills, tablets, sugar-coated tablets, and hard gelatin capsules, it is possible to use, for example, lactose, starch, for example, corn starch, or starch derivatives, talc, stearic acid, or salts thereof. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hydrogenated oils, etc. Carriers suitable for the manufacture of solutions, for example, injectable solutions, or emulsions or syrups are, for example, water, physiological sodium chloride solution, alcohols, such as ethanol, glycerol, polyols, sucrose, invert sugar, glucose, mannitol, vegetable oils, etc. It is also possible to freeze-dry compounds of Formula I and their pharmaceutically acceptable salts and use the resulting freeze-dried product, for example, to manufacture formulations for injection or infusion. Carriers suitable for microcapsules, implants, or rods are, for example, copolymers of glycolic acid and lactic acid.
[0545] Suitable solid or herbal preparation forms are, for example, granules, powders, coated tablets, tablets, (micro)capsules, suppositories, syrups, juices, suspensions, emulsions, drops, or injectable solutions and preparations having sustained release of the active substance, and in their preparation, conventional excipients, such as vehicles, disintegrants, binders, coating agents, swelling agents, lubricants or lubricants, flavoring agents, sweeteners, and solubilizers are used. Frequently used adjuvants that may be mentioned are magnesium carbonate, titanium dioxide, lactose, mannitol and other sugars, talc, lactose, gelatin, starch, cellulose and its derivatives, animal and vegetable oils, such as cod liver oil, sunflower, peanut or sesame oil, polyethylene glycol, and solvents, for example, sterile water, and monohydric or polyhydric alcohols, such as glycerol.
[0546] In addition to the active compound and carrier, the pharmaceutical formulation may also contain conventional additives, such as fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, dispersants, preservatives, sweeteners, coloring agents, flavoring agents, aromatics, thickeners, diluents, buffering materials, solvents, solubilizers, agents for achieving a deposit effect, salts for changing osmotic pressure, coating agents, or antioxidants.
[0547] The dosage of the active compound of Formula I and / or its pharmaceutically acceptable salt to be administered varies on an individual basis and, as is customary, must be adapted to the individual situation to achieve optimal effect. Accordingly, this depends on the nature and severity of the disorder, condition, or disease to be treated, as well as the sex, age, body weight, and individual responsiveness of the human or animal to be treated, the efficacy and duration of action of the compound used, whether the therapy is acute, chronic, or prophylactic, or whether other active compounds are administered in addition to the compound of Formula I.
[0548] Combination agent
[0549] The compounds of the present invention may be administered alone or in combination with one or more additional therapeutic agents or other suitable agents disclosed herein, depending on the condition to be treated. Accordingly, in some embodiments, one or more compounds of the present invention will be co-administered with other agents as described above. When used in combination therapy, the compounds described herein are administered simultaneously or individually with a second agent. Such combination administration may include simultaneous administration of two agents in the same dosage form, simultaneous administration in individual dosage forms, and individual administration. That is, the compound of Formula I and any agent described above may be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound of Formula (I) and any of the agents described above may be administered simultaneously, wherein both agents exist as individual formulations. In another alternative, any agent described above may be administered immediately after the compound of Formula I is administered, or vice versa. In some embodiments of the individual administration protocol, the compound of Formula (I) and any of the agents described above are administered at intervals of minutes, hours, or days.
[0550] Since one aspect of the present invention considers the treatment of a disease / condition using a combination of pharmaceutically active compounds that can be administered individually, the present invention further relates to combining individual pharmaceutical compositions in a kit form. The kit comprises two individual pharmaceutical compositions: a compound of formula (I) and a second pharmaceutical compound. The kit comprises a container for containing the individual compositions, such as a divided bottle or a divided foil packet. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for the use of the individual components. The kit form is particularly advantageous when the distinct components are preferably administered in different dosage forms (e.g., oral, parenteral; IV, transdermal, and subcutaneous), administered at different dosing intervals, or when titration of the individual components of the combination is required by a prescribing healthcare professional.
[0551] One or more additional pharmacological active agents may be administered in combination with the compound of Formula I. The additional active agent (or active agents) is intended to mean a pharmaceutical active agent (or active agents) that is active in the body, including a prodrug that is converted into a pharmaceutically active form after administration, which is different from the compound of Formula I, and also includes free acids, free bases, and pharmaceutically acceptable salts of said additional active agents. Generally, any suitable additional active agent or active agents, including but not limited to antihypertensive agents, anti-obesity agents, anti-inflammatory agents, antifibrotic agents, and anti-atherosclerotic agents, such as lipid-modifying compounds, antidiabetic agents, and / or anti-obesity agents, may be used in any combination with the compound of Formula I as a single-dose formulation (fixed-dose drug combination), or may be administered to the patient as one or more individual formulations that enable the co- or sequential administration of the active agents (co-administration of individual active agents).
[0552] Examples of additional active agents that may be used include, but are not limited to, the following: angiotensin-converting enzyme inhibitors (e.g., alacepril, benazepril, captopril, seronapril, silazapril, delapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moveeptipril, perindopril, quinapril, ramipril, spirapril, temocapril, or trandolapril), angiotensin II receptor antagonists (e.g., losartan, i.e., COZAAR®, valsartan, candesartan, olmesartan, telmesartan, and any of these drugs used in combination with hydrochlorothiazide, e.g., HYZAAR®); Neutral endopeptidase inhibitors (e.g., thiorphan and phosphoramidon), aldosterone antagonists, aldosterone synthase inhibitors, renin inhibitors (e.g., urea derivatives of di- and tri-peptides, amino acids and derivatives, amino acid chains linked by non-peptide bonds, di- and tri-peptide derivatives, peptidylaminodiol and peptidyl beta-aminoacylaminodiol carbamate; also, small molecule renin inhibitors including diol sulfonamides and N-morpholino derivatives, N-heterocyclic alcohols and pyrrolimidazolone;In addition, pepstatin derivatives of statone-containing peptides and fluoro- and chloro-derivatives, enalcrain, RO 42-5892, A 65317, CP 80794, ES 1005, ES 8891, SQ 34017, aliskiren (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]-octanamide hemifumarate) SPP600, SPP630, and SPP635), endothelin receptor antagonists, phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil, and vardenafil), vasodilators, calcium channel blockers (e.g., amlodipine, Nifedipine, verapamil, diltiazem, gallopamil, niludipine, nimodipine, nicardipine), potassium channel activators (e.g., nicorandil, finacidil, chromatecalim, minoxidil, aprilcalim, lofrazolam), diuretics (e.g., hydrochlorothiazide), sympathetic nerve blockers, beta-adrenergic blocking drugs (e.g., propranolol, atenolol, bisoprolol, carvedilol, metoprolol, or metoprolol tartate), alpha-adrenergic blocking drugs (e.g., doxazosin, prazosin, or alpha-methyldopa), central alpha-adrenergic agonists, peripheral vasodilators (e.g., hydralazine); Lipid-lowering agents, e.g., HMG-CoA reductase inhibitors, such as simvastatin and lovastatin (marketed as lactone prodrug forms ZOCOR® and MEVACOR®, and function as inhibitors after administration), and pharmaceutically acceptable salts of dihydroxy open-ring acid HMG-CoA reductase inhibitors, e.g., atorvastatin (particularly, the calcium salt marketed as LIPITOR®), rosuvastatin (particularly, the calcium salt marketed as CRESTOR®), pravastatin (particularly, the sodium salt marketed as PRAVACHOL®), fluvastatin (particularly, the sodium salt marketed as LESCOL®), cerivastatin, and pitavastatin;Any other lipid-lowering agents, e.g., the aforementioned HMG-CoA reductase inhibitors, in particular simvastatin (VYTORIN®) or cholesterol resorption inhibitors combined with atorvastatin calcium, e.g., ezetimibe (ZETIA®) and ezetimibe; niacin in immediate-release or controlled-release forms, and / or HMG-CoA reductase inhibitors; niacin receptor agonists, e.g., acipimox and asisran, as well as niacin receptor partial agonists; anti-cholesterol agents, e.g., PCSK9 inhibitors (alirocumab, evolocumab), Nexletol; TM(bempedosate, ACL inhibitors) and Vascepa® (icosapent ethyl); metabolic modifiers, e.g., insulin and insulin mimics (e.g., insulin degludec, insulin glargine, insulin lispro), dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin, alogliptin, omaglipin, linagliptin, vildagliptin); Insulin sensitizers, e.g., (i) β-cloto / FGFR1-activating monoclonal antibodies (e.g., MK-3655), pan FGFR1-4 / KLB modulators, FGF19 analogs (e.g., aldafermin); (ii) PPARγ agonists, e.g., glitazones (e.g., pioglitazone, AMG 131, CHS 131, MBX2044, mitoglitazone, lobeglitazone, IDR-105, rosiglitazone, and valaglitazone); and other PPAR ligands, e.g., (1) PPARα / γ dual agonists (e.g., ZYH2, ZYH1, GFT505, ciglitazar, muraglitazar, aleglitazar, sodelglitazar, and nabeglitazar); (2) PPARα agonists, e.g., fenofibrate derivatives (e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate), (3) selective PPARγ modifiers (SPPARγM) (e.g., modifiers disclosed in WO 02 / 060388, WO 02 / 08188, WO 2004 / 019869, WO 2004 / 020409, WO 2004 / 020408, and WO 2004 / 066963); (4) PPARγ partial agonists, (5) PPARα / δ dual agonists (e.g., elafibranor); (iii) biguanides, e.g., metformin and its pharmaceutically acceptable salts, particularly metformin hydrochloride, and its extended-release formulations, e.g., Glumetza TM , Fortamet TM , and GlucophageXR TM; and (iv) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g., ISIS-113715 and TTP814); insulin or insulin analogs (e.g., insulin detemir, insulin glulisin, insulin degludec, insulin glargine, insulin lispro and their respective inhaled formulations); leptin and leptin derivatives and agonists; amylin and amylin analogs (e.g., pramlintide); sulfonylurea and non-sulfonylurea insulin secretagogues (e.g., tolbutamide, glyburide, glipizide, glimepiride, mitiglinide, 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, e.g., GLP-1, GLP-1 analogs, derivatives, and mimics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide, albiglutide, exenatide, liraglutide, lixisenatide, tasfoglutide, CJC-1131, and BIM-51077 (including their intranasal, transdermal, and once-weekly formulations)), bile acid blockers (e.g., cholestylan, cholestemide, cholesevalam hydrochloride, colestipol, cholestyramine, and dialkylaminoalkyl derivatives of cross-linked dextran), acyl CoA:cholesterol acyltransferase inhibitors (e.g., abasimib); anti-obesity compounds; Agents for use in inflammatory conditions, e.g., aspirin, non-steroidal anti-inflammatory drugs or NSAIDs, glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors; glucokinase activators (GKAs) (e.g., AZD6370); inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (e.g., those disclosed in U.S. Patent No. 6,730,690 and LY-2523199); CETP inhibitors (e.g., anacetrapive, torcetrapive, and evacetrapive); fructose 1,Inhibitors of 6-bisphosphatase (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); inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2); AMP-activated protein kinase (AMPK) activators; other agonists of G-protein-coupled receptors: (i) GPR-109, (ii) GPR-119 (e.g., MBX2982 and PSN821), and (iii) GPR-40 (e.g., TAK875); SSTR3 antagonists (e.g., those disclosed in WO 2009 / 001836); Neuromedin U receptor agonists (e.g., those disclosed in WO 2009 / 042053, including but not limited to Neuromedin S (NMS); SCD modulators (e.g., Aramcol); GPR-105 antagonists (e.g., those disclosed in WO 2009 / 000087); SGLT inhibitors (e.g., ASP1941, SGLT-3, SGLT-2, e.g., empagliflozin, dapagliflozin, canagliflozin, and ertugliflozin, BI-10773, remogloflozin, TS-071, topogliflozin, ipragliflozin, and LX-4211); inhibitors of acyl coenzyme A carboxylase (ACC, MK-4074); Inhibitors of diacylglycerol acyltransferases 1 and 2 (DGAT-1 and DGAT-2); inhibitors of fatty acid synthases; acyl coenzyme A: inhibitors of monoacylglycerol acyltransferases 1 and 2 (MGAT-1 and MGAT-2); agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19, GPR131, and M-BAR); ileal bile acid transporter inhibitors; bile acid modulators; PACAP, PACAP mimics, and PACAP receptor 3 agonists; IL-1b antibodies (e.g.,XOMA052 and canakinumab); Antifibrotic agents and / or anti-inflammatory agents (CCR2 / CCR5 dual receptor antagonists (e.g., cenicriviroc); galectin 3 inhibitors (e.g., belapectin, GB-1107, GB-1211), siRNA against HSP 47 (e.g., BMS-986263); NSAIDs derived from pirfenidone (e.g., hydronidone), A3AR agonists (e.g., namodenosone, FM101); TGFTX4 (e.g., nitazoxanide); 5-lipoxygenase inhibitors (e.g., tipelukast), bifunctional urea inhibitors (e.g., ACQT1127), adiponectin receptor agonists (e.g., ALY688), TNF receptor antagonists (e.g., atorsimab), 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 permeability inhibitors (e.g., larazotide), CCR5 antagonists (e.g., ireronlimab), 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., proglumid), LOXL2 inhibitors (e.g., PXS-5338K, PXS-5382A), IL-11 inhibitors, MPYS protein inhibitors (e.g., cGAS / STING antagonists), kinase inhibitors RNase, membrane protein mAbs, tumor necrosis factor inhibitors, NRF2 activators (e.g., 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 modulators (e.g., anticoagulants, antiplatelet agents, pentoxifyllin, vitamin K, DDAVP); dual GIP and GLP-1 receptor agonists (e.g., tyrsepeptide); dual GLP-1 / GRA (e.g., cotadutide, ALT-801, DD-01, G49, PB-718); dual GLP-1 (e.g., CT-868); GLP-1 / GRA / GIP triple agonists (e.g., HM15211); GRP120 stimulator / inflammasome modulator / PPARγ dual agonists (e.g., KDT501); GLP-1 / FGF21 (e.g., YH25724); GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW-003); selective thyroid hormone receptor-β agonists (e.g., Resmetirom); Apoptosis modulators (JNK-1 inhibitors (e.g., CC-90001), peroxidase inhibitors (e.g., AZM198), ASK-1 inhibitors (e.g., CS-17919, SRT-015)); erythropoietin-stimulators (erythropoietin receptor agonists (e.g., sibinetide)); glucose pathway modulators (SGLT-2 inhibitors (e.g., Forxiga, Farxiga (dapagliflozin)); dual SGLT-1 / 2 inhibitors (e.g., ricogliflozin),Glucose-6-P 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., modesipimod), macrophage inhibitors via CD206 targeting (e.g., MT2002), TLR2 / 4 antagonists (e.g., VB-201, VB-703), immunomodulatory polyclonal antibodies (e.g., IMM-124E)); Incretin-based therapy (GLP-1 agonists (e.g., Ozempic (semaglutide sc), XW 003), GLP-1 / glucagon dual receptor agonists (e.g., HM12525A), mealtime insulin (e.g., ORMD 0801)); Lipid modulators (AMPK activators / glutathione transferases (e.g., oltipraz), THR-beta agonists (e.g., Resmetyrom, VK2809, MGL-3745, ALG-009, ASC41, CNPT-101101, TERN 501), IBAT inhibitors (e.g., Elrobixivat, CJ 14199), omega-6 fatty acids (e.g., Epeluton), FASN inhibitors (e.g., TVB2640, FT 4101, FT 8225), ANGPTL3 inhibitors (e.g., bufanorcene), PNPLA3 inhibitors (e.g., AZD2693), RAS domain kinase inhibitors (e.g., BioE1115), NTCP inhibitors (e.g., bulevirtide), P2Y13 receptor agonists (e.g., CER-209), omega-3 fatty acids, HSD17β13 inhibitors; metabolism Modifiers (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., Pegvelfermin, BMS-986171), non-biliary FXR agonists (e.g., Silofexer, EDP-305, EYP 001, Tropifexer, 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 acids Modifiers (e.g., Albiero), FGF21 analogs (e.g., BIO89-100), MOTSc analogs (e.g., CB4211), cyclophylline inhibitors (e.g., CRV 431), FGF19 (e.g., DEL 30), mitochondrial decoupling agents (e.g., GEN 3026), FXR / GPCR dual agonists (e.g., INT-767), cysteamine derivatives (e.g., KB-GE-001), dual amylin and calcitonin receptor agonists (e.g., KBP-089), transient FXR agonists (e.g., M 1217), anti-beta-cloto (KLB)-FGFR1c receptor complex mAbs (e.g., MK3655), GDF15 analogs (e.g., NGM395), cyclophylline inhibitors (e.g., NV556), LXR modifiers (e.g., PX 329, PX 655, PX 788), 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., ranifibranor), PPARα agonists (e.g., Parmodia), PPARγ agonists (e.g., CHS 131), MPC inhibitors (e.g., PXL065),PPAR δ / γ agonists (e.g., T3D 959)); RAAS mIM modulators (mineralocorticoid receptor antagonists (e.g., apararenone, eplerenone, spironolactone), angiotensin receptor blockers (e.g., losartan potassium)); neurotransmitter modulators (cannabinoid receptor modulators, CB1 receptor antagonists (e.g., CRB-4001, IM-102, nimacimab), TPH1 inhibitors (e.g., CU-02), GPR120 agonists (e.g., KBR2001), combinations of cannabinoids and phytoanti-inflammatory compounds (e.g., SCN-002)); PDE modulators (PDE4 inhibitors (e.g., ART 648)); CYP2E1 inhibitors (e.g., SNP-610); Cell therapy (e.g., HepaStem) and bromocriptine mesylate and its rapid-release formulations; or other drugs beneficial for the prevention or treatment of the aforementioned diseases, including nitroprusside and diazoxide (along with free acid, free base, and pharmaceutically acceptable salt forms of the said active agent where chemically possible).
[0553] The present invention includes salts of compounds defined herein that are permitted by the constraints of all structural formulas, embodiments, and classes defined herein. References to compounds of structural formula I include other general structural formulas, such as compounds of formulas and embodiments falling within the category of formula I.
[0554] Dosage of the compound of chemical formula (I)
[0555] If the patient responds or remains stable after the completion of the therapy cycle, the therapy cycle may be repeated at the discretion of a skilled clinician. Upon completion of the therapy cycle, the patient may maintain the same dose of the compound of the present invention administered in the treatment protocol. This maintenance dose may be continued until the patient progresses or can no longer tolerate the dose (in which case the dose may be reduced and the patient may continue to receive the reduced dose).
[0556] A person skilled in the art will recognize that the actual dosage and protocol for administration used in the method of the present invention may vary depending on the judgment of a skilled clinician. The actual dosage used may vary depending on the patient's requirements and the severity of the condition to be treated. Determining the appropriate dosage for a specific situation is within the scope of the art. Decisions to change the dosage and protocol for administration may be made by a skilled clinician after considering factors such as the patient's age, condition, and dimensions, as well as the severity of the condition to be treated and the patient's response to treatment.
[0557] The administration regimen using the compounds of the present invention is selected based on various factors including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the efficacy of the selected compounds to be administered; the route of administration; and the patient's renal and hepatic function. Consideration of these factors is within the authority of a clinician of ordinary skill for the purpose of determining the therapeutically effective or prophylactically effective dose required to prevent, respond to, or stop the progression of the condition. It is understood that the specific daily dose may simultaneously be both, for example, a therapeutically effective dose for the treatment of a tumor condition and, for example, a prophylactically effective dose for the prevention of a tumor condition.
[0558] Although individual needs vary, determining the optimal range of the effective amount of the compound of the present invention is within the scope of the art in the relevant field. For administration to humans for the curative or preventive treatment of conditions and disorders identified herein, for example, a typical dosage of the compound of the present invention may be about 0.05 mg / kg / day to about 50 mg / kg / day, for example, at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, or at least 0.5 mg / kg, preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, which may be, for example, about 2.5 mg / day (0.5 mg / kg x 5 kg) to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dosage of the compound is 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 It may be mg / day, about 5 mg / day to about 250 mg / day, about 10 mg / day to about 100 mg / day, about 3 mg / day to about 10 mg / day, or about 100 mg / day to about 250 mg / day. These doses may be administered as a single dose or divided into multiple doses.
[0559] Pharmaceutical composition
[0560] The compound of Formula I and its pharmaceutically acceptable salts may be administered to animals, preferably mammals, and particularly humans, as a pharmaceutical, either as itself, as a mixture with one another, or in the form of a pharmaceutical composition. The terms “subject” or “patient” include animals, preferably mammals, and particularly humans, using the active agent of the present invention for the prevention or treatment of a medical condition.
[0561] Administering a compound of Formula I to a subject includes both self-administration and administration to the patient by another person. The subject may require or desire treatment for an existing disease or medical condition, or may require or desire prophylactic treatment to prevent or reduce the risk of developing said disease or medical condition. As used herein, a subject "requiring" treatment or prophylactic treatment for an existing condition encompasses both the determination of need by a medical professional and the patient's desire for such treatment.
[0562] Safe and effective methods of administering most of these agents are known to those skilled in the art. Furthermore, their administration is described in standard literature.
[0563] If the patient responds or remains stable after the completion of the therapy cycle, the therapy cycle may be repeated at the discretion of a skilled clinician. Upon completion of the therapy cycle, the patient may maintain the same dose of the compound of the present invention administered in the treatment protocol. This maintenance dose may be continued until the patient progresses or can no longer tolerate the dose (in which case the dose may be reduced and the patient may continue to receive the reduced dose).
[0564] A person skilled in the art will recognize that the actual dosage and protocol for administration used in the method of the present invention may vary depending on the judgment of a skilled clinician. The actual dosage used may vary depending on the patient's requirements and the severity of the condition to be treated. Determining the appropriate dosage for a specific situation is within the scope of the art. Decisions to change the dosage and protocol for administration may be made by a skilled clinician after considering factors such as the patient's age, condition, and dimensions, as well as the severity of the condition to be treated and the patient's response to treatment.
[0565] The dosage and frequency of administration of the compound of Formula I and any additional agent will be adjusted at the judgment of the attending clinician (physician), taking into account factors such as the patient's age, condition, and dimensions, as well as the severity of the condition to be treated.
[0566] The compound of the present invention is also useful for manufacturing medicines useful for treating NASH and fibrosis.
[0567] The compounds of the present invention are also useful in combination with therapeutic agents, chemotherapy agents, and anticancer agents for the treatment of hepatocellular carcinoma. Combinations of the compounds disclosed herein with therapeutic agents, chemotherapy agents, and anticancer agents are within the scope of the present invention. Examples of such agents are found in the literature [Cancer Principles and Practice of Oncology by VT Devita and S. Hellman (editors), 9 thIt can be found in the [May 16, 2011, Lippincott Williams & Wilkins Publishers] edition. A person skilled in the art will be able to identify which combination of agents would be useful based on the specific characteristics of the drug and the associated cancer. These agents include estrogen receptor modulators, programmed cell death protein 1 (PD-1) inhibitors, programmed cell death-ligand 1 (PD-L1) inhibitors, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents / cell proliferation inhibitors, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, HIV protease inhibitors, reverse transscriptase inhibitors, inhibitors of cell proliferation and survival signaling, bisphosphonates, aromatase inhibitors, siRNA therapeutics, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTK), and agents that interfere with cell cycle checkpoints.
[0568] Chemotherapy agents may be administered according to treatment protocols widely known in the relevant art. It will be apparent to a person skilled in the art that the administration of chemotherapy agents may vary depending on the known effects of the agent on the cancer to be treated and the disease. Furthermore, depending on the knowledge of a skilled clinician, treatment protocols (e.g., dosage and timing of administration) may vary in terms of 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 chemotherapy agents will depend on the attending physician's diagnosis, his judgment regarding the patient's condition, and the appropriate treatment protocol.
[0569] Initial administration may be carried out according to established protocols known in the relevant technical field, and subsequently, the dosage, method of administration, and time of administration may be modified by a skilled clinician based on the observed effects.
[0570] The determination of the order of administration and the number of repetitions of chemotherapy agents during the treatment protocol is within the knowledge of a skilled physician following an assessment of the condition to be treated and the patient's condition.
[0571] Accordingly, based on experience and knowledge, the attending physician may modify the respective protocols for the administration of chemotherapy agents according to the individual patient's needs as treatment progresses. All such modifications are within the scope of the present invention.
[0572] The agent may be administered according to treatment protocols widely known in the relevant art. It will be apparent to a person skilled in the art that the administration of the anticancer agent may vary depending on the known effects of the agent on the cancer being treated and the disease.
[0573] Initial administration may be carried out according to established protocols known in the relevant technical field, and subsequently, the dosage, method of administration, and time of administration may be modified by a skilled clinician based on the observed effects.
[0574] The specific choice of agent will depend on the attending physician's diagnosis, his judgment of the patient's condition, and the appropriate treatment protocol.
[0575] The determination of the order of administration and the number of repeated doses of the agent during the treatment protocol is within the knowledge of a skilled physician following an evaluation of the cancer to be treated and the patient's condition.
[0576] Accordingly, based on experience and knowledge, the attending physician may modify the respective protocols for the administration of anticancer drugs according to the individual patient's needs as treatment progresses. All such modifications are within the scope of the present invention.
[0577] In determining whether the treatment is effective at the administered dosage, the attending clinician will consider the patient's overall well-being as well as clearer indications, such as the alleviation of cancer-related symptoms (e.g., pain), inhibition of tumor growth, actual reduction of the tumor, or inhibition of metastasis. Tumor size can be measured by standard methods, such as radiographic studies, e.g., CAT or MRI scans, and continuous measurements can be used to determine whether tumor growth has been delayed or even reversed. Relief of disease-related symptoms, such as pain, and improvement in the overall condition can also be used to help assess the efficacy of the treatment.
[0578] The compounds, compositions, and methods provided herein are useful 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: hepatocellular carcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.
[0579] PD-1 inhibitors include pembrolizumab (lambrolizumab), nivolumab, and MPDL3280A. PDL-inhibitors include atezolizumab, avelumab, and durvalumab.
[0580] The present invention relates to a method for treating hepatocellular carcinoma in a human patient, comprising further administering to the human patient a compound of the present invention (i.e., a compound of Formula I) and a PD-1 antagonist. The compound and the PD-1 antagonist of the present invention may be administered jointly or sequentially.
[0581] In certain embodiments, the PD-1 antagonist is an anti-PD-1 antibody or its antigen-binding fragment. In alternative embodiments, the PD-1 antagonist is an anti-PD-L1 antibody or its antigen-binding fragment. In some embodiments, the PD-1 antagonist is pembrolizumab (KEYTRUDA) TM, Merck & Co., Inc., Kenilworth, New Jersey, USA), nivolumab (Opdivo) TM , Bristol-Myers Squibb Company, Princeton, New Jersey, USA), Semiplimab (LIBTAYO) TM , Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA), atezolizumab (TECENTRIQ) TM , Genentech, San Francisco, California, USA), durvalumab (Imfinzi) TM , AstraZeneca Pharmaceuticals LP, Wilmington, Delaware) or avelumab (Bavencio) TM , Merck KGaA, Darmstadt, Germany.
[0582] In some embodiments, the PD-1 antagonist is pembrolizumab. In a specific sub-embodiment, the method comprises administering 200 mg of pembrolizumab to a patient approximately every 3 weeks. In another sub-embodiment, the method comprises administering 400 mg of pembrolizumab to a patient approximately every 6 weeks.
[0583] In an additional sub-embodiment, the method comprises administering 2 mg / kg of pembrolizumab to the patient approximately every 3 weeks. In a specific sub-embodiment, the patient is a pediatric patient.
[0584] In some embodiments, the PD-1 antagonist is nivolumab. In a specific sub-embodiment, the method comprises administering 240 mg of nivolumab to a patient approximately every 2 weeks. In another sub-embodiment, the method comprises administering 480 mg of nivolumab to a patient approximately every 4 weeks.
[0585] In some embodiments, the PD-1 antagonist is semiplimab. In certain embodiments, the method comprises administering 350 mg of semiplimab to a patient approximately every 3 weeks.
[0586] In some embodiments, the PD-1 antagonist is atezolizumab. In a specific sub-embodiment, the method comprises administering 1200 mg of atezolizumab to a patient approximately every 3 weeks.
[0587] In some embodiments, the PD-1 antagonist is durvalumab. In a specific sub-embodiment, the method comprises administering 10 mg / kg of durvalumab to a patient approximately every 2 weeks.
[0588] In some embodiments, the PD-1 antagonist is avelumab. In certain sub-embodiments, the method comprises administering 800 mg of avelumab to a patient approximately every 2 weeks.
[0589] The compounds of the present invention or pharmaceutically acceptable salts thereof may also be useful for treating cancer in combination with the following therapeutic agents: pembrolizumab (Keytruda®), abarelix (Plenaxis depot®); aldesleukin (Prokine®); aldesleukin (Proleukin®); alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretinoin (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); Bevacuzimab (Avastin®); Bexarotene capsules (Targretin®); Bexarotene gel (Targretin®); Bleomycin (Blenoxane®); Bortezomib (Velcade®); Busulfan intravenous (Busulfex®); Busulfan oral (Myleran®); Calosterone (Methosarb®); Capecitabine (Xeloda®); Carboplatin (Paraplatin®); Carmustine (BCNU®, BiCNU®); Carmustine (Gliadel®); Carmustine with polyfeprosan 20 implant (Gliadel Wafer®); Celecoxib (Celebrex®); Cetuximab (Erbitux®); Chlorambucil (Leukeran®); Cisplatin (Platinol®); Cladribin (Leustatin®, 2-CdA®); Cloparabine (Clolar®); Cyclophosphamide (Cytoxan®, Neosar®); Cyclophosphamide (Cytoxan Injection®);Cyclophosphamide (Cytosan Tablets®); Cytarabine (Cytosar-U®); Cytarabine Liposomes (DepoCyt®); Dacarbazine (DTIC-Dome®); Dactinomycin, Actinomycin D (Cosmegen®); Darbepoetin Alpha (Aranesp®); Daunorubicin Liposomes (DanuoXome®); Daunorubicin, Daunomycin (Daunorubicin®); Daunorubicin, Daunomycin (Cerubidine®); Denileukin Diptitox (Ontak®); Dexrazoxane (Zinecard®); Docetaxel (Taxotere®); Doxorubicin (Adriamycin PFS®); Doxorubicin (Adriamycin®, Rubex®); Doxorubicin (Adriamycin PFS Injection®); Doxorubicin Liposomes (Doxil®); Dromostanolone Propionate (Dromostanolone®); Dromostanolone Propionate (Masterone Injection®); Elliott's B Solution (Elliott's B Solution®); Epirubicin (Ellence®); Epoetin Alpha (Epogen®); Erlotinib (Tarceva®); Estramustine (Emcyt®); Etoposide phosphate (Etopophos®); Etoposide, VP-16 (Vepesid®); Exemestane (Aromasin®); Filgrastim (Neupogen®); Fluxuridine (intra-arterial) (FUDR®); Fludarabine (Fludara®); Fluorouracil, 5-FU (Adrucil®); Fulvestrant (Faslodex®); Gefitinib (Iressa®); Gemcitabine (Gemzar®); Gemtuzumab ozogamicin (Mylotarg®);Goserelin acetate (Zoladex Implant®); Goserelin acetate (Zoladex®); Histrelin acetate (Histrelin implant®); Hydroxyurea (Hydrea®); Ibritumomab tiuxetane (Zevalin®); Idarubicin (Idamycin®); Ifosfamide (IFEX®); Imatinib mesylate (Gleevec®); Interferon alpha 2a (Roferon A®); Interferon alpha-2b (Intron A®); Irinotecan (Camptosar®); Lenalidomide (Revlimid®); Letrozole (Femara®); Leucovorin (Wellcovorin®, Leucovorin®); leuprolide acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®); mechlorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxalene (Uvadex®); Mitomycin C (Mutamycin®); Mitotan (Lysodren®); Mitoxantrone (Novantrone®); Nandrolone fenpropionate (Durabolin-50®); Nelarabine (Arranon®); Nofetumomab (Verluma®); Ofrelbekin (Neumega®); Oxaliplatin (Eloxatin®); Paclitaxel (Paxene®); Paclitaxel (Taxol®);Paclitaxel protein-binding particles (Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); Pegademase (Adagen (Pegademase Bovine)®); Pegaspargase (Oncaspar)®); Pegfilgrastim (Neulasta)®); Pemetrexed disodium (Alimta)®); Pentostatin (Nipent)®); Pipobroman (Vercyte)®); Plicamycin, Mitramycin (Mithracin)®); Porfimer sodium (Photofrin)®); Procarbazine (Matulane)®); Quinacrine (Atabrine)®); Rasburicase (Elitek)®); Rituximab (Rituxan)®); Lidaphorolimus; Sargramostim (Leukine)®); Sargramostim (Prokine®); Sorafenib (Nexavar®); Streptozosin (Zanosar®); Sunitinib maleate (Sutent®); Talc (Sclerosol®); Tamoxifen (Nolvadex®); Temozolomide (Temodar®); Tenifoside, VM-26 (Vumon®); Testolactone (Teslac®); Thioguanine, 6-TG (Thioguanine®); Thiotepa (Thioplex®); Topotecan (Hycamtin®); Toremifene (Fareston®); Tocitumomab (Bexxar®); Tocitumomab / I-131 Tocitumomab (Bexxar®); Trastuzumab (Herceptin®); Tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); Valubicin (Valstar®); Vinblastine (Velban®);Vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®) and zoledronate (Zometa®) or their pharmaceutically acceptable salts.;
[0590] Method for preparing the compound of the present invention
[0591] The following examples are provided to help the invention be more fully understood. Unless otherwise indicated, starting materials are commercially available. These should not be construed as limiting the invention in any way.
[0592] Various methods for preparing the compounds of the present invention are described in the following reaction schemes and examples. Starting materials and intermediates are purchased, prepared from known procedures, or otherwise exemplified. Some frequently applied routes to the compounds of Formula I are also described by the following reaction schemes. In some cases, the order in which the steps of the reaction scheme are performed may be changed to facilitate the reaction or to avoid unwanted reaction products. In the case of stereoisomers, at the separation point, enantiomer A refers to the enantiomer that elutes faster / more quickly, and enantiomer B refers to the enantiomer that elutes slower / more slowly; this nomenclature is maintained throughout the rest of the synthesis sequence for a given enantiomer series, regardless of the possibility that subsequent intermediates and final compounds may have the same or opposite elution order.
[0593] Throughout the synthesis reaction formulas and examples, abbreviations and acronyms may be used with the following meanings unless otherwise indicated:
[0594] ACN = Acetonitrile
[0595] AcOH = Acetic acid
[0596] CDI = 1,1'-carbonyldiimidazole
[0597] Cu(OAc)2 = copper acetate
[0598] DAST = Diethylaminosulfur trifluoride
[0599] DIEA = Diisopropyl ethylamine
[0600] DMF = Dimethylformamide
[0601] DMS = Dimethyl sulfide
[0602] DMSO = Dimethyl sulfoxide
[0603] DCE = 1,2-dichloroethane
[0604] DCM = Dichloromethane
[0605] DIPEA = N,N-diisopropylethylamine
[0606] DPPA = Diphenylphosphoryl azide
[0607] dppf = 1,1'-bis(diphenylphosphino)ferrocene
[0608] Et = Ethyl
[0609] EtOAc = Ethyl acetate
[0610] EDC = N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
[0611] RP HPLC = Reverse-phase high-pressure liquid chromatography
[0612] h or hrs = time
[0613] HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide-hexafluorophosphate
[0614] Hex = Hexane
[0615] HOAc = Acetic acid
[0616] HOBT = Hydroxybenzotriazole
[0617] IPA = Iso-propanol
[0618] Me = methyl
[0619] mCPBA = meta-chloroperoxybenzoic acid
[0620] MgSO4 = magnesium sulfate
[0621] MP-Cyanoborohydride = Macroporous Polymer-Supported Cyanoborohydride
[0622] rt or RT = room temperature
[0623] nBu4LI = Tetra-n-butylammonium iodide
[0624] NBS = N-bromosuccinimide
[0625] NCS = N-chlorosuccinimide
[0626] NIS = N-iodosuccinimide
[0627] PdCl2(dppf) = bis(diphenylphosphino)ferrocene]dichloropalladium(II)
[0628] SFC = Supercritical Fluid Chromatography
[0629] SM = Starting material
[0630] t-Bu-OH = tert-butyl alcohol
[0631] tBuBrettPhos = 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl
[0632] THF = Tetrahydrofuran
[0633] TFA = Trifluoroacetic acid
[0634] Xphos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
[0635] XPhos Pd G2 = chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)
[0636] Also, aq. is aqueous, TLC is thin-layer chromatography; Ts is tosyl; UV is ultraviolet; W is watt; wt% is weight percentage; xg is gravitational multiplier; [α] Dis the specific optical rotation of the polarization at 589 nm; °C is the temperature in degrees Celsius; and % w / v is the weight percentage of the former agent relative to the volume of the latter agent.
[0637] LCMS Conditions: Column: SUPELCO Ascentis Express C18 3x100 mm, 2.7 µm. Solvent System: A - 0.05% TFA in water and B - 0.05% TFA in acetonitrile. Gradient Conditions: 10 - 99% B within 3.5 min.
[0638] General synthesis reaction equation
[0639] Although the present invention has been described with the specific embodiments presented above, many alternatives, variations, and modifications thereof will be apparent to those skilled in the art. In some cases, the order in which the steps of the reaction scheme are performed may be changed to facilitate the reaction or to avoid unwanted reaction products. All such alternatives, variations, and modifications are intended to fall within the spirit and scope of the present invention.
[0640] [General reaction equation]
[0641]
[0642] The compound of chemical formula I with 1-1 and R 1 1-2 was obtained by preparing from -X via a copper-mediated N-functionalization reaction using a Chan-Lam or Goldberg-type system. 1-2 was amide-coupled with a suitable amine to obtain a compound of Formula I as described in the reaction scheme. The order of steps for some examples may be changed to facilitate synthesis.
[0643] intermediate
[0644] Intermediate-1: 3-Bromo-5-(1,1,2,2-tetrafluoroethoxy)pyridine
[0645]
[0646] Step A: 3-Bromo-5-(2-Bromo-1,1,2,2-Tetrafluoroethoxy)pyridine
[0647] 1,2-dibromo-1,1,2,2-tetrafluoroethane (0.58 ml, 4.90 mmol) was added via syringe 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), and the reaction mixture was stirred at room temperature for 16 hours. 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(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–30% EtOAc / hexane gradient to obtain the title compound. LC / MS = 351 [M+1].
[0648] Step B: 3-Bromo-5-(1,1,2,2-tetrafluoroethoxy)pyridine
[0649] Zinc dust (0.79 g, 12.04 mmol) was agitated into 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(s), filtered, and concentrated under vacuum. The crude residue was purified by flash silica gel column chromatography using a 0–40% EtOAc / hexane gradient to obtain the title compound. LC / MS = 275 [M+1].
[0650] Intermediate-2: 3-Bromo-5-(1,1-difluoroethoxy)pyridine
[0651]
[0652] HF-pyridine (14.86 g, 150 mmol) was added to a solution of xenon difluoride (1.69 g, 10.00 mmol) and 1-(5-bromopyridine-3-yl)ethane-1-one (1.00 g, 5.00 mmol) in DCM (16.66 ml), and the reaction mixture was stirred at room temperature for 18 hours. 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(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–40% EtOAc / hexane gradient to obtain the title compound. LC / MS = 238 [M+1].
[0653] Intermediate-3: 3-Bromo-5-(2,2-difluoroethoxy)pyridine
[0654]
[0655] 2,2-difluoroethyl trifluoromethanesulfonate (380 μl, 2.87 mmol) was added via syringe to a stirred solution of 5-bromopyridine-3-ol (0.50 g, 2.87 mmol) and Cs2CO3 (1.87 g, 5.75 mmol) in DMF (14.4 ml), and the reaction mixture was stirred at room temperature for 16 hours. 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(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–40% EtOAc / hexane gradient to obtain the title compound. LCMS = 238 [M+1].
[0656] Intermediate-4: (3-bromo-4-fluorophenyl)(difluoromethyl)sulfan
[0657]
[0658] Diethyl (bromodifluoromethyl)phosphonate (1.72 ml, 9.66 mmol) was added dropwise via syringe at 0°C 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). The reaction mixture was allowed to naturally heat to 20°C over 16 hours. The reaction mixture was diluted with Et2O, washed with water and NaCl (saturated aqueous solution), dried over MgSO4(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using 100% hexane to obtain the title compound.
[0659] Intermediate-5: 3-iodo-5-(2,2-difluoroethoxy)-2-methylpyridine
[0660]
[0661] To a stirred mixture of sodium iodide (1.40 g, 9.33 mmol) and CuI (0.044 g, 0.23 mmol), 3-bromo-5-(2,2-difluoroethoxy)-2-methylpyridine (1.18 g, 4.67 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.066 g, 0.47 mmol) were added as a solution in dioxane (9.3 ml). The reaction mixture was heated at 110°C for 16 hours. The reaction mixture was diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0-30% EtOAc hexane gradient to obtain the title compound.
[0662] Examples
[0663] The following experimental procedure describes the preparation of specific embodiments of the present disclosure. The embodiments are for illustrative purposes only and are not intended to limit the scope of the present disclosure in any way.
[0664] Example 1: 1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-carboxamide
[0665]
[0666] Step A: 5'-Bromospiro[cyclobutane-1,3'-indoline]-2'-one
[0667] n-butyllithium (2.5 M in hexane, 2.57 mL, 6.41 mmol) was added to a solution of 5-bromoindolin-2-one (400 mg, 1.89 mmol) in THF (40 mL) at -10°C, and the reaction mixture was stirred under N2 at -10°C for 0.5 hours. Subsequently, N,N,N',N'-tetramethylethylenediamine (745 mg, 6.41 mmol) and 11,3-diiodopropane (0.214 mL, 1.868 mmol) were added to the mixture under N2 at -10°C. The reaction mixture was slowly heated to 25°C and stirred under N2 for 3 hours. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0–100% EtOAc / hexane) to obtain the title compound. LC / MS = 252 and 254 [M+1].
[0668] Step B: 5'-bromo-1'-(3-(difluoromethoxy)phenyl)spiro[cyclobutane-1,3'-indoline]-2'-one
[0669] K2CO3 (132 mg, 0.952 mmol), N,N'-dimethylethylenediamine (16.78 mg, 0.190 mmol), 1-bromo-3-(difluoromethoxy)benzene (0.401 mL, 2.86 mmol), and copper(I) iodide (18.13 mg, 0.095 mmol) were added in a glove box to a solution of 5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one (120 mg, 0.476 mmol) in acetonitrile (2.5 mL). The reaction mixture was stirred at 90°C for 14 hours, then quenched with water and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0–100% EtOAc / hexane) to obtain the title compound. LC / MS = 394 and 396 [M+1].
[0670] Step C: Ethyl 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-carboxylate
[0671] 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'-indolin]-2'-one (125 mg, 0.317 mmol) in EtOH (5 mL). The mixture was stirred under a CO2 balloon at 80°C for 14 hours. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to obtain the title compound. LC / MS = 388 [M+1].
[0672] Step D: 3-(1-carboxycyclobutyl)-4-((3-(difluoromethoxy)phenyl)amino)benzoic acid
[0673] Lithium hydroxide monohydrate (17.33 mg, 0.413 mmol) was added to a solution of ethyl 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-carboxylate (80 mg, 0.207 mmol) in MeOH (4 mL) and water (0.4 mL). The mixture was stirred at 25°C for 12 hours. The mixture was concentrated under reduced pressure and dissolved in H2O. HCl (1N in water) was added to the mixture to pH = 4. The mixture was then extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound. LC / MS = 378 [M+1].
[0674] Step E: 1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-carboxamide
[0675] 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 hours. Subsequently, 3-amino-3-methyltiethane 1,1-dioxide (9.31 mg, 0.069 mmol) was added to the mixture. The mixture was stirred at 25°C for 1 hour. The crude mixture was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% TFA modifier) to obtain the title compound. LC / MS = 477 [M+1]. 1H 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
[0676] Example 2: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0677]
[0678] Step A: Methyl 1-(3-(difluoromethoxy)phenyl)-1H-indole-5-carboxylate
[0679] Methyl 1H-indole-5-carboxylate (47.1 mg, 0.269 mmol), tribasic potassium phosphate (143 mg, 0.673 mmol), copper(I) iodide (4.27 mg, 0.022 mmol), and N,N'-dimethylethylenediamine (3.95 mg, 0.045 mmol) were added to a solution of 1-bromo-3-(difluoromethoxy)benzene (50 mg, 0.224 mmol) in toluene (1.5 mL) at 28°C under an N2 atmosphere. The mixture was stirred at 100°C for 12 hours, then poured into H2O and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to obtain the title compound. LC / MS = 318 [M+1].
[0680] Step B: Methyl 3-bromo-1-(3-(difluoromethoxy)phenyl)-1H-indole-5-carboxylate
[0681] NBS (43.2 mg, 0.243 mmol) was added to a solution of methyl 1-(3-(difluoromethoxy)phenyl)-1H-indole-5-carboxylate (70 mg, 0.221 mmol) in DMF (1.5 mL) at 28°C. The mixture was stirred at 28°C for 1 hour, then poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to obtain the title compound. LC / MS = 396 [M+1].
[0682] Step C: Methyl 1-(3-(difluoromethoxy)phenyl)-3-(prop-1-en-2-yl)-1H-indole-5-carboxylate
[0683] K2CO3 (73.3 mg, 0.530 mmol), potassium isopropenyltrifluoroborate (39.2 mg, 0.265 mmol), and PdCl2 (dppf) (12.93 mg, 0.018 mmol) were added to a solution of methyl 3-bromo-1-(3-(difluoromethoxy)phenyl)-1H-indole-5-carboxylate (70 mg, 0.177 mmol) in dioxane (1.5 mL) and water (0.3 mL) at 28°C under an N2 atmosphere. The mixture was stirred at 80°C for 1 hour. The mixture was poured into H2O, the precipitate was filtered, the precipitate was dissolved in ethyl acetate, and concentrated under reduced pressure to obtain the title compound LC / MS = 358 [M+1].
[0684] Step D: Methyl 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-indole-5-carboxylate
[0685] A mixture of methyl 1-(3-(difluoromethoxy)phenyl)-3-(prop-1-en-2-yl)-1H-indole-5-carboxylate (53 mg, 0.148 mmol) and wet Pd / C (15.78 mg, 0.148 mmol, 10%) in 5 mL of MeOH was stirred at 28°C for 1 hour under 15 psi of H2. The mixture was filtered through Celite, and the solvent was evaporated under reduced pressure to obtain the crude product. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to obtain the title compound. LC / MS = 360 [M+1].
[0686] Step E: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-indole-5-carboxylic acid
[0687] Potassium trimethylsilanoleate (37.5 mg, 0.292 mmol) was added to a solution of methyl 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-indole-5-carboxylate (35 mg, 0.097 mmol) in THF (1.5 mL) at 28°C. The mixture was stirred at 60°C for 5 hours, and then concentrated under reduced pressure to obtain the title compound. LC / MS = 346 [M+1].
[0688] Step F: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-1H-indole-5-carboxamide
[0689] DIEA (0.030 mL, 0.174 mmol) and HATU (26.4 mg, 0.069 mmol) were added to a solution of 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-1H-indole-5-carboxylic acid (20 mg, 0.058 mmol) in DMF (1 mL) at 28°C. The mixture was stirred for 5 minutes at 28°C, and then 3-amino-3-methyltiethane 1,1-dioxide (9.39 mg, 0.069 mmol) was added. The mixture was stirred for an additional 10 minutes at 28°C, then poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to obtain the title compound. LC / MS = 463 [M+1].
[0690] Step G: 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0691] NCS (4.76 mg, 0.036 mmol) was added at 26°C to a solution of 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-dioxydotiethane-3-yl)-1H-indole-5-carboxamide (15 mg, 0.032 mmol) in CH2Cl2 (1 mL). The mixture was stirred at 26°C for 1 hour. 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 hours and then concentrated to obtain the crude product. The crude mixture was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% TFA modifier) to obtain the title compound. LC / MS = 479 [M+1]. 1H NMR (500MHz, chloroform-d1) δ 7.89 (s, 1H), 7.78 (dd, J1 = 8.3 Hz, J2 = 1.0 Hz, 1H), 7.60 (t, J = 8.2 Hz, 1H), 7.26 (dd, J1 = 8.2 Hz, J2=2.1 Hz, 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
[0692] Example 3: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0693]
[0694] Step A: Methyl 3,3-dimethyl-2-oxoindolin-5-carboxylate
[0695] 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 at 80 °C for 15 hours under a CO2 atmosphere (50 psi). LCMS indicated that the target product was formed. The mixture was poured into H2O and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to obtain the title compound. LC / MS = 220 [M+1].
[0696] Step B: Methyl 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxylate
[0697] (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (5.19 mg, 0.036 mmol), potassium carbonate (76 mg, 0.547 mmol), copper(I) iodide (3.47 mg, 0.018 mmol), and 1-bromo-3-(difluoromethoxy)benzene (40.7 mg, 0.182 mmol) were added to a solution of methyl 3,3-dimethyl-2-oxoindoline-5-carboxylate (40 mg, 0.182 mmol) in dioxane (1 mL) under an N2 atmosphere. The mixture was stirred at 100°C for 15 hours, then poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (0-100% EtOAc / hexane) to obtain the title compound. LC / MS = 362 [M+1].
[0698] Step C: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid
[0699] LiOH·H2O (23.86 mg, 0.996 mmol) was added to a solution of methyl 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxylate (90 mg, 0.249 mmol) in MeOH (2 mL) / water (0.5 mL). The mixture was stirred at 30°C for 2 hours and then concentrated under reduced pressure. HCl (1N in water) was added to pH = 4. The mixture was then extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4(s), filtered, and concentrated under reduced pressure to obtain the title compound. LC / MS = 348 [M+1].
[0700] Step D: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0701] 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-oxoindolin-5-carboxylic acid (40 mg, 0.115 mmol) in DCM (1 mL). The mixture was stirred at 50°C for 10 minutes, and then 3-amino-3-methyltiethane 1,1-dioxide (18.68 mg, 0.138 mmol) was added at 50°C under an N2 atmosphere. The mixture was stirred at 50°C for 3 hours, then poured into H2O and extracted with DCM. The combined organic layer was washed with brine, dried over Na2SO4(s), filtered, and concentrated under reduced pressure. The crude material was purified by flash silica gel chromatography using a 0–100% EtOAc / hexane gradient to obtain the title compound. LC / MS = 465 [M+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
[0702] Examples 4a and 4b 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-dioxidotiethane-3-yl)-2-oxoindolin-5-carboxamide and 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-dioxidotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0703]
[0704] Step A: 3-ethyl-3-methylindolin-2-one
[0705] n-butyllithium (2.5 M in hexane, 1.794 mL, 4.48 mmol) was added to a mixture of 3-methylindolin-2-one (300 mg, 2.038 mmol) and N,N,N',N'-tetramethylethylenediamine (711 mg, 6.12 mmol) in THF (9 mL) at -78°C, and the reaction mixture was stirred under N2 at -78°C for 0.5 hours. Subsequently, a solution of iodoethane (477 mg, 3.06 mmol) in THF (3 mL) was added to the mixture under N2 at -78°C. The reaction mixture was slowly heated to -20°C and stirred for 1 hour. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 176 [M+1].
[0706] Step B: 5-bromo-3-ethyl-3-methylindolin-2-one
[0707] 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 under an N2 balloon at 25 °C for 12 hours. The reaction mixture was quenched with a saturated aqueous Na2SO3 solution, diluted with water, and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc / hexane) over silica to obtain the title compound. LC / MS = 254 and 256 [M+1].
[0708] Step C: 5-bromo-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methylindolin-2-one
[0709] K2CO3 (54.4 mg, 0.394 mmol), N,N'-dimethylethylenediamine (6.94 mg, 0.079 mmol), 1-bromo-3-(difluoromethoxy)benzene (0.193 mL, 1.377 mmol), and copper(I) iodide (7.49 mg, 0.039 mmol) were added in a glove box to a solution of 5-bromo-3-ethyl-3-methylindolin-2-one (50 mg, 0.197 mmol) in acetonitrile (1 mL). The reaction mixture was stirred at 90°C for 13 hours, then poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0–100% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 396 and 398 [M+1].
[0710] Step D: Ethyl 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-2-oxoindolin-5-carboxylate
[0711] 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-methylindolin-2-one (50 mg, 0.126 mmol) in EtOH (5 mL). The mixture was stirred under a CO2 balloon at 80°C for 13 hours. LCMS indicated that the starting material was completely consumed. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc / hexane) over silica to obtain the title compound. LC / MS = 390 [M+1].
[0712] Step E: 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-2-oxoindoline-5-carboxylic acid
[0713] 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-oxoindolin-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 hours, concentrated under reduced pressure, and dissolved in H2O. HCl (1N in water) was added to the mixture to pH = 4. The mixture was then extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound. LC / MS = 362 [M+1].
[0714] Step F: 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0715] 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-oxoindolin-5-carboxylic acid (37 mg, 0.102 mmol) in DMF (2 mL). The mixture was stirred at 25°C for 0.5 hours. Subsequently, 3-amino-3-methyltiethane 1,1-dioxide (18.00 mg, 0.133 mmol) was added, and the mixture was stirred at 25°C for 1 hour. The crude mixture was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% TFA modifier) to obtain the title compound. LC / MS = 479 [M+1].
[0716] Step G: 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-dioxidotiethane-3-yl)-2-oxoindolin-5-carboxamide and 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-dioxidotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0717] A mixture of two stereoisomers of 1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide (50 mg, 0.104 mmol) was purified by chiral SFC (IC-H column, 40% / 60% ethanol / CO2) to obtain isomer EX-4a (faster 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, 8.0 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]. 1H NMR (400 MHz, chloroform-d1) δ 7.71 (d, J = 1.6 Hz, 1H), 7.61 (dd, J = 1.6, 8.4 Hz, 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.
[0718] The following compounds were synthesized using appropriate reagents and a procedure similar to that described in Example 4. These compounds were characterized by LC / MS.
[0719]
[0720] Examples 6a and 6b: 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0721]
[0722] Step A: Methyl 1-(3-(difluoromethoxy)phenyl)-1H-indole-5-carboxylate
[0723] 1-bromo-3-(difluoromethoxy)benzene (1910 mg, 8.56 mmol), copper(I) iodide (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) were added in a glove box to a solution of methyl 1H-indole-5-carboxylate (500 mg, 2.85 mmol) in DMSO (5 mL). The reaction mixture was stirred at 110°C for 12 hours. TLC indicated that the target product was formed. The mixture was poured into H2O and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0-100% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 318 [M+1].
[0724] Step B: 1-(3-(difluoromethoxy)phenyl)-1H-indole-5-carboxylic acid
[0725] Lithium hydroxide monohydrate (800 mg, 19.06 mmol) was added to a mixture of methyl 1-(3-(difluoromethoxy)phenyl)-1H-indole-5-carboxylate (1 g, 3.15 mmol) in MeOH (10 mL), THF (3.00 mL), and water (1 mL). The mixture was stirred at 25°C for 13 hours. LCMS indicated that the target product was formed. HCl (1N in water) was added to the mixture to pH = 4, and then extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.
[0726] Step C: 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotiethane-3-yl)-1H-indole-5-carboxamide
[0727] 3-amino-3-methyltiethane 1,1-dioxide dihydrochloride (0.91 g, 4.37 mmol) was added to a mixture of 1-(3-(difluoromethoxy)phenyl)-1H-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) in DCM (20 mL). The mixture was stirred at 25°C for 0.5 hours. LCMS indicated that the target product was formed. The mixture was poured into H2O and then extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (0–100% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 421 [M+1].
[0728] Step D: 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxodotiethane-3-yl)-2,3-dioxoindolin-5-carboxamide
[0729] Chromium(VI) oxide (856 mg, 8.56 mmol) was added at 25°C to a solution of 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxydotiethane-3-yl)-1H-indole-5-carboxamide (900 mg, 2.141 mmol) in acetone (8 mL), acetic acid (6 mL), and water (3 mL). The mixture was stirred at room temperature for 3 hours. LCMS indicated that the target product was formed. The reaction mixture was poured into saturated NH4Cl and then extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc / hexane) over silica to obtain the title compound. LC / MS = 451 [M+1].
[0730] Step E: 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0731] A mixture of 1-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidotiethane-3-yl)-2,3-dioxoindolin-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 methyl magnesium bromide (1.8 mL, 3.60 mmol), and stirred at -70°C for 2 hours under an N2 atmosphere. LCMS indicated that the target product was formed. The reaction mixture was poured into saturated NH4Cl and extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% TFA modifier) to obtain the title compound as a TFA salt. LC / MS = 467 [M+1]. A mixture of the two stereoisomers was purified by chiral SFC (column Daicel chiral cell OD (250 mm x 30 mm x 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 IC50 = 3933 nM. EX-6b (slower elution): LC / MS = 467 [M+1]. 1¹H 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 IC50 = 290 nM.
[0732] The following compounds were synthesized using a procedure similar to that described in Example 6, using appropriate reagents. These compounds were characterized by LC / MS.
[0733]
[0734] Example 8: 1-(3-(difluoromethoxy)phenyl)-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0735]
[0736] Step A: 1-(3-(difluoromethoxy)phenyl)-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0737] Triethylsilane (1.3 g, 11.18 mmol) was added under an N2 atmosphere to a solution of 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-dioxydotiethane-3-yl)-2-oxoindolin-5-carboxamide (130 mg, 0.279 mmol) in TFA (3 mL). The resulting mixture was stirred at 80°C for 13 hours. LCMS indicated that the target product was formed. The reaction mixture was poured into saturated NH4Cl and then extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% TFA modifier) to obtain the title compound as a TFA salt. 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). Human DGAT2 IC50 = 2730 nM
[0738] Examples 9a and 9b: 1-(3-(difluoromethoxy)phenyl)-3-fluoro-3-methyl-N-(3-methyl-1,1-dioxidotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0739]
[0740] Step A: 1-(3-(difluoromethoxy)phenyl)-3-fluoro-3-methyl-N-(3-methyl-1,1-deoxydothioethane-3-yl)-2-oxoindolin-5-carboxamide
[0741] DAST (0.115 mL, 0.870 mmol) was added to a solution of 1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-dioxydotiethane-3-yl)-2-oxoindolin-5-carboxamide (100 mg, 0.214 mmol) in DCM (7 mL) at 0°C, and the reaction mixture was stirred under N2 at 0°C for 1 hour. LCMS indicated that the target product was formed. The reaction mixture was poured into saturated NaHCO3 and then extracted with DCM (x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-100% EtOAc / hexane) over silica to obtain 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) δ 8.11 (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=14.48 Hz, 2H), 4.17-4.27 (m, 2H), 1.85-1.93 (m, 3H), 1.83 (s, 3H). Hu DGAT2 IC50 = 339 nM. EX-9b (slower exudation): 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=14.48 Hz, 2H), 4.18-4.26 (m, 2H), 1.85-1.93 (m, 3H), 1.83 (s, 3H). Hu DGAT2 IC50 = 169 nM.
[0742] Example 10: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide
[0743]
[0744] Step A: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid
[0745] CuI (0.46 g, 2.44 mmol) was added to a stirred solution of 3,3-dimethyl-2-oxoindolin-5-carboxylic acid (5.0 g, 24.4 mmol), 1-(difluoromethoxy)-3-iodobenzene (9.9 g, 36.5 mmol), (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.69 g, 4.9 mmol), and potassium carbonate (10.1 g, 73.1 mmol) in acetonitrile (48.7 mL) aerated with nitrogen for 10 minutes. A double-walled pressure vessel was sealed and heated at 95°C for 18 hours. The reaction mixture was 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 on Na2SO4 (s) and dry-absorbed on SiO2. The crude material was purified by flash silica gel chromatography using a 0-100% EtOAc / hexane gradient to obtain the title compound LC / MS = 348 [M+1].
[0746] Step B: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide
[0747] HATU (57.5 mg, 0.15 mmol) was added to a stirred solution of 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxylic acid (50 mg, 0.14 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (23.5 mg, 0.14 mmol), and Finnig base (75 μl, 0.43 mmol) in DMF (1440 μl). The reaction mixture was stirred at room temperature for 16 hours, diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-driven reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain the title compound. LC / MS = 493 [M+1]. 1H 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 = 14.2 Hz, 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
[0748] The following compounds were synthesized using a procedure similar to that described in Example 10, using appropriate reagents. These compounds were characterized by LC / MS.
[0749]
[0750]
[0751]
[0752]
[0753]
[0754]
[0755]
[0756]
[0757] Example 62: 1-(4-(2,2-difluoroethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide
[0758]
[0759] Step A 1: 1-(4-(benzyloxy)pyridine-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid
[0760] Acetonitrile (9.7 mL) was added to a stirred mixture of 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-(benzyloxy)-2-bromopyridine (3861 mg, 14.62 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (693 mg, 4.87 mmol) under nitrogen, and the resulting solution was heated at 90°C for 16 hours. The reaction mixture was diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fraction was dried over Na2SO4, filtered through a silica plug, and concentrated under vacuum. The crude residue was purified by flash column chromatography (0-100% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 389 [M+1].
[0761] Step B: 1-(4-(benzyloxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide
[0762] HATU (958 mg, 2.52 mmol) was added to a stirred solution of 1-(4-(benzyloxy)pyridine-2-yl)-3,3-dimethyl-2-oxoindolin-5-carboxylic acid (932 mg, 2.4 mmol), DIEA (1.0 mL, 6.00 mmol), and 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (503 mg, 2.52 mmol) in DMF (24 mL). 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 flash column chromatography (0-70% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 534 [M+1].
[0763] Step C: 1-(4-hydroxypyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide
[0764] Triethylsilane (2.88 ml, 18.03 mmol) was added dropwise via syringe to a stirred solution of 1-(4-(benzyloxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide (0.96 g, 1.80 mmol) in ethanol (18.03 mL) under nitrogen. The reaction mixture was stirred for 3 hours, aerated with argon for 5 minutes, diluted with dichloromethane, and filtered through Celite. The solvent was removed under vacuum to obtain the crude title compound, which was used without further purification. LC / MS = 444 [M+1].
[0765] Step D: 1-(4-(2,2-difluoroethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide
[0766] 2,2-difluoroethyl trifluoromethanesulfonate (46.0 μl, 0.35 mmol) was added to a stirred solution of 1-(4-hydroxypyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide (155 mg, 0.35 mmol) and cesium carbonate (228 mg, 0.70 mmol) in DMF (1.7 mL), and the reaction mixture was stirred at 20°C for 3 hours. The solvent was removed under vacuum, and the crude reaction mixture was purified by flash column chromatography (0-100% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 508 [M+1]. 1 H NMR (500 MHz, DMSO-d6) δ 8.49 (d, J = 5.8 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.82 (dd, J = 8.4, 1.6 Hz, 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, 3.2 Hz, 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 IC50 = 61 nM.
[0767] Example 63: 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridine-2-yl)indolin-5-carboxamide
[0768]
[0769] Step A: 1-(4-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide
[0770] 1,2-dibromo-1,1,2,2-tetrafluoroethane (808 mg, 3.11 mmol) was added to a stirred solution of 1-(4-hydroxypyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide (919 mg, 2.07 mmol) and cesium carbonate (1.35 g, 4.14 mmol) in DMSO (10.4 mL). The reaction mixture was heated at 60°C for 16 hours. After cooling the mixture, the solvent was removed under vacuum to obtain the crude title compound. LC / MS = 624 [M+2]
[0771] Step B: 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(4-(1,1,2,2-tetrafluoroethoxy)pyridine-2-yl)indolin-5-carboxamide
[0772] The crude 1-(4-(2-bromo-1,1,2,2-tetrafluoroethoxy)pyridine-2-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-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 minutes. The reaction mixture was cooled, diluted with water, and extracted with 6:1 Et2O / DCM. The combined organic fraction was washed with NaCl (saturated aqueous solution), dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (0-100% EtOAc / hexane) on silica to obtain 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). Human DGAT2 IC50 = 0.8 nM.
[0773] The following compounds were synthesized using a procedure similar to that described in Example 63, using appropriate reagents. These compounds were characterized by LC / MS.
[0774]
[0775]
[0776]
[0777]
[0778] Example 88: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide
[0779]
[0780] Step A: 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide
[0781] 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (11.6 g, 18.3 mmol) was added to a stirred solution of 3,3-dimethyl-2-oxoindolin-5-carboxylic acid (2.5 g, 12.2 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (2.4 g, 12.2 mmol), and DIEA (4.24 ml, 24.4 mmol) in DMF (122 ml), and the reaction mixture was stirred at 20°C for 48 hours. The reaction mixture was concentrated under vacuum and purified by flash column chromatography (0-100% EtOAc / hexane) on silica to obtain the title compound. LC / MS = 350 [M+1].
[0782] Step B: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide
[0783] Acetonitrile (285 μl) was added to a stirred mixture of 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-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-dimethylcyclohexane-1,2-diamine (20.30 mg, 0.14 mmol) under nitrogen. The solution was heated to 95°C for 48 hours. The reaction mixture was cooled, diluted with EtOAc, filtered through a silica plug, and concentrated under vacuum. The crude material was purified on silica by flash column chromatography (0–100% EtOAc / hexane) to obtain the title compound (EX-88). LC / MS = 526 [M+1]. 1H 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 IC50 = 3.4 nM.
[0784] The following compounds were synthesized using appropriate reagents and a procedure similar to that described in Example 88. These compounds were characterized by LC / MS.
[0785]
[0786] Example 94: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide
[0787]
[0788] Step A: 6-fluoro-3,3-dimethyl-5-vinylindolin-2-one
[0789] 5-bromo-6-fluoro-3,3-dimethylindolin-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) were added to a vial. The vial was evacuated and refilled with nitrogen three times. Ethanol (64.6 ml) and water (6.5 mL) were added sequentially, and the reaction mixture was heated at 90°C for 6 hours. The reaction mixture was cooled, diluted with DCM, dried over MgSO4, filtered, and concentrated under vacuum. The crude residue was purified by flash column chromatography (0-50% EtOAc in hexane) on silica to obtain the title compound. LC / MS = 206 [M+1].
[0790] Step B: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-5-vinylindolin-2-one
[0791] Acetonitrile (1.9 ml) was added to a stirred mixture of 6-fluoro-3,3-dimethyl-5-vinylindolin-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-dimethylcyclohexane-1,2-diamine (139 mg, 0.98 mmol) under nitrogen. The reaction mixture was heated at 95°C for 48 hours, then diluted with EtOAc, filtered through a silica plug, and concentrated under vacuum. The crude residue was purified by flash column chromatography (0-100% EtOAc in hexane) on silica to obtain the title compound. LC / MS = 381 [M+1].
[0792] Step C: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindoline-5-carbaldehyde
[0793] NaIO4 (112 mg, 0.526 mmol) was added at 0°C to a stirred solution of 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-5-vinylindolin-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). The reaction mixture was stirred at 20°C for 3 hours. The reaction mixture was diluted with NaCl (saturated aqueous solution) and extracted with ethyl acetate. The combined organic fraction was dried over MgSO4, filtered, and concentrated under vacuum. The crude material was purified by flash column chromatography (0-50% EtOAc in hexane) on silica to obtain the title compound. LC / MS = 382 [M+1].
[0794] Step D: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindoline-5-carboxylic acid
[0795] Sodium hypochlorite (0.034 g, 0.38 mmol) was added at 0°C to a stirred solution of 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindolin-5-carbaldehyde (0.049 g, 0.127 mmol), 2-methylbut-2-ene (0.14 ml, 1.27 mmol), and sodium dihydrogen 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). The reaction mixture was stirred for 2 hours. The crude mixture was extracted with DCM. The combined organic fraction was dried over Na2SO4, filtered, and evaporated under vacuum. The crude material was used directly in the subsequent reaction. LC / MS = 399 [M+1].
[0796] Step E: 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide
[0797] HATU (44.1 mg, 0.12 mmol) was added to a stirred solution of 1-(2-(2,2-difluoroethoxy)-5-fluoropyridine-4-yl)-6-fluoro-3,3-dimethyl-2-oxoindolin-5-carboxylic acid (44 mg, 0.110 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (22.06 mg, 0.110 mmol), and DIEA (57.9 μl, 0.33 mmol) in DCM (1.1 ml). The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude material was purified by flash column chromatography (0-100% EtOAc / hexane) on silica to obtain the title compound (EX-94). LC / MS = 544 [M+1]. 1¹H 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). The signal for 2H was masked. Human DGAT2 IC50 = 0.6 nM.
[0798] The following compounds were synthesized using a procedure similar to that described in Example 94, using appropriate reagents. These compounds were characterized by LC / MS.
[0799]
[0800] Example 100: 3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indolin-5-carboxamide
[0801]
[0802] Step A: 3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide
[0803] Propanephosphonic anhydride (3.10 g, 4.87 mmol) was added to a stirred solution of 3,3-dimethyl-2-oxoindolin-5-carboxylic acid (1.00 g, 4.87 mmol) and 3-amino-3-methyltiethane 1,1-dioxide hydrochloride (1.26 g, 7.31 mmol) in DMF (48 mL). The reaction mixture was stirred at 20°C for 48 hours, then diluted with HCl (1 M aqueous solution) and extracted with DCM. The combined organic fractions were washed with HCl (1 M aqueous solution) and NaCl (saturated aqueous solution), dried over MgSO4(s), filtered, and concentrated under vacuum to obtain the title compound. LC / MS = 323 [M+1].
[0804] Step B: 3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxo-1-(5-(trifluoromethoxy)pyridine-3-yl)indolin-5-carboxamide
[0805] Pyridine (125 μl, 1.55 mmol) was added to a stirred solution of 3,3-dimethyl-N-(3-methyl-1,1-dioxydotiethane-3-yl)-2-oxoindolin-5-carboxamide (50 mg, 0.16 mmol), (5-(trifluoromethoxy)pyridine-3-yl)boronic acid (64.2 mg, 0.31 mmol), and Cu(OAc)2 (56.3 mg, 0.31 mmol) in DMF (310 μl). The vial was heated overnight at 90°C under air. The reaction mixture was diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-driven reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain the title compound. LC / MS = 484 [M+1]. 1¹H 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, 1.7 Hz, 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.
[0806] The following compounds were synthesized using appropriate reagents and a procedure similar to that described in Example 100. These compounds were characterized by LC / MS.
[0807]
[0808] Example 103: 1-[5-(2,2-difluoroethoxy)-3-pyridyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide
[0809]
[0810] (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (4.41 mg, 0.031 mmol) as a solution in acetonitrile (310 μl) and 3-bromo-5-(2,2-difluoroethoxy)pyridine (73.8 mg, 0.310 mmol) was added via syringe to a stirred mixture of 3,3-dimethyl-N-(3-methyl-1,1-dioxydotiethane-3-yl)-2-oxoindolin-5-carboxamide (50 mg, 0.16 mmol), CuI (2.95 mg, 0.016 mmol), and potassium carbonate (42.9 mg, 0.310 mmol) under nitrogen. The resulting solution was heated at 95°C for 16 hours, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain 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 = 2.3 Hz, 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
[0811] The following compounds were synthesized using a procedure similar to that described in Example 103, using appropriate reagents. These compounds were characterized by LC / MS.
[0812]
[0813]
[0814] Example 119: (R)-1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2'-oxosspiro[cyclopropane-1,3'-indolin]-5'-carboxamide
[0815]
[0816] Step A: 5'-bromo-1'-(3-(difluoromethoxy)phenyl)spiro[cyclopropane-1,3'-indoline]-2'-one
[0817] Pyridine (0.85 mL, 10.5 mmol) was added to a stirred solution of 5'-bromospiro[cyclopropane-1,3'-indolin]-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 under air at 75°C for 60 hours, 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(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–40% EtOAc / hexane gradient to obtain the title compound. LC / MS = 381 [M+1].
[0818] Step B: 1'-(3-(difluoromethoxy)phenyl)-5'-vinylspiro[cyclopropane-1,3'-indolin]-2'-one
[0819] At 20°C, 5'-bromo-1'-(3-(difluoromethoxy)phenyl)spiro[cyclopropane-1,3'-indolin]-2'-one (0.22 g, 0.58 mmol), trifluoro(vinyl)-l4-borane, potassium salt (0.078 g, 0.581 mmol), PdCl2(dppf) (0.043 g, 0.058 mmol), and Na2CO3 (0.19 g, 1.74 mmol) were filled into a 40 mL screw-stop vial equipped with a magnetic stirring rod. The vial was evacuated and refilled with nitrogen three times. Dioxane (4.8 mL) and water (1.0 mL) were added sequentially, and the reaction mixture was heated at 90°C for 6 hours. LCMS analysis showed a high conversion to the target product. The reaction mixture was diluted with DCM, dried over MgSO4(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 330 [M+1].
[0820] Step C: 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carbaldehyde
[0821] Sodium periodate (332 mg, 1.55 mmol) was added at 0°C to a stirred solution of 1'-(3-(difluoromethoxy)phenyl)-5'-vinylspiro[cyclopropane-1,3'-indolin]-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). The reaction mixture was stirred at 20°C for 3 hours. LCMS analysis indicated that the target product was formed with a high conversion rate. The reaction mixture was diluted with NaCl (saturated aqueous solution) and extracted with EtOAc. The combined organic fraction was dried over MgSO4(s), filtered, and concentrated under vacuum. The crude material was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 330 [M+1].
[0822] Step D: 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxylic acid
[0823] NaClO2 (0.04 g, 0.44 mmol) was added at 0°C to a stirred solution of 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-carbaldehyde (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). The reaction mixture was stirred for 16 hours. The crude mixture was extracted with DCM. The combined organic fractions were dried over Na2SO4(s), filtered, and evaporated under vacuum to obtain the title compound. LC / MS = 346 [M+1].
[0824] Step E: (R)-1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2'-oxosspiro[cyclopropane-1,3'-indolin]-5'-carboxamide
[0825] HATU (39.1 mg, 0.10 mmol) was added to a stirred solution of 1'-(3-(difluoromethoxy)phenyl)-2'-oxospiro[cyclopropane-1,3'-indolin]-5'-carboxylic acid (33.8 mg, 0.098 mmol), (R)-3-amino-3-methyltetrahydrothiophene 1,1-dioxide hydrochloride (18.20 mg, 0.098 mmol), and Finnig base (51.3 μl, 0.29 mmol) in DMF (980 μl). The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-driven reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain 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 = 8.3 Hz, 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). Human DGAT2 IC 50 = 118 nM
[0826] The following compounds were synthesized using a procedure similar to that described in Example 119 with appropriate reagents. These compounds were characterized by LC / MS.
[0827]
[0828] Example 128: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(5-methyl-1,1-dioxo-thiolan-3-yl)-2-oxo-indolin-5-carboxamide
[0829]
[0830] Step A: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid
[0831] 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), 1-(difluoromethoxy)-3-iodobenzene (1.97 g, 7.31 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.14 g, 0.98 mmol) were added as a solution in acetonitrile (9.8 mL), and the resulting solution was heated at 90°C for 16 hours. The reaction mixture was diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fraction was dried over Na2SO4(s), filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–80% EtOAc / hexane gradient to obtain the title compound. LC / MS = 348 [M+1].
[0832] Step B: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(5-methyltetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide
[0833] 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 Finnig base (0.15 mL, 0.86 mmol) in DCM (2.9 mL). The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum to obtain the crude title compound. LC / MS = 447 [M+1].
[0834] Step C: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide
[0835] m-CPBA (177 mg, 0.72 mmol) was added to a stirred solution of 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(5-methyltetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide (129 mg, 0.29 mmol) in DCM (2.9 mL). The reaction mixture was stirred at room temperature for 0.5 hours, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain the title compound. LC / MS = 479 [M+1].
[0836] Step D: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(5-methyl-1,1-dioxo-thiolan-3-yl)-2-oxo-indolin-5-carboxamide
[0837] A mixture of four stereoisomers of 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(5-methyl-1,1-dioxo-thiolan-3-yl)-2-oxo-indolin-5-carboxamide was purified by chiral SFC (IC column, 20% ethanol / CO2) to obtain isomers EX-128a and EX-128b as single peaks (fast elution).
[0838] A mixture of EX-128a and EX-128b was subsequently purified by chiral SFC (AD-H column, 15% ethanol / CO2) to obtain the isomer EX-128a (fast 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, 5.6 Hz, 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 (intermediate 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.
[0839] The following compounds were synthesized using a procedure similar to that described in Example 128, using appropriate reagents. These compounds were characterized by LC / MS.
[0840]
[0841]
[0842] Example 132: 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide
[0843]
[0844] Step A: 2-(2,5-dibromophenyl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide
[0845] 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 minutes. 2-fluoro-5-(trifluoromethoxy)aniline (0.66 g, 3.40 mmol) was added via syringe, and the reaction mixture was stirred at 50°C for 16 hours. 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 onto SiO2, and the title compound was obtained by flash silica gel column chromatography using a 0-40% EtOAc / hexane gradient. LC / MS = 470 [M+1].
[0846] Step B: 5-bromo-1-(2-fluoro-5-(trifluoromethoxy)phenyl)indolin-2-one
[0847] (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.094 g, 0.66 mmol) as a solution in acetonitrile (6.6 mL) was added to a stirred mixture of 2-(2,5-dibromophenyl)-N-(2-fluoro-5-(trifluoromethoxy)phenyl)acetamide (1.55 g, 3.29 mmol), CuI (0.063 g, 0.33 mmol), and K2CO3 (0.91 g, 6.58 mmol). The resulting reaction mixture was heated at 50°C for 16 hours, then diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fraction was dried over Na2SO4(s), filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 390 [M+1].
[0848] Step C: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-5-vinylindolin-2-one
[0849] Water (4.5 mL) was added under nitrogen to a stirred solution of 5-bromo-1-(2-fluoro-5-(trifluoromethoxy)phenyl)indolin-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). The reaction mixture was heated at 90°C for 16 hours, then diluted with DCM, dried over MgSO4(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 338 [M+1].
[0850] Step D: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-5-vinylindolin-2-one
[0851] MeI (359 μl, 5.76 mmol) was added dropwise via syringe to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-5-vinylindolin-2-one (648 mg, 1.92 mmol) and Cs2CO3 (1.88 g, 5.76 mmol) in DMF (7.7 mL). The reaction mixture was stirred at 20°C for 1 hour, then quenched with water and extracted with DCM. The combined organic fractions were washed with NaCl (saturated aqueous solution), dried over MgSO4(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–30% EtOAc / hexane gradient to obtain the title compound. LC / MS = 366 [M+1].
[0852] Step E: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carbaldehyde
[0853] NaIO4 (1.51 g, 7.10 mmol) was added at 0°C to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-5-vinylindolin-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). The reaction mixture was stirred at 20°C for 3 hours, then diluted with NaCl (saturated aqueous solution) and extracted with EtOAc. The combined organic fraction was dried over MgSO4(s), filtered, and concentrated under vacuum. The crude material was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 368 [M+1].
[0854] Step F: 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindoline-5-carboxylic acid
[0855] NaClO2 (0.32 g, 3.50 mmol) was added at 0°C to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carbaldehyde (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), and the reaction mixture was stirred at 20°C for 16 hours. The crude mixture was extracted with DCM. The combined organic fractions were dried over Na2SO4(s), filtered, and evaporated under vacuum to obtain the crude title compound. LC / MS = 384 [M+1].
[0856] Step G: 1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide
[0857] HATU (20.83 mg, 0.055 mmol) was added to a stirred solution of 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxylic acid (20.0 mg, 0.052 mmol), 3-amino-3-methyltiethane 1,1-dioxide hydrochloride (8.96 mg, 0.052 mmol), and Finnig base (27.3 μl, 0.16 mmol) in DMF (522 μl), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-driven reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain 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
[0858] The following compounds were synthesized using appropriate reagents and a procedure similar to that described in Example 132. These compounds were characterized by LC / MS.
[0859]
[0860] Example 136: 7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[5-(trifluoromethoxy)-3-pyridyl]indolin-5-carboxamide
[0861]
[0862] Step A: 7-fluoro-3,3-dimethyl-5-vinylindolin-2-one
[0863] Water (13.0 mL) was added under a nitrogen atmosphere to a stirred solution of 5-bromo-7-fluoro-3,3-dimethylindolin-2-one (2.02 g, 7.83 mmol), trifluoro(vinyl)-l4-borane, potassium salt (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). The reaction mixture was heated at 90°C for 6 hours, then diluted with DCM, dried over MgSO4(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 206 [M+1].
[0864] Step B: 7-fluoro-3,3-dimethyl-1-(5-(trifluoromethoxy)pyridine-3-yl)-5-vinylindolin-2-one
[0865] To a stirred mixture of 7-fluoro-3,3-dimethyl-5-vinylindolin-2-one (250 mg, 1.22 mmol), CuI (23.20 mg, 0.12 mmol), and K2CO3 (337 mg, 2.44 mmol), 3-bromo-5-(trifluoromethoxy)pyridine (590 mg, 2.44 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (34.7 mg, 0.24 mmol) were added as a solution in acetonitrile (2.4 mL). The reaction mixture
[0866] After heating at 95°C for 16 hours, the mixture was diluted with DCM, poured into HCl (1 M aqueous solution), and extracted with DCM. The combined organic fractions were dried over Na2SO4(s), filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using an EtOAc / hexane gradient to obtain the title compound. LC / MS = 367 [M+1]
[0867] Step C: 7-fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridine-3-yl)indolin-5-carbaldehyde
[0868] Sodium periodate (803 mg, 3.76 mmol) was added at 0°C to a stirred solution of 7-fluoro-3,3-dimethyl-1-(5-(trifluoromethoxy)pyridine-3-yl)-5-vinylindolin-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). The reaction mixture was stirred at 20°C for 3 hours, then diluted with NaCl (saturated aqueous solution) and extracted with EtOAc. The combined organic fraction was dried over MgSO4(s), filtered, and concentrated under vacuum. The crude material was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 369 [M+1].
[0869] Step D: 7-fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridine-3-yl)indolin-5-carboxylic acid
[0870] NaClO2 (0.23 g, 2.57 mmol) was added at 0°C to a stirred solution of 7-fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridine-3-yl)indolin-5-carbaldehyde (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). The reaction mixture was stirred at 0°C for 16 hours. The crude mixture was extracted with DCM. The combined organic fractions were dried over Na2SO4(s), filtered, and evaporated under vacuum to obtain the title compound. LCMS = 385 [M+1].
[0871] Step E: 7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-1-(5-(trifluoromethoxy)pyridine-3-yl)indolin-5-carboxamide
[0872] HATU (31.2 mg, 0.082 mmol) was added to a stirred solution of 7-fluoro-3,3-dimethyl-2-oxo-1-(5-(trifluoromethoxy)pyridine-3-yl)indoline-5-carboxylic acid (30 mg, 0.078 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide hydrochloride (15.59 mg, 0.078 mmol), and Finnig base (40.9 μl, 0.23 mmol) in DMF (781 μl). The reaction mixture was stirred at 20°C for 16 hours. The crude residue was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain 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.
[0873] The following compounds were synthesized using appropriate reagents and a procedure similar to that described in Example 136. These compounds were characterized by LC / MS.
[0874]
[0875]
[0876]
[0877] Example 154: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide
[0878]
[0879] Step A: Methyl 1-(3-(difluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
[0880] To a stirred mixture of methyl 1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.00 g, 5.68 mmol), CuI (0.11 g, 0.57 mmol), and K3PO4 (2.53 g, 11.92 mmol), 1-(difluoromethoxy)-3-iodobenzene (2.30 g, 8.51 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.161 g, 1.14 mmol) were added as a solution in toluene (5.7 mL). The resulting reaction mixture was heated at 95°C for 16 hours, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–30% EtOAc / hexane gradient to obtain the title compound. LC / MS = 319 [M+1].
[0881] Step B: Methyl 3,3-dibromo-1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
[0882] Pyridinium tribromide (5.14 g, 16.09 mmol) was added gradually over 30 minutes at 20°C to a stirred solution of methyl 1-(3-(difluoromethoxy)phenyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.60 g, 5.03 mmol) in t-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(s), filtered, and concentrated under vacuum to obtain the crude title compound. LC / MS = 491 [M+1]
[0883] Step C: Methyl 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
[0884] Zinc (3.27 g, 50.0 mmol) was added gradually over 30 minutes to a stirred suspension of methyl 3,3-dibromo-1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.46 g, 5.00 mmol) in acetic acid (25 mL). The suspension solidified, and the mixture was sonicated for 3 hours. A second portion of zinc (3.27 g, 50.0 mmol) was added, and the reaction mixture was sonicated for an additional 1 hour. The reaction mixture was diluted with DCM, filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0–50% EtOAc / hexane gradient to obtain the title compound. LC / MS = 335 [M+1].
[0885] Step D: Methyl 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate
[0886] MeI (168 μl, 2.69 mmol) was added dropwise via syringe to a stirred solution of methyl 1-(3-(difluoromethoxy)phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (300 mg, 0.90 mmol) and Cs2CO3 (877 mg, 2.69 mmol) in DMF (3.6 mL). The reaction mixture was stirred at 20°C for 1 hour, then quenched with water and extracted with DCM. The combined organic fraction was washed with NaCl (saturated aqueous solution), dried over MgSO4(s), filtered, and concentrated under vacuum. The crude residue was subjected to flash silica gel column chromatography using a 0-40% EtOAc / hexane gradient to obtain the title compound. LC / MS = 363 [M+1].
[0887] Step E: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
[0888] Water (1.5 mL) was added to a stirred solution of methyl 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (0.33 g, 0.90 mmol) and LiOH (0.22 g, 9.00 mmol) in THF (6.1 mL) and methanol (3.0 mL). The reaction mixture was stirred at 20°C for 3 hours, then acidified with 1 M HCl, diluted with water, and extracted with DCM. The combined organic fraction was dried over MgSO4(s), filtered, and concentrated under vacuum to obtain the title compound. LC / MS = 349 [M+1].
[0889] Step F: 1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide
[0890] HATU (28.7 mg, 0.075 mmol) was added to a stirred solution of 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (25 mg, 0.072 mmol), 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (11.72 mg, 0.072 mmol), and Finnig base (37.6 μl, 0.22 mmol) in DMF (718 μl). The reaction mixture was stirred at room temperature for 16 hours, then diluted with EtOAc, filtered through a SiO2 plug, and concentrated under vacuum. The crude residue was purified by mass-induced reverse-phase HPLC (ACN / water, containing 0.1% formic acid modifier) to obtain 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). Human DGAT2 IC 50 = 161 nM.
[0891] The following compounds were synthesized using appropriate reagents and a procedure similar to that described in Example 154. These compounds were characterized by LC / MS.
[0892]
[0893] black
[0894] Insect cell expression and membrane manufacturing
[0895] Sf-9 insect cells were maintained in Grace's insect cell culture medium containing 10% heat-inactivated fetal bovine serum, 1% Pluronic F-68, and 0.14 μg / ml kanamycin sulfate in a shaker incubator at 27°C. Cells were collected after infection with untagged baculovirus expressing human DGAT2 (hDGAT2) at an infection multiplicity (MOI) of 3 for 48 hours. The cell pellet was suspended in a buffer containing 10 mM Tris-HCl pH 7.5, 1 mM EDTA, 250 mM sucrose, and a complete protease inhibitor cocktail (Sigma Aldrich) and sonicated on ice. Cell debris was removed by centrifugation at 2000 xg for 15 minutes. The membrane fraction was isolated by ultracentrifugation (100,000 xg), resuspended in the same buffer, and frozen for subsequent use (-80℃). Protein concentration was determined using Pierce. TM The BCA protein assay kit (Thermo Fisher Scientific) was used to determine protein expression levels. Protein expression levels were analyzed by immunoblotting using rabbit anti-DGAT2 antibody (Abcam, ab102831) and donkey anti-rabbit IgG H&L Alexa Fluor® 647 (Abcam, ab150075), followed by detection using Typhoon FLA9000 (GE Healthcare).
[0896] LC / MS / MS analysis method
[0897] 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 the sample from the top organic layer of plate-in-liquid extraction was injected onto a Thermo Betabasic C4 column (2.1 mm x 20 mm, 5 μm particle size). The sample was then eluted using the following conditions: mobile phase: isopropanol:acetonitrile / 10 mM ammonium formate = 50 / 35 / 15 (v / v / v), flow rate: 0.8 mL / min, temperature: 25°C. Data were acquired in positive mode using a heated electrospray ionization (HESI) interface. The operating parameters for the TSQ Vantage MS / MS instrument were atomization voltage 3000 V, capillary temperature 280°C, vaporizer temperature 400°C, sheath gas 45 arbitrary units, Aux gas 10 arbitrary units, S-lens 165, and impingement gas 1.0 mTorr. 13 C 18 - Triolein (Q1: 920.8 > Q3: 621.3) and internal standards 13 C 21 The standard reference material (SRM) chromatogram of ε⁻triolein (Q1: 923.8 > Q3: 617.3) was collected for 33 seconds. The peak area was integrated using Xcalibur Quan software. The product generated in the reaction 13 C 18 Triolein and internal standards 13 C 21 - Spiked on triolein 13 C 18 Inhibition percentage and IC50 using the ratio between trioleins 50Values were generated. The percentage of compound inhibition was calculated by the following formula: Inhibition % = 1 - [(Compound Reaction - Low Control) / (High Control - Low Control)] x 100%. The strong compound was titrated, and the IC50 50 It was calculated using a 4-parameter S-shaped curve fitting equation.
[0898] DGAT2 Enzymatic Activity Test
[0899] Enzymatic product using the aforementioned membrane preparation 13 C 18 - Triolein ( 13 DGAT2 activity was determined by measuring the amount of C-1,2,3-tri(cis-9-octadecenoyl)glycerol. The assay was performed at room temperature in an ABgene 384-well assay plate 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 of diolein, and 5 μM of 13 C oleoyl-CoA and 8 ng / μL DGAT2 membrane.
Claims
Claim 1 Compound of the following chemical formula I or a pharmaceutically permissible salt thereof: Here: X, Y, and Z are independently N or C(R 5 Selected from ) and;R 1 is as follows: (1) unsubstituted or 1, 2 or 3 R 6 phenyl substituted with, or (2) an 8- to 10-membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O and S, wherein the heteroaryl is unsubstituted or has 1, 2 or 3 R atoms 6 Replaced with;R 2a and R 2b is independently selected from the following: (1) hydrogen, (2) halogen, (3) hydroxy, (4) (C 1-6 )alkyl,(5) (C 1-6 )haloalkyl,(6) R 2a and R 2b is connected, unsubstituted, or arbitrarily C 1-3 Spiro(C) monosubstituted or dissubstituted with alkyl, halogen, or OH groups 3-8 )to form a cycloalkyl group, or (7) R 2a and R 2b ... are connected to form a spiro 4- to 8-membered heterocyclyl containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or has one, two, or three R atoms 7 Substituted by;R 3 is as follows: (1) a 4- to 7-membered heterocyclil containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2) a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (3) -(C 1-6 )alkyl-heteroaryl, where the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(4) -(C 1-6 )alkyl-aryl,(5) -(C 1-6 )alkyl-heterocyclyl, where the heterocyclyl 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, where each cycloalkyl or heterocyclyl is unsubstituted or has 1, 2, or 3 R 9 It is substituted with, where each alkyl, aryl, or heteroaryl is unsubstituted or has 1, 2, or 3 R 10 Replaced with;R 4 is the following: (1) hydrogen, (2) (C 1-3 )alkyl, or R 3 and R 4 They combine with the nitrogen atoms to which they are attached to form a mono- or unicyclic heterocyclyl ring containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclyl ring is unsubstituted or has one, two, or three R atoms 11 Substituted by, and in the case where exists, each R 5 is selected from the following: (1) hydrogen, (2) (C 1-3 )alkyl,(3) (C 1-3 )haloalkyl, (4) cyano, or (5) halogen, if present, each R 6 is independently selected from: (1) cyano, (2) halogen, (3) -OC 1-6 alkyl (4) halogen or optionally substituted with OH (C 3-6 )cycloalkyl,(5) -(C=O)NH2,(6) (C 3-6 ) cycloalkyloxy, where the cycloalkyl is optionally substituted with a halogen or OH, (7) hydroxy, (8) -NR 11 R 11 ,(9) -NH(C=O)(C 1-6 )alkyl,(10) optionally substituted with 1 or 2 halogen substituents (C 2-6 )cyclic amine,(11) (C 1-6 )O(C optionally substituted with haloalkyl-(12)OH 1-6 )haloalkyl-,(13) -O(C optionally substituted with 1 or 2 halogens 0-3 )alkyl-(C 3-6 )cycloalkyl,(14) -SO2(C 1-6 )alkyl,(15) -SO2NH(C 1-6 )alkyl,(16) -SC 1-6 Alkyl, (17) -SC 1-6 haloalkyl, or (18) (C 1-6 )alkyl, in the presence of, each R 7 is independently selected from:(1) (C 1-3 )alkyl,(2) halogen,(3) (C 1-3 )alkoxy-,(4) (C 1-3 )haloalkyl-, or (5) hydroxyl, if present, R 8a and R 8b is independently selected from: (1) hydrogen, (2) (C 1-3 )alkyl, or(3) (C 3-7 )cycloalkyl; if present, each R 9 is independently selected from the following: (1) (C 1-3 )alkyl,(2) (C 1-3 )haloalkyl-,(3) oxo,(4) (C 3-6 )cycloalkyl,(5) -N(R 11 )2,(6) hydroxy,(7) (C 1-3 )Alkoxyl-,(8) Cyano,(9) Halogen,(10) -SO2(C 1-6 )alkyl,(11) -(C 1-6 )alkyl SO2(C 1-6 )alkyl,(12) -C(O)(C 1-3 )alkyl, or (13) O(C 1-3 )alkyl, if present, R 10 is independently selected from: (1) hydrogen, (2) (C 1-3 )alkyl,(3) (C 1-3 )alkoxy-,(4) hydroxy,(5) halogen,(6) (C 1-3 )alkyl-S-,(7) (C 1-3 )haloalkyl-, or (8) N(R 11 )2,R 11 is to do independently in the case where: (1) hydrogen, or (2) (C 1-3 )alkyl. Claim 2 In paragraph 1, R 1 The following compounds or pharmaceutically permissible salts thereof: a. Halogen, hydroxy, CN, C 1-3 Alkyl, C 1-3 C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, -OC 1-3 -OC optionally substituted with alkyl or OH 1-3 Haloalkyl, -OC 3-6 Cycloalkyl, -SC 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2C 1-3 Alkyl, -NH(C=O)C 1-3 Alkyl, C(O)NH2, S(O)2NHC 1-3 Alkyl, N(R 11 )2, or phenyl optionally substituted with 1 to 3 substituents independently selected from azetidinyl optionally substituted with 1 or 2 halogen substituents; or b. an 8- to 10-membered fused heteroaryl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the heteroaryl is unsubstituted or halogen, (C 1-3 )alkyl, (C 3-6 )cycloalkyl, (C 1-3 )haloalkyl-, OH or OC 1-3 Substituted with alkyl. Claim 3 In paragraph 1 or 2, R 1 The following compounds or their pharmaceutically permissible salts: a. Halogen, hydroxy, C 1-3 Alkyl, C 1-3 Haloalkyl, -OC 1-3 Alkyl, -OC 1-3 -O-cyclopropyl, -SC optionally substituted with a haloalkyl, halogen, or hydroxyl group 1-3 Alkyl, -SC 1-3 Haloalkyl, S(O)2NHCH3, S(O)2C 1-3 Alkyl, -NH(C=O)C 1-3 a. Azetidinyl optionally substituted with alkyl, CN, 1 or 2 fluorosubstituents, phenyl substituted with a substituent selected from C(O)NH2, N(CH3)2, wherein the phenyl is optionally further substituted with 1 or 2 fluorine atoms; or b. a 9 or 10-membered fused heteroaryl containing 1 or 2 heteroatoms independently selected from nitrogen or oxygen and optionally substituted with methyl. Claim 4 In paragraph 1 or 2, R 1 A compound or a pharmaceutically permissible salt thereof, wherein the phenyl is substituted with a substituent selected from -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, azetidinyl, or 3,3-difluoroazetidinyl, wherein the phenyl is optionally additionally substituted with one or two fluorine atoms. Claim 5 In paragraph 1 or 2, R 2a and R 2b a. A compound selected from one of the following or a pharmaceutically permissible salt thereof: a. R 2a and R 2b is hydrogen or, b. R 2a is hydrogen and R 2b is (C 1-6 )alkyl or R 2a is (C 1-6 )alkyl and R 2b is hydrogen or, c. R 2a is a halogen, and R 2b is (C 1-6 )alkyl or R 2a is (C 1-6 )alkyl and R 2b is a halogen, or d. R 2a is a hydroxyl and R 2b is (C 1-6 )alkyl or R 2a is (C 1-6 )alkyl and R 2b is a hydroxyl or, e.g., R 2a is a hydroxyl and R 2b is (C 1-6 )haloalkyl, or R 2a is (C 1-6 )haloalkyl and R 2b is a hydroxyl or, f. R 2a and R 2b are each independently (C 1-6 Selected from )alkyl, g. R 2a and R 2b ... are connected to form a spiro 4- to 8-membered heterocyclyl containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclyl is unsubstituted or has one, two, or three R atoms 7 Replaced by, or h. R 2a and R 2b is connected, unsubstituted, or C 1-6 Spiro(C) optionally monosubstituted or dissubstituted with alkyl, halogen, or OH. 3-8 ) Forms a cycloalkyl group. Claim 6 In paragraph 1 or 2, R 2a and R 2b H and C independently 1-3 Selected from alkyls, or together with spiro C 1-6 A compound that forms a cycloalkyl group or a salt thereof that is pharmaceutically permissible. Claim 7 In paragraph 1 or 2, R 3 A compound selected from the following or a pharmaceutically permissible salt thereof: (1) a 4- to 7-membered heterocyclyl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (2) a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S, (3) -(C 1-6 )alkyl-heteroaryl, where the heteroaryl is a 5- or 6-membered heteroaryl containing 1, 2 or 3 heteroatoms independently selected from N, O and S,(4) -(C 1-6 )alkyl-aryl,(5) -(C 1-6 )-heterocyclyl, where the heterocyclyl is a 3- to 6-membered ring containing 1 or 2 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-heterocyclyl, wherein the heterocyclyl is a 5-membered heterocyclyl containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein each aryl, heteroaryl, cycloalkyl, or heterocyclyl is unsubstituted or has 1, 2, or 3 R atoms 9 It is substituted with, where each alkyl, aryl, or heteroaryl is unsubstituted or has 1, 2, or 3 R 10 Replaced with. Claim 8 In paragraph 1 or 2, R 3 The following compound or a pharmaceutically permissible salt thereof: (1) a 4- to 6-membered heterocyclyl 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-heterocyclyl, wherein the heterocyclyl is a 5-membered heterocyclyl containing one O heteroatom, (7) a 5- to 6-membered heteroaryl containing one, two or three 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, wherein each cycloalkyl or heterocyclyl is unsubstituted or has 1, 2 or 3 R 9 It is substituted with, where each alkyl group is unsubstituted or has 1, 2, or 3 R groups. 10 Replaced with. Claim 9 In paragraph 1 or 2, R 3 this Phosphorus compound or its pharmaceutically permissible salt. Claim 10 In paragraph 1 or 2, R 3 this Phosphorus compound or its pharmaceutically permissible salt. Claim 11 In paragraph 1 or 2, R 3 this Phosphorus compound or its pharmaceutically permissible salt. Claim 12 In paragraph 1 or 2, R 3 this Phosphorus compound or its pharmaceutically permissible salt. Claim 13 In paragraph 1 or 2, R 4 A compound in which H or a salt thereof that is pharmaceutically permissible. Claim 14 In paragraph 1 or 2, R 5 A compound in which α is H, F, Cl, or CN, or a pharmaceutically acceptable salt thereof. Claim 15 In paragraph 1 or 2, R 6 This halogen, hydroxy, CN, -C 1-6 Alkyl, -C 1-6 -C optionally substituted with haloalkyl, halogen, or OH 3-6 Cycloalkyl, -OC 1-6 -OC optionally substituted with alkyl or OH 1-6 -O(C alkyl, optionally substituted with 1 or 2 halogen substituents) 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 haloalkyl, or NH(C=O)C 1-3 Alkyl, optionally substituted with 1 or 2 halogen substituents (C 2-6 )Cyclic amine, N(C 1-3 )alkyl, -O(C 3-6 ) A compound that is a cycloalkyl or a pharmaceutically acceptable salt thereof. Claim 16 In paragraph 1 or 2, R 6 This 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, azetidine 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 An alkyl compound or a pharmaceutically permissible salt thereof. Claim 17 In paragraph 1 or 2, R 8a and R 8b A compound independently selected from hydrogen and cyclohexyl or a pharmaceutically acceptable salt thereof. Claim 18 In paragraph 1 or 2, R 9 g =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 )alkyl SO2(C 1-3 )alkyl, C(O)C 1-3 An alkyl compound or a pharmaceutically permissible salt thereof. Claim 19 In paragraph 1 or 2, R 10 A compound that is hydrogen, OH, CH3, CH2CH3, F, CF3, CH2OH, or CH2SO2CH3, or a pharmaceutically acceptable salt thereof. Claim 20 In paragraph 1 or 2, X is N and Y is C(R 5 ) and Z is C(R 5 A compound or its pharmaceutically permissible salt. Claim 21 In paragraph 1 or 2, X is C(R 5 ) and Y is N and Z is C(R 5 A compound or its pharmaceutically permissible salt. Claim 22 In paragraph 1 or 2, X, Y, and Z are each C(R 5 A compound or its pharmaceutically permissible salt. Claim 23 In paragraph 1 or 2, X is N, Y is N, and Z is C(R 5 A compound or its pharmaceutically permissible salt. Claim 24 A compound selected from the following or a pharmaceutically permissible salt thereof: Claim 25 In claim 1, the following compound or its pharmaceutically permissible salt: 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide, 1-(3-(difluoromethoxy)phenyl)-3-isopropyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide, 1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-carboxamide, (R)-1-(3-(difluoro th-methoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,(S)-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,(R)-1-(3-(difluoromethoxy)phenyl)-3-ethyl-3-methyl-N-((S)-3-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,(S)-1-(3-(difluoromethoxy)phenyl Λ -N-[(1S,2R)-2-hydroxycyclopentyl]-3,3-dimethyl-2-oxo-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-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N -[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiethane-3-yl)-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide,3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2 -oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide,3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-1-[5-(1,1,2,2-tetrafluoroethoxy)-3-pyridyl]indoline-5-carboxamide,3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-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-methylpentane-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide,(S)-1-(3-(difluoromethoxy)phenyl)-N-(4-hydroxy-2-methylpentane-2-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide,3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-1-(3-quinolyl)indoline-5-carboxamide,N-[2-(cyclohexylsulfamoyl)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-indolin-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-N-(3-ethyl-1,1-dioxo-tiethane-3-yl)-3,3-dimethyl-2-oxo-indolin-5-carboxamide,1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indolin-5-carboxamide,1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1 -dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[3-(cyclopropoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-1-[3-(trifluoromethoxy)phenyl]indoline-5-carboxamide,1-[ 3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[(3S)-(3-methyl-1,1-dioxo-thiolan-3-yl)]-2-oxo-indolin-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-N-(3,3-difluoro-1-methyl-cyclobutyl)-3,3-dimethyl-2-oxo-indolin-5-carboxamide,1-[5-(2,2-difluoroethoxy)-2,3-difluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiethane-3-yl)-2-oxo-indolin-5-carboxamide,1-[5-(2,2-difluoroethoxy )-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indoline-5-carboxamide,1-[3-(2,2-difluoroethoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indoline-5-carboxamide,1-[5-(difluoromethylsulfanyl)-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2-oxo-indoline-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiethane-3-yl)-2-oxo-indoline-5-carboxamide,(R)-1'-(3-(difluoromethoxy)phenyl)-N-(3-methyl-1,1-dioxidotetrahydrothiophene-3-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-5'-carboxamide,1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-7-fluoro rho-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thiane-4-yl)-2-oxo-indoline-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiethane-3-yl)-2-oxo-indoline-5-carboxamide,1'-[3-(difluoromethoxy)phenyl]-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-carboxamide,1'-[3-(difluoromethoxy)phenyl]-N-(4-methyl-1,1 -dioxo-thian-4-yl)-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-carboxamide,1'-[3-(difluoromethoxy)phenyl]-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2'-oxo-spiro[cyclopentane-1,3'-indoline]-5'-carboxamide,1'-[3-(difluoromethoxy)phenyl]-N-(3-methyl-1,1-dioxo-tiethane-3-yl)-2'-oxo-spiro[cyclopropane-1,3'-indoline]-5'-carboxamide,1'-[3-(difluoromethoxy)phenyl]-N-(4-methyl-1,1-dioxo So-thian-4-yl)-2'-oxo-spiro[cyclopropane-1,3'-indoline]-5'-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,4R)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3R,4R)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindoline-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,4S)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3R,4S)-4-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,5R)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N- ((3R,5R)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3S,5S)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((3R,5S)-5-methyl-1,1-deoxydotetrahydrothiophene-3-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimeth thyl-N-((1S,2R)-2-(methylsulfonyl)cyclopentyl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((1R,2R)-2-(methylsulfonyl)cyclopentyl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((1S,2S)-2-(methylsulfonyl)cyclopentyl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-((1R,2S)-2-(methylsulfonyl)cyclopentyl)-2- oxo-indoline-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-thiethane-3-yl)-2-oxo-indoline-5-carboxamide,1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[2-fluoro-5-(trifluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-indoline-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiethane-3-yl)-2-oxo-indoline-5-carboxamide,1 -[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-indoline-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-7-fluoro-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2- oxo-indolin-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiethane-3-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,1-[5-(difluoromethoxy)-2-fluoro-phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1 ,1-dioxo-thiolan-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-thian-4-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(4-methyl-1,1-dioxo-thian-4-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiethane-3-yl)-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[(3R)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,1-[3-(difluoromethoxy)phenyl]-3,3-dimethyl-N-[(3S)-3-methyl-1,1-dioxo-thiolan-3-yl]-2-oxo-pyrrolo[2,3-b]pyridine-5-carboxamide,3,3-dimethyl-N-(3-methyl-1,1-dioxo-thiolan-3-yl)- 1-(2-methylbenzo[d]oxazole-6-yl)-2-oxoindolin-5-carboxamide,1-(4-acetamido-3-hydroxyphenyl)-3,3-dimethyl-N-(3-methyl-1,1-dioxidotiethane-3-yl)-2-oxoindolin-5-carboxamide,(R)-N-(1-(2,2-difluoroethyl)-3-methylpiperidine-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1-(methylsulfonyl)piperidine-3-yl)-2- Oxoindolin-5-carboxamide,(R)-N-(1-acetyl-3-methylpiperidin-3-yl)-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-N-(4-methoxy-4-(trifluoromethyl)cyclohexyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,7-cyano-1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl) 1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,7-(3-(difluoromethoxy)phenyl)-5,5-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-6-oxo-6,7-Dihydro-5H-pyrrolo[2,3-c]pyridazine-3-carboxamide,1-(5-(azetidine-1-yl)-2-fluorophenyl)-6-fluoro-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-N-((3-hydroxytetrahydrofuran-3-yl)methyl)-3,3-dimethyl-2-oxoindolin-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3,3-dimethyl-N-(5-methyl-1,3,4- Thiadiazole-2-yl)-2-oxoindoline-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-N-((1-ethyl-1H-pyrazole-4-yl)methyl)-3,3-dimethyl-2-oxoindoline-5-carboxamide,1-(3-cyclopropylphenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5-carboxamide,1-(3-isopropoxyphenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindoline-5 -Carboxamide,1-(3-fluorophenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,1-(3-cyanophenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide,(R)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-N-(3-methyl-1,1-deoxyditiethane-3-yl)-2-oxo-3-(trifluoromethyl)indolin-5-carboxamide ,(S)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxo-3-(trifluoromethyl)indoline-5-carboxamide,(R)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindoline-5-carboxamide,(S)-1-(3-(difluoromethoxy)phenyl)-3-hydroxy-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindoline-5-carboxamide,1-(3-(difluoromethoxy)phenyl)-3-methyl-N-(3-methyl-1,1-deoxydotiethane-3-yl)-2-oxoindolin-5-carboxamide,3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-1-(3-(N-methylsulfamoyl)phenyl)-2-oxoindolin-5-carboxamide,1-( 3-carbamoylphenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide, 3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-1-(3-(methylsulfonyl)phenyl)-2-oxoindolin-5-carboxamide, or 1-(3-(dimethylamino)phenyl)-3,3-dimethyl-N-(4-methyl-1,1-deoxydotetrahydro-2H-thiopyran-4-yl)-2-oxoindolin-5-carboxamide., Claim 26 In Paragraph 24, the following compounds or their pharmaceutically permissible salts: Claim 27 In paragraph 24, Phosphorus compound or its pharmaceutically permissible salt. Claim 28 In paragraph 24, Phosphorus compound or its pharmaceutically permissible salt. Claim 29 In paragraph 24, Phosphorus compound or its pharmaceutically permissible salt. Claim 30 In paragraph 24, Phosphorus compound or its pharmaceutically permissible salt. Claim 31 In paragraph 24, Phosphorus compound or its pharmaceutically permissible salt. Claim 32 A composition for treating a selected condition from hepatic steatosis, non-alcoholic fatty liver disease (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic disease and heart failure, comprising a compound of any one of claims 1, 2, and 24 to 31 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier. Claim 33 A composition comprising the compound of any one of claims 1, 2, and 24 to 31 or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicine for treating a selected condition from hepatic steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, type 2 diabetes, obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, cognitive decline, dementia, psychosomatic disease and heart failure.