Cyclopropanecarboxylic acid GPR120 modulators

Patent metadata

Field	Value
Publication number	US-9938222-B2
Application number	US-201515509214-A
Country	US
Kind code	B2
Filing date	Sep 8, 2015
Priority date	Sep 9, 2014
Publication date	Apr 10, 2018
Grant date	Apr 10, 2018

Abstract

The present invention provides compounds of Formula (I):

or a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein all of the variables are as defined herein. These compounds are GPR120 G protein-coupled receptor modulators which may be used as medicaments.

First claim

What is claimed is:

1. A compound of Formula (IIa), (IIb), (IIc), (IId) or (IIe):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:
R 1 is independently selected from: phenyl and a 5- to 6-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, NR b , O, and S(O) p ; wherein said phenyl and heteroaryl are substituted with 0-4 R 5 ;
R 2 , at each occurrence, is independently selected from: halogen, C 1-6 alkyl substituted with 0-1 R a , C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, and C 1-4 haloalkoxy;
R 3 and R 4 , at each occurrence, are independently selected from the group consisting of H, halogen, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl;
R 5 at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkyl, C 1-6 haloalkoxy, —O—C 2-6 alkenyl, SO 2 (C 1-4 alkyl), and —(O) 0-1 —(CH 2 ) 0-2 —R 6 ;
alternatively, two R 5 groups, when they are attached to two adjacent carbon atoms and together with the carbon atoms to which they are attached, combine to form a 5- to 6-membered carbocyclic or heterocyclic ring comprising carbon atoms and 0-3 heteroatoms selected from N, NR b , O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R c ;
R 6 is independently selected from: C 3-6 carbocycle and a 5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR b , O, and S; wherein said carbocycle and heterocycle are substituted with 0-3 R c ;
R a , at each occurrence, is independently selected from: C 1-4 alkoxy and C(═O)H;
R b , at each occurrence, is independently selected from: H, C 1-4 alkyl, and —(CH 2 ) 0-2 -phenyl;
R c , at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, CO 2 (C 1-4 alkyl), and COPh;
m is independently 0, 1, or 2; and
p is, independently at each occurrence, selected from 0, 1, and 2.

2. A compound according to claim 1 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:
R 2 is independently selected from: halogen and C 1-4 alkyl;
R 3 is independently H or halogen;
R 4 is independently H or C 1-4 alkyl; and
m is independently 0 or 1.

3. A compound according to claim 2 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:
R 1 is independently selected from: phenyl substituted with 0-3 R 5 , pyridyl substituted with 0-2 R 5 , thiazolyl substituted with 0-2 R 5 ,

 and
R 5 at each occurrence, is independently selected from: halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, —O—C 2-6 alkenyl, —O(C 3-6 cycloalkyl), —OCH 2 (C 3-6 cycloalkyl), —(O) 0-1 -(phenyl substituted with 0-2 R c ), and —(O) 0-1 -(pyridyl substituted with 0-2 R c ).

4. A compound according to claim 3
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a polymorph, or a solvate thereof, wherein:
R 3 is independently H or F; and
R 4 is independently H or Me.

5. A compound according to claim 4
or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof, wherein:
R 3 and R 4 are H.

6. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition according to claim 6 , further comprising one or more other suitable therapeutic agents selected from: a dipeptidyl peptidase-IV inhibitor, a sodium-glucose transporter-2 inhibitor and a 11b-HSD-1 inhibitor.

8. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, congestive heart failure, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, fatty liver disease, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), lipid disorders and liver diseases, NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease) or liver cirrhosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of at least a compound according to claim 1 .

9. A compound selected from:

or a stereoisomer, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of claim 4 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition according to claim 10 , further comprising one or more other suitable therapeutic agents selected from: a dipeptidyl peptidase-IV inhibitor, a sodium-glucose transporter-2 inhibitor and a 11b-HSD-1 inhibitor.

12. A method for the treatment of diabetes, hyperglycemia, impaired glucose tolerance, gestational diabetes, insulin resistance, hyperinsulinemia, retinopathy, neuropathy, nephropathy, diabetic kidney disease, acute kidney injury, cardiorenal syndrome, delayed wound healing, atherosclerosis and its sequelae, abnormal heart function, congestive heart failure, myocardial ischemia, stroke, Metabolic Syndrome, hypertension, obesity, fatty liver disease, dislipidemia, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low high-density lipoprotein (HDL), high low-density lipoprotein (LDL), lipid disorders and liver diseases, NASH (Non-Alcoholic SteatoHepatitis), NAFLD (Non-Alcoholic Fatty Liver Disease) or liver cirrhosis, comprising a

Assignees

• Bristol Myers Squibb Co

Inventors

• Shi Yan
• Cheng Peter T W
• Wang Ying
• Jusuf Sutjano
• Tao Shiwei
• Zhang Hao
• Wu Shung C
• Robl Jeffrey A

Classifications

• A61K31/426

  1,3-Thiazoles · CPC title

• A61K31/4418

  having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine · CPC title

• C07D213/55

  Acids; Esters · CPC title

• C07D307/82

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D307/79

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title