Bicyclo[2.2.2]acid GPR120 modulators

Patent metadata

Field	Value
Publication number	US-9598390-B2
Application number	US-201414774276-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 14, 2013
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

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 (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
L 1 is L 4 -O or O-L 4 ;
L 2 is a hydrocarbon linker substituted with 0-2 R c or a hydrocarbon-heteroatom linker substituted with 0-2 R c ; wherein said hydrocarbon linker has one to six carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to four carbon atoms and one group selected from O, —CO—, S, —SO—, —SO 2 —, NH and N(C 1-4 alkyl);
L 4 is a bond or a hydrocarbon linker; wherein said hydrocarbon linker has one to four carbon atoms and may be straight or branched;
R 1 is selected from: C 6-10 carbocycle and a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR b , O, and S(O) p ; wherein said carbocycle and heterocycle are substituted with 0-4 R 3 and 0-1 R 4 ;
R 2 is selected from: CO 2 H and —CONHSO 2 (C 1-4 alkyl);
R 3 , 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, C 1-4 haloalkylthio, and NO 2 ;
R 4 is independently -L 3 -R 5 ;
L 3 is independently selected from: a bond, O, and C(═O);
R 5 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 each ring moiety is substituted with 0-2 R a ;
R a , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl;
R b , at each occurrence, is independently selected from: H, C 1-4 alkyl, and —(CH 2 ) 0-2 -(phenyl substituted with 0-3 R d );
R c , at each occurrence, is independently selected from: halogen, OH, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkyoxy;
R d , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl; and
p is, independently at each occurrence, selected from 0, 1, and 2.

2. A compound according to claim 1 , wherein:
L 1 is L 4 -O or O-L 4 ;
L 2 is a hydrocarbon linker substituted with 0-1 R c or a hydrocarbon-heteroatom linker substituted with 0-1 R c ; wherein said hydrocarbon linker has one to six carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to four carbon atoms and one group selected from O, —CO— and S;
R 1 is selected from: phenyl, indanyl, naphthyl, and a 5- to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR b , O, and S(O) p ;
wherein each ring moiety is substituted with 0-4 R 3 and 0-1 R 4 ; and
R 4 is selected from: thienyl, oxadiazolyl, and -L 3 -phenyl; wherein each ring moiety is substituted with 0-2 R a .

3. A compound according to claim 1 , wherein the compound is of Formula (II):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
L 1 is L 4 -O or O-L 4 ;
L 2 is a hydrocarbon linker or a hydrocarbon-heteroatom linker; wherein said hydrocarbon linker has one to five carbon atoms and may be straight or branched, saturated or unsaturated; and said hydrocarbon-heteroatom linker has one to five carbon atoms and may be straight or branched, and has one to three carbon atoms and one O;
L 4 is a bond or CH 2 ;
R 1 is selected from:

R 3 , at each occurrence, is independently selected from: NO 2 , halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C 1-4 haloalkyl, C 1-4 haloalkoxy, and C 1-4 haloalkylthio;
R 4 is selected from: thienyl, oxadiazolyl, and -L 3 -phenyl; wherein each ring moiety is substituted with 0-2 R a ;
L 3 is independently a bond, O or C(═O);
R a , at each occurrence, is independently selected from: halogen and C 1-4 alkyl; and
R b is independently phenyl substituted with 0-2 halo.

4. A compound according to claim 1 , wherein:
L 2 is selected from: CH 2 CH 2 , CH 2 CH 2 CH 2 , CH═CH, CH 2 OCH 2 ; and
R 1 is independently selected from:

5. A compound according to claim 1 , wherein:
R 1 -L 1 - is independently selected from:

6. A compound according to claim 1 , wherein the compound is selected from
3-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
4-(4-((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)bicyclo[2.2.2]octan-1-yl)butanoic acid;
3-(4-((1-(4-Chlorophenyl)-3-methyl-1H-pyrazol-5-yl)methoxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
3-(4-(3-Phenoxybenzyloxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
3-(4-(2-Phenoxybenzyloxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
4-(4-(3-Methoxybenzyloxy)bicyclo[2.2.2]octan-1-yl)butanoic acid;
3-(4-(3-Fluoro-5-phenoxybenzyloxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
3-(4-(5-Fluoro-2-phenoxybenzyloxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
2-((4-(3-Phenoxybenzyloxy)bicyclo[2.2.2]octan-1-yl)methoxy)acetic acid;
3-(4-(3-Fluoro-5-isopropoxybenzyloxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
3-(4-(3-Fluoro-5-(4-fluorophenoxy)benzyloxy)bicyclo[2.2.2]octan-1-yl)propanoic acid;
(E)-3-(4-(((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)methyl)bicyclo[2.2.2]octan-1-yl)acrylic acid;
3-(4-(((2,2-Dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)methyl)bicyclo[2.2.2]octan-1-yl)propanoic acid;
3-(4-(((5-Chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)methyl)bicyclo[2.2.2]octan-1-yl)propanoic acid;
or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

7. 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.

8. The pharmaceutical composition according to claim 7 , further comprising one or more other suitable therapeutic agents selected from anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemic agents, anti-retinopathic agents, anti-neuropathic agents, anti-nephropathic agents, anti-atherosclerotic agents, anti-ischemic agents, anti-hypertensive agents, anti-obesity agents, anti-dyslipidemic agents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents, anti-hypercholesterolemic agents, anti-pancreatitis agents, lipid lowering agents, anorectic agents and appetite suppressants.

9. The pharmaceutical composition according to claim 7 , 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.

Assignees

• Bristol Myers Squibb Co

Inventors

• Shi Yan
• Zhang Hao
• Cheng Peter T W
• Tao Shiwei

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title