Bicyclo [2.2.1] acid gpr120 modulators

Patent metadata

Field	Value
Publication number	US-2016016880-A1
Application number	US-201414774289-A
Country	US
Kind code	A1
Filing date	Mar 13, 2014
Priority date	Mar 14, 2013
Publication date	Jan 21, 2016
Grant date	—

Abstract

The present invention provides compounds of Formula (I): (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

1 . A compound of Formula (I):

or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein:
L 1 is independently L 4 -O or O-L 4 ;
L 2 is independently a hydrocarbon linker substituted with 0-2 R c , a hydrocarbon-heteroatom linker substituted with 0-2 R c , or —(CH 2 ) 1-2 —(C 3-4 cycloalkyl substituted with 0-2 R c )—(CH 2 ) 0-1 —; 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, N(C 1-4 alkyl), —CONH—, and —NHCO—;
L 4 is independently 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 independently 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 independently selected from: OH, CO 2 H, CO 2 (C 1-4 alkyl), CONR e NR f , and —CONHSO 2 R f ;
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: ═O, halogen, OH, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
R d , at each occurrence, is independently selected from: halogen, C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 haloalkyl;
R e , at each occurrence, is independently selected from: H and C 1-4 alkyl;
R f , at each occurrence, is independently selected from: H, C 1-4 alkyl, —(CH 2 ) 0-2 -phenyl, and C 3-6 cycloalkyl substituted with 1-2 OH;
R e and R f may be combined with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocyclic ring comprising carbon atoms and 1 additional heteroatom selected from N, NR b , O, and S; wherein said heterocycle is substituted with and 0-1 OH; and
p is, independently at each occurrence, selected from 0, 1, and 2.

2 . A compound according to claim 1 , wherein:
L 1 is independently L 4 -O; L 2 is independently a hydrocarbon linker substituted with 0-1 R c ,
a hydrocarbon-heteroatom linker substituted with 0-1 R c , or —(CH 2 ) 1-2 —(C 3-4 cycloalkyl substituted with 0-1 R c )—(CH 2 ) 0-1 —; 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 and S;
R 1 is independently 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 substituted with 0-4 R 3 and 0-1 R 4 ; and
R 4 is independently 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 2 is independently a hydrocarbon linker a hydrocarbon-heteroatom linker, or —(CH 2 ) 1-2 -(cyclopropyl substituted with 0-1 R c )—(CH 2 ) 0-1 —; 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 three carbon atoms and one O;
L 4 is independently selected from: a bond, CH 2 and CH(C 1-4 alkyl);
R 1 is independently selected from:

 and a ring moiety substituted with 0-2 R 3 and selected from the group consisting of thienyl, isoxazolyl, pyrimidinyl, indanyl, naphthyl, benzothiophenyl, and

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 independently selected from: thienyl, oxadiazolyl, and -L 3 -phenyl; wherein each ring moiety is substituted with 0-2 R a ;
L 3 is independently selected from: a bond, O, and 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 independently selected from: CH 2 OCH 2 , OCH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH(C 1-2 alkyl)CH 2 , CH 2 CH 2 CH(C 1-2 alkyl), CH 2 CH═CH, and

R 1 -L 4 - is independently selected from:

R 3 , at each occurrence, is independently selected from: 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 independently selected from: thienyl and -L 3 -(phenyl substituted with 0-2 halo); and
L 3 is independently selected from: a bond, O, and C(═O).

5 . A compound according to claim 1 , wherein:
L 2 is independently selected from the group consisting of CH 2 OCH 2 , OCH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH(Me)CH 2 , CH 2 CH 2 CH(Me), CH 2 CH═CH, and

 and
R 1 -L 4 - is independently selected from:

6 . A compound according to claim 1 , wherein:
L 2 is independently selected from: OCH 2 CH 2 , CH 2 CH 2 CH 2 , and

 and
R 1 -L 4 - is independently selected from:

7 . A compound according to claim 1 , wherein:
R 1 -L 4 - is independently selected from:

8 . A compound according to claim 1 , wherein the compound is selected from the exemplified Examples 1 to 100 or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof.

9 . 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.

Assignees

• Bristol Myers Squibb Co

Inventors

• Shi Yan
• Cheng Peter T W
• Wang Ying
• Wu Shung C
• Zhang Hao

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · 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

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title