Antidiabetic compounds

Patent metadata

Field	Value
Publication number	US-10059667-B2
Application number	US-201515110894-A
Country	US
Kind code	B2
Filing date	Feb 3, 2015
Priority date	Feb 6, 2014
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

Novel compounds of the structural formula (I), and the pharmaceutically acceptable salts thereof, are agonists of G-protein coupled receptor 40 (GPR40) and may be useful in the treatment, prevention and suppression of diseases mediated by the G-protein-coupled receptor 40. The compounds of the present invention may be useful in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders, such as mixed or diabetic dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

First claim

What is claimed is:

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
A is selected from the group consisting of:
(1) —C 3-9 cycloalkyl,
(2) —C 3-9 cycloalkenyl, and
(3) —C 2-10 cycloheteroalkyl,

wherein each cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from R a ;
B is selected from the group consisting of:
(1) —(CH 2 ) u -aryl,
(2) —(CH 2 ) u -heteroaryl,
(3) —(CH 2 ) u —N(R g )—(CH 2 ) u -aryl, and
(4) —(CH 2 ) u —O—(CH 2 ) u -aryl,

wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one, two, three, four or five substituents selected from R b ;
T, U, V and W are CH;
Y is selected from: —O—, —(CH 2 ) x O— and —O—(CH 2 ) x , wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R i ;
Z is —CO 2 H;
R 1 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one, two or three halogens;
R 2 is —C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, —C 1-6 alkyl and —OC 1-6 alkyl;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH 2 ) s —OC 1-6 alkyl,
(4) —(CH 2 ) s —OH,
(5) —CN, and
(6) —C 1-6 alkyl,

wherein CH 2 and alkyl are unsubstituted or substituted with one, two or three substituents selected from halogen, OH, and OC 1-6 alkyl;
each R a is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —(CH 2 ) u —OC 1-6 alkyl,
(4) —OR e ,
(5) —S(O) u R e ,
(6) —S(O) u NR c R d ,
(7) —N(R c )S(O) p R e ,
(8) —NR c R d ,
(9) —C(O)R e ,
(10) —OC(O)R e ,
(11) —CO 2 R e ,
(12) —N(R c )C(O)R e ,
(13) —N(R c )C(O)OR e ,
(14) —N(R c )C(O)NR c R d ,
(15) —C(O)NR c R d ,
(16) —CN,
(17) —CF 3 ,
(18) —OCF 3 ,
(19) —OCHF 2 ,
(20) —(CH 2 ) r aryl,
(21) —(CH 2 ) r heteroaryl,
(22) —(CH 2 ) r C 3-6 cycloalkyl,
(23) —(CH 2 ) r —C 3-6 cycloalkenyl,
(24) —(CH 2 ) r —C 2-5 cycloheteroalkyl, and
(25) —(CH 2 ) r —O—(CH 2 ) r —C 3-6 cycloalkyl,

wherein each CH 2 , alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents selected from: halogen, —C 1-6 alkyl, —(CH 2 ) w —OH, —O—C 1-6 alkyl, —CF 3 , —CN, —(CH 2 ) v —C 3-6 cycloalkyl, SH, and —SO 2 —C 1-6 alkyl;
each R b is selected from the group consisting of:
1) —C 1-10 alkyl,
2) —C 2-10 alkenyl,
3) —(CH 2 ) v —CF 3 ,
4) —O(CH 2 ) v CF 3 ,
5) —OCHF 2 ,
6) halogen,
7) —(CH 2 ) v CN,
8) —(CH 2 ) v OH,
9) —(CH 2 ) v OC 1-10 alkyl,
10) —CO 2 R e ,
11) —NR c R d ,
12) —(CH 2 ) v C 3-6 cycloalkyl,
13) —(CH 2 ) v C 2-10 cycloheteroalkyl,
14) —(CH 2 ) v -aryl, and
15) —(CH 2 ) v -heteroaryl,

wherein each CH, CH 2 , alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one, two or three substituents selected from: halogen, —C 1-6 alkyl, —(CH 2 ) w —OH, —O—C 1-6 alkyl, —CF 3 , —CN, —(CH 2 ) v —C 3-6 cycloalkyl, SH, and —SO 2 —C 1-6 alkyl;
each R c is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R d is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R e is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R g is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C 1-6 alkyl, and
(4) C 3-6 cycloalkyl;

each R i is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —(CH 2 ) s —O—C 1-6 alkyl,
(5) —(CH 2 ) s OH,
(6) —N(R c )S(O) 2 R e ,
(7) —S(C 1-6 alkyl),
(8) —(CH 2 ) s SO 2 C 1-6 alkyl,
(9) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,
(10) —S(O) 2 NR c R d ,
(11) —NR c R d ,
(12) —C(O)R e ,
(13) —OC(O)R e ,
(14) —CO 2 R e ,
(15) —(CH 2 ) s CN,
(16) —C(O)NR c R d ,
(17) —N(R c )C(O)R e ,
(18) —N(R c )C(O)OR e ,
(19) —N(R c )C(O)NR c R d ,
(20) —CF 3 ,
(21) —OCF 3 ,
(22) —OCHF 2 ,
(23) —C 3-6 cycloalkyl, and
(24) —C 2-5 cycloheteroalkyl,

wherein each CH 2 , alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one, two, three or four substituents selected from: —C 1-6 alkyl and halogen;
n is 1;
m is 1;
each p is independently selected from: 0, 1 and 2;
each q is independently selected from: 0, 1 and 2;
each r is independently selected from: 1, 2, 3 and 4;
each s is independently selected from: 0, 1, 2 and 3;
each t is independently selected from: 0, 1, 2, 3 and 4;
each u is independently selected from: 0, 1, 2 and 3;
each v is independently selected from: 0, 1, 2, 3 and 4;
each w is independently selected from: 0, 1, 2 and 3; and
each x is independently selected from: 0, 1 and 2.

2. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
A is —C 2-10 cycloheteroalkyl, wherein each cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from R a ;
B is selected from the group consisting of:
(1) —(CH 2 ) u -aryl, and
(2) -heteroaryl,

wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one, two, three, four or five substituents selected from R b ;
T, U, V and W are CH;
Y is —(CH 2 ) x O—, wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R i ;
Z is —CO 2 H;
R 1 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein alkyl is unsubstituted or substituted with one, two or three halogens;
R 2 is —C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, —C 1-6 alkyl and —OC 1-6 alkyl;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH 2 ) s —OC 1-6 alkyl,
(4) —(CH 2 ) s —OH,
(5) —CN, and
(6) —C 1-6 alkyl,

wherein CH 2 and alkyl are unsubstituted or substituted with one, two or three substituents selected from halogen, OH, and OC 1-6 alkyl;
each R a is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —(CH 2 ) u —OC 1-6 alkyl,
(4) —OR e ,
(5) —S(O) u R e ,
(6) —S(O) u NR c R d ,

Assignees

• Merck Sharp & Dohme
• Chobanian Harry
• Demong Duane
• Guo Yan
• Hu Zhiyong
• Miller Michael
• Pio Barbara
• Plummer Christopher W
• Xiao Dong
• Yang Cangming
• Zhang Rui

Inventors

• Chobanian Harry
• Demong Duane
• Guo Yan
• Hu Zhiyong
• Miller Michael
• Pio Barbara
• Plummer Christopher W
• Xiao Dong
• Yang Cangming

Classifications

• C07C2601/02

  with a three-membered ring · CPC title

• C07D209/52

  condensed with a ring other than six-membered · CPC title

• C07D307/88

  with one oxygen atom directly attached in position 1 or 3 · CPC title

• C07D239/52

  Two oxygen atoms · CPC title

• C07D211/22

  by oxygen atoms · CPC title