Antidiabetic bicyclic compounds

Patent metadata

Field	Value
Publication number	US-9957219-B2
Application number	US-201415034189-A
Country	US
Kind code	B2
Filing date	Dec 1, 2014
Priority date	Dec 4, 2013
Publication date	May 1, 2018
Grant date	May 1, 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, B, C and D are CH;
T is CH;
U is CH;
V is CH;
W is CH;
X is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with one to three substituents selected from R a ;
Y is oxygen;
Z is selected from the group consisting of: —OH, and —O—C 1-6 alkyl;
each R 1 is independently 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;
each R 2 is independently selected from the group consisting of:
(1) —C 1-6 alkyl, and
(2) —C 3-6 cycloalkyl,

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

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

wherein each alkyl, alkenyl, cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one, two, or three substituents selected from R b ;
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) —OH, —S(O) u R e ,
(5) —S(O) u NR c R d ,
(6) —CN,
(7) —C(O)NR c R d ,
(8) —CF 3 ,
(9) —OCF 3 , and
(10) —OCHF 2 ,

wherein each alkyl is unsubstituted or substituted with C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
each R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —C 2-10 alkenyl,
(3) —CF 3 ,
(4) halogen,
(5) —CN,
(6) —OH,
(7) —OC 1-10 alkyl,
(8) —OC 2-10 alkenyl,
(9) —C(O)R e ,
(10) —OC(O)R e ,
(11) —CO 2 R e ,
(12) —C(O)NR c R d ,
(13) —NR c C(O)R e ,
(14) —NR c C(O)OR e ,
(15) —NR c C(O)NR c R d ,
(16) —OCF 3 ,
(17) —OCHF 2 ,
(18) —(CH 2 )vC 3-6 cycloalkyl, and
(19) —(CH 2 )vC 7-5 cycloheteroalkyl,

wherein each CH 2 , alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
each R c is independently selected from the group consisting of:
(1) hydrogen, and
(2) C 1-10 alkyl,

wherein each alkyl 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, and
(2) C 1-10 alkyl,

wherein each alkyl 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, and
(2) C 1-10 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each n is independently selected from: 1 and 2;
each m is independently selected from: 1 and 2;
each p is independently selected from: 1, 2, 3 and 4;
each q is independently selected from: 1, 2, 3 and 4;
each r is independently selected from: 1, 2, 3 and 4;
each s is independently selected from: 0, 1, 2, 3 and 4;
each t is independently selected from: 0, 1, 2, 3 and 4;
each u is independently selected from: 0, 1, 2, 3, and 4; and
each v is independently selected from: 0, 1, 2, 3 and 4.

2. The compound according to claim 1 wherein X is aryl, wherein aryl is unsubstituted or substituted with one to three substituents selected from R a ; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 wherein Z is —OH; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 wherein R 2 is —C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one, two or three halogens; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 wherein each R 3 is independently selected from the group consisting of:
(1) hydrogen, and
(2) halogen;

or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein R 4 is hydrogen; or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 wherein each R 5 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) heteroaryl,

wherein each heteroaryl is unsubstituted or substituted with one, two, or three substituents selected from R b ; or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 wherein
A, B, C and D are CH;
T is CH;
U is CH;
V is CH;
W is CH;
X is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,

wherein aryl and heteroaryl are unsubstituted or substituted with one to three substituents selected from R a ;
Y is oxygen;
Z is selected from the group consisting of: —OH, and —O—C 1-6 alkyl;
each R 1 is independently 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;
each R 2 is independently selected from the group consisting of:
(1) —C 1-6 alkyl, and
(2) —C 3-6 cycloalkyl,

wherein alkyl and cycloalkyl are unsubstituted or substituted with one, two or three halogens;
each R 3 is independently selected from the group consisting of:
(1) hydrogen, and
(2) halogen;

R 4 is hydrogen;
each R 5 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkenyl,
(3) halogen,
(4) —(CH 2 ) t —O—C 1-6 alkyl,
(5) —CN,
(6) aryl,
(7) heteroaryl, and
(8) —C 3-6 cycloalkyl,

wherein each alkyl, alkenyl, cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one, two, or three substituents selected from R b ;
or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 wherein
A, B, C and D are CH;
T is CH;
U is CH;
V is CH;
W is CH;
X is aryl, wherein aryl is unsubstituted or substituted with one to three substituents selected from R a ;
Y is oxygen;
Z is —OH;
each R 1 is independently 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 halogens;
each R 3 is independently selected from the group consisting of:
(1) hydrogen, and
(2) halogen;

R 4 is hydrogen; and
each R 5 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) heteroaryl,

wherein each heteroaryl is unsubstituted or substituted with one, two, or three substituen

Assignees

• Merck Sharp & Dohme

Inventors

• Bara Thomas
• Chobanian Harry R
• Guo Yan
• Josien Hubert
• Miller Michael
• Pio Barbara
• Plummer Christopher W
• Yang Cangming
• Xiao Dong

Classifications

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K31/404

  Indoles, e.g. pindolol · CPC title

• C07C2602/08

  the other ring being five-membered, e.g. indane · CPC title