Antidiabetic bicyclic compounds

Patent metadata

Field	Value
Publication number	US-9840512-B2
Application number	US-201414767815-A
Country	US
Kind code	B2
Filing date	Feb 20, 2014
Priority date	Feb 22, 2013
Publication date	Dec 12, 2017
Grant date	Dec 12, 2017

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 a single bond;
T is selected from the group consisting of:
(1) CH,
(2) N, and
(3) N-oxide;

U is selected from the group consisting of:
(1) CR 1 ,
(2) N, and
(3) N-oxide;

V is selected from the group consisting of:
(1) CR 2 ,
(2) N, and
(3) N-oxide;

W is selected from the group consisting of:
(1) CH,
(2) N, and
(3) N-oxide,

provided that no more than two of T, U, V and W are selected from N and N-oxide, further provided that if both T and W are N or N-oxide, then R 3 is absent, and further provided that both U and V are not N or N-oxide;
Y is selected from the group consisting of:
(1) oxygen,
(2) sulfur,
(3) —CR g R g ,
(4) C═O,
(5) —C(R g )OC 1-6 alkyl,
(6) —CF 2 , and
(7) —NR c ;

A is selected from the group consisting of:
(1) aryl,
(2) heteroaryl,
(3) C 3-6 cycloalkyl, and
(4) C 2-5 cycloheteroalkyl,

wherein A is unsubstituted or substituted with one to five substituents selected from R a ;
B is selected from the group consisting of:
(1) aryl,
(2) aryl-C 1-10 alkyl-,
(3) C 3-6 cycloalkyl,
(4) C 3-6 cycloalkyl-C 1-10 alkyl,
(5) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(6) C 2-5 cycloheteroalkyl,
(7) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,
(8) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,
(9) heteroaryl, and
(10) heteroaryl-C 1-10 alkyl-;

wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 and R 2 are each independently selected from:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein each alkyl is unsubstituted or substituted with one to three substituents selected from R L , and wherein one of R 1 and R 2 is substituted with a substituent selected from R 7 , or R 1 and R 2 together with the atom(s) to which they are attached form a C 3-6 cycloalkyl ring or a C 2-5 cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g , wherein each R 1 and R 2 is unsubstituted or substituted with one to three substituents selected from R L , and wherein one of R 1 and R 2 is substituted with a substituent selected from R 7 ;
R 3 is hydrogen;
R 4 is hydrogen;
R 5 is hydrogen;
R 6 is hydrogen;
R 7 is —CO 2 R 8 ;
R 8 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 3-6 cycloalkyl, and
(4) aryl-C 1-6 alkyl,

wherein each alkyl, cycloalkyl and aryl is unsubstituted or substituted with one to three substituents selected from R j ;
R a is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —OR e ,
(4) —NR c S(O) n R e ,
(5) —S(O) n R e ,
(6) —S(O) n NR c R d ,
(7) —NR c R d ,
(8) —C(O)R e ,
(9) —OC(O)R e ,
(10) —CO 2 R e ,
(11) —CN,
(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) —CF 3 ,
(17) —OCF 3 ,
(18) —OCHF 2 ,
(19) aryl,
(20) heteroaryl,
(21) C 3-6 cycloalkyl,
(22) —C 3-6 cycloalkenyl, and
(23) —C 2-5 cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
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) —O(CH 2 ) p OC 1-10 alkyl,
(10) —O(CH 2 ) p OC 3-6 cycloalkyl,
(11) —O(CH 2 ) p C 3-6 cycloalkyl-C 1-10 alkyl-,
(12) —O(CH 2 ) p C 2-5 cycloheteroalkyl,
(13) —O(CH 2 ) p C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(14) —O-aryl,
(15) —O-heteroaryl,
(16) —O-aryl-C 1-10 alkyl-,
(17) —O-heteroaryl-C 1-10 alkyl-,
(18) —O(CH 2 ) p NR c S(O) m R e ,
(19) —O(CH 2 ) p S(O) m R e ,
(20) —O(CH 2 ) p S(O) m NR c R d ,
(21) —O(CH 2 ) p NR c R d ,
(22) —C(O)R e ,
(23) —OC(O)R e ,
(24) —CO 2 R e ,
(25) —C(O)NR c R d ,
(26) —NR c C(O)R e ,
(27) —NR c C(O)OR e ,
(28) —NR c C(O)NR c R d ,
(29) —O(CH 2 ) p O—C 3-6 cycloalkyl,
(30) —O(CH 2 ) p O—C 2-5 cycloheteroalkyl,
(31) —OCF 3 ,
(32) —OCHF 2 ,
(33) —(CH 2 ) p C 3-6 cycloalkyl,
(34) —(CH 2 ) p C 2-5 cycloheteroalkyl,
(35) aryl,
(36) heteroaryl,
(37) aryl-C 1-10 alkyl-, and
(38) heteroaryl-C 1-10 alkyl-,

wherein each CH, CH 2 , alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with —C 1-6 alkyl, halogen, —O—C 1-6 alkyl and —CF 3 ;
R c and R d are each independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 2-10 alkenyl,
(4) C 3-6 cycloalkyl,
(5) C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) C 2-5 cycloheteroalkyl,
(7) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents independently selected from R f ,
or R c and R d together with the atom(s) to which they are attached form a C 2-5 cycloheteroalkyl ring containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g , wherein each R c and R d is unsubstituted or substituted with one to three substituents independently selected from R f ;
each R e is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 3-6 cycloalkyl,
(5) —C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) —C 2-5 cycloheteroalkyl,
(7) —C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) aryl-C 1-10 alkyl-,
(10) heteroaryl, and
(11) heteroaryl-C 1-10 alkyl-,

wherein each alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;
each R f is selected from the group consisting of:
(1) halogen,
(2) C 1-10 alkyl,
(3) —OH,
(4) —O—C 1-4 alkyl,
(5) —S(O) m —C 1-4 alkyl,
(6) —CN,
(7) —CF 3 ,
(8) —OCHF 2 , and
(9) —OCF 3 ,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C 1-6 alkyl, cyano and S(O) 2 C 1-6 alkyl;
each R g is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,

wherein each alkyl is unsubstituted or substituted with one to five halogens;
each R h is selected from the group consisting of:
(1) halogen,
(2) C 1-10 alkyl,
(3) —OH,
(4) —O—C 1-4 alkyl,
(5) —S(O) m —C 1-4 alkyl,
(6) —CN,
(7) —CF 3 ,
(8) —OCHF 2 , and
(9) —OCF 3 ,

wherein each alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, C 1-6 alkyl, cyano and S(O) 2 C 1-6 alkyl;
R j is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OR e ,
(3) —NR c S(O) m R e ,
(4) halogen,
(5) —S(O) m R e ,
(6) —S(O) m NR c R d ,
(7) —NR c R d ,
(8) —C(O)R e ,
(9) —OC(O)R e ,
(10) —CO 2 R e ,
(11) —CN,
(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) —CF 3 ,
(17) —OCF 3 ,
(18) —OCHF 2 ,
(19) —C 3-6 cycloalkyl, and
(20) —C 2-5 cycloheteroalkyl;

each R L is independently selected from the group consisting of:
(1) —CO 2 C 1-6 alkyl,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(

Assignees

• Merck Sharp & Dohme

Inventors

• Brockunier Linda L
• Chen Helen
• Chobanian Harry R
• Clements Matthew J H
• Crespo Alejandro
• Demong Duane E
• Guo Yan
• Hagmann William K
• Marcantonio Karen M
• Miller Michael
• Pio Barbara
• Plummer Christopher W
• Xiao Dong

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P3/06

  Antihyperlipidemics · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title