[5,6]—fused bicyclic antidiabetic compounds

Patent metadata

Field	Value
Publication number	US-10100042-B2
Application number	US-201515328672-A
Country	US
Kind code	B2
Filing date	Aug 3, 2015
Priority date	Aug 8, 2014
Publication date	Oct 16, 2018
Grant date	Oct 16, 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 a single bond or a double bond, provided that if “a” is a double bond, then R 5 and R 6 are absent;
T is CH; U is CR 1 ; V is CR 2 ; and W is CH;
X is oxygen;
A is selected from the group consisting of:
(1) aryl,
(2) C 1-6 alkyl-aryl, and
(3) heteroaryl,

wherein A is unsubstituted or substituted with one to five substituents independently selected from R a ;
B is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,

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

wherein one of R 1 and R 2 is —C 1-6 alkyl substituted with R 7 , and wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from R L ;
R 3 is absent or if present R 3 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —CN,
(5) —C 1-6 alkyl,
(6) —C 3-6 cycloalkyl, and
(7) C 3-6 cycloalkyl-C 1-3 alkyl-,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R i ;
R 4 is selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) OR e ,
(4) C 0-5 alkylNR c R d ,
(5) C 1-6 alkyl,
(6) C 1-6 alkyl-O—,
(7) C 3-6 cycloalkyl,
(8) C 3-6 cycloalkyl-O—,
(9) C 3-6 cycloalkyl-C 1-10 alkyl-,
(10) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(11) C 2-5 cycloheteroalkyl,
(12) C 2-5 cycloheteroalkyl-O—,
(13) C 2-5 cycloheteroalkyl-C 1-10 alkyl-,
(14) C 2-5 cycloheteroalkyl-C 1-10 alkyl-O—,
(15) aryl,
(16) aryl-O—,
(17) aryl-C 1-10 alkyl-,
(18) heteroaryl,
(19) heteroaryl-O—, and
(20) heteroaryl-C 1-10 alkyl-,

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

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R j ;
R 6 is absent or if present R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents independently selected from R j ;
R 7 is selected from the group consisting of:
(1) —CO 2 R 8 ,
(2) —C 1-6 alkyl-CO 2 R 8 ,
(3) —C 1-6 alkyl-CONHSO 2 R m ,
(4) —C 1-6 alkyl-SO 2 NHCOR m ,
(5) —C 1-6 alkyl-tetrazolyl, and
(6) a cycloheteroalkyl selected from the group consisting of:

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 independently selected from R j ;
R a is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —C 0-6 alkyl-OR e ,
(4) —C 0-6 alkyl-NR c S(O) n R e ,
(5) —C 0-6 alkyl-S(O) n R e ,
(6) —C 0-6 alkyl-S(O) n NR c R d ,
(7) —C 0-6 alkyl-NR c R d ,
(8) —C 0-6 alkyl-C(O)R e ,
(9) —C 1-6 alkyl-OC(O)R e ,
(10) —C 0-6 alkyl-CO 2 R e ,
(11) —C 0-6 alkyl-CN,
(12) —C 0-6 alkyl-C(O)NR c R d ,
(13) —C 0-6 alkyl-NR c C(O)R e ,
(14) —C 0-6 alkyl-NR c C(O)OR e ,
(15) —C 0-6 alkyl-NR c C(O)NR c R d ,
(16) —CF 3 ,
(17) —OCF 3 ,
(18) —OCHF 2 ,
(19) —C 0-6 alkyl-aryl,
(20) —C 0-6 alkyl-heteroaryl,
(21) —C 0-6 alkyl-C 3-10 cycloalkyl,
(22) —C 0-6 alkyl-C 3-10 cycloalkenyl, and
(23) —C 0-6 alkyl-C 2-10 cycloheteroalkyl,

wherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to five substituents independently selected from: —C 1-6 alkyl, halogen, OH, —O—C 1-6 alkyl, —S(O) 2 —C 1-4 alkyl, —CN, —OCHF 2 , —OCF 3 , —CF 3 , and —C 0-6 alkyl-NR c R d ;
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 C 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 one to five substituents independently selected from: —C 1-6 alkyl, halogen, OH, —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 2-10 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 independently 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 un

Assignees

• Merck Sharp & Dohme

Inventors

• Chen Helen
• Demong Duane
• Finke Paul E
• Plummer Christopher W

Classifications

• C07D405/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D307/80

  Radicals substituted by oxygen atoms · CPC title

• C07D405/04 Primary

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

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/343

  condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone · CPC title