Antidiabetic bicyclic compounds

Patent metadata

Field	Value
Publication number	US-10968193-B2
Application number	US-201515328735-A
Country	US
Kind code	B2
Filing date	Aug 6, 2015
Priority date	Aug 8, 2014
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

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;
Y is —CR g R g ;
T is CH;
U is CR 1 ;
V is CR 2 ;
W is CH;
A 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 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 selected from R b ;
R 1 and R 2 are each independently selected from:
(1) hydrogen, and
(2) C 1-6 alkyl,

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

wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from R j ;
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 selected from R j ;
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 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 selected from R j ;
R 9 is selected from the group consisting of:
(1) —C 1-6 alkyl-NR c R d , and
(2) —C 1-6 alkyl-C 2-5 cycloheteroalkyl,

wherein each alkyl and cycloheteroalkyl 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 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 0-6 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 selected from —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 2-10 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 selected from R h ;
each R f is selected from the gr

Assignees

• Merck Sharp & Dohme

Inventors

• Chen Helen
• Colletti Steven L
• Demong Duane
• Guo Yan
• Miller Michael
• Nair Anilkumar
• Plummer Christopher W
• Xiao Dong
• Yang De-Yi

Classifications

• C07D451/02

  containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof · CPC title

• A61K31/366

  having six-membered rings, e.g. delta-lactones · CPC title

• A61K31/397

  having four-membered rings, e.g. azetidine · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• A61K31/4985

  Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems · CPC title