Antidiabetic bicyclic compounds

Patent metadata

Field	Value
Publication number	US-2016002255-A1
Application number	US-201414767815-A
Country	US
Kind code	A1
Filing date	Feb 20, 2014
Priority date	Feb 22, 2013
Publication date	Jan 7, 2016
Grant date	—

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

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 6 is absent and Y is selected from the group consisting of: C—R g , —C—OC 1-6 alkyl, CF, and N;
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) hydrogen,
(2) aryl,
(3) aryl-O—,
(4) aryl-C 1-10 alkyl-,
(5) aryl-C 1-10 alkyl-O—,
(6) C 3-6 cycloalkyl,
(7) C 3-6 cycloalkyl-C 1-10 alkyl-,
(8) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(9) C 3-6 cycloalkenyl,
(10) C 3-6 cycloalkenyl-C 1-10 alkyl-,
(11) C 3-6 cycloalkenyl-C 1-10 alkyl-O—,
(12) C 2-5 cycloheteroalkyl,
(13) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,
(14) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,
(15) heteroaryl,
(16) heteroaryl-O—,
(17) heteroaryl-C 1-10 alkyl-, and
(18) heteroaryl-C 1-10 alkyl-O—,

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) a bond,
(2) hydrogen,
(3) halogen,
(4) —OR k ,
(5) —CN,
(6) —C 1-6 alkyl,
(7) —C 3-6 cycloalkyl,
(8) —C 3-6 cycloalkyl-C 1-3 alkyl-,
(9) —C 2-6 cycloheteroalkyl, and
(10) —C 2-6 cycloheteroalkyl-C 1-3 alkyl-,

wherein each alkyl, cycloalkyl and cycloheteroalkyl 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 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 1-33 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 ,
provided that when R 4 is selected from the group consisting of:
(1) OR e ,
(2) C 1-6 alkyl-O—,
(3) C 3-6 cycloalkyl-O—,
(4) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(5) C 2-5 cycloheteroalkyl-O—,
(6) C 2-5 cycloheteroalkyl-C 1-10 alkyl-O—,
(7) aryl-O—, and
(8) heteroaryl-O—,

then Y is selected from the group consisting of:
(1) —CR g R g ,
(2) C═O,
(3) —C(R g )OC 1-6 alkyl, and
(4) —CF 2 ;

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 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 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 —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 cycloheter

Assignees

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

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P43/00

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

• A61K31/422

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/436

  the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin · CPC title