Antidiabetic tricyclic compounds

Patent metadata

Field	Value
Publication number	US-10000454-B2
Application number	US-201515310488-A
Country	US
Kind code	B2
Filing date	May 19, 2015
Priority date	May 22, 2014
Publication date	Jun 19, 2018
Grant date	Jun 19, 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

The invention claimed is:

1. A compound of structural formula A:

or a pharmaceutically acceptable salt thereof; wherein
X is selected from the group consisting of:
(1) oxygen, and
(2) NR 7 ;

T is CH;
U is CH;
V is N;
W is CH;
A is selected from the group consisting of:

wherein A is unsubstituted or substituted with one to six substituents selected from R a , and wherein two R a substituents together with the carbon atom to which they are attached may form a 3-6 membered cycloalkyl ring or a 3-6 membered cycloheteroalkyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR 8 , and wherein each 3-6 membered cycloalkyl and each 3-6 membered cycloheteroalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from: —C 1-6 alkyl, —O—C 1-6 alkyl, halogen and OH;
B is selected from the group consisting of:
(1) C 1-6 alkyl,
(2) aryl,
(3) aryl-O—,
(4) C 3-6 cycloalkyl-,
(5) C 3-6 cycloalkyl-C 1-10 alkyl-,
(6) C 3-6 cycloalkyl-C 1-10 alkyl-O—,
(7) C 2-5 cycloheteroalkyl-,
(8) C 3-6 cycloheteroalkyl-C 1-10 alkyl-,
(9) C 3-6 cycloheteroalkyl-C 1-10 alkyl-O—,
(10) heteroaryl,
(11) heteroaryl-O—,
(12) aryl-C 1-10 alkyl-, and
(13) heteroaryl-C 1-10 alkyl-;

wherein B is unsubstituted or substituted with one to six substituents selected from R b ;
each R 1 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —CN,
(5) —C 1-6 alkyl, and
(6) —C 3-6 cycloalkyl,

wherein each alkyl and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R i ;
R 2 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 ;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —OR e ,
(4) —C 1-6 alkyl,
(5) —C 2-6 alkenyl,
(6) —C 2-6 alkynyl,
(7) —C 3-6 cycloalkyl, and
(8) —C 2-6 cycloheteroalkyl,

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

wherein each alkyl, alkenyl, alkynyl, and cycloalkyl is unsubstituted or substituted with one to three substituents selected from R L ;
R 5 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-3 alkyl, and
(3) halogen;

R 6 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-3 alkyl, and
(3) halogen, or

R 5 and R 6 can together form oxo;
R 7 is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,

wherein —C 1-10 alkyl is unsubstituted or substituted with one to five fluorines;
each R 8 is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,

wherein —C 1-10 alkyl is unsubstituted or substituted with one to five fluorines;
each R 9 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,

wherein —C 1-6 alkyl is unsubstituted or substituted with one to five fluorines;
each R a is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —O—C 1-6 alkyl,
(3) halogen,
(4) oxo,
(5) —OR e ,
(6) —N(R c )S(O) m R e ,
(7) —S(O) m R e ,
(8) —S(O) m NR c R d ,
(9) —NR c R d ,
(10) —C(O)R e ,
(11) —OC(O)R e ,
(12) —CO 2 R e ,
(13) —CN,
(14) —C(O)NR c R d ,
(15) —N(R c )C(O)R e ,
(16) —N(R c )C(O)OR e ,
(17) —N(R c )C(O)NR c R d ,
(18) —CF 3 ,
(19) —OCF 3 ,
(20) —OCHF 2 ,
(21) —(CH 2 ) p —C 3-6 cycloalkyl,
(22) —(CH 2 ) p —C 2-10 cycloheteroalkyl,
(23) —(CH 2 ) p -aryl, and
(24) —(CH 2 ) p -heteroaryl,

wherein R a is unsubstituted or substituted with one to three substituents selected from R m ;
each R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —O—C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) halogen,
(5) —OH,
(6) —OC 2-10 alkenyl,
(7) —O(CH 2 )pOC 1-10 alkyl,
(8) —O(CH 2 )pC 3-6 cycloalkyl,
(9) —O(CH 2 )pC 2-10 cycloheteroalkyl,
(10) —O(CH 2 )p-aryl,
(11) —O(CH 2 )p-heteroaryl,
(12) —N(R c )S(O) m R e ,
(13) —S(O) m R e ,
(14) —O(CH 2 )p-S(O) m R e ,
(15) —S(O) m NR c R d ,
(16) —NR c R d ,
(17) —C(O)R e ,
(18) —OC(O)R e ,
(19) —CO 2 R e ,
(20) —CN,
(21) —C(O)NR c R d ,
(22) —N(R c )C(O)R e ,
(23) —N(R c )C(O)OR e ,
(24) —N(R c )C(O)NR c R d ,
(25) —O(CH 2 )pO-C 3-6 cycloalkyl,
(26) —O(CH 2 )pO-C 2-10 cycloheteroalkyl,
(27) —CF 3 ,
(28) —OCF 3 ,
(29) —OCHF 2 ,
(30) —(CH 2 )p-C 3-6 cycloalkyl,
(31) —(CH 2 )p-C 2-10 cycloheteroalkyl,
(32) —(CH 2 )p-aryl, and
(33) —(CH 2 )p-heteroaryl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ;
each R c and R d 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 2-6 cycloheteroalkyl,
(7) C 2-6 cycloheteroalkyl-C 1-10 alkyl-,
(8) aryl,
(9) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-, or

R c and R d together with the atom(s) to which they are attached form a cycloheteroalkyl ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g , and 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) heteroaryl,
(10) aryl-C 1-10 alkyl-, and
(11) heteroaryl-C 1-10 alkyl-,

wherein each R e 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) —OC 1-6 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, cyano, and —S(O) 2 CH 3 ;
each R g is selected from the group consisting of:
(1) hydrogen,
(2) —C(O)R e , and
(3) —C 1-10 alkyl,

wherein alkyl is unsubstituted or substituted with one to five fluorines;
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, cyano, and —S(O) 2 CH 3 ;
R i is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OR e ,
(3) —N(R c )S(O) m R e ,
(4) halogen,
(5) —S(O) m R e ,
(6) —S(O)

Assignees

• Merck Sharp & Dohme
• Merck Sharp & Dohme

Inventors

• Biftu Tesfaye
• Biju Purakkattle
• Blizzard Timothy A
• Chen Zhengxia
• Clements Matthew J
• Cui Mingxiang
• Frie Jessica L
• Hagmann William K
• Hu Bin
• Josien Hubert
• Nair Anilkumar G
• Plummer Christopher W
• Zhu Cheng

Classifications

• A61P43/00

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07C2602/08

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

• A61K31/55

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• A61K31/397

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