Antidiabetic tricyclic compounds

Patent metadata

Field	Value
Publication number	US-9527875-B2
Application number	US-201314418147-A
Country	US
Kind code	B2
Filing date	Jul 31, 2013
Priority date	Aug 2, 2012
Publication date	Dec 27, 2016
Grant date	Dec 27, 2016

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:

wherein
n is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is selected from the group consisting of: phenyl and pyridine, wherein A is unsubstituted or substituted with one to five substituents selected from R a ;
B is selected from the group consisting of: phenyl, pyridine, pyrimidine, thiazole, benzimidazole, benzthiazole, benzoxazole, and benzisoxazole, wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 , R 2 , R 5 and R 6 are hydrogen;
R 3 and R 4 are selected from the group consisting of: hydrogen, halogen, and —C 1-6 alkyl, wherein each C 1-6 alkyl is unsubstituted or substituted with one to three substituents selected from R L ;
R a is selected from the group consisting of:
(1) halogen,
(2) —OR e ,
(3) —NR c S(O) m R e ,
(4) —S(O) m R e ,
(5) —S(O) m NR c R d ,
(6) —NR c R d ,
(7) —C(O)R e ,
(8) —OC(O)R e ,
(9) —CO 2 R e ,
(10) —CN,
(11) —C(O)NR c R d ,
(12) —NR c C(O)R e ,
(13) —NR c C(O)OR e ,
(14) —NR c C(O)NR c R d ,
(15) —CF 3 ,
(16) —OCF 3 , and,
(17) —OCHF 2 ;

R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) halogen,
(3) —OH,
(4) —OC 1-10 alkyl,
(5) —O(CH 2 )pOC 1-10 alkyl,
(6) —O(CH 2 ) P C 3-6 cycloalkyl,
(7) —O(CH 2 )pC 2-10 cycloheteroalkyl,
(8) —O(CH 2 )pO-C 3-6 cycloalkyl,
(9) —O(CH 2 )pO-C 2-10 cycloheteroalkyl,
(10) —CF 3 ,
(11) —OCF 3 ,
(12) —OCHF 2 ,
(13) —(CH 2 )p-C 2-10 cycloheteroalkyl, and
(14) —S(O) 2 C 1-10 alkyl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ;
R c and R d are each independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-10 alkyl, and
(3) —C 2-10 alkenyl,

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, and
(2) —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) —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 C 1-10 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 —C 1-10 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 C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, halogen, cyano, and —S(O) 2 CH 3 ;
each R k is independently selected from the group consisting of:
(1) halogen,
(2) —C 1-10 alkyl,
(3) —OH,
(4) oxo,
(5) halogen,
(6) —O—C 1-4 alkyl,
(7) —SO 2 —C 1-6 alkyl,
(8) —C 1-6 alkyl-SO 2 C 1-6 alkyl,
(9) —CN,
(10) —CF 3 ,
(11) —OCHF 2 ,
(12) —OCF 3 ,
(13) —NH 2 ,
(14) —NHSO 2 C 1-6 alkyl,
(15) —NHCOC 1-6 alkyl,
(16) ═N(OCH 3 ),
(17) —P(O)(OH) 2 , and
(18) —P(O)(OC 1-6 alkyl) 2 ,

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

each m is independently selected from: 0, 1 or 2; and
each p is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
or a pharmaceutically acceptable salt thereof.

2. A compound of structural formula I:

wherein:
n is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is selected from the group consisting of: phenyl and pyridine, wherein A is unsubstituted or substituted with one to five substituents selected from R a ;
B is selected from the group consisting of: phenyl, pyridine, pyrimidine, thiazole, benzimidazole, benzthiazole, benzoxazole, and benzisoxazole, wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen;
R a is selected from the group consisting of: —C 1-6 alkyl, halogen, and —CF 3 ;
R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) halogen,
(3) —OH,
(4) —OC 1-10 alkyl,
(5) —O(CH 2 )pOC 1-10 alkyl,
(6) —O(CH 2 )pC 3-6 cycloalkyl,
(7) —O(CH 2 )pC 2-10 cycloheteroalkyl,
(8) —O(CH 2 )pO-C 3-6 cycloalkyl,
(9) —O(CH 2 )pO-C 2-10 cycloheteroalkyl,
(10) —CF 3 ,
(11) —OCF 3 ,
(12) —OCHF 2 ,
(13) —(CH 2 )p-C 2-10 cycloheteroalkyl, and
(14) —S(O) 2 C 2-10 alkyl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ; and
each R k is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —O—C 1-4 alkyl,
(3) —OH,
(4) halogen,
(5) —SO 2 —C 1-6 alkyl,
(6) —C 1-6 alkyl-SO 2 C 1-6 alkyl,
(7) —CN,
(8) —NHSO 2 C 1-6 alkyl,
(9) ═N(OCH 3 ), and
(10) —P(O)(OC 1-6 alkyl) 2 ,

wherein each C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC 1-6 alkyl, halogen, cyano, and —S(O) 2 C 1-6 alkyl; and
each p is independently selected from: 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;
or a pharmaceutically acceptable salt thereof.

3. A compound of structural formula I:

wherein:
n is 1;
X is oxygen;
T is CH;
U is N;
V is CH;
A is phenyl, wherein phenyl is unsubstituted or substituted with one to five substituents selected from R a ;
B is selected from the group consisting of: phenyl and pyridine, wherein B is unsubstituted or substituted with one to five substituents selected from R b ;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrogen;
R a is selected from the group consisting of: —C 1-6 alkyl, halogen, and —CF 3 ;
R b is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) halogen,
(3) —OH,
(4) —OC 1-10 alkyl,
(5) —O(CH 2 )pC 2-10 cycloheteroalkyl,
(6) —CF 3 , and
(7) —(CH 2 )p-C 2-10 cycloheteroalkyl,

wherein each R b is unsubstituted or substituted with one to five substituents selected from R k ; and
each R k is independently selected from the group consisting of:
(1) —C 1-10 alkyl,
(2) —OH,
(3) halogen,
(4) —SO 2 —C 1-6 alkyl,
(5) —C 1-6 alkyl-SO 2 C 1-6 alkyl, and
(6) —CN,

wherein each C 1-10 alkyl is unsubstituted or substituted with one to three substituents independently selected from: —OH, —OC 1-6 alkyl, halogen, cyano, and —S(O) 2 C 1-

Assignees

• Merck Sharp & Dohme

Inventors

• Hagmann William K
• Nargund Ravi P
• Blizzard Timothy A
• Josien Hubert
• Biju Purakkattle
• Plummer Christopher W
• Dang Qun
• Li Bing
• Li Derun
• Lin Linus S
• Cui Mingxiang
• Hu Bin
• Hao Jinglai
• Chen Zhengxia

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/4433

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

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title