Antidiabetic tricyclic compounds

Patent metadata

Field	Value
Publication number	US-2016207887-A1
Application number	US-201415023124-A
Country	US
Kind code	A1
Filing date	Sep 30, 2014
Priority date	Oct 8, 2013
Publication date	Jul 21, 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 dyslip idemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

First claim

1 . A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
A is phenyl;
B is selected from the group consisting of:
(1) phenyl, and
(2) pyridyl;

R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —C 1-6 alkyl,
(4) —(CH 2 ) r —OC 1-6 alkyl,
(5) —(CH 2 ) r —C 3-6 cycloalkyl, and
(6) —(CH 2 ) r —O—(CH 2 ) r —C 3-6 cycloalkyl,

wherein each CH 2 , —C 1-6 alkyl, —OC 1-6 alkyl and —C 3-6 cycloalkyl is unsubstituted or substituted with one to four substituents selected from halogen, —C 1-6 alkyl and —(CH 2 ) v —C 3-6 cycloalkyl;
R 2 is halogen;
R 3 when present is selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 ) u —C 3-6 cycloalkyl,

wherein each C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
R 4 is selected from:
(1) —OC 1-6 alkyl, and
(2) —C 1-6 alkyl,

wherein —C 1-6 alkyl is unsubstituted or substituted with one, two, three or four substituents selected from R 5 ;
R 5 is selected from the group consisting of:
(1) —(CH 2 ) s halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s —O—C 1-6 alkyl,
(4) —(CH 2 ) s OH,
(5) —(CH 2 ) s SO 2 C 1-6 alkyl,
(6) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,
(7) —(CH 2 ) s C 3-6 cycloalkyl,
(8) —(CH 2 ) s —O—(CH 2 ) t —C 3-6 cycloalkyl, and

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen and (CH 2 ) w OH;
Y is selected from:
(1) —CH(OH)—,
(2) —C(C 1-6 alkyl)(OH)—,
(3) —C[(CH 2 ) t —C 3-6 cycloalkyl](OH)—,
(4) O,
(5) S, and
(6) SO 2 ,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen and (CH 2 ) w OH;
Z is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s —O—C 1-6 alkyl,
(4) —(CH 2 ) s —OH,
(5) —(CH 2 ) s SO 2 C 1-6 alkyl,
(6) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,
(7) —(CH 2 ) s C 3-6 cycloalkyl, and
(8) —(CH 2 ) s —O—(CH 2 ) t —C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
m is 0, 1, 2 or 3;
n is 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3, provided that p+q is at least 2;
r is 0, 1, 2 or 3;
s is 0, 1, 2 or 3;
t is 0, 1, 2 or 3;
u is 0, 1, 2 or 3;
v is 0, 1, 2 or 3; and
w is 0, 1, 2 or 3.

2 . A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
A is phenyl;
B is selected from the group consisting of:
(1) phenyl, and
(2) pyridyl;

R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —C 1-6 alkyl,
(4) —(CH 2 ) r —OC 1-6 alkyl,
(5) —(CH 2 ) r —C 3-6 cycloalkyl, and
(6) —(CH 2 ) r —O—(CH 2 ) r —C 3-6 cycloalkyl,

wherein each CH 2 , —C 1-6 alkyl, —OC 1-6 alkyl and —C 3-6 cycloalkyl is unsubstituted or substituted with one to four substituents selected from halogen, —C 1-6 alkyl and —(CH 2 ) v —C 3-6 cycloalkyl;
R 2 is halogen;
R 3 when present is selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl, and
(3) —(CH 2 )—C 3-6 cycloalkyl,

wherein each C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
R 4 is —OC 1-6 alkyl, wherein —C 1-6 alkyl is unsubstituted or substituted with one, two, three or four substituents selected from R 5 ;
R 5 is selected from the group consisting of:
(1) —(CH 2 ) s halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s —O—C 1-6 alkyl,
(4) —(CH 2 ) s OH,
(5) —(CH 2 ) s SO 2 C 1-6 alkyl,
(6) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,
(7) —(CH 2 ) s C 3-6 cycloalkyl,
(8) —(CH 2 ) r —O—(CH 2 ) t —C 3-6 cycloalkyl, and

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen and (CH 2 ) w OH;
Y is selected from:
(1) —CH(OH)—,
(2) —C(C 1-6 alkyl)(OH)—,
(3) —C [(CH 2 ) t —C 3-6 cycloalkyl](OH)—,
(4) O,
(5) S, and
(6) SO 2 ,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen and (CH 2 ) w OH;
Z is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s —O—C 1-6 alkyl,
(4) —(CH 2 ) s —OH,
(5) —(CH 2 ) s SO 2 C 1-6 alkyl,
(6) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,
(7) —(CH 2 ) s C 3-6 cycloalkyl, and
(8) —(CH 2 ) s —O—(CH 2 ) t —C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
m is 0, 1, 2 or 3;
n is 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3, provided that p+q is at least 2;
r is 0, 1, 2 or 3;
s is 0, 1, 2 or 3;
t is 0, 1, 2 or 3;
u is 0, 1, 2 or 3;
v is 0, 1, 2 or 3; and
w is 0, 1, 2 or 3.

3 . The compound of claim 1 of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein
A is phenyl;
B is selected from the group consisting of:
(1) phenyl, and
(2) pyridyl;

R 1 is selected from the group consisting of:
(1) halogen,
(2) —CN,
(3) —C 1-6 alkyl,
(4) —OC 1-6 alkyl, and
(5) —C 3-6 cycloalkyl,

wherein each —C 1-6 alkyl, —OC 1-6 alkyl and —C 3-6 cycloalkyl is unsubstituted or substituted with one to four substituents selected from halogen;
R 2 is halogen;
R 3 is selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl, and
(3) —C 3-6 cycloalkyl,

wherein each C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
R 4 is —OC 1-6 alkyl, wherein —C 1-6 alkyl is unsubstituted or substituted with one, two, three or four substituents selected from R 5 ;
R 5 is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —(CH 2 ) s OH,
(3) —(CH 2 ) s SO 2 C 1-6 alkyl,
(4) —(CH 2 ) s halogen,
(5) —(CH 2 ) s OC 1-6 alkyl,
(6) —(CH 2 ) s C 3-6 cycloalkyl, and

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
Y is selected from:
(1) O,
(2) S, and
(3) SO 2 ;

Z is selected from:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) s —O—C 1-6 alkyl,
(4) —(CH 2 ) s —OH, and
(5) —(CH 2 ) s C 3-6 cycloalkyl,

wherein each CH 2 , C 1-6 alkyl and C 3-6 cycloalkyl is unsubstituted or substituted with one to three substituents selected from halogen;
m is 0, 1, 2 or 3;
n is 1 or 2;
p is 0, 1, 2 or 3;
q is 0, 1, 2 or 3, provided that p+q is at least 2; a

Assignees

• Merck Sharp & Dohme

Inventors

• Biftu Tesfaye
• Biju Purakkattle
• Colletti Steven L
• Cui Mingxiang
• Hagmann William K
• Hu Bin
• Josien Hubert
• Kar Nam Fung
• Nair Anilkumar
• Nargund Ravi
• Sperbeck Donald M
• Zhu Cheng

Classifications

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61K31/435

  having six-membered rings with one nitrogen as the only ring hetero atom · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D221/16 Primary

  containing carbocyclic rings other than six-membered · CPC title