US 9,957,219 B2 · Antidiabetic bicyclic compounds

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.

A compound of structural formula I:

or a pharmaceutically acceptable salt thereof;
wherein
A, B, C and D are CH;
T is CH;
U is CH;
V is CH;
W is CH;
X is selected from the group consisting of:
(1) aryl, and
(2) heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with one to three substituents selected from Ra;
Y is oxygen;
Z is selected from the group consisting of:
—OH, and —O—C1-6alkyl;
each R1 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with one, two or three halogens;
each R2 is independently selected from the group consisting of:
(1) —C1-6alkyl, and
(2) —C3-6cycloalkyl,
wherein alkyl and cycloalkyl are unsubstituted or substituted with one, two or three halogens;
each R3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH2)s—OC1-6alkyl,
(4) —(CH2)s—OH,
(5) —CN, and
(6) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, and OC1-6 alkyl;
each R4 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen, and
(3) —C1-6alkyl,
wherein alkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, and OC1-6alkyl;
each R5 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C1-6alkenyl,
(3) halogen,
(4) —(CH2)t—O—C1-6alkyl,
(5) —CN,
(6) aryl,
(7) heteroaryl, and
(8) C3-6cycloalkyl,
wherein each alkyl, alkenyl, cycloalkyl, aryl and heteroaryl is unsubstituted or substituted with one, two, or three substituents selected from Rb;
each Ra is independently selected from the group consisting of:
(1) —C1-6 alkyl,
(2) halogen,
(3) —(CH2)u—OC1-6alkyl,
(4) —OH, —S(O)uRe,
(5) —S(O)uNRcRd,
(6) —CN,
(7) —C(O)NRcRd,
(8) —CF3,
(9) —OCF3, and
(10) —OCHF2,
wherein each alkyl is unsubstituted or substituted with C1-6alkyl, halogen, —O—C1-6alkyl and —CF3;
each Rb is independently selected from the group consisting of:
(1) —C1-10alkyl,
(2) —C2-10alkenyl,
(3) —CF3,
(4) halogen,
(5) —CN,
(6) —OH,
(7) —OC1-10alkyl,
(8) —OC2-10alkenyl,
(9) —C(O)Re,
(10) —OC(O)Re,
(11) —CO2Re,
(12) —C(O)NRcRd,
(13) —NRcC(O)Re,
(14) —NRcC(O)ORe,
(15) —NRcC(O)NRcRd,
(16) —OCF3,
(17) —OCHF2,
(18) —(CH2)vC3-6 cycloalkyl, and
(19) —(CH2)vC7-5 cycloheteroalkyl,
wherein each CH2, alkyl, alkenyl, cycloalkyl, and cycloheteroalkyl is unsubstituted or substituted with —C1-6alkyl, halogen, —O—C1-6alkyl and —CF3;
each Rc is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-10alkyl,
wherein each alkyl is unsubstituted or substituted with one to three substituents selected from C1-6 alkyl;
each Rd is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-10alkyl,
wherein each alkyl is unsubstituted or substituted with one to three substituents selected from C1-6 alkyl;
each Re is independently selected from the group consisting of:
(1) hydrogen, and
(2) C1-10alkyl,
wherein each alkyl is unsubstituted or substituted with one to three substituents selected from C1-6 alkyl;
each n is independently selected from:
1 and 2;
each m is independently selected from:
1 and 2;
each p is independently selected from:
1, 2, 3 and 4;
each q is independently selected from:
1, 2, 3 and 4;
each r is independently selected from:
1, 2, 3 and 4;
each s is independently selected from:
0, 1, 2, 3 and 4;
each t is independently selected from:
0, 1, 2, 3 and 4;
each u is independently selected from:
0, 1, 2, 3, and 4;
and
each v is independently selected from:
0, 1, 2, 3 and 4.

106 more elements

Antidiabetic bicyclic compounds

Life of this patent

Antidiabetic bicyclic compounds

Life of this patent

Abstract

Claims13