Antidiabetic compounds
View Patent ↗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.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
A is selected from the group consisting of:
(1) —C 3-9 cycloalkyl,
(2) —C 3-9 cycloalkenyl, and
(3) —C 2-10 cycloheteroalkyl,
wherein each cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from R a ;
B is selected from the group consisting of:
(1) —(CH 2 ) u -aryl,
(2) —(CH 2 ) u -heteroaryl,
(3) —(CH 2 ) u —N(R g )—(CH 2 ) u -aryl, and
(4) —(CH 2 ) u —O—(CH 2 ) u -aryl,
wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one, two, three, four or five substituents selected from R b ;
T, U, V and W are CH;
Y is selected from: —O—, —(CH 2 ) x O— and —O—(CH 2 ) x , wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R i ;
Z is —CO 2 H;
R 1 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one, two or three halogens;
R 2 is —C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, —C 1-6 alkyl and —OC 1-6 alkyl;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH 2 ) s —OC 1-6 alkyl,
(4) —(CH 2 ) s —OH,
(5) —CN, and
(6) —C 1-6 alkyl,
wherein CH 2 and alkyl are unsubstituted or substituted with one, two or three substituents selected from halogen, OH, and OC 1-6 alkyl;
each R a is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —(CH 2 ) u —OC 1-6 alkyl,
(4) —OR e ,
(5) —S(O) u R e ,
(6) —S(O) u NR c R d ,
(7) —N(R c )S(O) p R e ,
(8) —NR c R d ,
(9) —C(O)R e ,
(10) —OC(O)R e ,
(11) —CO 2 R e ,
(12) —N(R c )C(O)R e ,
(13) —N(R c )C(O)OR e ,
(14) —N(R c )C(O)NR c R d ,
(15) —C(O)NR c R d ,
(16) —CN,
(17) —CF 3 ,
(18) —OCF 3 ,
(19) —OCHF 2 ,
(20) —(CH 2 ) r aryl,
(21) —(CH 2 ) r heteroaryl,
(22) —(CH 2 ) r C 3-6 cycloalkyl,
(23) —(CH 2 ) r —C 3-6 cycloalkenyl,
(24) —(CH 2 ) r —C 2-5 cycloheteroalkyl, and
(25) —(CH 2 ) r —O—(CH 2 ) r —C 3-6 cycloalkyl,
wherein each CH 2 , alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents selected from: halogen, —C 1-6 alkyl, —(CH 2 ) w —OH, —O—C 1-6 alkyl, —CF 3 , —CN, —(CH 2 ) v —C 3-6 cycloalkyl, SH, and —SO 2 —C 1-6 alkyl;
each R b is selected from the group consisting of:
1) —C 1-10 alkyl,
2) —C 2-10 alkenyl,
3) —(CH 2 ) v —CF 3 ,
4) —O(CH 2 ) v CF 3 ,
5) —OCHF 2 ,
6) halogen,
7) —(CH 2 ) v CN,
8) —(CH 2 ) v OH,
9) —(CH 2 ) v OC 1-10 alkyl,
10) —CO 2 R e ,
11) —NR c R d ,
12) —(CH 2 ) v C 3-6 cycloalkyl,
13) —(CH 2 ) v C 2-10 cycloheteroalkyl,
14) —(CH 2 ) v -aryl, and
15) —(CH 2 ) v -heteroaryl,
wherein each CH, CH 2 , alkyl, alkenyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one, two or three substituents selected from: halogen, —C 1-6 alkyl, —(CH 2 ) w —OH, —O—C 1-6 alkyl, —CF 3 , —CN, —(CH 2 ) v —C 3-6 cycloalkyl, SH, and —SO 2 —C 1-6 alkyl;
each R c is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R d is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R e is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R g is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C 1-6 alkyl, and
(4) C 3-6 cycloalkyl;
each R i is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —(CH 2 ) s —O—C 1-6 alkyl,
(5) —(CH 2 ) s OH,
(6) —N(R c )S(O) 2 R e ,
(7) —S(C 1-6 alkyl),
(8) —(CH 2 ) s SO 2 C 1-6 alkyl,
(9) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,
(10) —S(O) 2 NR c R d ,
(11) —NR c R d ,
(12) —C(O)R e ,
(13) —OC(O)R e ,
(14) —CO 2 R e ,
(15) —(CH 2 ) s CN,
(16) —C(O)NR c R d ,
(17) —N(R c )C(O)R e ,
(18) —N(R c )C(O)OR e ,
(19) —N(R c )C(O)NR c R d ,
(20) —CF 3 ,
(21) —OCF 3 ,
(22) —OCHF 2 ,
(23) —C 3-6 cycloalkyl, and
(24) —C 2-5 cycloheteroalkyl,
wherein each CH 2 , alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one, two, three or four substituents selected from: —C 1-6 alkyl and halogen;
n is 1;
m is 1;
each p is independently selected from: 0, 1 and 2;
each q is independently selected from: 0, 1 and 2;
each r is independently selected from: 1, 2, 3 and 4;
each s is independently selected from: 0, 1, 2 and 3;
each t is independently selected from: 0, 1, 2, 3 and 4;
each u is independently selected from: 0, 1, 2 and 3;
each v is independently selected from: 0, 1, 2, 3 and 4;
each w is independently selected from: 0, 1, 2 and 3; and
each x is independently selected from: 0, 1 and 2.
2. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
A is —C 2-10 cycloheteroalkyl, wherein each cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from R a ;
B is selected from the group consisting of:
(1) —(CH 2 ) u -aryl, and
(2) -heteroaryl,
wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one, two, three, four or five substituents selected from R b ;
T, U, V and W are CH;
Y is —(CH 2 ) x O—, wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R i ;
Z is —CO 2 H;
R 1 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one, two or three halogens;
R 2 is —C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, —C 1-6 alkyl and —OC 1-6 alkyl;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —(CH 2 ) s —OC 1-6 alkyl,
(4) —(CH 2 ) s —OH,
(5) —CN, and
(6) —C 1-6 alkyl,
wherein CH 2 and alkyl are unsubstituted or substituted with one, two or three substituents selected from halogen, OH, and OC 1-6 alkyl;
each R a is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —(CH 2 ) u —OC 1-6 alkyl,
(4) —OR e ,
(5) —S(O) u R e ,
(6) —S(O) u NR c R d ,
(7) —N(R c )S(O) p R e ,
(8) —NR c R d ,
(9) —C(O)R e ,
(10) —OC(O)R e ,
(11) —CO 2 R e ,
(12) —N(R c )C(O)R e ,
(13) —N(R c )C(O)OR e ,
(14) —N(R c )C(O)NR c R d ,
(15) —C(O)NR c R d ,
(16) —CN,
(17) —CF 3 ,
(18) —OCF 3 ,
(19) —OCHF 2 ,
(20) —(CH 2 ) r aryl,
(21) —(CH 2 ) r heteroaryl,
(22) —(CH 2 ) r —C 3-6 cycloalkyl,
(23) —(CH 2 ) r —C 3-6 cycloalkenyl,
(24) —(CH 2 ) r —C 2-5 cycloheteroalkyl, and
(25) —(CH 2 ) r —O—(CH 2 ) r —C 3-6 cycloalkyl,
wherein each CH 2 , alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to four substituents selected from: halogen, —C 1-6 alkyl, —(CH 2 ) w —OH, —O—C 1-6 alkyl, —CF 3 , —CN, —(CH 2 ) v —C 3-6 cycloalkyl, SH, and —SO 2 —C 1-6 alkyl;
each R b is selected from the group consisting of:
1) —C 1-10 alkyl,
2) —C 2-10 alkenyl,
3) —(CH 2 ) v —CF 3 ,
4) —O(CH 2 ) v CF 3 ,
5) —OCHF 2 ,
6) halogen,
7) —(CH 2 ) v CN,
8) —(CH 2 ) v OH,
9) —(CH 2 ) v OC 1-10 alkyl, and
10) —(CH 2 ) v C 3-6 cycloalkyl,
wherein each CH, CH 2 , alkyl, alkenyl and cycloalkyl is unsubstituted or substituted with one, two or three substituents selected from: halogen, —C 1-6 alkyl, —(CH 2 ) w —OH, —CF 3 —CN, —(CH 2 ) v —C 3-6 cycloalkyl, SH, and —SO 2 —C 1-6 alkyl;
each R c is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R d is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R e is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-10 alkyl,
(3) C 3-6 cycloalkyl,
(4) C 2-5 cycloheteroalkyl,
(5) aryl, and
(6) heteroaryl,
wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl is unsubstituted or substituted with one to three substituents selected from C 1-6 alkyl;
each R g is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) C 1-6 alkyl, and
(4) C 3-6 cycloalkyl;
each R i is independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —(CH 2 ) s —O—C 1-6 alkyl,
(5) —(CH 2 ) s OH,
(6) —N(R c )S(O) 2 R e ,
(7) —S(C 1-6 alkyl),
(8) —(CH 2 ) s SO 2 C 1-6 alkyl,
(9) —(CH 2 ) s SO 2 —(CH 2 ) t —C 3-6 cycloalkyl,
(10) —S(O) 2 NR c R d ,
(11) —NR c R d ,
(12) —C(O)R e ,
(13) —OC(O)R e ,
(14) —CO 2 R e ,
(15) —(CH 2 ) s CN,
(16) —C(O)NR c R d ,
(17) —N(R c )C(O)R e ,
(18) —N(R c )C(O)OR e ,
(19) —N(R c )C(O)NR c R d ,
(20) —CF 3 ,
(21) —OCF 3 ,
(22) —OCHF 2 ,
(23) —C 3-6 cycloalkyl, and
(24) —C 2-5 cycloheteroalkyl,
wherein each CH 2 , alkyl, cycloalkyl and cycloheteroalkyl is unsubstituted or substituted with one, two, three or four substituents selected from: —C 1-6 alkyl and halogen;
each n is 1;
each m is 1;
each p is independently selected from: 0, 1 and 2;
each q is independently selected from: 0, 1 and 2;
each r is independently selected from: 1, 2, 3 and 4;
each s is independently selected from: 0, 1, 2 and 3;
each t is independently selected from: 0, 1, 2, 3 and 4;
each u is independently selected from: 0, 1, 2 and 3;
each v is independently selected from: 0, 1, 2, 3 and 4;
each w is independently selected from: 0, 1, 2 and 3; and
each x is independently selected from: 0, 1 and 2.
3. The compound according to claim 1 wherein Y is selected from: —O—, —CH 2 —O—, and —O—CH 2 — wherein CH 2 is unsubstituted or substituted with one or two substituents selected from C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 wherein Y is selected from: —O— and —CH 2 —O—, wherein CH 2 is unsubstituted or substituted with one or two substituents selected from C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 wherein R 3 is hydrogen; or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 wherein
T, U, V and W are CH;
A is selected from the group consisting of:
(1) —C 3-6 cycloalkyl,
(2) —C 3-6 cycloalkenyl, and
(3) —C 2-10 cycloheteroalkyl,
wherein each cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from R a ;
Y is selected from: —O—, —(CH 2 ) x O— and —O—(CH 2 ) x , wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R i ;
R 3 is hydrogen;
or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 wherein
T, U, V and W are CH;
A is selected from the group consisting of:
(1) —C 3-6 cycloalkyl,
(2) —C 3-6 cycloalkenyl, and
(3) —C 2-10 cycloheteroalkyl,
wherein each cycloalkyl, cycloalkenyl and cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from R a ;
B is selected from the group consisting of:
(1) —(CH 2 ) u -aryl,
(2) —(CH 2 ) u -heteroaryl,
(3) —(CH 2 ) u —NR g (CH 2 ) u -aryl, and
(4) —(CH 2 ) u —O—(CH 2 ) u -aryl,
wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one, two, three, four or five substituents selected from R b ;
Y is —(CH 2 ) x O—, wherein CH 2 is unsubstituted or substituted with one or two substituents selected from R i ;
R 3 is hydrogen;
or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 wherein
T, U, V and W are CH;
A is —C 2-10 cycloheteroalkyl, wherein each cycloheteroalkyl is unsubstituted or substituted with one, two or three substituents selected from R a ;
B is selected from the group consisting of:
(1) —(CH 2 ) u -aryl, and
(2) -heteroaryl,
wherein each CH 2 , aryl and heteroaryl is unsubstituted or substituted with one, two, three, four or five substituents selected from R b ;
Y is selected from: —O— and —CH 2 —O—, wherein CH 2 is unsubstituted or substituted with one or two substituents selected from C 1-6 alkyl;
Z is —CO 2 H;
R 1 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one, two or three halogens;
R 2 is —C 3-6 cycloalkyl, wherein cycloalkyl is unsubstituted or substituted with one, two or three substituents selected from halogen, OH, —C 1-6 alkyl and —OC 1-6 alkyl;
R 3 is hydrogen;
or a pharmaceutically acceptable salt thereof.
9. A compound selected from:
and pharmaceutically acceptable salts thereof.
10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
11. A method of treating type 2 diabetes mellitus in a patient in need of treatment comprising the administration to the patient of a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.