Quinolinyl glucagon receptor modulators
View Patent ↗The present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , A 1 , A 2 , A 3 , B 1 , B 2 , B 3 and B 4 are as defined herein. The compounds of Formula I have been found to act as glucagon antagonists or inverse agonists. Consequently, the compounds of Formula I and the pharmaceutical compositions thereof are useful for the treatment of diseases, disorders, or conditions mediated by glucagon.
1. A compound of Formula Ia′
or a pharmaceutically acceptable salt thereof, wherein
R 1 is (C 1 -C 6 )alkyl which is optionally substituted with one to three fluoro, hydroxy or methoxy; (C 3 -C 7 )cycloalkyl which is optionally substituted with one to two fluoro or one to two (C 1 -C 3 )alkyl which are each optionally substituted with one to three fluoro and wherein one carbon of the (C 3 -C 7 )cycloalkyl can be replaced with an O; or (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl wherein the (C 3 -C 7 )cycloalkyl group of said (C 3 -C 7 )cycloalkyl-(C 1 -C 6 )alkyl is optionally substituted with one to two (C 1 -C 3 )alkyl which are each optionally substituted with one to three fluoro;
R 2 is hydrogen or (C 1 -C 3 )alkyl;
R 3 ′ is —(CH 2 ) 2 CO 2 R, —CH 2 CHFCO 2 R, or —CH 2 CH(OH)CO 2 R;
R is (C 1 -C 4 )alkyl, benzyl, para-methoxybenzyl, or diphenylmethylene;
A 1 and A 2 are each independently CR 4 ;
R 4 at each occurrence is independently hydrogen, halo, cyano, (C 1 -C 3 )alkyl optionally substituted with one to three fluoro, (C 1 -C 3 )alkoxy optionally substituted with one to three fluoro, or (C 3 -C 5 )cycloalkyl;
B 1 , B 2 , B 3 and B 4 are each independently CR 5 ; and
R 5 at each occurrence is independently hydrogen, halo, cyano, (C 1 -C 3 )alkyl optionally substituted with one to three fluoro, or (C 1 -C 3 )alkoxy optionally substituted with one to three fluoro, or (C 3 -C 5 )cycloalkyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 2 is hydrogen;
R 3 ′ is —(CH 2 ) 2 CO 2 R; and
R is methyl, ethyl, or t-butyl.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is ethyl, propyl, isopropyl, isobutyl, t-butyl, pentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclopropylmethyl each optionally substituted with 1 to 3 fluoro and wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are each optionally substituted with 1 to 2 methyl.
4. The compound according to claim 3 , or a pharmaceutically acceptable salt thereof, wherein
R 4 at each occurrence is independently hydrogen, fluoro, chloro, methyl or ethyl; and
R 5 at each occurrence is independently hydrogen, fluoro, chloro, methyl, trifluoromethyl or methoxy.
5. A compound of structure
or a pharmaceutically acceptable salt thereof.
6. A compound of structure
or a pharmaceutically acceptable salt thereof.
7. A compound of structure
or a pharmaceutically acceptable salt thereof.
8. A compound of structure
or a pharmaceutically acceptable salt thereof.