Glucagon receptor modulators

摘要

The present invention provides a compound of Formula (I);
or a pharmaceutically acceptable salt thereof wherein R1, R2, R3, A1, A2, A3, A4, L, B1, B2, B3 and B4 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.

主权项

1. A compound of Formula Ior a pharmaceutically acceptable salt thereof, wherein
R1 is phenyl substituted with halo or trifluoromethyl;or a 6-membered heteroaryl group which is optionally fused with a (C4-C7)cycloalkyl, phenyl or 5 to 6 membered heteroaryl, and wherein the optionally fused 6-membered heteroaryl group is optionally substituted with one to four substituents each independently selected from halo, —S(O)2—(C1-3)alkyl, hydroxy, —C(O)NRaRb, cyano, (C1-C6)alkyl optionally substituted with one to three fluoro, or (C1-C6)alkoxy optionally substituted with one to three fluoro;
Ra and Rb are each independently H or (C1-C3)alkyl; R2 is H; R3 is —(CH2)2CO2H; A1, A2, A3 and A4 are each independently CR4 or N, with the proviso that one of A1, A2, A3 and A4 is N and the remaining are CR4; R4 at each occurrence is independently H, halo, cyano, (C1-C3)alkyl optionally substituted with one to three fluoro, or (C1-C3)alkoxy optionally substituted with one to three fluoro; L is —CH(R5)—X—; X is NH; R5 is (C1-C6)alkyl which is optionally substituted with one to three fluoro, hydroxy or methoxy; (C3-C7)cycloalkyl which is optionally substituted with one to two (C1-C3)alkyl which are optionally substituted with one to three fluoro or one to two (C1-C3)alkyl and wherein one to two carbons of the (C3-C7)cycloalkyl can be replaced with a NH, N(C1-C3)alkyl, O or S; or (C3-C7)cycloalkyl-(C1-C6)alkyl wherein the (C3-C7)cycloalkyl group of said (C3-C7)cycloalkyl-(C1-C6)alkyl is optionally substituted with one to two (C1-C3)alkyl which are optionally substituted with one to three fluoro; B1, B2, B3 and B4 are each independently CR6 or N, with the proviso that one of B1, B2, B3 and B4 is N and the remaining are CR6; and R6 at each occurrence is independently H, halo, (C1-C3)alkyl optionally substituted with one to three fluoro, or (C1-C3)alkoxy optionally substituted with one to three fluoro.