Glucagon receptor modulators

1. A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein

R 1 is a 5 membered heteroaryl group attached through either a carbon or nitrogen atom and which is optionally fused to a (C 4 -C 7 )cycloalkyl, phenyl or 6 membered heteroaryl; wherein the optionally fused 5 membered heteroaryl is optionally substituted with one to four substituents each independently selected from halo, —S(O) 2 —(C 1 -C 3 )alkyl, —S—(C 1 -C 3 )alkyl, hydroxy, —C(O)NR a R b , (C 3 -C 5 )cycloalkyl, cyano, phenyl which is optionally substituted with one to three halo, cyano, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy, 6 membered heteroaryl which is optionally substituted with one to three halo, cyano, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy, (C 1 -C 6 )alkyl optionally substituted with one to three fluoro, or (C 1 -C 6 )alkoxy optionally substituted with one to three fluoro;

R a and R b are each independently H or (C 1 -C 3 )alkyl;

R 2 is H or methyl;

R 3 is tetrazolyl, —CH 2 -tetrazolyl, —(CH 2 ) 2 SO 3 H or —(CH 2 ) 2 CO 2 H, —CH 2 CHFCO 2 H or —CH 2 CHOHCO 2 H;

A 1 , A 2 , A 3 and A 4 are each independently CR 4 or N, with the proviso that no more than two of A 1 , A 2 , A 3 and A 4 are N;

R 4 at each occurrence is independently H, 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;

L is —X—CH(R 5 )— or —CH(R 5 )—X—;

X is CH 2 , 0 or NH;

R 5 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 (C 1 -C 3 )alkyl which are optionally substituted with one to three fluoro and wherein one to two carbons of the (C 3 -C 7 )cycloalkyl can be replaced with a NH, N(C 1 -C 3 )alkyl, O or S; 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 optionally substituted with one to three fluoro;

B 1 , B 2 , B 3 and B 4 are each independently CR 6 or N, with the proviso that no more than two of B 1 , B 2 , B 3 and B 4 are N; and

R 6 at each occurrence is independently H, halo, (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.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein L is —X—CH(R 5 )—; R 1 is a 5 membered heteroaryl attached through a nitrogen atom to the carbon between A 1 and A 4 of the ring containing A 1 , A 2 , A 3 and A 4 ;

R 2 is hydrogen; and R 3 is —(CH 2 ) 2 CO 2 H.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein X is O.

4. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein X is NH.

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof wherein A 1 and A 4 are each N and A 2 and A 3 are each CR 4 ; R 4 at each B 2 , occurrence is independently H or methyl; B 1 , B 2 , B 3 and B 4 are each CR 6 ; and R 6 at each occurrence is H.

6. The compound of claim 4 or a pharmaceutically acceptable salt thereof wherein A 4 is N and A 1 , A 2 and A 3 are each CR 4 ; R 4 at each occurrence is independently H or methyl; B 1 , B 2 , B 3 and B 4 are each CR 6 ; and R 6 at each occurrence is independently H or methyl.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof wherein R 5 is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.

8. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein R 5 is ethyl, propyl, isopropyl, isobutyl, neopentyl, cyclopropyl, cyclobutyl, dimethylcycobutyl, cyclopentyl or cyclopropylmethyl.

9. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R 1 is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro.

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R 1 is imidazolyl, pyrazolyl, triazolyl or indazolyl optionally substituted with one to two substituents each independently selected from methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, t-butyl, methoxy, ethoxy, cyano, chloro or fluoro.

11. The compound of claim 7 or a pharmaceutically acceptable salt thereof wherein R 1 is 4-trifluoromethylpyrazol-1-yl.

12. The compound of claim 8 or a pharmaceutically acceptable salt thereof wherein R 1 is 4-trifluoromethylpyrazol-1-yl or 4-tert-butylpyrazol-1-yl.

13. 3-(4-((3,3-dimethylcyclobutyl)(2-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyrimidin-5-yloxy)methyl)benzamido)propanoic acid, Isomer 1, or a pharmaceutically acceptable salt thereof.

14. 3-(4-(1-(6-(4-tert-butyl-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoic acid, Isomer 2, or a pharmaceutically acceptable salt thereof.

15. 3-(4-(cyclopentyl(6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine-3-ylamino)methyl)benzamido)propanoic acid, Isomer 1, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising (i) a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and (ii) a pharmaceutically acceptable excipient, diluent, or carrier.

17. A method for treating or delaying the progression or onset of Type 2 diabetes in a human comprising the step of administering to the human in need of such treatment a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. A method for treating or delaying the progression or onset of Type 2 diabetes in a human comprising the step of administering to the human in need of such treatment the pharmaceutical composition of claim 16 .