GLP-1 receptor modulators

1. A method of treating type II diabetes in a patient, comprising administering an effective amount of a compound to the patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient, wherein the compound has the structure of Formula I-R or I-S or a pharmaceutically acceptable isolated optical isomer, enantiomer, racemate, salt, hydrate or solvate thereof:

wherein

A is pyrimidine optionally substituted with one or more of R 4 ;

B is aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;

C is aryl, aralkyl, heterocyclyl or heterocyclylalkyl;

Y 1 and Y 2 are both null, or one of Y 1 or Y 2 is —NH— or —O— and the other Y 1 or Y 2 is null;

Z is —C(O)— or —S(O) 2 —;

each R 1 is independently H or C 1-4 alkyl;

R 2 is —OH, —O—R 8 , —N(R 1 )—SO 2 —R 7 , —NR 41 R 42 , —N(R 1 )—(CR a R b ) m —COOR 8 , —N(R 1 )—(CR a R b ) m —CO—N(R 1 )(R 40 ), —N(R 1 )—(CR a R b ) m —N(R 1 )C(O)O(R 8 ), —N(R 1 )—(CR a R b ) m —N(R 1 )(R 40 ), —N(R 1 )—(CR a R b ) m —CO—N(R 1 )— heterocyclyl, or —N(R 1 )—(CR a R b ) m -heterocyclyl, which heterocyclyl may be optionally (singly or multiply) substituted with R 7 ;

each R 3 and R 4 is independently H, halo, alkyl, alkyl substituted (singly or multiply) with R 31 , alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, —OH, —OR 7 , —CN, —NO 2 , —NR 1 R 7 , —C(O)R 7 , —C(O)NR 1 R 7 , —NR 1 C(O)R 7 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —OS(O) 2 R 7 , —S(O) 2 NR 1 R 7 , —NR 1 S(O) 2 R 7 , —(CR a R b ) m NR 1 R 7 , —(CR a R b ) m O(CR a R b ) m R 7 , —(CR a R b ) m NR 1 (CR a R b ) m R 7 or —(CR a R b ) m NR 1 (CR a R b ) m COOR 8 ; or any two R 3 or R 4 groups on the same carbon atom taken together form oxo;

each R 31 is independently H, halo, hydroxyl, —NR 41 R 42 , or alkoxy;

each R 40 is independently H, R 7 , alkyl which may be optionally (singly or multiply) substituted with R 7 , or R 40 and R 1 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl which may be optionally (singly or multiply) substituted with R 7 ;

each R 41 and R 42 is independently R 40 , —(CHR 40 ) n —C(O)O—R 40 , —(CHR 40 ) n —C(O)—R 40 , —(CH 2 ) n —N(R 1 )(R 7 ), aryl or heteroaryl any of which aryl or heteroaryl may be optionally (singly or multiply) substituted with R 7 ; or any two R 41 and R 42 taken together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl which may be optionally (singly or multiply) substituted with R 7 ;

W 1 is null or 1 1 -(CR a R b ) m -L 1 -R 6 ;

each L 1 is independently, from the proximal to distal end of the structure of Formula I-R or I-S, null, —C(O)O—, —S(O 2 )—, —S(O)—, —S—, —N(R 1 )—C(O)—N(R 1 )—, C(O)—O—, —C(O)— or —S(O 2 )—NR 1 —;

each R a and R b is independently H, halo, alkyl, alkoxy, aryl, aralkyl, heterocyclyl, heterocyclylalkyl (any of which alkyl, alkoxy, aryl, aralkyl, heterocyclyl or heterocyclylalkyl may be optionally (singly or multiply) substituted with R 7 ), —(CHR 40 ) m C(O)OR 40 , —(CHR 40 ) m OR 40 , —(CHR 40 ) m SR 40 , —(CHR 40 ) m NR 41 R 42 , —(CHR 40 ) m C(O)NR 41 R 42 , —(CHR 40 ) m C(O)N(R 1 )(CHR 40 ) m —NR 41 R 42 , —(CHR 40 ) m C(O)—N(R 1 )(CHR 40 ) m C(O)NR 41 R 42 , —(CHR 40 ) m C(O)N(R 1 )—(CHR 40 ) m C(O)OR 40 , or —(CHR 40 ) m —S—S—R 40 ; or any two R a and R b taken together with the carbon atom(s) to which they are attached form a cycloalkyl or heterocyclyl optionally substituted (singly or multiply) with R 7 ; or R 1 and any one of R a or R b taken together with the atom(s) to which they are attached form heterocyclyl optionally substituted (singly or multiply) with R 7 ;

R 5 is R 7 , —(CR a R b ) m -L 2 -(CR a R b ) m —R 7 , or -(-L 3 -(CR a R b ) r -) s -L 3 -R 7 , wherein the carbon atoms of any two adjacent —(CR a R b ) m or —(CR a R b ) r groups may be taken together to form a double bond (—(C(R a )═(C(R a )—) or triple bond (—C≡C—);

R 6 is H, alkyl, aryl, heteroaryl, heterocyclyl, heterocycloalkyl, any of which may be optionally substituted (singly or multiply) with R 7 or —(CR a R b ) m -L 2 -(CR a R b ) m —R 7 ;

each R 7 is independently R 10 ; a ring moiety selected from cycloalkyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl, where such ring moiety is optionally singly or multiply substituted with R 10 ; or when a carbon atom bears two R 7 groups such two R 7 groups are taken together to form oxo or thioxo, or are taken together to form a ring moiety selected from cycloalkyl, aryl, heterocyclyl or heterocyclyl, wherein such ring moiety is optionally singly or multiply substituted with R 10 ;

each R 10 is independently H, halo, alkyl, haloalkyl, perhaloalkyl, —(CR a R b ) m OH, —(CR a R b ) m OR 8 , —(CR a R b ) m CN, —(CR a R b ) m NH(C═NH)NH 2 , —(CR a R b ) m NR 1 R 8 , —(CR a R b ) m O(CR a R b ) m R 8 , —(CR a R b ) m NR 1 (CR a R b ) m R 8 , —(CR a R b ) m C(O)R 8 , —(CR a R b ) m C(O)OR 8 , —(CR a R b ) m C(O)NR 1 R 8 , —(CR a R b ) m NR 1 (CR a R b ) m C(O)OR 8 , —(CR a R b ) m NR 1 C(O)R 8 , —(CR a R b ) m C(O)NR 1 S(O) 2 R 8 , —(CR a R b ) m SR 8 , —(CR a R b ) m S(O)R 8 , —(CR a R b ) m S(O) 2 R 8 , —(CR a R b ) m S(O) 2 NR 1 R 8 or —(CR a R b ) m NR 1 S(O) 2 R 8 ;

each R 8 is independently H, alkyl, aryl, —(CR a R b ) m -L 2 -(CR a R b ) m —R 1 or -(-L 3 -(CR a R b ) r -) s -L 3 -R 1 ;

L 2 is independently, from the proximal to distal end of the structure of Formula I-R or I-S, null, —O—, —OC(O)—, —NR 1 —, —C(O)NR 1 —, —N(R 1 )—C(O)—, —S(O 2 )—, —S(O)—, —S—, —C(O)— or —S(O 2 )—N(R 1 )—;

each L 3 is independently null, —O—, or —N(R 1 )—

each m is independently 0, 1, 2, 3, 4, 5 or 6;

each n is independently 0 or 1 or 2;

p is 0, 1, 2 or 3;

q is 0, 1, 2 or 3;

each r is independently 2, 3, or 4; and

each s is independently 1, 2, 3, or 4.

2. The method of claim 1 wherein the compound has the following structure:

3. The method of claim 1 wherein the compound has the following structure:

4. The method of claim 2 wherein B is phenyl and the compound has the following structure:

5. The method of claim 3 wherein B is phenyl and the compound has the following structure:

6. The method of claim 2 wherein B is thiophenyl and the compound has following structure:

7. The method of claim 3 wherein B is thiophenyl and the compound has following structure:

8. The method of claim 4 wherein the compound has the following structure:

9. The method of claim 5 wherein the compound has the following structure:

10. The method of claim 6 wherein the compound has the following structure:

11. The method of claim 7 wherein the compound has the following structure:

12. The method of claim 8 wherein the compound has the following structure:

13. The method of claim 10 wherein the compound has the following structure:

14. The method of claim 8 wherein the compound has the following structure:

15. The method of claim 10 wherein the compound has the following structure:

16. The method of claim 8 wherein the compound has the following structure:

17. The method of claim 10 wherein the compound has the following structure:

18. The method of claim 8 wherein the compound has the following structure:

19. The method of claim 10 wherein the compound has the following structure:

20. The method of claim 8 wherein the compound has the following structure:

21. The method of claim 10 wherein the compound has the following structure:

22. The method of claim 18 wherein the compound has the following structure:

23. The method of claim 19 wherein the compound has the following structure:

24. The method of claim 8 wherein the compound has the following structure:

25. The method of claim 10 wherein the compound has the following structure:

26. The method of claim 8 wherein the compound has the following structure:

27. The method of claim 10 wherein the compound has the following structure:

28. The method of claim 8 wherein the compound has the following structure:

29. The method of claim 10 wherein the compound has the following structure:

30. The method of claim 1 wherein the compound has the following structure:

31. The method of claim 1 wherein the compound has the following structure:

32. The method of claim 1 wherein the compound has the following structure:

33. The method of claim 1 wherein the compound has the following structure:

34. The method of claim 1 wherein the compound has the following structure:

35. The method of claim 1 wherein the compound has the following structure:

36. The method of claim 1 wherein the compound has the following structure:

37. The method of claim 1 wherein the compound has the following structure:

38. The method of claim 1 wherein the compound has the following structure:

39. The method of claim 1 wherein the compound has the following structure:

40. The method of claim 1 wherein the compound has the following structure:

41. The method of claim 1 wherein the compound has the following structure:

42. The method of claim 40 wherein the compound has the following structure:

43. The method of claim 41 wherein the compound has the following structure:

44. The method of claim 40 wherein the compound has the following structure:

45. The method of claim 41 wherein the compound has the following structure:

46. The method of claim 40 wherein the compound has the following structure:

47. The method of claim 41 wherein the compound has the following structure:

48. The method of claim 1 wherein the compound has the following structure:

49. The method of claim 1 wherein the compound has the following structure:

50. The method of claim 1 wherein the compound has the following structure:

51. The method of claim 1 wherein the compound has the following structure:

52. The method of claim 1 wherein the compound has the following structure:

53. The method of claim 1 wherein the compound has the following structure:

54. The method of claim 1 wherein the compound has the following structure:

55. The method of claim 1 wherein the compound has the following structure:

56. The method of claim 1 wherein the compound has one of the following structures: