GLP-1 receptor stabilizers and modulators

1. A compound having the structure of Formula I-R or I-S or a pharmaceutically acceptable isomer, enantiomer, racemate, or salt thereof:

wherein

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

R 2 is —OH, —O—R 8 , —N(R 1 )—SO 2 —R 8 , —N(R 1 )—(CR a R b ) m —COOH, or —N(R 1 )-tetrazolyl;

each R 3 and R 4 is independently H, alkyl, alkoxy, halo, —NO 2 , —CN, perhaloalkyl, perhaloalkoxy, haloalkyl, alkyl substituted with R 31 , —OR 40 , —NR 41 R 42 ;

each R 40 is independently H or alkyl;

each R 41 and R 42 is independently H or alkyl, —(CH 2 ) n —COO—R 40 , —C(O)—R 40 , aryl, heteroaryl, or two taken together with the N atom to which they are attached can form a 3- to 7-membered heterocyclic ring;

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

each A is independently, from the proximal to distal end of the structure of Formula I-R or I-S, —OC(O)—;

W 1 is null or -L 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, A, —C(O)O—, —S(O 2 )—, —S—, —N(R 1 )—C(O)—N(R 1 )—, —N(R 1 )—C(O)—O—, —C(O)— or —S(O 2 )—NR 1 —;

each R a and R b is independently H, alkyl, alkoxy, aralkyl, or two taken together with the carbon to which they are attached form a cycloalkyl;

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

R 7 is H, halo, alkyl, alkoxy, —OH, —CN, —S(O)—R 8 , —S(O) 2 —R 8 , —S(O) 2 —NR 1 R 8 , —NR 1 —S(O) 2 —R 8 , or a ring moiety selected from cycloalkyl, phenyl, aryl, heteroaryl, heterocyclyl, or heterocycloalkyl, where such ring moiety may be optionally singly or multiply substituted with halo, alkyl, alkoxy, perhaloalkyl, perhaloalkoxy, haloalkyl, hydroxy, cyano, —S(O)—R 8 , —S(O) 2 —R 8 , —S(O) 2 —NR 1 R 8 , or —NR 1 —S(O) 2 —R 8 ;

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 )—, —C(O)— or —S(O 2 )—N(R 1 )—;

R 5 is straight chain or branched ethyloxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy or octyloxy;

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

each R 8 is independently H, C 1-7 alkyl, cycloalkyl or aryl;

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

each n is independently 0 or 1;

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 compound of claim 1 wherein the compound has the structure of Formula I-R or a pharmaceutically acceptable salt, hydrate or solvate thereof.

3. The compound of claim 1 wherein the compound has the structure of Formula I-S or a pharmaceutically acceptable salt, hydrate or solvate thereof.

4. The compound of claim 1 wherein the compound is substantially enantiomerically pure.

5. The compound of claim 1 wherein W 1 is -L 1 -(CR a R b ) m -L 1 -R 6 .

6. The compound of claim 5 wherein W 1 is -L 1 -(CR a R b ) m —R 6 .

7. The compound of claim 6 wherein one of L 1 is —O—.

8. The compound of claim 6 wherein one of L 1 is —C(O)O—.

9. The compound of claim 6 wherein one of L 1 is —S(O 2 )—.

10. The compound of claim 6 wherein one of L 1 is —S—.

11. The compound of claim 6 wherein one of L 1 is —N(R 1 ).

12. The compound of claim 6 wherein one of L 1 is —N(R 1 )—C(O)—N(R 1 )—.

13. The compound of claim 6 wherein one of L 1 is —N(R 1 )—C(O)—.

14. The compound of claim 6 wherein one of L 1 is —S(O 2 )—N(R 1 )—.

15. The compound of claim 1 wherein R 1 is H.

16. The compound of claim 1 wherein one of L 1 is —O—.

17. The compound of claim 6 wherein both R a and R b are H.

18. The compound of claim 6 wherein one of R a and R b is methyl.

19. The compound claim 6 wherein one of R a and R b is methoxy.

20. The compound of claim 6 wherein in at least one instance R a and R b taken together with the carbon to which they are attached form a cycloalkyl.

21. The compound of claim 1 wherein R 6 is alkyl substituted with R 7 and R 7 is phenyl.

22. The compound of claim 5 wherein W 1 is —NHC(O)—(CH 2 ) m -L 1 -R 6 .

23. The compound of claim 22 wherein R 6 is H or alkyl.

24. The compound of claim 22 wherein R 6 is cycloalkyl, aryl, heteroaryl, or heterocycloalkyl, and any of which may be optionally singly or multiply substituted with alkyl, alkoxy or halo.

25. The compound of claim 24 wherein R 6 is cyclopentyl, cyclohexyl, phenyl, pyridinyl, naphthyl, furyl, thiophenyl, benzo[b]furanyl, oxazolyl, isoxazolyl, benzothiazolyl, tetrahydro-2H-pyranyl, pyrazolyl, benzo[b]thiophenyl, quinoxalinyl, quinolinyl, thiazolyl, pyrolidinyl, pyrrolyl, pyrazolo[1,5-c]pyridinyl, imidazolyl, benzo[d]isoxazolyl, and R 6 may be optionally singly or multiply substituted with methyl, methoxy, chloro or fluoro.

26. The compound of claim 1 wherein m is 0, 1 or 2.

27. The compound of claim 1 wherein W 1 is attached in the para position.

28. The compound of claim 1 wherein W 1 is null.

29. The compound of claim 28 wherein each R 3 is independently H, methyl, ethyl, t-butyl, methoxy, isopropoxy, ethoxy, chloro, fluoro, —CF 3 , —OCF 3 , —OCF 2 H, —CN, or —NO 2 .

30. The compound of claim 29 wherein each R 3 is independently H, t-butyl, or methoxy.

31. The compound of claim 29 wherein p is 1.

32. The compound of claim 1 wherein R 1 is H.

33. The compound of claim 1 wherein R 2 is —OH.

34. The compound of claim 1 wherein R 4 is H.

35. The compound of claim 1 wherein R 4 is alkoxy.

36. The compound of claim 35 wherein R 4 is methoxy.

37. The compound of claim 1 wherein p is 1.

38. The compound of claim 1 wherein R 5 is n-heptyloxy.

39. The compound of claim 1 wherein n is 1.

40. Currently Amended) The compound of claim 1 wherein the compound is selected from any of the following compounds:

or a pharmaceutically acceptable isomer, enantiomer, racemate, or salt thereof.

41. The compound of claim 1 wherein the compound is selected from any of the following compounds:

or a pharmaceutically acceptable isomer, enantiomer, racemate, or salt thereof.

42. A pharmaceutical composition comprising a compound of claim 1 together with at least one pharmaceutically acceptable carrier, diluent or excipient.

43. A pharmaceutical combination comprising the compound of claim 1 and a second medicament.

44. A pharmaceutical combination of claim 43 wherein such second medicament is a peptidic GLP-1 agonist or a DPP-4 inhibitor.