GLP-1 receptor stabilizers and modulators

1. A method of activation or agonism of a glucagon-like peptide 1 (GLP-1) receptor comprising contacting the receptor with an effective amount of 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 —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 )—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, —(O)—, —OC(O)—, —NR 1 —, —NR 1 —CH 2 —, —C(O)NR 1 —, —N(R 1 )—C(O)—, or —N(R 1 )—S(O 2 )—,

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 substitutued 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 R 7 , —(CH 2 ) m -L 2 -(CH 2 ) m —R 7 , or -(-L 3 -(CR a R b ) r —) s -L 3 -R 7 .

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. A method of activation or agonism of a glucagon-like peptide 1 (GLP-1) receptor in a subject in need thereof, said method comprising administering to the subject 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 —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, —(O)—, —OC(O)—, —NR 1 —, —NR 1 —CH 2 —, —C(O)NR 1 —, —N(R 1 )—C(O)—, or —N(R 1 )—S(O 2 )—;

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 substitutued 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 R 7 , —(CH 2 ) m -L 2 -(CH 2 ) m —R 7 , or -(-L 3 -(CR a R b ) r —) s -L 3 -R 7 ;

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.

3. The method of claim 2 wherein subject is a human being.

4. A method of treatment of a malcondition, selected from the group consisting of type I diabetes, type II diabetes, gestational diabetes, obesity, excessive appetite, insufficient satiety, and metabolic disorder, in a subject for which activation or agonism of a glucagon-like peptide 1 (GLP-1) receptor is medically indicated, comprising administering an effective amount of a compound having the structure of Formula I-R or I-S or a pharmaceutically acceptable isomer, enantiomer, racemate, or salt thereof to the subject at a frequency and for a duration of time sufficient to provide a beneficial effect to the subject:

wherein

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

R 2 is —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 —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, —(O)—, —OC(O)—, —NR 1 —, —NR 1 —CH 2 —, —C(O)NR 1 —, —N(R 1 )—C(O)—, or —N(R 1 )—S(O 2 )—,

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 substitutued 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 R 7 , —(CH 2 ) m -L 2 -(CH 2 ) m —R 7 , or -(-L 3 -(CR a R b ) r —) s -L 3 -R 7 ;

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.

5. The method of claim 4 , wherein the malcondition is selected from type II diabetes, obesity and metabolic disorder.

6. The method of claim 4 any of claims 4 wherein the method additionally comprises administering to the subject a second medicament selected from the group of peptidic GLP-1 agonists and DPP-4 inhibitors.

7. The method of claim 6 wherein the second medicament is exenatide or sitagliptin.

8. The method of claim 4 wherein the compound has the structure of Formula I-R or a pharmaceutically acceptable isomer, enantiomer, racemate, or salt thereof

9. The method of claim 4 wherein the compound has the structure of Formula I-S or a pharmaceutically acceptable isomer, enantiomer, racemate, or salt thereof.

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

11. The method of claim 10 wherein W i is -L 1 -(CR a R b;) m -L 1 -R 6 .

12. The method of claim 10 wherein W 1 is -L 1 -(CR a R b ) m —R 6 .

13. The method of claim 10 wherein one of L 1 is —O—.

14. The method of claim 10 wherein one of L 1 is —C(O)O—.

15. The method of claim 10 wherein one of L 1 is —S(O 2 )—.

16. The method of claim 10 wherein one of L 1 is —S—.

17. The method of claim 10 wherein one of L 1 is —N(R 1 ).

18. The method of claim 10 wherein one of L 1 is —N(R 1 )—C(O)—N(R 1 )—.

19. The method of claim 10 wherein one of L 1 is —N(R 1 )—C(O)—.

20. The method of claim 10 wherein one of L 1 is —S(O 2 )—N(R 1 )—.

21. The method of claim 10 wherein R 1 is H.

22. The method of claim 10 wherein one of L 1 is —O—.

23. The method of claim 10 wherein both R a and R b are H.

24. The method of claim 10 wherein one of R a and R b is methyl.

25. The method of claim 10 wherein one of R a and R b is methoxy.

26. The method of claim 10 wherein at least one instance R a and R b taken together with the carbon to which they are attached form a cycloalkyl.

27. The method of claim 10 wherein R 6 is alkyl substituted with R 7 and R 7 is phenyl.

28. The method of claim 10 wherein W 1 is —NHC(O)—(CH 2 ) m -L 1 -R 6 .

29. The method of claim 28 wherein R 6 is H or alkyl.

30. The method of claim 28 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.

31. The method of claim 30 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-α]pyridinyl, imidazolyl, benzo[d]isoxazolyl, and R 6 may be optionally singly or mulitply substituted with methyl, methoxy, chloro or fluoro.

32. The method of claim 10 wherein m is 0, 1 or 2.

33. The method of claim 10 wherein W 1 is attached in the para position.

34. The method of claim 10 wherein W 1 is null.

35. The method of claim 34 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 .

36. The method of claim 35 wherein each R 3 is independently H, t-butyl, or methoxy.

37. The method of claim 34 wherein p is 1.

38. The method of claim 10 wherein R 1 is H.

39. The method of claim 10 wherein R 4 is H.

40. The method of claim 10 wherein R 4 is alkoxy.

41. The method of claim 40 wherein R 4 is methoxy.

42. The method of claim 10 wherein A is —OC(O)—, —N(R 1 )—S(O 2 )—, —O—, or —N(R 1 )—C(O)—.

43. The method of claim 42 wherein A is —OC(O)—.

44. The method of claim 43 wherein A is in the para position.

45. The method of claim 10 wherein p is 1.

46. The method of claim 10 wherein R 5 is alkoxy.

47. The method of claim 46 wherein R 5 is heptoxy.

48. The method of claim 10 wherein n is 1.