GLP-1 receptor modulators

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

wherein

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

B is aryl, aralkyl, heterocyclyl, or heterocyclylalkyl;

C is aryl, aralkyl, heterocyclyl or heterocyclylalkyl, and when C is phenyl and Y 2 is null then A and C may be taken together to form a fused bicyclic ring system between the pyridine of A and the phenyl of C;

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 NR 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 -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, —C(O)O—, —S(O 2 )—, —S(O)—, —S—, —N(R 1 )—C(O)—N(R 1 )—, —(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 compound of claim 1 , wherein the compound has the structure of any one of the following compounds or a pharmaceutically acceptable diastereomer, enantiomer, racemate, salt, hydrate or solvate thereof:

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

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

5. A method of treating type II diabetes, comprising administering an effective amount of the compound of claim 1 to a patient at a frequency and for a duration of time sufficient to provide a beneficial effect to the patient.

6. The compound of claim 1 having the following structure:

7. The compound of claim 1 having the following structure:

8. The compound of claim 1 having the following structure:

9. The compound of claim 8 wherein B is aryl.

10. The compound of claim 8 wherein B is phenyl.

11. The compound of claim 8 wherein B is heteroaryl.

12. The compound of claim 8 wherein B is thiophenyl.

13. The compound of claim 8 wherein R 2 is —OH.

14. The compound of claim 8 wherein R 2 is —N(R 1 )(CR a R b ) m COOR 8 .

15. The compound of claim 8 wherein R 2 is —N(R 1 )SO 2 R 7 .

16. The compound of claim 8 wherein R 2 is —NHCH 2 COOH.

17. The compound of claim 8 wherein R 2 is —NH(CHR b )COOH where R b is alkyl optionally substituted with R 7 , —(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 .

18. The compound of claim 8 wherein R 2 is —NH(CR a R b ) m COOH where R a and R b are independently H, alkyl optionally substituted with R 7 , —(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 .

19. The compound of claim 8 wherein R 2 is —NR 1 (CHR b ) m COOH where R 1 and R b taken together form heterocyclyl.

20. The compound of claim 8 wherein R 2 is —NR 1 (CR a R b )—COOH where R 1 and one of R b taken together form heterocyclyl.

21. The compound of claim 8 wherein any two R a and R b taken together with the carbon to which they are attached form a cycloalkyl.

22. The compound of claim 8 wherein R 2 is —NH(CR a R b ) m COOH where one of R a and R b is H and the other R a and R b is aryl substituted with R 7 .

23. The compound of claim 8 wherein p is 1 or 2 and each R 3 is independently alkyl, alkoxy, —OH, perhaloalkyl or —C(O)R 8 .

24. The compound of claim 8 wherein p is 1 and each R 3 is alkyl.

25. The compound of claim 8 wherein q is 1 and R 5 is —(CR a R b ) m -L 2 -(CR a R b ) m —R 7 , and in more specific embodiments where q is 1 and R 5 is —(CH 2 ) m -L 2 -(CH 2 ) m —R 7 .

26. The compound of claim 8 wherein q is 1 and R 5 is alkoxy.