GLP-1 receptor modulators

1. A method for treating a condition for which increasing fatty acid oxidation, decreasing lipogenesis, and/or improving hepatic glucose metabolism provides a beneficial effect to 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 the beneficial effect, the compound having the structure of Formula I-R or I-S:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof wherein

A is pyrimidinyl, pyridinyl, pyridazinyl or pyrazinyl, each of which may be optionally substituted with one or more of R 4 ;

B is phenyl or heterocycle;

C is a nonaromatic carbocyclyl or nonaromatic carbocyclylalkyl;

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 , —(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;

R 5 is R 7 , —(CR a R b ) m —(CR a R b ) m —R 7 , or -(-L 3 -(CR a R b ) r -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 heterocyclylalkyl, wherein such ring moiety is optionally singly or multiply substituted with R 10 ;

each R 8 is independently H, alkyl, haloalkyl, 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 ;

each R 10 is independently H, halo, alkyl, haloalkyl, haloalkoxy, perhaloalkyl, perhaloalkoxy, —(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 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 ;

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 atoms to which they are attached form heterocyclyl optionally substituted (singly or multiply) with R 7 ;

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 , the compound having one of the following structures:

3. The method of claim 1 , the compound having one of the following structures:

4. The method of claim 1 , the compound having one of the following structures:

5. The method of claim 1 wherein B is pyrimidinyl, pyrazolyl, pyridinyl or indolyl.

6. The method of claim 1 wherein C is nonaromatic carbocyclyl.

7. The method of claim 6 wherein nonaromatic carbocyclyl is cycloalklyl.

8. The method of claim 6 wherein nonaromatic carbocyclyl is cycloalkenyl.

9. The method of claim 6 wherein C is:

10. The method of claim 1 , the compound having one of the following structures:

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

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

13. The method of claim 10 wherein q is one.

14. The method of claim 13 wherein R 5 is alkyl.

15. The method of claim 13 wherein p is one.

16. The method of claim 15 wherein R 3 is alkyl.

17. The method of claim 16 wherein alkyl is a straight or branched alkyl.

18. The method of claim 16 wherein alkyl is cycloalky.

19. The method of claim 1 , the compound having one of the following structures:

20. The method of claim 1 , the compound having one of the following structures:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

21. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

22. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

23. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

24. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

25. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

26. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

27. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

28. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

29. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

30. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

31. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

32. The method of claim 1 , the compound having the following structure:

or a pharmaceutically acceptable enantiomer, diastereomer, racemate, salt, hydrate or solvate thereof.

33. The method of any one of claims 1 or 20 - 32 , wherein the condition is non-alcoholic fatty liver disease (NAFLD).

34. The method of any one of claims 1 or 20 - 32 , wherein the condition is non-alcoholic steatohepatitis (NASH).