GLP-1 receptor modulators

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

wherein

A is a 5-, 6- or 7-membered heteroaryl having one, two or three heteroatoms where each such heteroatom is independently selected from O, N, and S, and where any ring atom of such heteroaryl may be optionally substituted with one or more of R 4 ;

B is heterocyclyl or heterocyclylalkyl;

C is aryl or arylalkyl;

Y 1 and Y 2 are both null;

Z is —C(O)—;

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

R 2 is —O—R 8 , —N(R 1 )—SO 2 —R 8 , —NR 41 R 42 , —N(R 1 )—(CR a R b ) m —COOH, —N(R 1 )—(CR a R b ) m —CO—N(R 1 )-heterocyclyl, —N(R 1 )—(CR a R b ) m —CO—N(R 1 )(R 7 ), or —N(R 1 )-heterocyclyl, wherein R 2 is not —OH or —NH 2 ;

each R 3 and R 4 is independently H, halo, alkyl, alkyl substituted with R 31 , alkoxy, haloalkyl, perhaloalkyl, haloalkoxy, perhaloalkoxy, aryl, heterocyclyl, —OH, —OR 8 , —CN, —NO 2 , —NR 1 R 8 , —C(O)R 8 , —C(O)NR 1 R 8 , —NR 1 C(O)R 8 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —OS(O) 2 R 8 , —S(O) 2 NR 1 R 8 , —NR 1 S(O) 2 R 8 , —(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 or —(CR a R b ) m NR 1 (CR a R b ) m COOH; 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 or alkyl;

each R 41 and R 42 is independently R 40 or —(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 heterocyclyl;

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—, —N(R 1 )—C(O)—N(R 1 )—, —N(R 1 )—C(O)—O—, —(O)— or —S(O 2 )—NR 1 —;

each R a and R b is independently H, alkyl, alkoxy, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, any of which alkyl, alkoxy, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl may be optionally (singly or multiply) substituted with R 7 , or —(CH 2 ) m C(O)OR 40 , —(CH 2 ) m OR 40 , —(CH 2 ) m SR 40 , —(CH 2 ) m NR 41 R 42 , —(CH 2 ) m C(O)NR 41 R 42 ; or any two R a and R b taken together with the carbon to which they are attached form a cycloalkyl or heterocyclyl; or R 1 and any one of R a or R b taken together form heterocyclyl;

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 ;

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, haloalkyl, perhaloalkyl, alkoxy, —OH, —OR 8 , —CN, —NR 1 R 8 , —(CR a R b ) m O(CR a R b ) m R 8 , —NR 1 (CR a R b ) m R 8 , —C(O)R 8 , —NR 1 (CR a R b ) m COOH, —NR 1 C(O)R 8 , —C(O)NR 1 R 8 , —SR 8 , —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, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, where such ring moiety is optionally singly or multiply substituted with halo, —OH, —CN, alkyl, alkoxy, haloalkyl or perhaloalkyl;

each R 8 is independently H, alkyl, cycloalkyl or aryl;

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 )—;

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 A is a 5- or 6-membered heteroaryl group.

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

4. The compound of claim 1 wherein C is aryl.

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

6. The compound of claim 1 wherein B is heterocyclyl.

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

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

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

10. The pharmaceutical combination of claim 9 wherein the second medicament is an agonist or modulator for glucagon receptor, GIP receptor, GLP-2 receptor, or PTH receptor, or glucagon-like peptide 1 (GLP-1) receptor.

11. The pharmaceutical combination of claim 9 wherein the second medicament is exenatide, liraglutide, taspoglutide, albiglutide, or lixisenatide.

12. The pharmaceutical combination of claim 9 wherein the second medicament is a DPPIV inhibitor.