Spiro-imidazolone derivatives as glucagon receptor antagonists

1. A compound, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A):

wherein ring A, ring B, L 1 , L 2 , R 1 , R 3 , and Z are selected independently of each other and wherein:

L 1 is selected from the group consisting of a bond, —N(R 4 )—, —N(R 4 )—(C(R 5A ) 2 )—(C(R 5 ) 2 ) q —, —(C(R 5A ) 2 )—(C(R 5 ) 2 ) r —(C(R 5A ) 2 )—N(R 4 )—, —O—, —O—(C(R 5A ) 2 )—(C(R 5 ) 2 ) q —, —(C(R 5A ) 2 )—(C(R 5 ) 2 ) r —(C(R 5A ) 2 )—O—, and —(C(R 5A ) 2 )—(C(R 5 ) 2 ) s —,

each q is independently an integer from 0 to 5;

each r is independently an integer from 0 to 3;

s is an integer from 0 to 5;

L 2 is selected from the group consisting of

a bond, —N(R 4 )—, —N(R 4 )—(C(R 5A ) 2 )—(C(R 5 ) 2 ) t —, —(C(R 5 ) 2 ) u —(C(R 5A ) 2 )—N(R 4 )—, —O—, —O—(C(R 5A ) 2 )—(C(R 5 ) 2 ) t —, —(C(R 5 ) 2 ) u —(C(R 5A ) 2 )—O—, —S—, —S—(C(R 5A ) 2 )—(C(R 5 ) 2 ) t —, (C(R 5 ) 2 ) u —(C(R 5A ) 2 )—S—, —S(O)—, —S(O)—(C(R 5A ) 2 )—(C(R 5 ) 2 ) t —, —(C(R 5 ) 2 ) u —(C(R 5A ) 2 )—S(O)—, —S(O) 2 —, —S(O) 2 —(C(R 5A ) 2 )—(C(R 5 ) 2 ) t —, —(C(R 5 ) 2 ) u —(C(R 5A ) 2 )—S(O) 2 —, —(C(R 5 ) 2 ) v —;

each t is independently an integer from 0 to 3;

each u is independently an integer from 0 to 3;

v is an integer from 1 to 5;

ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R 2 groups,

or, alternatively, ring A represents a spiroheterocycloalkyl ring or a spiroheterocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R 2 groups, and wherein said ring A is optionally further substituted on one or more available ring nitrogen atoms (when present) with from 0 to 3 R 2A groups;

ring B is a phenyl ring, wherein said phenyl ring is (in addition to the -L 1 - and —C(O)N(R 3 )—Z moieties shown) optionally further substituted with one or more substituents R a , wherein each R a (when present) is independently selected from the group consisting of halo, —OH, —SF 5 , —OSF 5 , alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, and —O-haloalkyl,

or ring B is a 5-membered heteroaromatic ring containing from 1 to 3 ring heteroatoms independently selected from N, O, and S, wherein said 5-membered heteroaromatic ring is (in addition to the -L 1 - and —C(O)N(R 3 )—Z moieties shown) optionally further substituted with one or more substituents R a , wherein each R a (when present) is independently selected from the group consisting of halo, —OH, —SF 5 , —OSF 5 , alkyl, haloalkyl, heteroalkyl, hydroxyalkyl, alkoxy, and —O-haloalkyl,

or ring B is a 6-membered heteroaromatic ring containing from 1 to 3 ring nitrogen atoms, wherein said 6-membered heteroaromatic ring is (in addition to -L 1 - and —C(O)N(R 3 )Z moieties shown) optionally further substituted with one or more substituents R a , wherein each R a (when present) is independently selected from the group consisting of halo, —OH, —SF 5 , —OSF 5 , alkyl, haloalkyl, hydroxyalkyl, alkoxy, and —O-haloalkyl;

R 1 is independently selected from the group consisting of aryl and heteroaryl,

wherein said aryl and said heteroaryl of R 1 are unsubstituted or substituted with one or more groups independently selected from:

(1) halo, —OH, —CO 2 R 6 , —C(O)R 6 , —SR 7 , —S(O)R 7 , —SO 2 R 7 , —SF 5 , —OSF 5 , CN, NO 2 , —C(O)NR 8 R 9 , —NR 8 R 9 , —NR 10 —C(O)—NR 8 R 9 , —NR 10 —CO 2 R 6 , —NR 10 —C(O)R 6 , —NR 10 —SO 2 R 6 , —SO 2 —NR 8 R 9 , —C(O)NR 8 R 9 , and —OC(O)NR 8 R 9 ,

(2) alkyl, alkoxy, heteroalkyl, —O-heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl,

wherein each of said alkyl, alkoxy, heteroalkyl, —O-heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl, are unsubstituted or optionally independently substituted with one or more groups each independently selected from:

halo, OH, —CO 2 R 6 , —C(O)R 6 , —SR 7 , —S(O)R 7 , —SO 2 R 7 , CN, NO 2 , —C(O)NR 8 R 9 , —NR 8 R 9 , —O-haloalkyl, —NR 10 —C(O)—NR 8 R 9 , —NR 10 —CO 2 R 6 , —NR 10 —C(O)R 6 , —NR 10 —SO 2 R 6 , —SO 2 —NR 8 R 9 , —C(O)NR 8 R 9 , and —OC(O)NR 8 R 9 , and

(3) aryl, —O-aryl, —C(O)-aryl, —S-aryl, —S(O)-aryl, —S(O) 2 -aryl, —N(R 4 )-aryl, —C(O)—N(R 4 )-aryl, —N(R 4 )—C(O)-aryl, heteroaryl, —O-heteroaryl, —C(O)-heteroaryl, —S-heteroaryl, —S(O)-heteroaryl, —S(O) 2 -heteroaryl, —N(R 4 )-heteroaryl, —C(O)—N(R 4 )-heteroaryl, —N(R 4 )—C(O)-heteroaryl, cycloalkyl, —O— cycloalkyl, —C(O)-cycloalkyl, —S-cycloalkyl, —S(O)-cycloalkyl, —S(O) 2 -cycloalkyl, —N(R 4 )— cycloalkyl, —C(O)—N(R 4 )-cycloalkyl, —N(R 4 )—C(O)-cycloalkyl, heterocycloalkyl, —O-heterocycloalkyl, —C(O)— heterocycloalkyl, —S-heterocycloalkyl, —S(O)-heterocycloalkyl, —S(O) 2 -heterocycloalkyl, —N(R 4 )-heterocycloalkyl, —C(O)—N(R 4 )-heterocycloalkyl, —N(R 4 )—C(O)-heterocycloalkyl, cycloalkenyl, —O-cycloalkenyl, —C(O)— cycloalkenyl, —S-cycloalkenyl, —S(O)-cycloalkenyl, —S(O) 2 -cycloalkenyl, —N(R 4 )-cycloalkenyl, —C(O)—N(R 4 )-cycloalkenyl, —N(R 4 )—C(O)-cycloalkenyl, heterocycloalkenyl, —O-heterocycloalkenyl, —C(O)-heterocycloalkenyl, —S-heterocycloalkenyl, —S(O)-heterocycloalkenyl, —S(O) 2 -heterocycloalkenyl, —N(R 4 )-heterocycloalkenyl, —C(O)—N(R 4 )-heterocycloalkenyl, and —N(R 4 )—C(O)-heterocycloalkenyl,

each of which is unsubstituted or optionally independently substituted with from 1 to 2 groups each independently selected from (1) and (2) above;

each R 2 (when present) is independently selected from the group consisting of:

(a) phenyl substituted with from 0 to 5 groups independently selected from —OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 —CO 2 R 6 groups, alkoxy, —O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 —CO 2 R 6 groups, —C(O)R 6 , —CO 2 R 6 , CN, —SO 2 R 7 , —SF 5 , —OSF 5 , —C(O)NR 8 R 9 , and —NO 2 ,

(b) alkyl or heteroalkyl, each substituted with from 0 to 5 groups independently selected from —OH, oxo, halo, heteroalkyl, deuteroalkyl, alkoxy, —O-haloalkyl, —CO 2 R 6 , and phenyl substituted with from 0 to 5 groups independently selected from —OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, —O-haloalkyl, haloheteroalkyl, —CO 2 R 6 , CN, —S(O)R 7 , —S(O) 2 R 7 , —SF 5 , —OSF 5 , —C(O)NR 8 R 9 , and —NO 2 ,

(c) —NR 10 —C(O)—NR 8 R 9 , —NR 10 —CO 2 R 6 , —NR 10 —C(O)R 6 , —NR 8 R 9 , —NR 10 SO 2 R 6 , —SO 2 —NR 8 R 9 , —C(O)NR 8 R 9 , and —OC(O)—NR 8 R 9 ;

(d) cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl, each substituted with from 0 to 5 groups independently selected from —OH, oxo, halo, heteroalkyl, alkoxy, —O-haloalkyl, —CO 2 R 6 , and phenyl substituted with from 0 to 5 groups independently selected from —OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, —O-haloalkyl, haloheteroalkyl, —CO 2 R 6 , CN, —S(O)R 7 , —S(O) 2 R 7 , —SF 5 , —OSF 5 , —C(O)NR 8 R 9 , —NR 10 —C(O)R 6 , —SO 2 —NR 8 R 9 , and —NO 2 ,

(e) heteroaryl substituted from 0 to 5 groups independently selected from —OH, oxo, halo, heteroalkyl, alkoxy, —O-haloalkyl, —CO 2 R 6 , and phenyl substituted with from 0 to 5 groups independently selected from —OH, halo, aryl, substituted aryl, alkyl, alkoxy, heteroalkyl, haloalkyl, —O-haloalkyl, haloheteroalkyl, —CO 2 R 6 , CN, —S(O)R 7 , —S(O) 2 R 7 , —C(O)NR 8 R 9 , —NR 10 —C(O)R 6 , —SO 2 —NR 8 R 9 , —SF 5 , —OSF 5 , and —NO 2 , and

(f) —Si(alkyl) 3 ;

or, alternatively, two R 2 groups attached to the same atom of ring A are taken together to form a moiety selected from the group consisting of carbonyl, oxime, substituted oxime (said oxime substituents being independently selected from the group consisting of alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl), spirocycloalkyl, spiroheterocycloalkyl, spirocycloalkenyl, and spiroheterocycloalkenyl;

or, alternatively, two R 2 groups attached to adjacent ring atoms of ring A are taken together to form a 5-6-membered aromatic or heteroaromatic ring;

each R 2A (when present) is independently selected from the group consisting of —C(O)NR 8 R 9 , —CO 2 R 6 , —C(O)R 6 , —SO 2 R 7 , alkyl, heteroalkyl, haloalkyl, hydroxyl-substituted alkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl-, heteroaryl,

R 3 is selected from H and lower alkyl;

Z is a moiety selected from —(C(R 11 ) 2 )—(C(R 12 R 13 )) m —C(O)OH, —(C(R 11 ) 2 )—(C(R 14 ) 2 ) n —C(O)OH, from —(C(R 11 ) 2 )—(C(R 12 R 13 )) m —C(O)Oalkyl, —(C(R 11 ) 2 )—(C(R 14 ) 2 ) n —C(O)Oalkyl,

—(C(R 11 ) 2 )—(C(R 12 R 13 )) m -Q, and —(C(R 11 ) 2 )—(C(R 14 ) 2 ) n -Q,

wherein Q is a moiety selected from the group consisting of:

m is an integer from 0 to 5;

n is an integer from 0 to 5;

p is an integer from 0 to 5;

each R 4 is independently selected from H, —OH, lower alkyl, haloalkyl, alkoxy, heteroalkyl, cyano-substituted lower alkyl, hydroxy-substituted lower alkyl, cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, and heterocycloalkyl, —O-heterocycloalkyl, and —O-alkyl-heterocycloalkyl;

each R 5A is independently selected from H, alkyl, -alkyl-Si(CH 3 ) 3 , haloalkyl, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, cycloalkyl, -alkyl-cycloalkyl, and heterocycloalkyl, -alkyl-heterocycloalkyl,

or, alternatively, two R 5A groups are taken together with the carbon atom to which they are attached to form a carbonyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group, an oxime group, or a substituted oxime group (said oxime substituents being independently selected from alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl);

each R 5 is independently selected from H, —OH, alkyl, -alkyl-Si(CH 3 ) 3 , haloalkyl, alkoxy, heteroalkyl, cyano-substituted alkyl, hydroxy-substituted alkyl, cycloalkyl, -alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl, and heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl, and —O-alkyl-heterocycloalkyl,

or, alternatively, two R 5 groups bound to the same carbon atom are taken together with the carbon atom to which they are attached to form a carbonyl group, a spirocycloalkyl group, a spiroheterocycloalkyl group, an oxime group, or a substituted oxime group (said oxime substituents being independently selected from alkyl, haloalkyl, hydroxyl-substituted alkyl, and cycloalkyl);

each R 6 is independently selected from H, alkyl, haloalkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, and heteroalkynyl;

each R 7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl;

each R 8 is independently selected from H and alkyl;

each R 9 is independently selected from H and alkyl,

or alternatively R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-, 6-, or 7-membered saturated heterocyclic ring, or a 5-, 6-, or 7-membered unsaturated heterocyclic ring, which ring contains (including said nitrogen) from 1 to 2 ring heteroatoms each independently selected from N,N-oxide, 0, S, S(O), or S(O) 2 ,

or alternatively R 8 and R 9 are taken together with the nitrogen to which they are attached to form a 5-membered heteroaromatic ring containing (including the nitrogen to which R 8 and R 9 are attached) from 1 to 3 ring nitrogens;

each R 10 is independently selected from H and alkyl;

each R 11 is independently selected from H and lower alkyl;

each R 12 is independently selected from H, lower alkyl, —OH, hydroxy-substituted lower alkyl;

each R 13 is independently selected from H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from hydroxyl and alkoxy, or R 12 and R 13 are taken together to form an oxo; and

each R 14 is independently selected from H and fluoro.

2. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A-1):

3. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A-1a):

4. A compound of claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (A-1b):

5. A compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown Formula (I):

wherein ring A, L 1 , L 2 , R 1 , R 3 , and Z are selected independently of each other and wherein:

L 1 is selected from the group consisting of: a bond, —N(R 4 )—, —N(R 4 )—(C(R 5A ) 2 )—, —O—, —O—(C(R 5A ) 2 )—, and —(C(R 5A ) 2 )—(C(R 5 ) 2 ) s —;

s is 0-3;

L 2 is selected from the group consisting of bond, —N(R 4 )—, —N(R 4 )—(C(R 5A ) 2 )—, —(C(R 5A ) 2 )—N(R 4 )—, —(C(R 5 ) 2 ) u —(C(R 5A ) 2 )—N(R 4 )—, —O—, —O—(C(R 5A ) 2 )—, —(C(R 5A ) 2 )—O— and —(C(R 5 ) 2 ) v —, wherein u is 0 to 2 and v is 1-3;

R 3 is selected from the group consisting of H and lower alkyl;

Z is a moiety selected from —(C(R 11 ) 2 )—(C(R 12 R 13 )), —C(O)OH, —(C(R 11 ) 2 )—(C(R 14 ) 2 ) n —C(O)OH, and

m is an integer from 0 to 5;

n is an integer from 0 to 5;

p is an integer from 0 to 5;

each R 4 is independently selected from H, lower alkyl, cycloalkyl, heterocycloalkyl, heteroalkyl, and haloalkyl;

each R 5A is independently selected from H, lower alkyl, -lower alkyl-Si(CH 3 ) 3 , lower haloalkyl, and hydroxy-substituted lower alkyl;

each R 5 is independently selected from H, —OH, lower alkyl, -lower alkyl-Si(CH 3 ) 3 , lower haloalkyl, and hydroxy-substituted lower alkyl;

each R 6 is independently selected from H, alkyl, and haloalkyl;

each R 7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl;

each R 8 is independently selected from H and alkyl;

each R 9 is independently selected from H and alkyl,

each R 11 is independently selected from H and lower alkyl;

each R 12 is independently selected from H, lower alkyl, —OH, hydroxy-substituted lower alkyl;

each R 13 is independently selected from H, unsubstituted lower alkyl, lower alkyl substituted with one or more groups each independently selected from hydroxyl and alkoxy, or R 12 and R 13 are taken together to form an oxo; and

each R 14 is independently selected from H and fluoro.

6. A compound of claim 5 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein:

ring A represents a spirocycloalkyl ring or a spirocycloalkenyl ring, wherein said ring A is substituted on one or more available ring carbon atoms with from 0 to 5 independently selected R 2 groups;

R 1 is selected from the group consisting of:

aryl and heteroaryl,

wherein each of said aryl and said heteroaryl are unsubstituted or substituted with from 1 to 3 groups each independently selected from:

(1) halo, —SO 2 R 7 , —SF 5 , —OSF 5 , CN,

(2) alkyl, alkoxy, heteroalkyl, —O-heteroalkyl,

wherein each of said alkyl, alkoxy, heteroalkyl, and —O-heteroalkyl, is unsubstituted or optionally independently substituted with from 1 to 3 groups each independently selected from:

halo, OH, —CO 2 R 6 , —C(O)R 6 , —SR 7 , —S(O)R 7 , —SO 2 R 7 , CN, NO 2 , —C(O)NR 8 R 9 , —NR 8 R 9 , —O-haloalkyl, —NR 10 —C(O)—NR 8 R 9 , —NR 10 —CO 2 R 6 , —NR 10 —C(O)R 6 , —NR 10 —SO 2 R 6 , —SO 2 —NR 8 R 9 , —C(O)NR 8 R 9 , and —OC(O)NR 8 R 9 , and

(3) aryl, —O-aryl, —S-aryl, —S(O)-aryl, —S(O) 2 -aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycloalkenyl,

each of which is unsubstituted or optionally independently substituted with

from 1 to 2 groups each independently selected from (1) and (2) above; and

each R 2 (when present) is independently selected from the group consisting of —Si(CH 3 ) 3 and alkyl, wherein said alkyl is substituted with from 0 to 5 groups independently selected from —OH, oxo, halo, heteroalkyl, alkoxy, —O-haloalkyl, —CO 2 R 6 , and phenyl substituted with from 0 to 5 groups independently selected from —OH, halo, aryl, substituted aryl, alkyl, alkoxy, —O-haloalkyl, heteroalkyl, haloalkyl, haloheteroalkyl, —CO 2 R 6 , CN, —S(O)R 7 , —S(O) 2 R 7 , —SF 5 , —C(O)NR 8 R 9 , and —NO 2 .

7. A compound, or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, having the general structure shown in Formula (II):

wherein L 1 , L 2 , R 1 , each R 2 , R 3 , and Z are selected independently of each other and wherein:

L 1 is selected from the group consisting of: a bond, and —(C(R 5A ) 2 )—(C(R 5 ) 2 ) s —;

s is 0-1;

L 2 is selected from the group consisting of: a bond, —(C(R 5 ) 2 ) u —(C(R 5A ) 2 )—N(R 4 )—, and —(C(R 5 ) 2 ) v —;

u is 0-2;

v is 1-2;

R 1 is selected from the group consisting of:

phenyl,

wherein said phenyl is unsubstituted or substituted with one or more groups each independently selected from:

halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, —O-haloalkyl, and cycloalkyl;

each R 2 is independently selected from the group consisting of —Si(CH 3 ) 3 and alkyl, wherein said alkyl is substituted with from 0 to 5 groups independently selected from —OH, halo, alkyl, haloalkyl, hydroxyalkyl, alkyl substituted with from 1 to 2 —CO 2 R 6 groups, alkoxy, —O-haloalkyl, hydroxyalkoxy, alkoxy substituted with from 1 to 2 —CO 2 R 6 groups, —CO 2 R 6 , CN, —SO 2 R 7 , —C(O)NR 8 R 9 , and —NO 2 ;

R 3 is selected from the group consisting of H and lower alkyl;

Z is a moiety selected from the group consisting of: —(CH 2 )—(CH(CH 3 ))—C(O)OH, —(CH 2 )—(CH 2 )—(CH 2 )—C(O)OH, —(CH 2 )—C(CH 3 ) 2 —C(O)OH, —(CH 2 )—C(CH 3 )(OH)—C(O)OH, —CH 2 —CH 2 —C(O)OH, —CH 2 —CH(OH)—C(O)OH, —CH(CH 3 )—CH 2 —C(O)OH, —C(CH 3 ) 2 —CH 2 —C(O)OH, —CH 2 —CH(F)—C(O)OH, —CH 2 —CF 2 —C(O)OH, —CH(CH 3 )—CF 2 —C(O)OH, —CH 2 —CH 2 —CF 2 —C(O)OH, and

wherein p is an integer from 0 to 1, and R 11 (when present) is selected from the group consisting of H and lower alkyl;

each R 5A is independently selected from H, lower alkyl, -lower alkyl-Si(CH 3 ) 3 , lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl;

each R 5 is independently selected from H, —OH, lower alkyl, -lower alkyl-Si(CH 3 ) 3 , lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl;

each R 6 is independently selected from H, alkyl, and haloalkyl;

each R 7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl;

each R 8 is independently selected from H and alkyl; and

each R 9 is independently selected from H and alkyl.

8. A compound of claim 7 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (II-a):

9. A compound of claim 7 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, said compound having the general structure shown in Formula (II-b):

10. A compound of claim 9 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein:

L 1 is selected from the group consisting of: a bond, straight or branched lower alkyl, and —CH(lower alkyl-Si(CH 3 ) 3 )—;

L 2 is selected from the group consisting of: a bond and straight or branched lower alkyl;

R 1 is selected from the group consisting of:

phenyl,

wherein said phenyl is unsubstituted or substituted with from 1 to 3 groups each independently selected from:

halo, alkyl, haloalkyl, heteroalkyl, haloheteroalkyl, alkoxy, and —O-haloalkyl;

each R 2 is independently selected from the group consisting of H, straight or branched lower alkyl, and —Si(CH 3 ) 3 ;

R 3 is selected from the group consisting of H and lower alkyl;

Z is a moiety selected from the group consisting of: —(CH 2 )—(CH(CH 3 ))—C(O)OH, —(CH 2 )—(CH 2 )—(CH 2 )—C(O)OH, —(CH 2 )—C(CH 3 ) 2 —C(O)OH, —(CH 2 )—C(CH 3 )(OH)—C(O)OH, —CH 2 —CH 2 —C(O)OH, —CH 2 —CH(OH)—C(O)OH, —CH(CH 3 )—CH 2 —C(O)OH, —C(CH 3 ) 2 —CH 2 —C(O)OH, —(C(R 11 ) 2 )—(C(R 14 ) 2 ) n —C(O)OH, —CH 2 —CH(F)—C(O)OH, —CH 2 —CF 2 —C(O)OH, —CH(CH 3 )—CF 2 —C(O)OH, —CH 2 —CH 2 —CF 2 —C(O)OH, —(CH 2 )—(CH(CH 3 ))—C(O)OCH 3 , —(CH 2 )—(CH 2 )—(CH 2 )—C(O)OCH 3 , —(CH 2 )—C(CH 3 ) 2 —C(O)OCH 3 , —(CH 2 )—C(CH 3 )(OH)—C(O)OCH 3 , —CH 2 —CH 2 —C(O)OCH 3 , —CH 2 —CH(OH)—C(O)OCH 3 , —CH(CH 3 )—CH 2 —C(O)OCH 3 , —C(CH 3 ) 2 —CH 2 —C(O)OCH 3 , —(C(R 11 ) 2 )—(C(R 14 ) 2 ) n —C(O)OCH 3 , —CH 2 —CH(F)—C(O)OCH 3 , —CH 2 —CF 2 —C(O)OCH 3 , —CH(CH 3 )—CF 2 —C(O)OCH 3 , —CH 2 —CH 2 —CF 2 —C(O)OCH 3 , and

wherein p is an integer from 0 to 1, and R 11 (when present) is selected from the group consisting of H and lower alkyl;

each R 5 is independently selected from H, —OH, lower alkyl, lower haloalkyl, and lower alkyl substituted with from 1 to 2 hydroxyl;

each R 6 is independently selected from H, alkyl, and haloalkyl;

each R 7 is independently selected from H, alkyl, heteroalkyl, and haloalkyl;

each R 8 is independently selected from H and alkyl; and

each R 9 is independently selected from H and alkyl.

11. A compound of claim 10 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein:

L 1 is selected from the group consisting of: a bond,

12. A compound of claim 10 , or a pharmaceutically acceptable salt, solvate, tautomer, or isomer of said compound, wherein:

L 1 is selected from the group consisting of

and

Z is selected from the group consisting of —CH 2 —CH 2 OC(O)OH and

wherein p is 1 and R 11 is H.

13. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, said compound selected from the group consisting of:

Ex.

Structure

2.1 

2.2 

2.3 

2.4 

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2.27 

2.33 

2.34 

2.28 

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2.41 

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2.35 

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2.40 

2.47 

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2.53 

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2.48 

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2.59 

2.60 

2.56 

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2.58 

2.66 

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2.61 

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2.72 

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2.70 

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2.78 

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2.74 

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2.87 

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2.97 

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2.98 

2.99 

2.100

2.101

2.102

2.93 

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2.95 

2.96 

2.104

2.105

2.106

2.103

2.116

2.117

2.118

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2.120

2.121

2.107

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2.109

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2.111

2.112

2.122

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2.125

2.126

2.127

2.113

2.114

2.115

2.128

2.129

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2.134

2.135

2.136

2.137

3.1 

3.3 

2.132

2.133

4.1 

4.2 

4.3 

4.4 

4.11 

4.5 

4.6 

4.7 

4.8 

4.9 

4.10 

4.12 

1.1 

1.2 

1.3 

1.4 

1.5 

1.6 

1.7 

1.8 

1.9 

1.10 

1.11 

1.12 

1.13 

1.14 

1.15 

1.16 

1.17 

1.18 

1.19 

1.20 

1.21 

1.22 

1.30 

1.31 

1.32 

1.33 

1.34 

1.35 

1.23 

1.24 

1.25 

1.26 

1.27 

1.28 

1.36 

1.37 

1.38 

1.39 

1.40 

1.41 

1.29 

1.43 

1.44 

1.45 

1.46 

1.47 

1.48 

1.42 

1.49 

1.50 

1.60 

1.61 

1.62 

1.63 

1.68 

1.69 

1.70 

1.71 

1.72 

1.73 

1.74 

1.64 

1.65 

1.66 

1.67 

1.79 

1.80 

1.81 

1.75 

1.76 

1.77 

1.78 

1.85 

1.86 

1.87 

1.82 

1.83 

1.84 

1.92 

1.93 

1.94 

1.95 

1.88 

1.89 

1.90 

1.91 

1.98 

1.99 

1.96 

1.97 

1.980

1.104

1.105

1.106

1.100

1.101

1.102

1.103

1.110

1.111

1.107

1.108

1.109

1.116

1.117

1.118

1.112

1.113

1.114

1.115

1.122

1.123

1.119

1.120

1.121

1.128

1.129

1.130

1.124

1.125

1.126

1.127

1.135

1.136

1.131

1.132

1.133

1.134

1.142

1.143

1.137

1.138

1.139

1.140

1.141

1.148

1.144

1.145

1.146

1.147

1.154

1.155

1.149

1.150

1.151

1.152

1.153

1.160

1.156

1.157

1.158

1.159

1.166

1.167

1.161

1.162

1.163

1.164

1.165

1.172

1.168

1.169

1.170

1.171

1.178

1.179

1.173

1.174

1.175

1.176

1.177

1.184

1.180

1.181

1.182

1.183

1.198

1.199

1.185

1.186

1.187

1.188

1.189

1.190

1.191

1.200

1.201

1.202

1.203

1.204

1.205

1.206

1.192

1.193

1.194

1.195

1.196

1.197

1.213

1.207

1.208

1.209

1.210

1.211

1.212

1.220

1.214

1.215

1.216

1.217

1.218

1.219

1.227

1.221

1.222

1.223

1.224

1.225

1.226

1.234

1.228

1.229

1.230

1.231

1.232

1.233

1.241

1.235

1.236

1.237

1.238

1.239

1.240

1.255

1.242

1.243

1.244

1.245

1.246

1.247

1.248

1.256

1.257

1.258

1.259

1.260

1.261

1.262

1.249

1.250

1.251

1.252

1.253

1.254

1.269

1.263

1.264

1.265

1.266

1.267

1.268

1.276

1.270

1.271

1.272

1.273

1.274

1.275

1.277

1.278

1.279

1.280

1.281

1.293

1.282

1.283

1.284

1.285

1.286

1.290

1.294

1.295

1.287

1.288

1.289

1.296

1.291

1.292

1.299

1.300

1.301

1.302

1.297

1.298

1.310

1.311

1.312

1.313

1.303

1.304

1.305

1.306

1.307

1.308

1.314

1.315

1.316

1.317

1.318

1.319

1.309

1.321

1.322

1.323

1.324

1.320

1.326

1.327

1.328

1.329

1.325

1.331

1.332

1.333

1.334

1.330

1.336

1.337

1.338

1.339

1.335

1.341

1.342

1.343

1.344

1.340

1.347

1.348

1.349

1.350

1.345

1.346

1.353

1.354

1.351

1.352

1.358

1.359

1.355

1.356

1.357

1.369

1.370

1.360

1.361

1.362

1.363

1.364

1.371

1.372

1.373

1.374

1.375

1.365

1.366

1.367

1.368

1.500

1.376

1.377

1.378

1.379

1.380

1.506

1.507

1.501

1.502

1.503

1.504

1.505

1.512

1.513

1.508

1.509

1.510

1.511

1.518

1.519

1.520

1.514

1.515

1.516

1.517

1.524

1.525

1.526

1.520

1.521

1.522

1.523

1.530

1.531

1.527

1.528

1.529

1.536

1.537

1.538

1.532

1.533

1.534

1.535

1.543

1.544

1.539

1.540

1.541

1.542

1.549

1.550

1.545

1.546

1.547

1.548

1.555

1.556

1.551

1.552

1.553

1.554

1.561

1.562

1.557

1.558

1.559

1.560

1.567

1.568

1.563

1.564

1.565

1.566

1.573

1.574

1.569

1.570

1.571

1.572

1.903

1.904

1.575

1.900

1.901

1.902

1.910

1.911

1.905

1.906

1.907

1.908

1.909

1.916

1.912

1.913

1.914

1.915

1.922

1.923

1.917

1.918

1.919

1.920

1.921

1.928

1.924

1.925

1.926

1.927

1.934

1.935

1.929

1.930

1.931

1.932

1.933

1.940

1.936

1.937

1.938

1.939

1.946

1.947

1.941

1.942

1.943

1.944

1.945

1.952

1.948

1.949

1.950

1.959

1.960

1.953

1.954

1.955

1.956

1.957

1.958

1.966

1.961

1.962

1.963

1.964

1.965

1.978

1.973

1.967

1.969

1.970

1.981

1.971

1.983

1.974

1.975

1.976

1.982

1.977

1.984

1.985

1.972

14. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

15. A composition of claim 14 , further comprising one or more antidiabetic agents other than a compound of claim 1 .

16. A composition of claim 15 , further comprising at least one pharmaceutically acceptable carrier.

17. A composition of claim 14 , further comprising at least one additional therapeutic agent selected from the group consisting of: DPP-IV inhibitor, an insulin sensitizer, insulin, an insulin mimetic, an insulin secretagogue, a GLP-1 mimetic, a glucosidase inhibitor, an alpha glucosidase inhibitor, a glucagon receptor antagonist other than a compound of claim 1 , glucophage, glucophage XR, an antihypertensive agent, a meglitinide, an alpha-glucosidase inhibitor, amlintide, pramlintide, exendin, a histamine H 3 receptor antagonist, dapagliflozin, sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku), a cholesterol lowering agent, a PACAP, a PACAP mimetic, a PACAP receptor 3 agonist, a PPAR delta agonist, an antiobesity agent, an ileal bile acid transporter inhibitor, an NSAID, and a CB1 receptor antagonist, and a CB1 receptor inverse agonist.

18. A compound of claim 1 , or a pharmaceutically acceptable salt or tautomer of said compound, having the structure: