OXYMETHYLENE ARYL COMPOUNDS AND USES THEREOF

1 . A method of treating diabetes comprising administering to a patient in need thereof a compound of Formula (I) and a DPP IV inhibitor,

wherein,

D is selected from the group consisting of O, S, and NR 8 ;

X, Y, and Z are independently selected from the group consisting of O, N, NR 8 , S, and CR 3 and at least one of X, Y, and Z is O, N, NR 8 , or S;

J, K, T, and U are each independently selected from the group consisting of C, CH, and N;

the subscript p is an integer of from 0 to 4;

the subscript q is an integer of from 0 to 4;

R 1 is a member selected from the group consisting of H, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —X 1 −COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, —CN, —NR a COR b , —NR a CONR a R b , —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b , or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring, and X 1 is selected from the group consisting of a bond, C 2-6 alkene, C 2-6 alkyne, —C(O)—, and —C(O)—(CH 2 ) 1-4 —, wherein the aliphatic portions of X 1 are optionally substituted with one to three members selected from halogen, C 1-4 alkyl, C 1-4 substituted alkyl and C 1-4 haloalkyl;

each R 2 is a member independently selected from the group consisting of halogen, C 1-5 alkyl, C 1-5 substituted alkyl, C 3-7 cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SOR a R b , —SO 2 R a and —SO 2 NR a R b , and wherein when the subscript q is 2 and R 2 is alkyl or substituted alkyl, the two R 2 members can optionally cyclize to form a ring;

R 3 is a member selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;

each R 7 is independently selected from the group consisting of halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , CO 2 R a , CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b and wherein the subscript m is an integer of from 0 to 2, or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring;

R 8 is a member independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;

and each R a and R b is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a and R b is optionally substituted with from one to three members selected from the group consisting of halo, —OR n , —OCOR n , —OC(O)N(R n ) 2 , —SR n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R n , —C(O)N(R n ) 2 , —C(O)R n , —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2 and —NR n S(O) 2 N(R n ) 2 , wherein each R n is independently hydrogen or an unsubstituted C 1-6 alkyl;

and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from

halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2 and —NR m S(O) 2 N(R m ) 2 , wherein each R m is independently hydrogen or an unsubstituted C 1-6 alkyl;

or a pharmaceutically acceptable salt or ester thereof; and

wherein the molecular weight of said compound is less than 1200.

2 . The method of claim 1 wherein said compound of Formula I is selected from the group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182, 184, 185, and 195.

3 . The method of claim 2 wherein said compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

4 . The method of claim 1 wherein said DPP-IV inhibitor is selected from the group consisting of sitagliptin, vildagliptin, Denagliptin, saxagliptin, and alogliptin.

5 . The method of claim 1 wherein said DPP-IV inhibitor is sitagliptin or vildagliptin.

6 . A method of lowering blood levels of glucose comprising administering to a patient in need thereof a compound of Formula (I) and a DPP IV inhibitor,

wherein,

D is selected from the group consisting of O, S, and NR 8 ;

X, Y, and Z are independently selected from the group consisting of O, N, NR 8 , S, and CR 3 and at least one of X, Y, and Z is O, N, NR 8 , or S;

J, K, T, and U are each independently selected from the group consisting of C, CH, and N;

the subscript p is an integer of from 0 to 4;

the subscript q is an integer of from 0 to 4;

R 1 is a member selected from the group consisting of H, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —X 1 —COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, —CN, —NR a COR b , —NR a CONR a R b , —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b , or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring, and X 1 is selected from the group consisting of a bond, C 2-6 alkene, C 2-6 alkyne, —C(O)—, and —C(O)—(CH 2 ) 1-4 —, wherein the aliphatic portions of X 1 are optionally substituted with one to three members selected from halogen, C 1-4 alkyl, C 1-4 substituted alkyl and C 1-4 haloalkyl;

each R 2 is a member independently selected from the group consisting of halogen, C 1-5 alkyl, C 1-5 substituted alkyl, C 3-7 cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SOR a R b , —SO 2 R a and —SO 2 NR a R b , and wherein when the subscript q is 2 and R 2 is alkyl or substituted alkyl, the two R 2 members can optionally cyclize to form a ring;

R 3 is a member selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;

each R 7 is independently selected from the group consisting of halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b and wherein the subscript m is an integer of from 0 to 2, or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring;

R 8 is a member independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;

and each R a and R b is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a and R b is optionally substituted with from one to three members selected from the group consisting of halo, —OR n , —OCOR n , —OC(O)N(R n ) 2 , —SR n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R n , —C(O)N(R n ) 2 , —C(O)R n , —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2 and —NR n S(O) 2 N(R n ) 2 , wherein each R n is independently hydrogen or an unsubstituted C 1-6 alkyl;

and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2 and —NR m S(O) 2 N(R m ) 2 , wherein each R m is independently hydrogen or an unsubstituted C 1-6 alkyl;

or a pharmaceutically acceptable salt or ester thereof; and wherein the molecular weight of said compound is less than 1200.

7 . The method of claim 6 wherein said compound of Formula I is selected from the group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182, 184, 185, and 195.

8 . The method of claim 7 wherein said compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

9 . The method of claim 6 wherein said DPP-IV inhibitor is selected from the group consisting of sitagliptin, vildagliptin, Denagliptin, saxagliptin, and alogliptin.

10 . The method of claim 6 wherein said DPP-IV inhibitor is sitagliptin or vildagliptin.

11 . A method of lowering blood levels of insulin comprising administering to a patient in need thereof a compound of Formula (I) and a DPP IV inhibitor.

wherein,

D is selected from the group consisting of O, S, and NR 8 ;

X, Y, and Z are independently selected from the group consisting of O, N, NR 8 , S, and CR 3 and at least one of X, Y, and Z is O, N, NR 8 , or S;

J, K, T, and U are each independently selected from the group consisting of C, CH, and N;

the subscript p is an integer of from 0 to 4;

the subscript q is an integer of from 0 to 4;

R 1 is a member selected from the group consisting of H, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —X 1 —COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, —CN, —NR a COR b , —NR a CONR a R b , —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b , or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring, and X 1 is selected from the group consisting of a bond, C 2-6 alkene, C 2-6 alkyne, —C(O)—, and —C(O)—(CH 2 ) 1-4 —, wherein the aliphatic portions of X 1 are optionally substituted with one to three members selected from halogen, C 1-4 alkyl, C 1-4 substituted alkyl and C 1-4 haloalkyl;

each R 2 is a member independently selected from the group consisting of halogen, C 1-5 alkyl, C 1-5 substituted alkyl, C 3-7 cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SOR a R b , —SO 2 R a and —SO 2 NR a R b , and wherein when the subscript q is 2 and R 2 is alkyl or substituted alkyl, the two R 2 members can optionally cyclize to form a ring;

R 3 is a member selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;

each R 7 is independently selected from the group consisting of halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b and wherein the subscript m is an integer of from 0 to 2, or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring;

R 8 is a member independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;

and each R a and R b is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a and R b is optionally substituted with from one to three members selected from the group consisting of halo, —OR n , —OCOR n , —OC(O)N(R n ) 2 , —SR n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R e , —C(O)N(R n ) 2 , —C(O)R n , —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2 and —NR n S(O) 2 N(R n ) 2 , wherein each R n is independently hydrogen or an unsubstituted C 1-6 alkyl;

and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2 and —NR m S(O) 2 N(R m ) 2 , wherein each R m is independently hydrogen or an unsubstituted C 1-6 alkyl;

or a pharmaceutically acceptable salt or ester thereof; and

wherein the molecular weight of said compound is less than 1200.

12 . The method of claim 11 wherein said compound of Formula I is selected from the group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182, 184, 185, and 195.

13 . The method of claim 12 wherein said compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

14 . The method of claim 11 wherein said DPP-IV inhibitor is selected from the group consisting of sitagliptin, vildagliptin, Denagliptin, saxagliptin, and alogliptin.

15 . The method of claim 11 wherein said DPP-IV inhibitor is sitagliptin or vildagliptin.

16 . A method of increasing blood levels of incretins comprising administering to a patient in need thereof a compound of Formula (I) and a DPP IV inhibitor.

wherein,

D is selected from the group consisting of O, S, and NR 8 ;

X, Y, and Z are independently selected from the group consisting of O, N, NR 8 , S, and CR 3 and at least one of X, Y, and Z is O, N, NR 8 , or S;

J, K, T, and U are each independently selected from the group consisting of C, CH, and N;

the subscript p is an integer of from 0 to 4;

the subscript q is an integer of from 0 to 4;

R 1 is a member selected from the group consisting of H, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —X 1 —COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, —CN, —NR a COR b , —NR a CONR a R b , —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b , or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring, and X 1 is selected from the group consisting of a bond, C 2-6 alkene, C 2-6 alkyne, —C(O)—, and —C(O)—(CH 2 ) 1-4 —, wherein the aliphatic portions of X 1 are optionally substituted with one to three members selected from halogen, C 1-4 alkyl, C 1-4 substituted alkyl and C 1-4 haloalkyl;

each R 2 is a member independently selected from the group consisting of halogen, C 1-5 alkyl, C 1-5 substituted alkyl, C 3-7 cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SOR a R b , —SO 2 R a and —SO 2 NR a R b , and wherein when the subscript q is 2 and R 2 is alkyl or substituted alkyl, the two R 2 members can optionally cyclize to form a ring;

R 3 is a member selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;

each R 7 is independently selected from the group consisting of halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b and wherein the subscript m is an integer of from 0 to 2, or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring;

R 8 is a member independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;

and each R a and R b is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a and R b is optionally substituted with from one to three members selected from the group consisting of halo, —OR n , —OCOR n , —OC(O)N(R n ) 2 , —SR n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R n , —C(O)N(R n ) 2 , —C(O)R n , —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2 and —NR n S(O) 2 N(R n ) 2 , wherein each R n is independently hydrogen or an unsubstituted C 1-6 alkyl;

and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2 and —NR m S(O) 2 N(R m ) 2 , wherein each R m is independently hydrogen or an unsubstituted C 1-6 alkyl;

or a pharmaceutically acceptable salt or ester thereof; and

wherein the molecular weight of said compound is less than 1200.

17 . The method of claim 16 wherein said compound of Formula I is selected from the group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182, 184, 185, and 195.

18 . The method of claim 17 wherein said compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

19 . The method of claim 16 wherein said DPP-IV inhibitor is selected from the group consisting of sitagliptin, vildagliptin, Denagliptin, saxagliptin, and alogliptin.

20 . The method of claim 16 wherein said DPP-IV inhibitor is sitagliptin or vildagliptin.

21 . The method 16 wherein said incretin is selected from the group consisting of GLP-1 and GIP.

22 . A method of lowering blood levels of triglycerides comprising administering to a patient in need thereof a compound of Formula (I) and a DPP IV inhibitor.

wherein,

D is selected from the group consisting of O, S, and NR 8 ;

X, Y, and Z are independently selected from the group consisting of O, N, NR 8 , S, and CR 3 and at least one of X, Y, and Z is O, N, NR 8 , or S;

J, K, T, and U are each independently selected from the group consisting of C, CH, and N;

the subscript p is an integer of from 0 to 4;

the subscript q is an integer of from 0 to 4;

R 1 is a member selected from the group consisting of H, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —X 1 —COR a , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, —CN, —NR a COR b , —NR a CONR a R b , —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b , or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring, and X 1 is selected from the group consisting of a bond, C 2-6 alkene, C 2-6 alkyne, —C(O)—, and —C(O)—(CH 2 ) 1-4 —, wherein the aliphatic portions of X 1 are optionally substituted with one to three members selected from halogen, C 1-4 alkyl, C 1-4 substituted alkyl and C 1-4 haloalkyl;

each R 2 is a member independently selected from the group consisting of halogen, C 1-5 alkyl, C 1-5 substituted alkyl, C 3-7 cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SOR a R b , —SO 2 R a and —SO 2 NR a R b , and wherein when the subscript q is 2 and R 2 is alkyl or substituted alkyl, the two R 2 members can optionally cyclize to form a ring;

R 3 is a member selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;

each R 7 is independently selected from the group consisting of halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, —CN, —NO 2 , —OR a , —NR a R b , COR a , CO 2 R a , —CONR a R b , —NR a COR b , R a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b and wherein the subscript m is an integer of from 0 to 2, or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring;

R 8 is a member independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;

and each R a and R b is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a and R b is optionally substituted with from one to three members selected from the group consisting of halo, —OR n , —OCOR n , —OC(O)N(R n ) 2 , —SR n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R n , —C(O)N(R n ) 2 , —C(O)R n , —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2 and —NR n S(O) 2 N(R n ) 2 , wherein each R n is independently hydrogen or an unsubstituted C 1-6 alkyl;

and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2 and —NR m S(O) 2 N(R m ) 2 , wherein each R m is independently hydrogen or an unsubstituted C 1-6 alkyl;

or a pharmaceutically acceptable salt or ester thereof; and wherein the molecular weight of said compound is less than 1200.

23 . The method of claim 22 wherein said compound of Formula I is selected from the group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182, 184, 185, and 195.

24 . The method of claim 23 wherein said compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

25 . The method of claim 22 wherein said DPP-IV inhibitor is selected from the group consisting of sitagliptin, vildagliptin, Denagliptin, saxagliptin, and alogliptin.

26 . The method of claim 22 wherein said DPP-IV inhibitor is sitagliptin or vildagliptin.

27 . A method of increasing glucose dependent insulin production comprising administering to a patient in need thereof a compound of Formula (I) and a DPP IV inhibitor.

wherein,

D is selected from the group consisting of O, S, and NR 8 ;

X, Y, and Z are independently selected from the group consisting of O, N, NR 8 , S, and CR 3 and at least one of X, Y, and Z is O, N, NR 8 , or S;

J, K, T, and U are each independently selected from the group consisting of C, CH, and N;

the subscript p is an integer of from 0 to 4;

the subscript q is an integer of from 0 to 4;

R 1 is a member selected from the group consisting of H, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —X 1 —COR 3 , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SO 2 R a , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said cycloalkyl group, heterocyclo group, aryl group and heteroaryl group is optionally substituted with from 1 to 4 substituents independently selected from halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, —CN, —NR a COR b , —NR a CONR a R b , —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —S(O) m R a , —NR a S(O) 2 R b , and —SO 2 NR a R b , or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring, and X 1 is selected from the group consisting of a bond, C 2-6 alkene, C 2-6 alkyne, —C(O)—, and —C(O)—(CH 2 ) 14 —, wherein the aliphatic portions of X 1 are optionally substituted with one to three members selected from halogen, C 1-4 alkyl, C 1-4 substituted alkyl and C 1-4 haloalkyl;

each R 2 is a member independently selected from the group consisting of halogen, C 1-5 alkyl, C 1-5 substituted alkyl, C 3-7 cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —OR a , —NR a R b , —NR a COR b , —SOR a R b , —SO 2 R a and —SO 2 NR a R b , and wherein when the subscript q is 2 and R 2 is alkyl or substituted alkyl, the two R 2 members can optionally cyclize to form a ring;

R 3 is a member selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl;

each R 7 is independently selected from the group consisting of halo, C 1-10 alkyl, C 1-10 substituted alkyl, C 3-7 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, —CN, —NO 2 , —OR a , —NR a R b , —COR a , —CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a S(O) m R b , —SO 2 NR a R b , a 4- to 7-membered heterocyclo group, aryl and a 5- to 10-membered heteroaryl group, wherein each of said heterocyclo groups, said aryl and heteroaryl groups are optionally substituted with from one to four substituents independently selected from halo, oxo, C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, —CN, —NO 2 , —OR a , —NR a R b , COR a , CO 2 R a , —CONR a R b , —NR a COR b , —NR a CO 2 R b , —NR a CONR a R b , —S(O) m R a , —NR a SO 2 R b , and —SO 2 NR a R b and wherein the subscript m is an integer of from 0 to 2, or optionally R a and R b are combined to form a 4-, 5- or 6-membered ring;

R 8 is a member independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;

and each R a and R b is independently selected from the group consisting of hydrogen, C 1-10 alkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, heterocyclyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, 5- to 6-membered heteroaryl and arylC 1-4 alkyl; and wherein the aliphatic portions of each of said R a and R b is optionally substituted with from one to three members selected from the group consisting of halo, —OR n , —OCOR n , —OC(O)N(R n ) 2 , —SR n , —S(O)R n , —S(O) 2 R n , —S(O) 2 N(R n ) 2 , —NR n S(O) 2 R n , —C(O)N(R n ) 2 , —C(O)R n , —NR n C(O)R n , —NR n C(O)N(R n ) 2 , —CO 2 R n , —NR n CO 2 R n , —CN, —NO 2 , —N(R n ) 2 and —NR n S(O) 2 N(R n ) 2 , wherein each R n is independently hydrogen or an unsubstituted C 1-6 alkyl;

and wherein the aryl and heteroaryl portions are optionally substituted with from one to three members selected from halogen, —OR m , —OC(O)N(R m ) 2 , —SR m , —S(O)R m , —S(O) 2 R m , —S(O) 2 N(R m ) 2 , —NR m S(O) 2 R m , —C(O)N(R m ) 2 , —C(O)R m , —NR m C(O)R m , —NR m C(O)N(R m ) 2 , —CO 2 R m , —NR m CO 2 R m , —CN, —NO 2 , —N(R m ) 2 and —NR m S(O) 2 N(R m ) 2 , wherein each R m is independently hydrogen or an unsubstituted C 1-6 alkyl;

or a pharmaceutically acceptable salt or ester thereof; and

wherein the molecular weight of said compound is less than 1200.

28 . The method of claim 27 wherein said compound of Formula I is selected from the group consisting of the compound of example 52, 76, 77, 95, 148, 162, 170, 171, 182, 184, 185, and 195.

29 . The method of claim 28 wherein said compound of Formula (I) is

or a pharmaceutically acceptable salt thereof.

30 . The method of claim 27 wherein said DPP-IV inhibitor is selected from the group consisting of sitagliptin, vildagliptin, Denagliptin, saxagliptin, and alogliptin.

31 . The method of claim 27 wherein said DPP-IV inhibitor is sitagliptin or vildagliptin.