Claims for Patent: 8,173,663

Summary for Patent: 8,173,663

Title:	Dipeptidyl peptidase inhibitors
Abstract:	Compounds, pharmaceuticals, kits and methods are provided for use with DPP-IV and other S9 proteases that comprise a compound comprising: wherein M is N or CR4; Q1 and Q2 are each independently selected from the group consisting of CO, SO, SO2, and C═NR9; and each L, X, R1, R2, and R3 are as defined herein.
Inventor(s):	Jun Feng, Stephen L. Gwaltney, Jeffrey A. Stafford, Zhiyuan Zhang, Bruce J. Elder, Paul K. Isbester, Grant J. Palmer, Jonathon S. Salsbury, Luckner G. Ulysse
Assignee:	Takeda Pharmaceutical Co Ltd
Application Number:	US11/929,593
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,173,663
Patent Claims:	1. A method of treating type II diabetes in a patient in need thereof, the method comprising administering to said patient a therapeutically effective amount of a compound having the formula wherein Q1 and Q2 are each CO; R2 is hydrogen or selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, (C3-12)cycloalkyl(C1-5)alkyl, hetero(C3-12)cycloalkyl(C1-5)alkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, hetero(C4-12)bicycloaryl(C1-5)alkyl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R3 comprises the formula; R10 and R11 are each independently selected from the group consisting of hydrogen, perhalo(C1-10)alkyl, amino, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl (C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, and sulfinyl group, each substituted or unsubstituted, or R10 and R11 are taken together to form a 4, 5, 6, or 7 membered ring, each substituted or unsubstituted; R4 is hydrogen or is selected from the group consisting of halo, perhalo(C1-10)alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; -L-X taken together is selected from the group consisting of —(CH2)-(2-cyano)phenyl; —(CH2)-(3-cyano)phenyl; —(CH2)-(2-hydroxy)phenyl; —(CH2)-(3-hydroxy)phenyl; —(CH2)-(2-alkenyl)phenyl; —(CH2)-(3-alkenyl)phenyl; —(CH2)-(2-alkynyl)phenyl; —(CH2)-(3-alkynyl)phenyl; —(CH2)-(2-methoxy)phenyl; —(CH2)-(3-methoxy)phenyl; —(CH2)-(2-nitro)phenyl; —(CH2)-(3-nitro)phenyl; —(CH2)-(2-carboxy)phenyl; —(CH2)-(3-carboxy)phenyl; —(CH2)-(2-carboxamido)phenyl; —(CH2)-(3-carboxamido)phenyl; —(CH2)-(2-sulfonamido)phenyl; —(CH2)-(3-sulfonamido)phenyl; —(CH2)-(2-tetrazolyl)phenyl; —(CH2)-(3-tetrazolyl)phenyl; —(CH2)-(2-aminomethyl)phenyl; —(CH2)-(3-aminomethyl)phenyl; —(CH2)-(2-hydroxymethyl)phenyl; —(CH2)-(3-hydroxymethyl)phenyl; —(CH2)-(2-phenyl)phenyl; —(CH2)-(3-phenyl)phenyl; —(CH2)-(2-halo)phenyl; —(CH2)-(3-halo)phenyl; —(CH2)-(2-CONH2)phenyl; —(CH2)-(3-CONH2)phenyl; —(CH2)-(2-CONH(C1-7)alkyl)phenyl; —(CH2)-(3-CONH(C1-7)alkyl)phenyl; —(CH2)-(2-CO2(C1-7)alkyl)phenyl; —(CH2)-(3-CO2(C1-7)alkyl)phenyl; —(CH2)-(2-NH2)phenyl; —(CH2)-(3-NH2)phenyl; —(CH2)-(2-(C3-7)alkyl)phenyl; —(CH2)-(3-(C3-7)alkyl)phenyl; —(CH2) (2-(C3-7)cycloalkyl)phenyl; —(CH2)-(3-(C3-7)cycloalkyl)phenyl; —(CH2)-(2-aryl)phenyl; —(CH2)-(3-aryl)phenyl; —(CH2)-(2-heteroaryl)phenyl; —(CH2)-(3-heteroaryl)phenyl; —(CH2)-2-bromo-5-fluoro phenyl; —(CH2)-2-chloro-5-fluoro phenyl; —(CH2)-2-cyano-5-fluoro phenyl; —(CH2)-2,5-dichloro phenyl; —(CH2)-2,5-difluoro phenyl; —(CH2)-2,5-dibromo phenyl; —(CH2)-2-bromo-3,5-difluoro phenyl; —(CH2)-2-chloro-3,5-difluoro phenyl; —(CH2)-2,3,5-trifluoro phenyl; —(CH2)-2,3,5,6-tetrafluorophenyl; —(CH2)-2-bromo-3,5,6-trifluoro phenyl; —(CH2)-2-chloro-3,5,6-trifluoro phenyl; —(CH2)-2-cyano-3,5-difluoro phenyl; —(CH2)-2-cyano-3,5,6-trifluoro phenyl; —(CH2)-(2-heterocycloalkyl)phenyl; and —(CH2)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted. 2. A method of treating breast cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula wherein Q1 and Q2 are each CO; R2 is hydrogen or selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, (C3-12)cycloalkyl(C1-5)alkyl, hetero(C3-12)cycloalkyl(C1-5)alkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, hetero(C4-12)bicycloaryl(C1-5)alkyl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R3 comprises the formula; R10 and R11 are each independently selected from the group consisting of hydrogen, perhalo(C1-10)alkyl, amino, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl (C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, and sulfinyl group, each substituted or unsubstituted, or R10 and R11 are taken together to form a 4, 5, 6, or 7 membered ring, each substituted or unsubstituted; R4 is hydrogen or is selected from the group consisting of halo, perhalo(C1-10)alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; -L-X taken together is selected from the group consisting of —(CH2)-(2-cyano)phenyl; —(CH2)-(3-cyano)phenyl; —(CH2)-(2-hydroxy)phenyl; —(CH2)-(3-hydroxy)phenyl; —(CH2)-(2-alkenyl)phenyl; —(CH2)-(3-alkenyl)phenyl; —(CH2)-(2-alkynyl)phenyl; —(CH2)-(3-alkynyl)phenyl; —(CH2)-(2-methoxy)phenyl; —(CH2)-(3-methoxy)phenyl; —(CH2)-(2-nitro)phenyl; —(CH2)-(3-nitro)phenyl; —(CH2)-(2-carboxy)phenyl; —(CH2)-(3-carboxy)phenyl; —(CH2)-(2-carboxamido)phenyl; —(CH2)-(3-carboxamido)phenyl; —(CH2)-(2-sulfonamido)phenyl; —(CH2)-(3-sulfonamido)phenyl; —(CH2)-(2-tetrazolyl)phenyl; —(CH2)-(3-tetrazolyl)phenyl; —(CH2)-(2-aminomethyl)phenyl; —(CH2)-(3-aminomethyl)phenyl; —(CH2)-(2-hydroxymethyl)phenyl; —(CH2)-(3-hydroxymethyl)phenyl; —(CH2)-(2-phenyl)phenyl; —(CH2)-(3-phenyl)phenyl; —(CH2)-(2-halo)phenyl; —(CH2)-(3-halo)phenyl; —(CH2)-(2-CONH2)phenyl; —(CH2)-(3-CONH2)phenyl; —(CH2)-(2-CONH(C1-7)alkyl)phenyl; —(CH2)-(3-CONH(C1-7)alkyl)phenyl; —(CH2)-(2-CO2(C1-7)alkyl)phenyl; —(CH2)-(3-CO2(C1-7)alkyl)phenyl; —(CH2)-(2-NH2)phenyl; —(CH2)-(3-NH2)phenyl; —(CH2)-(2-(C3-7)alkyl)phenyl; —(CH2) (3-(C3-7)alkyl)phenyl; —(CH2)-(2-(C3-7)cycloalkyl)phenyl; —(CH2)-(3-(C3-7)cycloalkyl)phenyl; —(CH2)-(2-aryl)phenyl; —(CH2)-(3-aryl)phenyl; —(CH2)-(2-heteroaryl)phenyl; —(CH2)-(3-heteroaryl)phenyl; —(CH2)-2-bromo-5-fluoro phenyl; —(CH2)-2-chloro-5-fluoro phenyl; —(CH2)-2-cyano-5-fluoro phenyl; —(CH2)-2,5-dichloro phenyl; —(CH2)-2,5-difluoro phenyl; —(CH2)-2,5-dibromo phenyl; —(CH2)-2-bromo-3,5-difluoro phenyl; —(CH2)-2-chloro-3,5-difluoro phenyl; —(CH2)-2,3,5-trifluoro phenyl; —(CH2)-2,3,5,6-tetrafluorophenyl; —(CH2)-2-bromo-3,5,6-trifluoro phenyl; —(CH2)-2-chloro-3,5,6-trifluoro phenyl; —(CH2)-2-cyano-3,5-difluoro phenyl; —(CH2)-2-cyano-3,5,6-trifluoro phenyl; —(CH2)-(2-heterocycloalkyl)phenyl; and —(CH2)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted. 3. A method of treating type I diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound having the formula wherein Q1 and Q2 are each CO; R2 is hydrogen or selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, (C3-12)cycloalkyl(C1-5)alkyl, hetero(C3-12)cycloalkyl(C1-5)alkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, hetero(C4-12)bicycloaryl(C1-5)alkyl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; R3 comprises the formula; R10 and R11 are each independently selected from the group consisting of hydrogen, perhalo(C1-10)alkyl, amino, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl (C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, sulfonyl group, and sulfinyl group, each substituted or unsubstituted, or R10 and R11 are taken together to form a 4, 5, 6, or 7 membered ring, each substituted or unsubstituted; R4 is hydrogen or is selected from the group consisting of halo, perhalo(C1-10)alkyl, amino, cyano, thio, (C1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted; -L-X taken together is selected from the group consisting of —(CH2)-(2-cyano)phenyl; —(CH2)-(3-cyano)phenyl; —(CH2)-(2-hydroxy)phenyl; —(CH2)-(3-hydroxy)phenyl; —(CH2)-(2-alkenyl)phenyl; —(CH2)-(3-alkenyl)phenyl; —(CH2)-(2-alkynyl)phenyl; —(CH2)-(3-alkynyl)phenyl; —(CH2)-(2-methoxy)phenyl; —(CH2)-(3-methoxy)phenyl; —(CH2)-(2-nitro)phenyl; —(CH2)-(3-nitro)phenyl; —(CH2)-(2-carboxy)phenyl; —(CH2)-(3-carboxy)phenyl; —(CH2)-(2-carboxamido)phenyl; —(CH2)-(3-carboxamido)phenyl; —(CH2)-(2-sulfonamido)phenyl; —(CH2)-(3-sulfonamido)phenyl; —(CH2)-(2-tetrazolyl)phenyl; —(CH2)-(3-tetrazolyl)phenyl; —(CH2)-(2-aminomethyl)phenyl; —(CH2)-(3-aminomethyl)phenyl; —(CH2)-(2-hydroxymethyl)phenyl; —(CH2)-(3-hydroxymethyl)phenyl; —(CH2)-(2-phenyl)phenyl; —(CH2)-(3-phenyl)phenyl; —(CH2)-(2-halo)phenyl; —(CH2)-(3-halo)phenyl; —(CH2)-(2-CONH2)phenyl; —(CH2)-(3-CONH2)phenyl; —(CH2)-(2-CONH(C1-7)alkyl)phenyl; —(CH2)-(3-CONH(C1-7)alkyl)phenyl; —(CH2)-(2-CO2(C1-7)alkyl)phenyl; —(CH2)-(3-CO2(C1-7)alkyl)phenyl; —(CH2)-(2-NH2)phenyl; —(CH2)-(3-NH2)phenyl; —(CH2)-(2-(C3-7)alkyl)phenyl; —(CH2)-(3-(C3-7)alkyl)phenyl; —(CH2)-(2-(C3-7)cycloalkyl)phenyl; —(CH2)-(3-(C3-7)cycloalkyl)phenyl; —(CH2)-(2-aryl)phenyl; —(CH2)-(3-aryl)phenyl; —(CH2)-(2-heteroaryl)phenyl; —(CH2)-(3-heteroaryl)phenyl; —(CH2)-2-bromo-5-fluoro phenyl; —(CH2)-2-chloro-5-fluoro phenyl; —(CH2)-2-cyano-5-fluoro phenyl; —(CH2)-2,5-dichloro phenyl; —(CH2)-2,5-difluoro phenyl; —(CH2)-2,5-dibromo phenyl; —(CH2)-2-bromo-3,5-difluoro phenyl; —(CH2)-2-chloro-3,5-difluoro phenyl; —(CH2)-2,3,5-trifluoro phenyl; —(CH2)-2,3,5,6-tetrafluorophenyl; —(CH2)-2-bromo-3,5,6-trifluoro phenyl; —(CH2)-2-chloro-3,5,6-trifluoro phenyl; —(CH2)-2-cyano-3,5-difluoro phenyl; —(CH2)-2-cyano-3,5,6-trifluoro phenyl; —(CH2)-(2-heterocycloalkyl)phenyl; and —(CH2)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted. 4. The method according to claim 1, wherein R3 is a substituted or unsubstituted 4, 5, 6, or 7 membered heterocycloalkyl. 5. The method according to claim 1, wherein R3 is a substituted or unsubstituted heteroaryl. 6. The method according to claim 1, wherein R3 is selected from the group consisting of wherein p is 0-12 and each R8 is independently selected from the group consisting of halo, perhalo(C1-10)alkyl, CF3, cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, carbonyl group, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted. 7. The method according to claim 6, wherein at least one R8 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein. 8. The method according to claim 7, wherein the basic nitrogen atom forms part of a primary, secondary or tertiary amine. 9. The method according to claim 7, wherein the basic nitrogen atom is a nitrogen ring atom of a heterocycloalkyl comprising a nitrogen ring atom or a heteroaryl comprising a nitrogen ring atom. 10. The method according to claim 6, wherein at least one R8 is a primary, secondary or tertiary amine. 11. The method according to claim 6, wherein at least one R8 is a substituted or unsubstituted heterocycloalkyl comprising a nitrogen ring atom or a substituted or unsubstituted heteroaryl comprising a nitrogen ring atom. 12. The method according to claim 6, wherein at least one R8 is selected from the group consisting of —NH2, —NH(C1-5 alkyl), —N(C1-5 alkyl)2, piperazine, imidazole, and pyridine. 13. The method according to claim 1, wherein R3 is a substituted or unsubstituted heteroaryl selected from the group consisting of furan, thiophene, pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridine, quinoxaline, phthalazine, and benzothiazole, each substituted or unsubstituted. 14. The method according to claim 1, wherein R3 is substituted such that R3 comprises a substituent selected from the group consisting of a primary, secondary or tertiary amine, a heterocycloalkyl comprising a nitrogen ring atom, and a heteroaryl comprising a nitrogen ring atom. 15. The method according to claim 1, wherein R3 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein. 16. The method according to claim 15, wherein the basic nitrogen of R3 is separated from the ring atom to which R3 is attached by between 1-5 atoms. 17. The method according to claim 15, wherein the basic nitrogen atom forms part of a primary, secondary or tertiary amine. 18. The method according to claim 15, wherein the basic nitrogen atom is a nitrogen ring atom of a heterocycloalkyl or a heteroaryl. 19. The method according to claim 1, wherein R3 is selected from the group consisting of 3-amino-piperidinyl-1-yl, 3-aminomethyl-pyrrolidin-1-yl, 3-aminoazetidin-1-yl, 3-amino-3-methylpiperidin-1-yl, 3 aminohexahydroazepin-1-yl, piperazin-1-yl, homopiperazin-1-yl, 3-amino-pyrrolidin-1-yl, R-3-aminopiperidin-1-yl, R-3-amino-3-methylpiperidin-1-yl, and 3-amino-pyrrolidin-1-yl, each substituted or unsubstituted. 20. The method according to claim 1, wherein R2 is a substituted or unsubstituted (C1-10)alkyl. 21. The method according to claim 1, wherein R2 is a substituted or unsubstituted (C1-4)alkyl. 22. The method according to claim 1, wherein R2 is —Y—Z wherein Y a linker providing 1, 2 or 3 atom separation between Z and the ring to which Y is attached, wherein the atoms of the linker providing the separation are selected from the group consisting of carbon, oxygen, nitrogen, and sulfur; and Z is hydrogen or selected from the group consisting of (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl(C1-5)alkyl, (C9-12)bicycloaryl, hetero(C4-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, sulfonyl (C1-3)alkyl, sulfinyl (C1-3)alkyl, imino (C1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, cyano, imino group, sulfonyl group and sulfinyl group, each substituted or unsubstituted. 23. The method according to claim 1, wherein R2 is selected from the group consisting of wherein A is S, O or NR24; B is CR23 or N; R23 is independently selected from the group consisting of hydrogen, halo, perhalo(C1-10)alkyl, amino, thio, cyano, CF3, nitro, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl (C1-5)alkyl, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and sulfinyl group, each substituted or unsubstituted; and R24 is independently selected from the group consisting of hydrogen, perhalo(C1-10)alkyl, amino, (C1-10)alkyl, (C3-12)cycloalkyl, hetero(C3-12)cycloalkyl, aryl(C1-10)alkyl, heteroaryl (C1-5)alkyl, (C9-12)bicycloaryl, hetero(C8-12)bicycloaryl, carbonyl (C1-3)alkyl, thiocarbonyl (C1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, imino group, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and sulfinyl group, each substituted or unsubstituted. 24. The method according to claim 1, wherein R2 is selected from the group consisting of wherein t is 0, 1, 2, 3, 4, or 5; and each R18 is independently selected from the group consisting of halo, perhalo(C1-10)alkyl, CF3, (C1-10)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, carbonyl group, imine group, sulfonyl group and sulfinyl group, each substituted or unsubstituted. 25. The method according to claim 1 wherein the compound is selected from the group consisting of: 2-{6-[3-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 2-{6-[Azepan-3 (±)-ylamino]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile (14); 2-{6-[3 (±)-Amino-azepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-[6-(2-Amino-ethylamino)-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile; 3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic acid methyl ester; 3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic acid; 6-[3-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione; 2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 6-[3(R)-Amino-piperidin-1-yl]-1-(2,5-di-chloro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-3,6-di-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; and (R)-2-((6-(3-amino-3-methylpiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile. 26. The method according to claim 1 wherein the compound is selected from the group consisting of: 2-{6-[3(R)-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione; 2-{6-[3(R)-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile 2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile; 6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile; 3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic acid methyl ester; 3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoic acid; and 6-[3(R)-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione. 27. The method according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt. 28. The method according to claim 1, wherein the compound is present in a mixture of stereoisomers. 29. The method according to claim 1, wherein the compound comprises a single stereoisomer.