Details for Patent: 8,288,539

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: ##STR00001## wherein M is N or CR.sub.4; Q.sup.1 and Q.sup.2 are each independently selected from the group consisting of CO, SO, SO.sub.2, and C.dbd.NR.sub.9; and each L, X, R.sub.1, R.sub.2, and R.sub.3 are as defined herein.
Inventor(s):	Feng; Jun (Carlsbad, CA), Gwaltney; Stephen L. (San Diego, CA), Stafford; Jeffrey A. (San Diego, CA), Zhang; Zhiyuan (San Diego, CA), Elder; Bruce J. (Wynantskill, NY), Isbester; Paul K. (Castleton, NY), Palmer; Grant J. (Clifton Park, NY), Salsbury; Jonathon S. (Albany, NY), Ulysse; Luckner G. (Albany, NY)
Assignee:	Takeda Pharmaceutical Company Limited (Osaka, JP)
Filing Date:	Oct 30, 2007
Application Number:	11/929,482
Claims:	1. A compound having the formula: ##STR00064## wherein M is CR.sub.4; Q.sup.1 and Q.sup.2 are each CO; R.sub.2 is hydrogen or selected from the group consisting of (C.sub.1-10)alkyl, (C.sub.3 -12)cycloalkyl, (C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl, hetero(C.sub.3-12)cycloalkyl(C.sub.1-5)alkyl, hetero(C.sub.3-12)cycloalkyl, aryl(C.sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl, (C.sub.9-12)bicycloaryl, hetero(C.sub.4 -12)bicycloaryl, hetero(C.sub.4-12)bicycloaryl(C.sub.1-5)alkyl, carbonyl (C.sub.1-3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, sulfonyl (C.sub.1-3)alkyl, sulfinyl (C.sub.1-3)alkyl, imino (C.sub.1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, and carbonyl group, each substituted or unsubstituted; R.sub.3 has the formula ##STR00065## R.sub.10 and R.sub.11 are each independently selected from the group consisting of hydrogen, perhalo(C.sub.1-10)alkyl, (C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl, hetero(C.sub.3-12) cycloalkyl, aryl(C.sub.1-10)alkyl, heteroaryl (C.sub.1-5)alkyl, (C.sub.9-12)bicycloaryl, hetero(C.sub.4 -12)bicycloaryl, carbonyl (C.sub.1-3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, and carbonyl group, each substituted or unsubstituted, or R.sub.10 and R.sub.11 are taken together to form a 4, 5, 6, or 7 membered ring, each substituted or unsubstituted; R.sub.4 is hydrogen or is selected from the group consisting of halo, perhalo(C.sub.1-10)alkyl, amino, cyano, thio, (C.sub.1-10)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl (C.sub.1-3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, sulfonyl (C.sub.1-3)alkyl, sulfinyl (C.sub.1-3)alkyl, imino (C.sub.1-3)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, and carbonyl group, each substituted or unsubstituted; and -L-X taken together is selected from the group consisting of --(CH.sub.2)-(2-cyano)phenyl; --(CH.sub.2)-(3-cyano)phenyl; --(CH.sub.2)-(2-hydroxy)phenyl; --(CH.sub.2)-(3-hydroxy)phenyl; --(CH.sub.2)-(2-alkenyl)phenyl; --(CH.sub.2)-(3-alkenyl)phenyl; --(CH.sub.2)-(2-alkynyl)phenyl; --(CH.sub.2)-(3-alkynyl)phenyl; --(CH.sub.2)-(2-methoxy)phenyl; --(CH.sub.2)-(3-methoxy)phenyl; --(CH.sub.2)-(2-nitro)phenyl; --(CH.sub.2)-(3-nitro)phenyl; --(CH.sub.2)-(2-carboxy)phenyl; --(CH.sub.2)-(3-carboxy)phenyl; --(CH.sub.2)-(2-carboxamido)phenyl; --(CH.sub.2)-(3-carboxamido)phenyl; --(CH.sub.2)-(2-sulfonamido)phenyl; --(CH.sub.2)-(3-sulfonamido)phenyl; --(CH.sub.2)-(2-tetrazolyl)phenyl; --(CH.sub.2)-(3-tetrazolyl)phenyl; --(CH.sub.2)-(2-aminomethyl)phenyl; --(CH.sub.2)-(3-aminomethyl)phenyl; --(CH.sub.2)-(2-hydroxymethyl)phenyl; --(CH.sub.2)-(3-hydroxymethyl)phenyl; --(CH.sub.2)-(2-phenyl)phenyl; --(CH.sub.2)-(3-phenyl)phenyl; --(CH.sub.2)-(2-halo)phenyl; --(CH.sub.2)-(3-halo)phenyl; --(CH.sub.2)-(2-CONH.sub.2)phenyl; --(CH.sub.2)-(3-CONH.sub.2)phenyl; --(CH.sub.2)-(2-CONH(C.sub.1-7)alkyl)phenyl; --(CH.sub.2)-(3-CONH(C.sub.1-7)alkyl)phenyl; --(CH.sub.2)-(2-CO.sub.2(C.sub.1-7) alkyl)phenyl; --(CH.sub.2)-(3-CO.sub.2(C.sub.1-7)alkyl)phenyl; --(CH.sub.2)-(2-NH.sub.2)phenyl; --(CH.sub.2)-(3-NH.sub.2) phenyl; --(CH.sub.2)-(2-(C.sub.3-7)alkyl)phenyl; --(CH.sub.2)-(3-(C.sub.3-7)alkyl)phenyl; --(CH.sub.2) -(2-(C.sub.3-7)cycloalkyl)phenyl; --(CH.sub.2)-(3-(C.sub.3-7)cycloalkyl)phenyl; --(CH.sub.2)-(2-aryl)phenyl; --(CH.sub.2)-(3-aryl)phenyl; --(CH.sub.2)-(2-heteroaryl)phenyl; --(CH.sub.2)-(3-heteroaryl)phenyl; --(CH.sub.2)-2-bromo-5-fluoro phenyl; --(CH.sub.2)-2-chloro-5-fluoro phenyl; --(CH.sub.2)-2-cyano-5-fluoro phenyl; --(CH.sub.2)-2,5-dichloro phenyl; --(CH.sub.2)-2,5-difluoro phenyl; --(CH.sub.2)-2,5-dibromo phenyl; --(CH.sub.2)-2-bromo-3,5-difluoro phenyl; --(CH.sub.2)-2-chloro-3,5-difluoro phenyl; --(CH.sub.2)-2,3,5-trifluoro phenyl; --(CH.sub.2) -2,3,5,6-tetrafluorophenyl; --(CH.sub.2)-2-bromo-3,5,6-trifluoro phenyl; --(CH.sub.2)-2-chloro-3,5,6-trifluoro phenyl; --(CH.sub.2)-2-cyano-3,5-difluoro phenyl; --(CH.sub.2)-2-cyano -3,5,6-trifluoro phenyl; --(CH.sub.2) -(2-heterocycloalkyl)phenyl; and --(CH.sub.2)-(3-heterocycloalkyl)phenyl, each substituted or unsubstituted; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R.sub.3 is a substituted or unsubstituted 3, 4, 5, 6, or 7 membered ring. 3. The compound according to claim 1, wherein R.sub.3 is a substituted or unsubstituted 4, 5, 6, or 7 membered heterocycloalkyl. 4. The compound according to claim 1, wherein R.sub.3 is a substituted or unsubstituted heteroaryl. 5. The compound according to claim 1, wherein R.sub.3 is selected from the group consisting of ##STR00066## wherein p is 0-12 and each R.sub.8 is independently selected from the group consisting of halo, perhalo(C.sub.1-10)alkyl, CF.sub.3, cyano, nitro, hydroxy, alkyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, alkoxy, and carbonyl group, each substituted or unsubstituted. 6. The compound according to claim 5, wherein at least one R.sub.8 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein. 7. The compound of claim 6, wherein the basic nitrogen atom forms part of a primary, secondary or tertiary amine. 8. The compound of claim 6, 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. 9. The compound according to claim 5, wherein at least one R.sub.8 is a primary, secondary or tertiary amine. 10. The compound according to claim 5, wherein at least one R.sub.8 is a substituted or unsubstituted heterocycloalkyl comprising a nitrogen ring atom or a substituted or unsubstituted heteroaryl comprising a nitrogen ring atom. 11. The compound according to claim 5, wherein at least one R.sub.8 is selected from the group consisting of --NH.sub.2, --NH(C.sub.1-5 alkyl), --N(C.sub.1-5 alkyl) .sub.2, piperazine, imidazole, and pyridine. 12. The compound according to claim 1, wherein R.sub.3 is a substituted or unsubstituted heteroaryl selected from the group consisting of pyrrole, pyrazole, triazole, isoxazole, oxazole, thiazole, isothiazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, imidazole, benzimidazole, indole, isoindole, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, quinoxaline, phthalazine, and benzothiazole, each substituted or unsubstituted. 13. The compound according to claim 1, wherein R.sub.3 is substituted such that R.sub.3 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. 14. The compound according to claim 1, wherein R.sub.3 comprises a basic nitrogen atom that is capable of interacting with a carboxylic acid side chain of an active site residue of a protein. 15. The compound of claim 14, wherein the basic nitrogen of R.sub.3 is separated from the ring atom to which R.sub.3 is attached by between 1-5 atoms. 16. The compound of claim 14, wherein the basic nitrogen atom forms part of a primary, secondary or tertiary amine. 17. The compound of claim 14, wherein the basic nitrogen atom is a nitrogen ring atom of a heterocycloalkyl or a heteroaryl. 18. The compound according to claim 1, wherein M is CH; R.sub.7 is a substituted or unsubstituted (C.sub.1-10)alkyl; and R.sub.3 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, R-3 aminopiperidin-1-yl, R-3-amino-3-methylpiperidin-1-yl, and 3-amino-pyrrolidin-1-yl, each substituted or unsubstituted. 19. The compound according to claim 1, wherein R.sub.4 is selected from the group consisting of ##STR00067## wherein A is S, O or NR.sub.24; B is CR.sub.23 or N; R.sub.23 is independently selected from the group consisting of hydrogen, halo, perhalo(C.sub.1-10)alkyl, amino, thio, cyano, CF.sub.3, nitro, (C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl(C.sub.1-10)alkyl, heteroaryl (C.sub.1-5)alkyl, (C.sub.9-12)bicycloaryl, hetero(C.sub.8-12)bicycloaryl, carbonyl (C.sub.1-3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl, each substituted or unsubstituted; and R.sub.24 is independently selected from the group consisting of hydrogen, perhalo(C.sub.1 -10)alkyl, amino, (C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl(C.sub.1-10)alkyl, heteroaryl (C.sub.1-5)alkyl, (C.sub.9-12)bicycloaryl, hetero(C.sub.8-12)bicycloaryl, carbonyl (C.sub.1 -3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl, each substituted or unsubstituted. 20. The compound according to claim 1, wherein R.sub.4 is selected from the group consisting of ##STR00068## wherein u is 0, 1, 2, 3, 4, or 5; and each R.sub.18 is independently selected from the group consisting of halo, perhalo(C.sub.1 -10)alkyl, CF.sub.3, (C.sub.1-10)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, and carbonyl group, each substituted or unsubstituted. 21. The compound according to claim 1, wherein R.sub.4 is selected from the group consisting of ##STR00069## wherein s is 0, 1, 2, or 3; and each R.sub.7 is independently selected from the group consisting of halo, perhalo(C.sub.1 -10)alkyl, CF.sub.3, (C.sub.1-10)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, and carbonyl group, each substituted or unsubstituted. 22. The compound according to claim 1, wherein R.sub.2 is a substituted or unsubstituted (C.sub.1-10)alkyl. 23. The compound according to claim 1, wherein R.sub.2 is a substituted or unsubstituted (C.sub.1-4)alkyl. 24. The compound according to claim 1, wherein R.sub.2 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 (C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl(C .sub.1-10)alkyl, heteroaryl(C.sub.1-5)alkyl, (C.sub.9 -12)bicycloaryl, hetero(C.sub.4-12)bicycloaryl, carbonyl (C.sub.1-3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, sulfonyl (C.sub.1-3)alkyl, sulfinyl (C.sub.1-3)alkyl, imino (C.sub.1-3)alkyl, amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl, carbonyl group, and cyano, each substituted or unsubstituted. 25. The compound according to claim 1, wherein R.sub.2 is selected from the group consisting of ##STR00070## wherein A is S, O or NR.sub.24; B is CR.sub.23 or N; R.sub.23 is independently selected from the group consisting of hydrogen, halo, perhalo(C.sub.1-10)alkyl, amino, thio, cyano, CF.sub.3, nitro, (C .sub.1-10)alkyl, (C.sub.3 -12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl(C.sub.1-10)alkyl, heteroaryl (C.sub.1-5)alkyl, (C.sub.9 -12)bicycloaryl, hetero(C.sub.8-12)bicycloaryl, carbonyl (C.sub.1-3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl, each substituted or unsubstituted; and R.sub.24 is independently selected from the group consisting of hydrogen, perhalo(C.sub.1 -10)alkyl, amino, (C.sub.1-10)alkyl, (C.sub.3-12)cycloalkyl, hetero(C.sub.3-12)cycloalkyl, aryl(C.sub.1-10)alkyl, heteroaryl (C.sub.1-5)alkyl, (C.sub.9-12)bicycloaryl, hetero(C.sub.8-12)bicycloaryl, carbonyl (C.sub.1 -3)alkyl, thiocarbonyl (C.sub.1-3)alkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonyl group, aminosulfonyl, alkylsulfonyl, arylsulfonyl, and heteroarylsulfonyl, each substituted or unsubstituted. 26. The compound according to claim 1, wherein R.sub.2 is selected from the group consisting of ##STR00071## wherein t is 0, 1, 2, 3, 4, or 5; and each R.sub.18 is independently selected from the group consisting of halo, perhalo(C.sub.1 -10)alkyl, CF.sub.3, (C.sub.1-10)alkyl, alkenyl, alkynyl, aryl, heteroaryl, aminosulfonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aryloxy, heteroaryloxy, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, amino, thio, cyano, nitro, hydroxy, alkoxy, and carbonyl group, each substituted or unsubstituted. 27. A compound 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-ylmeth- yl}-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-pyr- imidin-1-ylmethyl}-benzonitrile (14); 2-{6-[3(.+-.)-Amino-azepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimi- din-1-ylmethyl}-benzonitrile; 2-[6-(2-Amino-ethylamino)-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl- methyl]-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-dih- ydro-2H -pyrimidin-1-ylmethyl}-benzonitrile; 2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihy- dro-2H -pyrimidin-1-ylmethyl}-benzonitrile; 6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-py- rimidin-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-pyrimi- din-1-ylmethyl}-benzonitrile; 6-[3(R)-Amino-piperidin-1-yl]-1-(2,5-di-chloro-benzyl)-3-methyl-1H-pyrimi- dine-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-dihydro- pyrimidin -1(2H)-yl)methyl)-4-fluorobenzonitrile. 28. A compound selected from the group consisting of: 2-{6-[3(R)-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimid- in-1-ylmethyl}-benzonitrile; 2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylm- ethyl}-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-d- ihydro-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-py- rimidine-2,4-dione; or a pharmaceutically acceptable salt of each of the above-mentioned compounds. 29. The compound according to claim 1, wherein the compound is in the form of a pharmaceutically acceptable salt. 30. The compound according to claim 1, wherein the compound is present in a mixture of stereoisomers. 31. The compound according to claim 1, wherein the compound is present in a single stereoisomer.