NOVEL FUNCTIONALIZED PURINE-2,6-DIONES AND THEIR USE IN MEDICINE

Abstract

There is provided compounds of formula (I), or pharmaceutically-acceptable salts thereof, wherein R.sup.1 to R.sup.4 and X.sup.1 to X.sup.5 have meanings provided in the description, which compounds are useful in the treatment of cancers.

##STR00001##

Claims

1. A compound of formula I ##STR00185## or a pharmaceutically-acceptable salt and/or prodrug thereof, wherein: any one to three of X.sup.1 to X.sup.5 represents a heteroatom selected from N, O and S, with the provisos that only one of X.sup.1 to X.sup.5 may represent O or S, if representing a heteroatom, X.sup.1 and X.sup.4 may only represent N, and X.sup.1 and X.sup.4 may not both represent N, with the remainder of X.sup.1 and X.sup.4 representing C, and the remainder of X.sup.2, X.sup.3 and X.sup.5 representing CR.sup.5; R.sup.1 represents (i) heteroaryl optionally substituted by one or more groups selected from E.sup.1, or heterocyclyl optionally substituted by one or more groups independently selected from E.sup.2, such as wherein each such heteroaryl or heterocyclyl group is attached via a constituent heteroatom, (ii) —NR.sup.a1R.sup.a2, —OR.sup.a3, —S(O).sub.pR.sup.a4 or —S(O).sub.qNR.sup.a5, (iii) C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-10 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from E.sup.3, (i) aryl optionally substituted by one or more groups independently selected from E.sup.4, or (ii) halo; R.sup.2 and R.sup.3 each independently represent H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl or C.sub.2-4 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from G.sup.a1; R.sup.4 represents aryl optionally substituted by one or more groups independently selected from E.sup.5, or heteroaryl optionally substituted by one or more groups independently selected from E.sup.6; R.sup.5 represents H, C.sub.1-4 alkyl, C.sub.2-4 alkenyl or C.sub.2-4 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from G.sup.a2, aryl optionally substituted by one or more groups independently selected from G.sup.a3, heterocycyl optionally substituted by one or more groups independently selected from G.sup.a4, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.a5; R.sup.a1 to R.sup.a5 each independently represent C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-10 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from G.sup.b1, aryl optionally substituted by one or more groups independently selected from G.sup.b2, or heteroaryl optionally substituted by one or more groups independently selected from G.sup.b3, or one of R.sup.a1 and R.sup.a2 may alternatively represent H; each of E.sup.1 to E.sup.6 independently represents halo, ═O, —NR.sup.b1R.sup.b2, —OR.sup.b3, —S(O).sub.pR.sup.b4, —S(O).sub.qNR.sup.b5, —C(O)R.sup.b6, —NR.sup.b7C(O)R.sup.b8, C.sub.1-8 alkyl, C.sub.2-8 alkenyl or C.sub.2-8 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from G.sup.c1, heterocyclyl optionally substituted by one or more groups independently selected from G.sup.c2, or aryl optionally substituted by one or more groups independently selected from G.sup.c3; each of G.sup.a1 to G.sup.a5, G.sup.b1 to G.sup.b3, and G.sup.c1 to G.sup.c3 independently represent halo, ═O, —NR.sup.c1R.sup.c2, —OR.sup.c3, —S(O).sub.pR.sup.c4, —S(O).sub.qNR.sup.c5, —C(O)R.sup.c6, —NR.sup.c7C(O)R.sup.c8, C.sub.1-8 alkyl, C.sub.2-8 alkenyl or C.sub.2-8 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from W.sup.a1, heterocyclyl optionally substituted by one or more groups independently selected from W.sup.a2, heteroaryl optionally substituted by one or more groups independently selected from W.sup.a3, or aryl optionally substituted by one or more groups independently selected from W.sup.a4; each of R.sup.b1 to R.sup.b8, and R.sup.c1 to R.sup.c8 independently represents H, C.sub.1-8 alkyl, C.sub.2-8 alkenyl or C.sub.2-8 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from W.sup.b1, heterocyclyl optionally substituted by one or more groups independently selected from W.sup.b2, heteroaryl optionally substituted by one or more groups independently selected from W.sup.b3, or aryl optionally substituted by one or more groups independently selected from W.sup.b4, or alternatively any of R.sup.b1 and R.sup.b2, R.sup.b7 and R.sup.b8, R.sup.c1 and R.sup.c2, and R.sup.c7 and R.sup.c8 may be linked, together with the atoms to which they are attached, to form a 4- to 6-membered ring, which ring optionally contains one further heteroatom and which ring optionally is substituted by one or more groups independently selected from halo, C.sub.1-3 alkyl optionally substituted by one or more halo, and ═O; each of W.sup.a1 to W.sup.a4, and W.sup.b1 to W.sup.b4 independently represents halo, ═O, —NR.sup.d1R.sup.d2, —OR.sup.d3, —S(O).sub.pR.sup.d4, —S(O).sub.qNR.sup.d5, —C(O)R.sup.d6, —NR.sup.d7C(O)R.sup.d8, C.sub.1-8 alkyl, C.sub.2-8 alkenyl or C.sub.2-8 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from Z.sup.1, heterocyclyl optionally substituted by one or more groups independently selected from Z.sup.2, or aryl optionally substituted by one or more groups independently selected from Z.sup.3; each R.sup.d1 to R.sup.d8 independently represents H, C.sub.1-3 alkyl, C.sub.2-3 alkenyl or C.sub.2-3 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more fluoro; each Z.sup.1 to Z.sup.3 independently represents halo, ═O, —NR.sup.e1R.sup.e2, —OR.sup.e3, —S(O).sub.pR.sup.e4, —S(O).sub.qNR.sup.e5, —C(O)R.sup.e6, —NR.sup.e7C(O)R.sup.e8; each R.sup.e1 to R.sup.e8 represents H or C.sub.1-3 alkyl, wherein the alkyl group is optionally substituted by one or more fluoro; and each p and q independently represents 0, 1 or 2.

2. A compound as claimed in claim 1, wherein: X.sup.1 and X.sup.4 represent C; and any one to three of X.sup.2, X.sup.3 and X.sup.5 represents a heteroatom selected from N, O and S, with the proviso that only one of X.sup.2, X.sup.3 and X.sup.5 may represent O or S.

3. A compound as claimed in claim 1, wherein: X.sup.1 and X.sup.4 represent C; X.sup.2 represents N; X.sup.3 represents N or CR.sup.5; and X.sup.5 represents O.

4. A compound as claimed in claim 1, wherein: X.sup.1 and X.sup.4 represent C; X.sup.2 represents N; X.sup.3 represents N; and X.sup.5 represents O.

5. A compound as claimed in claim 1, wherein R.sup.1 represents: (i) heteroaryl optionally substituted by one or more groups selected from E.sup.1, or heterocyclyl optionally substituted by one or more groups independently selected from E.sup.2, such as wherein each such heteroaryl or heterocyclyl group is attached via a constituent heteroatom; (ii) —NR.sup.a1R.sup.a2, —OR.sup.a3, —S(O).sub.pR.sup.a4 or —S(O).sub.qNR.sup.a5; or (iii) C.sub.1-10 alkyl, C.sub.2-10 alkenyl or C.sub.2-10 alkynyl, wherein each such alkyl, alkenyl or alkynyl group is optionally substituted by one or more groups independently selected from E.sup.3.

6. A compound as claimed in claim 1, wherein R.sup.1 represents: (i) heterocyclyl optionally substituted by one or more groups independently selected from E.sup.2, such as wherein each such heteroaryl or heterocyclyl group is attached via a constituent heteroatom; (ii) —NR.sup.a1R.sup.a2, —OR.sup.a3, —S(O).sub.pR.sup.a4 or —S(O).sub.qNR.sup.a5, wherein p represents 0 or 2; or (iii) C.sub.1-10 alkyl, optionally substituted by one or more groups independently selected from E.sup.3.

7. A compound as claimed in claim 1, wherein: R.sup.a1 represents H, C.sub.1-10 alkyl or C.sub.2-10 alkenyl, each optionally substituted with one or more groups independently selected from G.sup.b1; R.sup.a2 represents C.sub.1-10 alkyl or C.sub.2-10 alkenyl, each optionally substituted with one or more groups independently selected from G.sup.b1; R.sup.a3 represents C.sub.1-10 alkyl, optionally substituted with one or more groups independently selected from G.sup.b1; and/or R.sup.a4 represents C.sub.1-10 alkyl, optionally substituted with one or more groups independently selected from G.sup.b1.

8. A compound as claimed in claim 1, wherein where R.sup.1 represents heterocyclyl, the heterocyclyl group may: (a) be saturated; and/or (b) comprise 4 to 8 atoms.

9. A compound as claimed in claim 1, wherein where R.sup.1 represents heterocyclyl, the heterocyclyl may be selected from: piperidinyl, octahydro-1H-isoindolyl, azetidinyl, morpholinyl, piperazinyl, azepanyl, pyrrolidinyl, and diazepanyl, optionally substituted by one or more groups selected from E.sup.2.

10. A compound as claimed in claim 1, wherein: (I) each E.sup.2 group, where present, may represent halo, —NR.sup.b1R.sup.b2, —OR.sup.b3, C.sub.1-8 alkyl optionally substituted by one or more groups independently selected from G.sup.c1, heterocyclyl optionally substituted by one or more groups independently selected from G.sup.c2, or aryl optionally substituted by one or more groups independently selected from G.sup.c3; and/or (II) each E.sup.3 group, where present, may represent aryl optionally substituted by one or more groups independently selected from G.sup.c3.

11. A compound as claimed in claim 1, wherein: R.sup.b1 and R.sup.b2 may independently represent H or C.sub.1-3 alkyl optionally substituted by one or more group selected from ═O and —O.sup.tBu; R.sup.b3 may represent H or C.sub.1-3 alkyl (e.g. methyl); G.sup.c1 may represent ═O, —NR.sup.c1R.sup.c2 or —OR.sup.c3, particularly where R.sup.c1 and R.sup.c2 represent H and/or (e.g. and) R.sup.c3 represents H or C.sub.1-4 alkyl (e.g. methyl or .sup.tBu); and/or (e.g. and) G.sup.c2 may represent ═O.

12. A compound as claimed in claim 1, wherein R.sup.1 is selected from the following groups: ##STR00186## ##STR00187## wherein the dashed bond indicates the position of attachment.

13. A compound as claimed in claim 1, wherein: R.sup.2 and R.sup.3 each independently represent C.sub.1-4 alkyl optionally substituted by one or more groups independently selected from G.sup.a1.

14. A compound as claimed in claim 1, wherein: R.sup.2 and R.sup.3 each represent methyl.

15. A compound as claimed in claim 1, wherein: R.sup.4 represents aryl optionally substituted by one or more groups independently selected from E.sup.5.

16. A compound as claimed in claim 1, wherein: R.sup.4 represents phenyl optionally substituted by one or more groups independently selected from E.sup.5.

17. A compound as claimed in claim 1, wherein the compound of formula I is a compound of formula Ia ##STR00188## wherein R.sup.1, R.sup.2, R.sup.3 and E.sup.5 are as defined in claim 1, and wherein r represents 0 to 5.

18. A compound as claimed in claim 1, wherein: each E.sup.5 independently represents halo, or C.sub.1-8 alkyl optionally substituted by one or more groups independently selected from G.sup.c1.

19. A compound as claimed in claim 1, wherein: each E.sup.5 independently represents halo, or C.sub.1-3 alkyl optionally substituted by one or more groups independently selected from G.sup.c1.

20. A compound as claimed in claim 1, wherein: each E.sup.5 independently represents chloro or methyl.

21. A compound as claimed in claim 1, wherein the compound of formula I is a compound of formula Ib ##STR00189## wherein R.sup.2, R.sup.3, E.sup.5 and r are as defined in claim 1, and wherein: Q.sup.1 and Q.sup.2 represent a group as defined herein for R.sup.a1 and R.sup.a2, respectively, or Q.sup.1 and Q.sup.2 are linked to form, together with the N to which they are attached, heterocyclyl optionally substituted by one or more groups independently selected from E.sup.2, as defined herein for R.sup.1.

22-23. (canceled)

24. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof.

25. (canceled)

26. The method of claim 24, wherein the cancer is a solid tumour cancer, such as a cancer selected from sarcomas, carcinomas, and lymphomas.

27. The method of claim 24, wherein the cancer is a hormone-responsive cancer.

28. The method of claim 24, wherein the cancer is hormone-responsive breast cancer.

29. The method of claim 24, wherein the cancer is oestrogen-responsive (ER) or progesterone-responsive (PR) breast cancer.

30. A pharmaceutical composition comprising a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically-acceptable excipient.

31. (canceled)

32. A combination product comprising: (I) a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof; and (II) one or more other therapeutic agent that is useful in the treatment of cancer, wherein each of components (I) and (II) is formulated in admixture, optionally with one or more a pharmaceutically-acceptable excipient.

33. A kit-of-parts comprising: (a) a pharmaceutical formulation as defined in claim 30; and (b) one or more other therapeutic agent that is useful in the treatment of cancer, optionally in admixture with one or more pharmaceutically-acceptable excipient, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

34. A process for the preparation of a compound as defined in claim 1, or a pharmaceutically acceptable salt thereof, comprising the step of: (i) reacting a compound of formula II ##STR00190## wherein R.sup.2 to R.sup.4 and X.sup.1 to X.sup.5 are as defined in claim 1 and LG.sup.1 represents a suitable leaving group, with a compound of formula III
H—R.sup.1  (III) wherein R.sup.1 is as defined in claim 1, in the presence of a suitable solvent; (ii) reacting a compound of formula IV ##STR00191## wherein R.sup.1 to R.sup.3 are as defined in claim 1, with a compound of formula V ##STR00192## wherein X.sup.1 to X.sup.5 and R.sup.4 are as defined in claim 1, and LG.sup.2 represents a suitable leaving group, in the presence of a suitable solvent and a suitable base; (iii) reaction of a protected derivative of a compound of formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, under conditions suitable for the removal of the protecting group(s).

35. A compound as defined in claim 1, selected from 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-methoxy-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[(2-hydroxyethyl)amino]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(dimethylamino)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(diethylamino)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(methylamino)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(ethylsulfanyl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(cyclohexylsulfanyl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[bis(prop-2-en-1-yl)amino]-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperidin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(4-methylpiperidin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(octahydro-1H-isoindol-2-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(morpholin-4-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, tert-butyl 4-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylate, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4-hexylpiperazin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(4-butylpiperazin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4-ethylpiperazin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(4-methylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4-(2-hydroxyethyl)piperidin-1-yl]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(azepan-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1,3,8-triazaspiro[4.5]decane-2,4-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(ethanesulfonyl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(cyclohexanesulfonyl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(3-aminopyrrolidin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, tert-butyl N-[1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)azetidin-3-yl]carbamate, 8-(1,4-diazepan-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(pyrrolidin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3,5-dimethylpiperazin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[4-(2-aminoethyl)piperazin-1-yl]-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4-(2-hydroxyethyl)piperazin-1-yl]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(4-acetylpiperazin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(3-methylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3-hydroxypyrrolidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3-hydroxyazetidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(azetidin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4-hydroxypiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[4-(aminomethyl)piperidin-1-yl]-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, methyl 1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidine-4-carboxylate, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4-(hydroxymethyl)piperidin-1-yl]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3-fluoropiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(cyclopropylamino)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4-methoxypiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3-hydroxypiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4-(dimethylamino)piperidin-1-yl]-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-[(3S)-3-methylpiperazin-1-yl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-[(3R)-3-methylpiperazin-1-yl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(dimethylamino)-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(propylamino)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(benzylamino)-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4-methylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-methoxy-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(4-hexylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(4-butylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(4-ethylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[4-(2-hydroxyethyl)piperazin-1-yl]-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[4-(2-methoxyethyl)piperazin-1-yl]-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4-phenylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(4-cyclohexylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,8-trimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-propyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(propan-2-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-benzyl-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, tert-butyl N-{2-[4-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazin-1-yl]ethyl}carbamate, tert-butyl N-{[1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-4-yl]methyl}carbamate, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(1H-imidazol-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(1H-pyrazol-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, ethyl 1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-1H-pyrazole-4-carboxylate, 8-chloro-7-{[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[2-(3,4-dichlorophenyl)-1,3-oxazol-4-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[2-(3,4-dichlorophenyl)-1,3-oxazol-4-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetra hydro-1H-purine-2,6-dione, 7-{[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[2-(4-chlorophenyl)-1,3-thiazol-5-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[2-(4-chlorophenyl)-1,3-thiazol-5-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[3-(4-methoxyphenyl)-1,2-oxazol-5-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[3-(4-methoxyphenyl)-1,2-oxazol-5-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-7-{[5-(4-methylphenyl)-1,2-oxazol-3-yl]methyl}-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-1,3-dimethyl-7-{[5-(4-methylphenyl)-1,2-oxazol-3-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, ethyl 7-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate, 2-[(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)amino]ethane-1-sulfonic acid, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(3-oxopiperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, tert-butyl 2-[(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)amino]acetate, 4-{[(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)amino]methyl}piperidine-1-carboximidamide, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-{[(2,4-dimethoxyphenyl)methyl]amino}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-amino-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(3-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 4-{5-[(8-chloro-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-7-yl)methyl]-1,3,4-oxadiazol-2-yl}benzonitrile 8-chloro-1,3-dimethyl-7-{[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(6-chloropyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-1,3-dimethyl-7-{[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(4-chloro-3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(4-chloro-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(3-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, tert-butyl 4-(1,3-dimethyl-7-{[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylate, 8-chloro-7-{[5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-1,3-dimethyl-7-({5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-({5-[4-(methanesulfonylmethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, tert-butyl 4-(7-{[5-(4-aminophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylate, 8-chloro-1,3-dimethyl-7-{[5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-7-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 4-(5-{[1,3-dimethyl-2,6-dioxo-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purin-7-yl]methyl}-1,3,4-oxadiazol-2-yl)benzonitrile 1,3-dimethyl-8-(piperazin-1-yl)-7-{[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-8-(piperazin-1-yl)-7-({5-[6-(piperazin-1-yl)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-7-{[5-(4-nitrophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(4-chloro-3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(4-chloro-3-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-8-(piperazin-1-yl)-7-({5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-({5-[4-(methanesulfonylmethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(1H-indazol-5-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1,3-dimethyl-7-{[5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[4-(dimethylamino)piperidin-1-yl]-7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[4-(aminomethyl)piperidin-1-yl]-7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 4-{[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)amino]methyl}piperidine-1-carboximidamide, 7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-[3-(trifluoromethyl)piperazin-1-yl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-[4-(hydroxymethyl)piperidin-1-yl]-7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-(1,4-diazepan-1-yl)-7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 3-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)amino]propanamide, N-{2-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)amino]ethyl}methanesulfonamide, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-8-[3-(trifluoromethyl)piperazin-1-yl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-{[2-(dimethylamino)ethyl](methyl)amino}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidine-4-carboxamide, 8-{[2-(dimethylamino)ethyl](methyl)amino}-7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 1-(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperidine-4-carboxamide, 8-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, tert-butyl N-{2-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)sulfanyl]ethyl}carbamate, N-{2-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)sulfanyl]ethyl}acetamide, 8-[(2-aminoethyl)sulfanyl]-7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, 8-chloro-7-{[1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione, and 7-{[1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione; or a pharmaceutically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0254] FIG. 1 shows NUDT5 stabilization by inhibitors when added to cell lysates, as described in Biological Assay 2.

[0255] FIG. 2 shows NUDT5 stabilization by inhibitors added to cells in culture, as described in Biological Assay 2.

[0256] FIG. 3 shows the isothermal dose response fingerprint for certain inhibitors, as described in Biological Assay 2.

[0257] FIG. 4(a) shows thin layer chromatography (TLC) of products formed following processing of .sup.32P-PAR by recombinant PARG and NUDT5 in the absence or presence of Compound 19 and PP.sub.i in vitro, as described in Biological Assay 3.

[0258] FIG. 4(b) shows the concentration of inhibitors used in T47D.sup.WT/M cell culture experiments, as well as the chemical structures and IC.sub.50 values, as described in Biological Assay 3.

[0259] FIG. 4(c) shows serum-starved T47D.sup.WT cells expressing Nuc-luc FRTTO luciferase construct in the absence or presence of NUDT5 inhibitors prior to treatment with 10 nM R5020 and luminescence measurement, as described in Biological Assay 3. Top, a representative measurement of bioluminescence intensity over 60 minutes of R5020 treatment; bottom, box-and-whisker plots of bioluminescence quantitations from six independent experiments (center line, median; box limits, upper and lower quartiles; whiskers, minima and maxima; individual data points also shown). ns—not significant, *—p<0.05, **—p<0.01, ***—p<0.001; repeated measures two-way ANOVA analysis.

[0260] FIG. 4(d) shows histone displacement determined by chromatin immunoprecipitation (ChIP) using a histone H1-specific antibody prior to (Starved) or following 30 minutes of R5020 (+R5020) in the presence or absence of NUDT5 inhibitors in T47D.sup.M cells, as described in Biological Assay 3. Data from a representative experiment is presented as mean fold change (+R5020/Starved)±SD of five different histone H1 contact regions.

[0261] FIG. 4(e) shows progesterone-dependent and -independent gene expression analysis in the presence or absence (−) of NUDT5 inhibitors following R5020 treatment (6 hours) by RT-qPCR with T47D.sup.M cells, as described in Biological Assay 3. Data represents the mean±SEM log(mRNA abundance) normalized to serum-starved cells without R5020 treatment from three (progesterone-dependent) or two (progesterone-independent) independent experiments. ns—not significant, *—p<0.05, **—p<0.01; one-way ANOVA analysis.

[0262] FIG. 4(f) shows R5020-induced cell proliferation of T47D.sup.M cells in the absence or presence of NUDT5 inhibitors was assayed by BrdU incorporation after 24 hours, as described in Biological Assay 3. Mean±SEM of individual BrdU chemiluminescence signals are displayed without R5020 treatment (Starved) and following R5020 treatment (+R5020) from two independent experiments. RLU; relative luminescence units. ns—not significant, **—p<0.01, ****—p<0.0001; one-way ANOVA analysis.

[0263] FIG. 5 shows the results of CETSA experiments performed with cells treated in culture, as described in Biological Assay 2. Means±SEM from two independent experiments are shown. NUDT5 stabilization was relative to the 37° C. DMSO control and SOD1 was used as a loading control. ns—not significant; *—p<0.05; one-way ANOVA.

[0264] For the avoidance of doubt, the numbering used in figure legends refers to the numbering of compounds of the examples as provided herein.

EXAMPLES

[0265] The present invention will be further described by reference to the following examples, which are not intended to limit the scope of the invention in any way.

[0266] In the event that there is a discrepancy between nomenclature and any compounds depicted graphically, then it is the latter that presides (unless contradicted by any experimental details that may be given or unless it is clear from the context).

Experimental Procedures

[0267] Starting materials and intermediates used in the synthesis of compounds described herein are commercially available or can be prepared by the methods described herein or by methods known in the art.

[0268] Experiments were generally carried out under inert atmosphere (nitrogen or argon), particularly in cases where oxygen- or moisture-sensitive reagents or intermediates were used.

[0269] Mass spectrometry data are reported from liquid chromatography-mass spectrometry (LC-MS) using electrospray ionization. Chemical shifts for NMR data are expressed in parts per million (ppm, δ) referenced to residual peaks from the deuterated solvent used.

[0270] For syntheses referencing general procedures, reaction conditions (such as length of reaction or temperature) may vary. In general, reactions were followed by thin layer chromatography or LC-MS, and subjected to work-up when appropriate. Purifications may vary between experiments: in general, solvents and the solvent ratios used for eluents/gradients were chosen to provide an appropriate R.sub.f and/or retention time.

[0271] Where applicable, compound names indicated in respect of the following examples have been generated using the structure naming function of ChemBioDraw Ultra, Version 12.0.

General Procedures

General Procedure A: Synthesis of Substituted 2-chloromethyl oxadiazoles

[0272] ##STR00025##

i) The corresponding acid chloride (1 equiv.) was dissolved in dichloromethane (0.2 mol/L) and then added dropwise to a stirring solution of hydrazine hydrate (4 equiv.) in EtOH (0.8 mol/L) at 0° C. The reaction was allowed to warm to room temperature and monitored for completion using TLC. Upon completion, the dichloromethane was removed under reduced pressure. The resultant suspension was then cooled to 0° C. and the precipitated product was collected by suction filtration and washed with cold water. This crude product was dried overnight in vacuo and used without further purification.
ii) Benzohydrazide (1 equiv.) was added to 2-chloroacetic acid (1 equiv.) dissolved in POCl.sub.3 (0.1-0.5 mol/L). The vessel was thoroughly flushed with nitrogen gas and sealed, then the mixture was heated to 150° C. for 15 minutes in a Biotage microwave reactor. Solids were then rinsed down into the solution with a small amount of POCl.sub.3 and the reaction was heated at 150° C. for an additional 5 minutes. Upon completion, POCl.sub.3 was removed under reduced pressure. The crude mixture was purified using silica gel chromatography in a mixture of iso-hexane and ethyl acetate.

General Procedure B: Alkylation of 8-Functionalized theophyllines

[0273] ##STR00026##

[0274] The corresponding 2-chloromethyl-oxadizole was added to a suspension of 8-functionalized theophylline (1.1 equiv.) and K.sub.2CO.sub.3 (1.2 equiv.) in DMF (˜0.2 mol/L) and stirred at 70° C. overnight in a sealed vessel. Upon completion, the reaction mixture was diluted with H.sub.2O and organics were extracted with EtOAc. The combined organics were washed with 1 M HCl, saturated NaHCO.sub.3, H.sub.2O and brine, followed by additional drying over MgSO.sub.4. The crude mixture was then purified by automated flash chromatography in a mixture of iso-hexane and ethyl acetate.

General Procedure B′: Alkylation of 8-bromo- or 8-chloro-theophylline

[0275] ##STR00027##

[0276] The corresponding R.sub.4 substituted, 2-chloromethyl-heterocycles were added to a suspension of 8-bromo- or 8-chloro-theophylline (1.1 equiv.) and K.sub.2CO.sub.3 (1.2 equiv.) in DMF (˜0.2 mol/L) and stirred at 70° C. overnight in a sealed vessel. Upon completion, the reaction mixture was diluted with H.sub.2O and organics were extracted with EtOAc. The combined organics were washed with 1 M HCl, saturated NaHCO.sub.3, H.sub.2O and brine, followed by additional drying over MgSO.sub.4. The crude mixture was then purified by automated flash chromatography in a mixture of iso-hexane and ethyl acetate.

General Procedure C: Aromatic Substitution of 8-bromotheophylline

[0277] ##STR00028##

[0278] Amines or thiols (2-5 equivalents) were added to functionalized 8-Br-theophylline suspended in ethanol, heated to 70° C. and stirred overnight. Upon completion, the reaction mixture was cooled to 0° C. and the precipitated product was collected by suction filtration. In cases where the product did not precipitate or was of insufficient purity, the crude mixture was purified using automated flash chromatography in mixtures of iso-hexane and ethyl acetate or dichloromethane and methanol.

General Procedure C′: Aromatic Substitution of 8-bromo- or 8-chloro-theophylline

[0279] ##STR00029##

[0280] Amines or thiols (2-5 equivalents) were added to functionalized 8-Br- or 8-Cl-theophylline suspended in ethanol, heated to 70° C. and stirred overnight. Upon completion, the reaction mixture was cooled to 0° C. and the precipitated product was collected by suction filtration. In cases where the product did not precipitate or was of insufficient purity, the crude mixture was purified using preparative HPLC, crystallization, or automated flash chromatography in mixtures of iso-hexane and ethyl acetate or dichloromethane and methanol.

General Procedure D: Synthesis of 8-alkyl-theophylline Derivatives

[0281] ##STR00030##

[0282] 8-alkyl theophylline derivatives were prepared as previously reported (Merlos, M., et al. Eur. J. Med. Chem. 25, 653-658 (1990)). Briefly, 5,6-diamino-1,3-dimethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione was dissolved in methanol followed by the addition of the desired carboxylic acid and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCl). Upon disappearance of the starting material (˜24 hours), methanol was evaporated and the crude mixture was purified by silica gel chromatography. The resultant carboxamide was then dissolved in a mixture of MeOH and 10% NaOH in H.sub.2O w/w (1:2) and stirred at 100° C. for 3 hours. Upon completion, the mixture was cooled to room temperature, acidified with HCl and the precipitated product was collected by suction filtration and washed with water.

General Procedure D′: t-butoxycarbonyl (Boc) or 2,4-dimethoxybenzyl (Dmb) Deprotection of R.SUB.1 .Derivatives

[0283] ##STR00031## ##STR00032##

[0284] In some instances, a t-butoxycarbonyl (Boc) or a 2,4-dimethoxybenzyl (DMB) protecting group was present on the nucleophilic R.sub.1 groups used in General Procedure C′. In these cases, the subsequent deprotection to give the unprotected R.sub.1 was carried out under standard acidic Boc/DMB-deprotection conditions. Briefly, trifluoroacetic acid (TFA) was added to functionalized Boc-protected intermediates dissolved in dichloromethane (CH.sub.2Cl.sub.2). Reaction progress was monitored by thin layer chromatography or LC-MS. Upon completion, CH.sub.2Cl.sub.2 and TFA were removed under reduced pressure and the resultant residue was either used without subsequent purification, or could be purified by flash column chromatography, preparative HPLC or crystallization.

General Chemical Syntheses

[0285] ##STR00033##

##STR00034##

Synthesis of Intermediates

[0286] ##STR00035##

[0287] 2-(chloromethyl)-5-(3,4-dichlorophenyl)-1,3,4-oxadiazole was prepared according to General Procedure A on a 5 mmol scale. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.79 (s, 2H), 7.63 (d, J=8.37 Hz, 1H), 7.93 (dd, J=8.37, 2.05 Hz, 1H), 8.18 (d, J=2.05 Hz, 1H). .sup.13C NMR (101 MHz, CHLOROFORM-d) ppm 32.9, 123.1, 126.1, 128.8, 131.4, 133.9, 136.8, 162.6, 164.2. HPLC-MS t.sub.R=1.94 minutes, 100% purity, m/z calculated for [C.sub.9H.sub.5Cl.sub.3N.sub.2O+H]=263, found 263 (713 mg, 55%).

##STR00036##

[0288] 8-bromo-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione was prepared according to General Procedure B on a 5 mmol scale. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 3.41 (s, 3H), 3.60 (s, 3H), 5.91 (s, 2H), 7.61 (d, J=8.37 Hz, 1H), 7.86 (dd, J=8.37, 2.05 Hz, 1H), 8.11 (d, J=1.90 Hz, 1H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 28.1, 30.0, 41.3, 108.8, 122.9, 126.1, 128.3, 128.8, 131.3, 133.8, 136.9, 148.4, 151.1, 154.3, 160.5, 164.1. HPLC-MS t.sub.R=1.84 minutes, 100% purity, m/z calculated for [C.sub.16H.sub.11BrCl.sub.2N.sub.6O.sub.3+H]=485.0, found 485.0, (1.03 g, 44% yield).

##STR00037##

[0289] 2-(chloromethyl)-5-(3-methylphenyl)-1,3,4-oxadiazole was prepared as outlined in general procedure A on a 10 mmol scale. .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.45 (s, 3H), 4.79 (s, 2H), 7.30-7.47 (m, 2H), 7.82-7.94 (m, 2H). HPLC-MS t.sub.R=1.80 minutes, 90% purity, m/z calculated for [C.sub.10H.sub.9ClN.sub.2O+H]=209, found 209 (1.72 g, 83%).

##STR00038##

[0290] 8-bromo-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione was prepared as outlined in general procedure B on a 0.9 mmol scale. .sup.1H NMR (400 MHz, CHLOROFORM-d) ppm 2.43 (s, 3H), 3.41 (s, 3H), 3.59 (s, 3H), 5.90 (s, 2H), 7.32-7.44 (m, 2H), 7.73-7.82 (m, 1H), 7.84 (dt, J=1.50, 0.83 Hz, 1H). .sup.13C NMR (101 MHz, CHLOROFORM-d) ppm 21.3, 28.1, 30.0, 41.4, 108.9, 123.0, 124.2, 127.6, 128.3, 129.0, 133.0, 139.0, 148.3, 151.2, 154.2, 159.9, 166.1. HPLC-MS t.sub.R=1.70 minutes, 95.9% purity, m/z calculated for [C.sub.17H.sub.15BrN.sub.6O.sub.3+H]=431.1, found 431.1 (199 mg, 55%).

Example Compounds

[0291] Compounds of the examples are described in Table 1 below. These compounds were prepared in accordance with the general procedures indicated.

TABLE-US-00001 TABLE 1 Structure Name General .sup.1H-NMR, .sup.13C-NMR Example Procedure MS [M + H].sup.+ 1 C.sup.(1) [00039] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- methoxy-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 3.18 (s, 3 H), 3.41 (s, 3 H, 4.14 (s, 3 H), 5.64 (s, 2 H), 7.85-7.95 (m, 2 H), 8.13 (s, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 27.8, 29.9, 37.8, 58.4, 102.7, 123.1, 126.0, 128.7, 131.3, 133.8, 136.6, 146.7, 151.6, 154.7, 156.3, 161.6, 163.9. 437 2 C [00040] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- [(2-hydroxyethyl)amino]-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 3.14 (s, 3 H), 3.38 (s, 3 H), 3.43 (q, J = 6.1 Hz, 2 H), 3.56 (q, J = 5.7 Hz, 2 H), 4.77 (t, J = 6.0 Hz, 1 H), 5.68 (s, 2 H), 7.44 (t, J = 5.5 Hz, 1 H), 7.88-7.96 (m, 2 H), 8.18 (d, J = 1.7 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 27.8, 29.9, 37.3, 46.1, 62.3, 102.2, 122.6, 126.1, 128.8, 131.4, 133.9, 137.1, 148.2, 151.5, 154.1, 154.3, 161.7, 164.3. 466 3 C [00041] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- (dimethylamino)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.04 (s, 6 H), 3.37 (s, 3 H), 3.56 (s, 3 H), 5.71 (s, 2 H), 7.59 (d, J = 8.34 Hz, 1 H), 7.84 (dd, J = 8.34, 2.02 Hz, 1 H), 8.10 (d, J = 2.02 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 27.8, 29.8, 40.4, 41.9, 104.1, 123.1, 126.0, 128.8, 131.3, 133.8, 136.7, 148.3, 151.7, 154.6, 157.9, 162.2, 163.9. 450 4 C [00042] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- (diethylamino)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3 H), 2.57 (br. s., 4 H), 3.37 (s, 6 H), 3.57 (s, 3 H), 5.64 (s, 2 H), 7.60 (d, J = 8.34 Hz, 1 H), 7.79-7.93 (m, 1 H), 8.11 (d, J = 1.77 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 13.0, 27.7, 29.8, 40.1, 46.3, 104.2, 123.1, 126.0, 128.7, 131.3, 133.7, 136.6, 148.3, 151.7, 154.6, 156.7, 162.2, 163.7. 478 5 C [00043] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazo-2-yl]methyl}-1,3- dimethyl-8-(methylamino)-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 2.92 (d, J = 4.58 Hz, 3 H), 3.14 (s, 3 H), 3.40 (s, 3 H), 5.64 (s, 2 H), 7.36 (q, J = 4.53 Hz, 1 H), 7.86-7.96 (m, 2 H), 8.10-8.19 (m, 1 H). 436 6 C [00044] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- (ethylsulfanyl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43 (t, J = 7.35 Hz, 3 H), 3.32 (q, J = 7.42 Hz, 2 H), 3.40 (s, 3 H), 3.60 (s, 3 H), 5.83 (s, 2 H), 7.59 (d, J = 8.53 Hz, 1 H), 7.86 (dd, J = 8.45, 1.97 Hz, 1 H), 8.11 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 14.9, 27.9, 28.0, 29.9, 39.9, 107.8, 123.0, 126.1, 128.8, 131.3, 133.8, 136.7, 140.8, 148.9, 151.4, 154.4, 161.1, 164.0. 467 7 C [00045] 8-(cyclohexylsulfanyl)-7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27-1.35 (m, 1 H), 1.37-1.64 (m, 5 H), 1.77 (dt, J = 13.11, 3.95 Hz, 2 H), 2.01-2.16 (m, 2 H), 3.39 (s, 3 H), 3.61 (s, 3 H), 3.76- 3.92 (m, 1 H), 5.85 (s, 2 H), 7.53-7.65 (m, 1 H), 7.86 (dd, J = 8.45, 1.97 Hz, 1 H), 8.10 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 25.4, 25.8, 28.0, 29.9, 33.4, 40.1, 48.3, 107.7, 123.1, 126.1, 128.8, 131.3, 133.8, 136.7, 148.9, 151.5, 151.5, 154.5, 161.3, 163.9. 521 8 C [00046] 8-[bis(prop-2-en-1-yl)amino]-7-{[5-(3,4-dichlorophenyl)- 1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.35 (3 H, s), 3.55 (s, 3 H), 3.94 (dt, J = 5.69, 1.26 Hz, 4 H), 5.17-5.29 (m, 4 H), 5.66 (s, 2 H), 5.80-5.94 (m, 2 H), 7.58 (d, J = 8.53 Hz 1 H), 7.81-7.89 (m, 1 H), 8.09 (d, J = 1.90 Hz, 1 H) 502 9 C [00047] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(piperidin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.58-1.71 (m, 6 H), 3.20-3.29 (m, 4 H), 3.37 (s, 3 H), 3.61 (s, 3 H), 5.63 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.45, 1.97 Hz, 1 H), 8.11 (d, J = 2.05 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 23.8, 25.4, 27.8, 29.8, 40.3, 51.6, 104.5, 123.1, 126.0, 128.7, 131.3, 133.8, 136.6, 148.1, 151.7, 154.8, 157.5, 162.2, 163.8. 490 10 C [00048] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(4-methylpiperidin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98 (d, J = 6.63 Hz, 3 H), 1.30 (qd, J = 12.32, 3.95 Hz, 2 H), 1.57 (ddd, J = 11.06, 6.95, 3.79 Hz, 1 H), 1.73 (dd, J = 12.72, 2.29 Hz, 2 H), 3.02 (td, J = 12.48, 2.53 Hz, 2 H), 3.37 (s, 3 H), 3.51 (d, J = 12.48 Hz, 2 H), 3.56-3.62 (m, 3 H), 5.63 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.37, 2.05 Hz, 1 H), 8.11 (d, J = 2.05 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 21.7, 27.8, 29.8, 30.4, 33.6, 40.3, 51.0, 104.5, 123.1, 126.0, 128.7, 131.3, 133.8, 136.6, 148.1, 151.7, 154.8, 157.5, 162.2, 163.8 504 11 C [00049] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(octahydro-1H-isoindol-2-yl)-2,3,6,7-tetrahydro- 1H-purine-2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 1.29-1.59 (m, 8 H), 2.17-2.30 (m, 2 H), 3.15 (s, 3 H), 3.36 (s, 3 H), 3.52- 3.55 (m, 2 H), 3.62-3.66 (m, 2 H), 5.86 (s, 2 H), 7.85-7.94 (m, 2 H), 8.06-8.15 (m, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 22.6, 25.6, 27.7, 29.8, 37.3, 39.7, 53.8, 102.9, 123.0, 126.0, 128.8, 131.3, 133.8, 136.7, 149.3, 151.8, 154.2, 155.4, 162.5, 163.9 530 12 C [00050] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-{2-oxa-6-azaspiro[3.3]heptan-6-yl}-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 3.15 (s, 3 H), 3.37 (s, 3H), 4.42 (s, 4 H), 4.69 (s, 4 H), 5.61 (s, 2 H), 7.91 (q, J = 8.1 Hz, 2 H), 8.15 (s, 1 H). 504 13 C [00051] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(morpholin-4-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.20-3.34 (m, 4 H), 3.38 (s, 3 H), 3.57 (s, 3 H), 3.74-3.92 (m, 4 H), 5.68 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.45, 1.97 Hz, 1 H), 8.11 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 28.2, 30.2, 40.3, 51.0, 66.5, 105.1, 123.3, 126.3, 129.1, 131.7, 134.1, 137.1, 148.1, 151.9, 155.2, 156.4, 162.3, 164.3. 492 14 C [00052] tert-butyl 4-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)piperazine-1-carboxylate .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.47 (s, 9 H), 3.18-3.31 (m, 4 H), 3.38 (s, 3 H), 3.48-3.63 (m, 7 H), 5.68 (s, 2 H), 7.55-7.65 (m, 1 H), 7.87 (dd, J = 8.37, 2.05 Hz, 1 H), 8.12 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 27.8, 28.4, 29.9, 40.0, 50.4, 50.4, 80.3, 104.8, 123.0, 126.0, 128.8, 131.4, 133.8, 136.8, 147.7, 151.6, 154.5, 154.9, 156.1, 161.9, 164.0. 591 15 C [00053] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4- hexylpiperazin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.82-0.95 (m, 3 H), 1.30 (br. s., 6 H), 1.56 (br. s., 2 H), 2.48 (br. s., 2 H), 2.69 (br. s., 4 H), 3.37 (s, 3 H), 3.44 (br. s., 4 H), 3.56 (s, 3 H), 5.64 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.37, 2.05 Hz, 1 H), 8.11 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 14.0, 22.5, 27.0, 27.8, 29.9, 31.6, 40.2, 49.9 (br), 52.1, 58.5, 104.7, 123.0, 126.0, 128.8, 131.3, 133.8, 136.7, 147.8, 151.6, 154.8, 157.3, 162.0, 163.9. 575 16 C [00054] 8-(4-butylpiperazin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J = 7.35 Hz, 3 H), 1.38 (dq, J = 14.89, 7.41 Hz, 2 H), 1.67 (br. s., 4 H), 2.67 (br. s., 2 H), 2.91 (br.s., 2 H), 3.37 (s, 3 H), 3.43-3.65 (m, 7 H), 5.65 (s, 2 H), 7.61 (d, J = 8.37 Hz, 1 H), 7.87 (dd, J = 8.37, 2.05 Hz, 1 H), 8.12 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, DMSO-d.sup.6) δ ppm 13.9, 16.6, 20.1, 27.4, 28.2, 29.5, 49.7, 52.1, 57.4, 103.9, 123.5, 126.6, 128.1, 132.0, 132.4, 135.0, 147.3, 150.9, 153.8, 156.3, 162.6, 163.1 547 17 C [00055] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4- ethylpiperazin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.26 (br. s., 3 H), 2.71 (br. s., 2 H), 2.77-2.98 (m, 4 H), 3.37 (s, 3 H), 3.56 (s, 7 H), 5.65 (s, 2 H), 7.61 (d, J = 8.37 Hz, 1 H), 7.87 (dd, J = 8.45, 1.97 Hz, 1 H), 8.12 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, DMSO-d.sup.6) δ ppm 11.8, 27.4, 29.6, 49.7, 51.6, 51.7 (br), 104.0, 123.5, 126.6, 128.1, 132.0, 132.4, 135.0, 147.3, 150.9, 153.8, 156.3, 162.6, 163.1. 519 18 C [00056] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(4-methylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.56 (br. s., 3 H), 2.88 (br. s., 4 H), 3.37 (s, 3 H), 3.49-3.65 (m, 7 H), 5.65 (s, 2 H), 7.61 (d, J = 8.37 Hz, 1 H), 7.87 (dd, J = 8.45, 1.97 Hz, 1 H), 8.12 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, DMSO- d.sup.6) δ ppm 27.4, 29.5, 40.7, 45.7, 49.5, 53.9, 103.9, 123.5, 126.6, 128.1, 132.0, 132.4, 135.0, 147.3, 150.9, 153.8, 156.3, 162.6, 163.1. 505 19 C [00057] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 2.70-2.79 (m, 4 H), 3.12-3.21 (m, 7 H), 3.40 (s, 3 H), 5.69 (s, 2 H), 7.85-7.96 (m, 2 H), 8.15 (dd, J = 1.90, 0.32 Hz, 1 H). .sup.13C NMR (101 MHz, DMSO-d.sup.6) δ ppm 27.6, 29.7, 40.6, 45.1, 50.9, 104.1, 123.7, 126.8, 128.3, 132.2, 132.7, 135.2, 147.6, 151.1, 154.0, 156.8, 162.8, 163.3. 491 20 C [00058] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4- (2-hydroxyethyl)piperidin-1-yl]-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 1.13-1.27 (m, 2 H), 1.35 (q, J = 6.5 Hz, 2 H), 1.49-1.62 (m, 1 H), 1.64-1.74 (m, 2 H), 2.86-2.99 (m, 2 H), 3.40 (s, 3 H), 3.14 (s, 3 H), 3.41- 3.46 (m, 2 H), 3.55 (d, J = 12.6 Hz, 2 H), 4.37 (t, J = 5.1 Hz, 1 H), 5.66 (s, 2 H), 7.84-7.98 (m, 2 H), 8.14 (d, J = 1.7 Hz, 1 H). .sup.13C NMR (101 MHz, DMSO-d.sup.6) δ ppm 27.4, 29.5, 31.4, 31.5, 40.2, 40.4, 50.2, 58.1, 103.8, 123.5, 126.6, 128.1, 132.0, 132.4, 135.0, 147.5, 150.9, 153.7, 156.9, 162.6, 163.2. 534 21 C [00059] 8-(azepan-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol- 2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 1.59-1.46 (m, 4 H), 1.80-1.67 (m, 4 H), 3.15 (s, 3 H), 3.38 (s, 3 H), 3.61-3.51 (m, 4 H), 5.75 (s, 2 H), 7.94-7.83 (m, 2 H), 8.12 (d, J = 1.6 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 27.2, 27.7, 28.5, 29.8, 40.7, 51.8, 103.6, 123.1, 126.0, 128.7, 131.3, 133.7, 136.6, 148.9, 151.8, 154.4, 158.0, 162.4, 163.8. 504 22 C [00060] 8-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}- 1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)- 1,3,8-triazaspiro[4.5]decane-2,4-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 1.62-1.65 (m, 2 H), 1.92-2.04 (m, 2 H), 3.15 (s, 3 H), 3.22-3.33 (m, 2 H), 3.41 (s, 3 H), 3.52-3.61 (m, 2 H), 5.70 (s, 2 H), 7.87-7.96 (m, 2 H), 8.16 (d, J = 1.9 Hz, 1 H), 8.59 (br s, 1 H), 10.73 (br s, 1 H). 574 23 C.sup.(2) [00061] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- (ethanesulfonyl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 1.25 (t, J = 7.3 Hz, 3 H), 3.23 (s, 3 H), 3.47 (s, 3 H), 3.67 (q, J = 7.4 Hz, 2 H), 6.28 (s, 2 H), 7.86-7.98 (m, 2 H), 8.16 (d, J = 1.9 Hz, 1 H). 500 24 C.sup.(3) [00062] 8-(cyclohexanesulfonyl)-7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 1.47-1.07 (m, 4 H), 1.64-1.53 (m, 2 H), 1.81-1.70 (m, 2 H), 2.02-1.91 (m, 2 H), 3.22 (s, 3 H), 3.48 (s, 3 H), 3.69-3.55 (m, 1 H), 6.27 (s, 2 H), 7.98-7.86 (m, 2 H), 8.16 (dd, J = 0.6, 1.8 Hz, 1 H). 554 25 C [00063] 8-(3-aminopyrrolidin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.84-2.02 (m, 1 H), 2.22 (d, J = 7.58 Hz, 1 H), 3.37 (s, 3 H), 3.48-3.60 (m, 4 H), 3.70 (ddd, J = 9.64, 8.29, 5.45 Hz, 1 H), 3.78-3.98 (m, 3 H), 5.78-5.94 (m, 2 H), 7.56 (d, J = 8.37 Hz, 1 H), 7.78 (dd, J = 8.45, 1.97 Hz, 1 H), 8.04 (d, J = 1.90 Hz, 1 H). 491 26 C [00064] tert-butyl N-[1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)azetidin-3-yl]carbamate .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9 H), 3.38 (s, 3 H), 3.53 (s, 3 H), 4.13 (dd, J = 8.53, 5.84 Hz, 2 H), 4.51 (t, J = 7.98 Hz, 2 H), 5.62 (s, 2 H), 7.59 (d, J = 8.37 Hz, 1 H), 7.84 (dd, J = 8.37, 2.05 Hz, 1 H), 8.10 (d, J = 2.05 Hz, 1 H). 577 27 C [00065] 8-(1,4-diazepan-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.27 (br. s., 2 H), 3.38 (s, 3 H), 3.40-3.48 (m, 2 H), 3.50-3.59 (m, 5 H), 3.63-3.75 (m, 2 H), 3.85 (br. s., 2 H), 5.75 (s, 2 H), 7.56- 7.65 (m, 1 H), 7.81-7.90 (m, 1 H), 8.10 (d, J = 1.90 Hz, 1 H). 505 28 C [00066] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(pyrrolidin-1-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.89-2.09 (m, 4 H), 3.38 (s, 3 H), 3.54 (s, 3 H), 3.68 (t, J = 6.56 Hz, 4 H), 5.85 (s, 2 H), 7.58 (d, J = 8.37 Hz, 1 H), 7.81 (dd, J = 8.37, 1.90 Hz, 1 H), 8.07 (d, J = 1.90 Hz, 1 H). 476 29 C [00067] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- (3,5-dimethylpiperazin-1-yl)-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09-1.24 (m, 6 H), 1.28 (d, J = 6.00 Hz, 1 H), 2.84 (br. s., 2 H), 3.15 (br. s., 2 H), 3.37 (s, 3 H), 3.44 (d, J = 12.16 Hz, 2 H), 3.56 (s, 3 H), 5.65 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.77-7.94 (m, 1 H), 8.11 (s, 1 H). 519 30 C [00068] 8-[4-(2-aminoethyl)piperazin-1-yl]-7-{[5-(3,4- dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.52-2.69 (m, 6 H), 2.99 (t, J = 5.77 Hz, 2 H), 3.25-3.44 (m, 7 H), 3.51- 3.61 (m, 3 H), 5.55-5.72 (m, 2 H), 7.55-7.65 (m, 1 H), 7.79-7.89 (m, 1 H), 8.04-8.14 (m, 1 H). 534 31 C [00069] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4- (2-hydroxyethyl)piperazin-1-yl]-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.64-2.74 (m, 2 H), 2.74-2.84 (m, 4 H), 3.37 (s, 3 H), 3.39-3.50 (m, 4 H), 3.56 (s, 3 H), 3.71 (t, J = 5.13 Hz, 2 H), 5.66 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.85 (dd, J = 8.37, 2.05 Hz, 1 H), 8.10 (d, J = 1.90 Hz, 1 H). 535 32 C [00070] 8-(4-acetylpiperazin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (s, 3 H), 3.31 (br. s., 4 H), 3.37 (s, 3 H), 3.55 (s, 3 H), 3.69 (br. s., 4 H), 5.69 (s, 2 H), 7.60 (d, J = 7.58 Hz, 1 H), 7.86 (d, J = 7.11 Hz, 1 H), 8.11 (s, 1 H). 533 33 C [00071] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(3-methylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23 (d, J = 6.48 Hz, 3 H), 2.92-3.03 (m, 1 H), 3.04-3.23 (m, 3 H), 3.24-3.34 (m, 1 H), 3.37 (s, 3 H), 3.43-3.53 (m, 2 H), 3.56 (s, 3 H), 5.65 (s, 2 H), 7.56-7.65 (m, 1 H), 7.82-7.91 (m, 1 H), 8.12 (s, 1 H). 505 34 C [00072] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3- hydroxypyrrolidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.02-2.19 (m, 3 H), 3.39 (s, 3 H), 3.57 (s, 3 H), 3.72-3.82 (m, 2 H), 3.82-3.90 (m, 1 H), 3.90-4.02 (m, 1 H), 4.53-4.66 (m, 1 H), 5.81 (d, J = 17.38 Hz, 1 H), 5.92 (d, J = 17.38 Hz, 1 H), 7.59 (d, J = 8.37 Hz, 1 H), 7.83 (dd, J = 8.45, 1.97 Hz, 1 H), 8.09 (d, J = 1.90 Hz, 1 H). 492 35 C [00073] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3- hydroxyazetidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 3.16 (s, 3 H), 3.38 (s, 3 H), 4.01 (dd, J = 8.92, 4.98 Hz, 2 H), 4.42 (dd, J = 8.21, 7.27 Hz, 2 H), 4.50-4.65 (m, 1 H), 5.63 (s, 2 H), 5.81 (d, J = 6.32 Hz, 1 H), 7.86-7.98 (m, 2 H), 8.16 (dd, J = 1.90, 0.47 Hz, 1 H). 478 36 C [00074] 8-(azetidin-1-yl)-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol- 2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.46 (t, J = 7.74 Hz, 2 H), 3.39 (s, 3 H), 3.51-3.57 (m, 3 H), 4.22-4.35 (m, 4 H), 5.63 (s, 2 H), 7.59 (d, J = 8.37 Hz, 1 H), 7.84 (dd, J = 8.37, 2.05 Hz, 1 H), 8.09 (d, J = 1.89 Hz, 1 H) 462 37 C [00075] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4- hydroxypiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-1.75 (m, 2 H), 1.93-2.06 (m, 2 H), 3.15 (ddd, J = 12.79, 9.32, 3.16 Hz, 2 H), 3.37 (s, 3 H), 3.47-3.61 (m, 5 H), 3.93 (dt, J = 8.21, 4.26 Hz, 1 H), 5.64 (s, 2 H), 7.55-7.65 (m, 1 H), 7.86 (dd, J = 8.37, 2.05 Hz, 1 H), 8.11 (d, J = 2.05 Hz, 1 H) 506 38 C [00076] 8-[4-(aminomethyl)piperidin-1-yl]-7-{[5-(3,4-dichlorophenyl)- 1,3,4-oxadiazol-2-yl)methyl}-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, DMSO-d.sup.6) δ ppm 1.16 (qd, J = 12.3, 3.6 Hz, 2 H), 1.32-1.43 (m, 1 H), 1.69-1.77 (m, 2 H), 2.40 (d, J = 6.3 Hz, 2 H), 2.92 (td, J = 12.2, 2.1 Hz, 2 H), 3.15 (s, 3 H), 3.40 (s, 3 H), 3.57 (d, J = 12.3 Hz, 2 H), 5.66 (s, 2 H), 7.88-7.91 (m, 1 H), 7.92-7.95 (m, 1 H), 8.15 (d, J = 1.9 Hz, 1 H) 519 39 C [00077] methyl 1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)piperidine-4-carboxylate .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.79-1.94 (m, 2 H), 1.96-2.10 (m, 2 H), 2.43-2.60 (m, 1 H), 3.01- 3.15 (m, 2 H), 3.36 (s, 3 H), 3.47-3.60 (m, 5 H), 3.70 (s, 3 H), 5.62 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.37, 2.05 Hz, 1 H), 8.11 (d, J = 1.90 Hz, 1 H) 548 40 C [00078] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4- (hydroxymethyl)piperidin-1-yl]-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39 (qd, J = 12.43, 4.11 Hz, 2 H), 1.66-1.78 (m, 1 H), 1.78-1.89 (m, 2 H), 3.04 (td, J = 12.48, 2.37 Hz, 2 H), 3.37 (s, 3 H), 3.52- 3.61 (m, 7 H), 5.64 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.37, 2.05 Hz, 1 H), 8.11 (d, J = 1.90 Hz, 1 H) 520 41 C [00079] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3- fluoropiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.60-1.74 (m, 2 H), 1.92-2.09 (m, 2 H), 3.09-3.23 (m, 1 H), 3.28- 3.47 (m, 5 H), 3.49-3.63 (m, 4 H), 4.73 (dt, J = 5.17, 2.55 Hz, 1 H), 4.85 (dt, J = 5.09, 2.59 Hz, 1 H), 5.55-5.75 (m, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.87 (dd, J = 8.37, 2.05 Hz, 1 H), 8.13 (d, J = 1.74 Hz, 1 H). 508 42 C [00080] 8-(cyclopropylamino)-7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.72 (t, J = 5.37 Hz, 2 H), 3.43 (s, 3 H), 3.56 (s, 4 H), 3.97-4.08 (m, 2 H), 6.01 (s, 2 H), 7.58 (d, J = 8.37 Hz, 1 H), 7.82 (dd, J = 8.45, 1.97 Hz, 1 H), 8.07 (d, J = 1.90 Hz, 1 H). 462 43 C [00081] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(4- methoxypiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-1.74 (m, 2 H), 1.97 (ddt, J = 12.99, 6.87, 3.34, 3.34 Hz, 2 H), 3.13 (ddd, J = 12.56, 8.77, 3.32 Hz, 2 H), 3.34-3.39 (m, 6 H), 3.41 (td, J = 7.70, 3.87 Hz, 1 H), 3.45-3.53 (m, 2 H), 3.56 (s, 3 H), 5.63 (s, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.45, 1.97 Hz, 1 H), 8.11 (d, J = 1.74 Hz, 1 H) 520 44 C [00082] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-(3- hydroxypiperidin-1-yl)-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.54-1.66 (m, 1 H), 1.73-1.87 (m, 2 H), 1.93-2.08 (m, 1 H), 3.25 (ddd, J = 12.79, 9.95, 3.16 Hz, 1 H), 3.33-3.53 (m, 6 H), 3.55-3.59 (m, 3 H), 3.93-4.05 (m, 1 H), 5.57-5.81 (m, 2 H), 7.60 (d, J = 8.53 Hz, 1 H), 7.86 (dd, J = 8.45, 1.97 Hz, 1 H), 8.11 (d, J = 1.74 Hz, 1 H) 506 45 C [00083] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8-[4- (dimethylamino)piperidin-1-yl]-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.75 (d, J = 10.58 Hz, 2 H), 2.02 (d, J = 11.85 Hz, 2 H), 2.47 (br. s., 7 H), 3.00-3.10 (m, 2 H), 3.35-3.39 (m, 3 H), 3.56 (s, 3 H), 3.62 (d, J = 13.11 Hz, 2 H), 5.64 (s, 2 H), 7.61 (d, J = 8.37 Hz, 1 H), 7.87 (dd, J = 8.37, 2.05 Hz, 1 H), 8.12 (d, J = 1.90 Hz, 1 H) 533 46 C [00084] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-[(3S)-3-methylpiperazin-1-yl]-2,3,6,7-tetrahydro- 1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14 (d, J = 6.32 Hz, 3 H), 2.82 (dd, J = 12.24, 10.35 Hz, 1 H), 2.95- 3.24 (m, 4 H), 3.33-3.49 (m, 5 H), 3.54-3.60 (m, 3 H), 5.59- 5.71 (m, 2 H), 7.56-7.64 (m, 1 H), 7.80-7.93 (m, 1 H), 8.11 (d, J = 1.90 Hz, 1 H) 505 47 C [00085] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-[(3R)-3-methylpiperazin-1-yl]-2,3,6,7-tetrahydro- 1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14 (d, J = 6.32 Hz, 3 H), 2.81 (dd, J = 12.32, 10.43 Hz, 1 H), 2.95- 3.23 (m, 4 H), 3.35-3.48 (m, 5 H), 3.52-3.61 (m, 3 H), 5.58- 5.71 (m, 2 H), 7.60 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.45, 1.97 Hz, 1 H), 8.11 (d, J = 1.90 Hz, 1 H) 505 48 C [00086] 8-(dimethylamino)-1,3-dimethyl-7-{[5-(3-methylphenyl)- 1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.42 (s, 3 H), 2.98-3.11 (m, 6 H), 3.38 (s, 3 H), 3.55 (s, 3 H), 5.73 (s, 2 H), 7.30-7.46 (m, 2 H), 7.73-7.80 (m, 1 H), 7.80-7.86 (m, 1 H). 396 49 C [00087] 1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-8-(propylamino)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (t, J = 7.42 Hz, 3 H), 1.62-1.77 (m, 2 H), 2.43 (s, 3 H), 3.42 (s, 3 H), 3.47 (t, J = 6.95 Hz, 2 H), 3.55 (s, 3 H), 5.71 (s, 2 H), 7.32- 7.44 (m, 2 H), 7.79-7.91 (m, 2 H) 410 50 C [00088] 8-(benzylamino)-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4- oxadiazo-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.43 (s, 3 H), 3.42 (s, 3 H), 3.54 (s, 3 H), 4.62-4.75 (m, 2 H), 5.72 (s, 2 H), 5.93 (br. s., 1 H), 7.27-7.45 (m, 7 H), 7.77-7.90 (m, 2 H) 458 51 C [00089] 1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-8-(4-methylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.36 (s, 3 H) 2.42 (s, 3 H) 2.54-2.63 (m, 4 H) 3.34-3.40 (m, 7 H) 3.55 (s, 3 H) 5.65 (s, 2 H) 7.31-7.42 (m, 2 H) 7.74-7.81 (m, 1 H) 7.82-7.86 (m, 1 H) 451 52 C [00090] 8-methoxy-1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4- oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.42 (s, 3 H) 3.39 (s, 3 H) 3.56 (s, 3 H) 4.17 (s, 3 H) 5.64 (s, 2 H) 7.30- 7.45 (m, 2 H) 7.78 (d, J = 7.07 Hz, 1 H) 7.84 (s, 1 H) 383 53 C [00091] 8-(4-hexylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.82-0.94 (m, 3 H) 1.26-1.39 (m, 6 H) 1.68-1.83 (m, 2 H) 2.43 (s, 3 H) 2.99-3.10 (m, 2 H) 3.13 (br. s., 2 H) 3.37 (s, 3 H) 3.54 (s, 3 H) 3.59-3.77 (m, 6 H) 5.69 (s, 2 H) 7.33-7.46 (m, 2 H) 7.74-7.80 (m, 1 H) 7.82 (s, 1 H) 521 54 C [00092] 8-(4-butylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98 (t, J = 7.35 Hz, 3 H), 1.36-1.47 (m, 2 H), 1.83-1.91 (m, 4 H), 2.44 (s, 3 H), 2.96-3.03 (m, 2 H), 3.12 (br. s., 2 H), 3.35-3.39 (m, 3 H), 3.55 (s, 3 H), 3.66 (d, J = 13.43 Hz, 2 H), 4.03 (d, J = 12.95 Hz, 2 H), 5.69 (s, 2 H), 7.35-7.45 (m, 2 H), 7.80 (dt, J = 6.87, 1.62 Hz, 1 H), 7.83-7.87 (m, 1 H). 493 55 C [00093] 8-(4-ethylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.09 (t, J = 7.27 Hz, 3 H) 2.37-2.50 (m, 5 H) 2.50-2.60 (m, 4 H) 3.29-3.43 (m, 7 H) 3.56 (s, 3 H) 5.66 (s, 2 H) 7.31-7.45 (m, 2 H) 7.78 (d, J = 7.11 Hz, 1 H) 7.84 (s, 1 H) 465 56 C [00094] 8-[4-(2-hydroxyethyl)piperazin-1-yl]-1,3-dimethyl-7-{[5-(3- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) □ ppm 2.42 (s, 3 H), 3.31 (br. s., 4 H), 3.34-3.38 (m, 3 H), 3.54 (s, 3 H), 3.72 (br. s., 6 H), 4.03 (br. s., 2 H), 5.71 (s, 2 H), 7.35-7.43 (m, 2 H), 7.76 (d, J = 3.95 Hz, 1 H), 7.80 (s, 1 H). 481 57 C [00095] 8-[4-(2-methoxyethyl)piperazin-1-yl]-1,3-dimethyl-7-{[5-(3- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 2.44 (s, 3 H), 3.32 (d, J = 5.84 Hz, 4 H), 3.37 (s, 3 H), 3.38 (s, 3 H), 3.56 (s, 3 H), 3.69 (br. s., 2 H), 3.77 (br. s., 2 H), 3.80 (br. s., 4 H), 5.69 (s, 2 H), 7.34-7.45 (m, 2 H), 7.80 (d, J = 6.48 Hz, 1 H), 7.84 (s, 1 H). 495 58 C [00096] 1,3-dimethyl-7-{[5-(3-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-8-(4-phenylpiperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 2.43 (s, 3 H), 3.32 (br. s., 4 H), 3.39 (s, 3 H), 3.50 (br. s., 4 H), 3.58 (s, 3 H), 5.71 (s, 2 H), 6.96 (br. s., 3 H), 7.28-7.44 (m, 4 H), 7.74- 7.89 (m, 2 H). 514 59 C [00097] 8-(4-cyclohexylpiperazin-1-yl)-1,3-dimethyl-7-{[5-(3- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-2,3,6,7- tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) d ppm 1.06-1.34 (m, 5 H), 1.67-1.99 (m, 6 H), 2.43 (s, 3 H), 2.70-2.99 (m, 4 H), 3.37 (s, 3 H), 3.38-3.55 (br. s., 4 H), 3.56 (s, 3 H), 5.66 (s, 2 H), 7.33-7.44 (m, 2 H), 7.74-7.83 (m, 1 H), 7.83-7.88 (m, 1 H) 519 60 D, B .sup.(4) [00098] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}- 1,3,8-trimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.61 (s, 3 H), 3.43 (s, 3 H), 3.61 (s, 3 H), 5.89 (s, 2 H), 7.61 (d, J = 8.37 Hz, 1 H), 7.86 (dd, J = 8.37, 2.05 Hz, 1 H), 8.12 (d, J = 1.90 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 13.3, 27.9, 29.8, 39.3, 106.6, 122.8, 126.1, 128.8, 131.4, 133.8, 135.4, 136.9, 148.2, 151.5, 155.1, 161.2, 164.2. 421 61 D, B .sup.(4) [00099] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-propyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.98 (t, J = 7.45 Hz, 3 H), 1.72-1.92 (m, 2 H), 2.77 (t, J = 7.58 Hz, 2 H), 3.36 (s, 3 H), 3.55 (s, 3 H), 5.85 (s, 2 H), 7.54 (d, J = 8.34 Hz, 1 H), 7.79 (dd, J = 8.34, 1.77 Hz, 1 H), 8.03 (d, J = 1.77 Hz, 1 H). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 13.8, 21.1, 27.9, 28.7, 29.8, 39.1, 106.4, 122.9, 126.1, 128.8, 131.4, 133.8, 136.9, 148.4, 151.6, 155.1, 155.2, 161.5, 164.1. 449 62 D, B .sup.(4) [00100] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(propan-2-yl)-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.34 (d, J = 6.57 Hz, 6 H), 3.10-3.26 (m, 1 H), 3.38 (s, 3 H), 3.54- 3.63 (m, 3 H), 5.88 (s, 2 H), 7.57 (d, J = 8.34 Hz, 1 H), 7.76- 7.90 (m, 1 H), 8.07 (s, 1 H). 13C NMR (101 MHz, CHLOROFORM-d) δ ppm 21.4, 26.3, 27.9, 29.9, 38.9, 106.1, 122.9, 126.0, 128.8, 131.3, 133.8, 136.8, 148.4, 151.6, 155.3, 159.8, 161.7, 164.1. 449 63 D, B .sup.(4) [00101] 8-benzyl-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione .sup.1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.39 (s, 3 H), 3.63 (s, 3 H), 4.28 (s, 2 H), 5.73 (s, 2 H), 7.10-7.22 (m, 3 H), 7.22-7.29 (m, 2 H), 7.56 (d, J = 8.34 Hz, 1 H), 7.74 (dd, J = 8.34, 2.02 Hz, 1 H), 7.97 (d, J = 2.02 Hz, 1 H). .sup.13C NMR (101 MHz, CHLOROFORM-d) δ ppm 28.0, 29.9, 33.6, 39.3, 107.1, 122.8, 126.0, 127.5, 128.3, 128.7, 129.1, 131.3, 133.7, 134.3, 136.7, 148.1, 151.5, 152.9, 155.2, 161.2, 163.9. 497 .sup.(1)Example 1 was prepared by analogy with General Procedure C, with the exception that methanol was used as the solvent and sodium methoxide was used to displace the bromine. .sup.(2)Example 23 was prepared from Example 6, which itself was prepared using General Procedure C. Thiothers (0.08 mmol) were suspended in methanol (1 mL) and diluted with water (1 mL). Oxone (0.16 mmol) was then added to the suspension and the reaction mixture was stirred at rt overnight. 3 additional equivalents of oxone were then added and the reaction was left for a further 24 hours. The mixture was then concentratred in vacuo and products were isolated by preparative liquid chromatography. .sup.(3)Example 24 was prepared from Example 7, which itself was prepared using General Procedure G. The procedure used was identical to that used for Example 23. .sup.(4) General Procedure D was used to prepare an intermediate which was further reacted under General Procedure B.

[0292] Further compounds of the examples and prodrugs thereof are described in Table 2 below. These compounds were prepared in accordance with the general procedures indicated or the specific procedures indicated below.

TABLE-US-00002 TABLE 2 Structure General Name Example Procedure MS [M + H].sup.+ 64 C′ [00102] tert-butyl N-{2-[4-(7-{[5-(3,4-dichlorophenyl)- 1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6- dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazin-1- yl]ethyl}carbamate m/z 634 65 C′ [00103] tert-butyl N-{[1-(7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo- 2,3,6,7-tetrahydro-1H-purin-8-yl)piperidin-4- yl]methyl}carbamate m/z 619 66 C′ [00104] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-8-(1H-imidazol-1-yl)-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 473 67 C′ [00105] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-(1H-pyrazol-1-yl)- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 473 68 C′ [00106] ethyl 1-(7-{[5-(3,4-dichlorophenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo- 2,3,6,7-tetrahydro-1H-purin-8-yl)-1H-pyrazole-4- carboxylate m/z 545 69 B′ [00107] 8-chloro-7-{[3-(4-chlorophenyl)-1,2,4-oxadiazol-5- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 407 70 C′ [00108] 7-{[3-(4-chlorophenyl)-1,2,4-oxadiazol-5- yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 457 71 B′ [00109] 8-chloro-7-{[2-(3,4-dichlorophenyl)-1,3-oxazol-4- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 440 72 C′ [00110] 7-{[2-(3,4-dichlorophenyl)-1,3-oxazol-4-yl]methyl}- 1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 490 73 B′ [00111] 8-chloro-7-{[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 403 74 C′ [00112] 7-{[5-(4-methoxyphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 453 75 B′ [00113] 8-chloro-7-{[2-(4-chlorophenyl)-1,3-thiazol-5- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 422 76 C′ [00114] 7-{[2-(4-chlorophenyl)-1,3-thiazol-5-yl]methyl}- 1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 472 77 B′ [00115] 8-chloro-7-{[3-(4-methoxyphenyl)-1,2-oxazol-5- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 402 78 C′ [00116] 7-{[3-(4-methoxyphenyl)-1,2-oxazol-5-yl]methyl}- 1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 452 79 C′ [00117] 1,3-dimethyl-7-{[5-(4-methylphenyl)-1,2-oxazol-3- yl]methyl}-8-(piperazin-1-yl)-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 436 80.sup.(1) B′ [00118] 8-chloro-1,3-dimethyl-7-{[5-(4-methylphenyl)-1,2-oxazol- 3-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 386 81 C′ [00119] ethyl 7-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2- carboxylate m/z 600 82 C′ [00120] 2-[(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)amino]ethane-1-sulfonic acid LCMS [M + H.sub.3O]+ 548 83 C′ [00121] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}- 1,3-dimethyl-8-(3-oxopiperazin-1-yl)-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 505 84 C′ [00122] tert-butyl 2-[(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)amino]acetate m/z 536 85 C′ [00123] 4-{[(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)amino]methyl}piperidine-1-carboximidamide m/z 561 86 C′ [00124] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- {[(2,4-dimethoxyphenyl)methyl]amino}-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 572 87 D′ [00125] 8-amino-7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 422 88 B′ [00126] 8-chloro-1,3-dimethyl-7-[(5-phenyl-1,3,4-oxadiazol-2- yl)methyl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 373 89 B′ [00127] 8-chloro-7-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 407 90 B′ [00128] 8-chloro-7-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 391 91 B′ [00129] 8-chloro-7-{[5-(3-fluorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 391 92 B′ [00130] 8-chloro-7-{[5-(3-methoxyphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 403 93 B′ [00131] 4-{5-[(8-chloro-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-7-yl)methyl]-1,3,4-oxadiazol-2-yl}benzonitrile m/z 398 94 B′ [00132] 8-chloro-1,3-dimethyl-7-{[5-(pyridin-3-yl)-1,3,4-oxadiazol- 2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 373 95 B′ [00133] 8-chloro-7-{[5-(6-chloropyridin-3-yl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 408 96 B′ [00134] 8-chloro-1,3-dimethyl-7-{[5-(4-nitrophenyl)-1,3,4- oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 418 97 B′ [00135] 8-chloro-7-{[5-(4-chloro-3-methylphenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 421 98 B′ [00136] 8-chloro-7-{[5-(4-chloro-3-methoxyphenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 437 99 B′ [00137] 8-chloro-7-{[5-(3-chloro-4-methoxyphenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 437 100 [00138] tert-butyl 4-(1,3-dimethyl-7-{[5-(4-nitrophenyl)-1,3,4- oxadiazol-2-yl]methyl}-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)piperazine-1-carboxylate m/z 568 101 B′ [00139] 8-chloro-7-{[5-(1H-indol-6-yl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 412 102 B′ [00140] 8-chloro-1,3-dimethyl-7-({5-[4-(trifluoromethyl)phenyl]- 1,3,4-oxadiazol-2-yl}methyl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 441 103 B′ [00141] 8-chloro-7-({5-[4-(methanesulfonylmethyl)phenyl]-1,3,4- oxadiazol-2-yl}methyl)-1,3-dimethyl-2,3,6,7-tetrahydro- 1H-purine-2,6-dione m/z 465 104 B′ [00142] 8-chloro-7-{[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 433 105 [00143] tert-butyl 4-(7-{[5-(4-aminophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)piperazine-1-carboxylate m/z 538 106 B′ [00144] 8-chloro-1,3-dimethyl-7-{[5-(6-methylpyridin-3-yl)-1,3,4- oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 388 107 C′ [00145] 1,3-dimethyl-7-[(5-phenyl-1,3,4-oxadiazol-2-yl)methyl]-8- (piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 423 108 C′ [00146] 7-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione m/z 457 109 C′ [00147] 7-{[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione m/z 441 110 C′ [00148] 7-{[5-(3-fluorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione m/z 441 111 C′ [00149] 7-{[5-(3-methoxyphenyl)-1,3,4-oxadiazol-2-yl]methyl}- 1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 453 112 C′ [00150] 4-(5-{[1,3-dimethyl-2,6-dioxo-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purin-7-yl]methyl1-1,3,4-oxadiazol-2- yl)benzonitrile m/z 448 113 C′ [00151] 1,3-dimethyl-8-(piperazin-1-yl)-7-{[5-(pyridin-3-yl)-1,3,4- oxadiazol-2-yl]methyl}-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 424 114 C′ [00152] 1,3-dimethyl-8-(piperazin-1-yl)-7-({5-[6-(piperazin-1- yl)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 508 115 C′ [00153] 1,3-dimethyl-7-{[5-(4-nitrophenyl)-1,3,4-oxadiazol-2- yl]methyl}-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 468 116 C′ [00154] 7-{[5-(4-chloro-3-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 471 117 C′ [00155] 7-{[5-(4-chloro-3-methoxyphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 487 118 C′ [00156] 7-{[5-(3-chloro-4-methoxyphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 487 119 C′ [00157] 7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 467 120 C′ [00158] 7-{[5-(1H-indol-6-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione m/z 462 121 C′ [00159] 1,3-dimethyl-8-(piperazin-1-yl)-7-({5-[4- (trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}methyl)- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 491 122 C′ [00160] 7-({5-[4-(methanesulfonylmethyl)phenyl]-1,3,4- oxadiazol-2-yl}methyl)-1,3-dimethyl-8-(piperazin-1-yl)- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 515 123 C′ [00161] 7-{[5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 483 124 C′ [00162] 7-{[5-(1H-indazol-5-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3- dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H-purine- 2,6-dione m/z 463 125 C′ [00163] 1,3-dimethyl-7-{[5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol- 2-yl]methyl}-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 438 126 C′ [00164] 8-[4-(dimethylamino)piperidin-1-yl]-7-{[5-(3-methoxy-4- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 509 127 C′ [00165] 8-[4-(aminomethyl)piperidin-1-yl]-7-{[5-(3-methoxy-4- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 495 128 C′ [00166] 4-{[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)amino]methyl}piperidine-1-carboximidamide m/z 537 129 C′ [00167] 7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-8-[3-(trifluoromethyl)piperazin-1- yl]-2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 535 130 C′ [00168] 8-[4-(hydroxymethyl)piperidin-1-yl]-7-{[5-(3-methoxy-4- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 496 131 C′ [00169] 8-(1,4-diazepan-1-yl)-7-{[5-(3-methoxy-4-methylphenyl)- 1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 481 132 C′ [00170] 3-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)amino]propanamide m/z 469 133 C′ [00171] N-{2-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-8- yl)amino]ethyl}methanesulfonamide m/z 519 134 C′ [00172] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}- 1,3-dimethyl-8-[3-(trifluoromethyl)piperazin-1-yl]-2,3,6,7- tetrahydro-1H-purine-2,6-dione m/z 559 135 C′ [00173] 7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-8- {[2-(dimethylamino)ethyl](methyl)amino}-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 507 136 C′ [00174] 1-(7-{[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)piperidine-4-carboxamide m/z 533 137 C′ [00175] 8-{[2-(dimethylamino)ethyl](methyl)amino}-7-{[5-(3- methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}- 1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 483 138 C′ [00176] 1-(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4-oxadiazol-2- yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H- purin-8-yl)piperidine-4-carboxamide m/z 509 139 C′ [00177] 8-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-7-{[5-(3- methoxy-4-methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}- 1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 495 140 C′ [00178] tert-butyl N-{2-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-8-yl)sulfanyl]ethyl}carbamate m/z 558 141 C′ [00179] N-{2-[(7-{[5-(3-methoxy-4-methylphenyl)-1,3,4- oxadiazol-2-yl]methyl}-1,3-dimethyl-2,6-dioxo-2,3,6,7- tetrahydro-1H-purin-8-yl)sulfanyl]ethyl}acetamide m/z 500 142 D′ [00180] 8-[(2-aminoethyl)sulfanyl]-7-{[5-(3-methoxy-4- methylphenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3-dimethyl- 2,3,6,7-tetrahydro-1H-purine-2,6-dione m/z 458 143 B′ [00181] 8-chloro-7-{[1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4- yl]methyl}-1,3-dimethyl-2,3,6,7-tetrahydro-1H-purine-2,6- dione m/z 440 144 C′ [00182] 7-{[1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl]methyl}- 1,3-dimethyl-8-(piperazin-1-yl)-2,3,6,7-tetrahydro-1H- purine-2,6-dione m/z 490 .sup.(1)For Example 80, a mesylate leaving group was employed in place of the chlorine atom in the R.sup.4 substituted intermediates. These reactions were done under analogous conditions.

Synthesis of Example 100

[0293] ##STR00183##

[0294] Di-tert-butyl dicarbonate (1.1 equiv.) was added to the compound of Example 115 (1.0 equiv.) dissolved in CH.sub.2Cl.sub.2 (0.1 mol/L) and the resulting mixture was stirred at room temperature. Upon completion the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with CH.sub.2Cl.sub.2×3. The combined extracts were dried, concentrated, and purified by silica gel chromatography in a mixture of iso-hexane and ethyl acetate.

Synthesis of Example 105

[0295] ##STR00184##

[0296] A mixture of the compound of Example 100 (1.0 equiv.) and Pd/C (0.05 equiv.) was stirred in tetrahydrofuran at room temperature for 24 h under hydrogen atmosphere provided by a balloon. Upon completion, Pd/C was removed by suction filtration and the reaction mixture was concentrated and purified by silica gel chromatography in a mixture of iso-hexane and ethyl acetate.

Biological Assays

[0297] The biological activity of example compounds as described herein above was assessed using the following biological assays.

Biological Assay 1: NUDT5 Inhibitor Activity by Malachite Green Reporter Assay

[0298] NUDT5 inhibitors were evaluated using a coupled enzymatic assay with detection of inorganic phosphate (Pi) using the malachite green assay. Following enzymatic hydrolysis of ADP-Ribose (Sigma-Aldrich A0572) by NUDT5, to yield AMP and ribose-5-phosphate, the latter product is continuously processed by a significant excess of alkaline phosphatase (Sigma-Aldrich, P0114). Formation of Pi is quantified based on the green complex (that absorbs at 630 nm) formed between malachite green and molybdate according to published procedure (Baykov, A. A., Evtushenko, O. A. and Avaeva, S. M., Anal Biochem, 171, 266-270 (1988)). Assay buffer consisted of 10 mM Tris-acetate at pH 8.0, 40 mM sodium chloride, 10 mM magnesium acetate, 0.005% Tween-20 and 1 mM dithiothreitol (DTT). The final conditions consisted of 6 nM recombinant human NUDT5, 50 μM ADP-Ribose and 10 U/ml of calf intestine alkaline phosphatase. The plates with compounds, enzymes and substrate were incubated at room temperature for 15 minutes, after which the reaction was terminated and the signal developed by the addition of the malachite green reagent using a MultiDrop (Thermo Scientific). Following vigorous shaking on plate shakers for a minimum of eight minutes the absorbance was read in a microplate reader (HidexSense) using a filter at 630 nm and a read time of 0.1 s per well. Inhibitors were used in dilutions from 100 μM to 1.7 nM in 3-fold dilution steps. Experiments were run in duplicate and confirmed in two independent experiments. IC.sub.50 values were determined by curve fitting using ExcelFit.

[0299] Results obtained for the example compounds as described in Table 1 are provided in Table 3 below, and results obtained for the example compounds as described in Table 2 are provided in Table 4 below.

TABLE-US-00003 TABLE 3 Malachite Green Ex. Assay [nM] 1 29.1 2 23.7 3 111 4 >1000 5 12.5 6 36.9 7 65.9 8 162 9 15.0 10 22.9 11 84.6 12 42.5 13 759 14 164 15 432 16 53.8 17 39.0 18 151 19 29.1 20 30 21 50.3 22 35.1 23 24.4 24 22.7 25 30 26 324 27 19.3 28 37 29 43.8 30 33.2 31 105.8 32 76.7 33 17.8 34 24.7 35 34.8 36 34.0 37 19.8 38 18.5 39 32.7 40 20.3 41 24.2 42 26.4 43 26.8 44 21.5 45 14.9 46 12.0 47 11.9 48 69.4 49 356 50 144 51 31.3 52 378 53 806 54 >1000 55 221 56 922 57 >1000 58 >1000 59 >1000 60 28.4 61 246 62 >1000 63 >1000

TABLE-US-00004 TABLE 4 Malachite Green Assay Ex. [nM] 64 226 65 33.8 66 58.2 67 200 68 214 69 296 70 57.4 71 81.6 72 21.0 73 1260 74 198 75 239 76 376 77 19700 78 491 79 530 80 3791 81 149 82 454 83 20.2 84 93.6 85 19.5 86 184 87 16.5 88 3588 89 620 90 4385 91 2146 92 596 93 918 94 6907 95 1380 96 1505 97 64.8 98 378 99 73.0 100 9436 101 358 102 484 103 61612 104 >100000 105 24510 106 2920 107 212 108 99 109 345 110 129 111 119 112 255 113 1694 114 28984 115 286 116 21.6 117 64.2 118 17.4 119 35.7 120 80.5 121 51.6 122 24383 123 169 124 309 125 216 126 39.1 127 32.9 128 128 129 911 130 205 131 60.7 132 157 133 352 134 140 135 96.3 136 8.27 137 24.1 138 33.4 139 265 140 262 141 306 142 49.2 143 14000 144 155

Biological Assay 2: Measurement of Target Engagement in Cells

[0300] Compounds showing potent activity by malachite green assay were then screened for NUDT5 engagement in cell lysates by thermal shift assay. Target engagement in cells was determined by the cellular thermal shift assay (CETSA), as described previously (Jafari, R., et al., Nature Protocols, 9, 2100-2122 (2014)).

[0301] Briefly, cell lysate thermal shift assays were performed with 1×10.sup.6 HL-60 cells per temperature/condition. Cells were collected and washed once with PBS and resuspended in 1× Tris-buffered saline (TBS) with protease inhibitor cocktail (Mini cOmplete, EDTA-free, Roche) at 60 μL/1×10.sup.6 cells. The cells were then aliquoted and lysed by freeze-thawing three times with three-minute incubations (3×, 3 min.+3 min.) using an ethanol/dry ice bath and water bath at 37° C. The lysates were then centrifuged at 20 000×g for 20 minutes at 4° C. to remove cellular debris. Supernatants were then transferred to PCR strip tubes and treated with 0.5 μL DMSO (0.8% v/v final) or 20 μM inhibitor for 20 minutes at room temperature. Lysates with compounds were heated at the indicated temperature in a Veriti Thermal Cycler (Applied Biosystems) for 3 minutes, then another 3 minutes at room temperature. They were then centrifuged at 20 000×g for 20 minutes at 4° C. to pellet protein aggregates and 45 μL was removed and prepared for western blotting analysis.

[0302] For CETSA experiments with cells treated in culture, 1×10.sup.6 HL-60 were treated with DMSO (0.2% v/v final) or 20 μM compound for 3 hours at 37° C. and 5% C.sub.02 in a humidified incubator. T47D.sup.WT cells were treated instead with 15 μM Compounds 16/17, and 1.5 μM Compound 19. The results are shown in FIG. 5. The cells were harvested, washed twice with PBS and resuspended in TBS with protease inhibitors, as above. Heating was identical as before, except that immediately following heating, the cell suspensions were snap frozen in a dry ice/ethanol bath and freeze-thawed as previously to lyse cells. Centrifugation at 20 000×g for 20 minutes at 4° C. removed cellular debris and protein aggregates, and lysates were prepared for western blotting.

[0303] Treatments, heating and lysis procedures for ITDRF.sub.CETSA were performed identically to those for CETSA experiments, except NUDT5 inhibitors were added to cells at serial dilutions from 20 to 0.08 μM or 10 to 0.04 μM as indicated.

[0304] Gel electrophoresis and western blotting were performed as before. Primary antibodies were incubated overnight at 4° C. in 1:1 Li-Cor Blocking Buffer/TBS+0.05% Tween-20 (TBS-T) at the following concentrations: anti-NUDT5 (EZBiolabs+lab-purified, 1:1 000), or SOD1 (Santa Cruz, 1:1 000). Secondary antibodies were diluted at 1:15 000 in 1:1 Li-Cor blocking buffer/TBS-T and incubated for 1 hour at room temperature. Bands were visualized with an Odyssey Fc Imager and analyzed with Image Studio Software (Li-Cor Biosciences).

[0305] The results of these experiments are shown in the figures. FIG. 1 shows NUDT5 stabilization by inhibitors when added to HL-60 cell lysates. FIG. 2 shows NUDT5 stabilization by inhibitors added to HL-60 cells in culture. FIG. 3 shows the isothermal dose response fingerprint for certain inhibitors in HL-60 cells. FIG. 5 shows NUDT5 stabilization by inhibitors added to T47D cells in culture.

Biological Assay 3: Assessment of the Utility of NUDT5 Inhibitors in Breast Cancer

[0306] Thin layer chromatography (TLC) of products formed following processing of .sup.32P-PAR by purified PARG and NUDT5 in the absence or presence of Compound 19 and PP.sub.i in vitro, was performed (Wright, R. H. G. et al., Science, 352, 1221-1225 (2016)). The results obtained are shown in FIG. 4a.

[0307] Certain example compounds were used at varying concentrations to determine their effect on hormone signaling and breast cancer with T47D breast adenocarcinoma cells (Compound 19, was used at 1.5 μM whereas the less potent derivatives Compound 16 and Compound 17 were used at 15 μM). The results obtained are shown in FIG. 4b and the selected concentrations were used to generate data obtained in FIGS. 4c, 4d, 4e and 4f.

[0308] In HR+ breast cancer cells, NUDT5 activity is required to produce ATP in the nucleus following hormone stimulation (Wright, R. H. G. et al., Science, 352, 1221-1225 (2016)). A nuclear-targeted luciferase reporter system was employed to monitor ATP production after hormone stimulation. The results obtained are shown in FIG. 4c.

[0309] Hormone-starved T47D.sup.WT cells were treated with example compounds as described herein for two hours and then stimulated with the progesterone receptor agonist, R5020, for the time points indicated. Strong luminescence was seen from cells treated with Compound 16, Compound 17 or DMSO, the Compound 19-treated cells had reduced nuclear luminescence, indicating impaired nuclear ATP production. Quantification of the results obtained are shown in FIG. 4c.

[0310] Nuclear ATP is used by ATP-dependent chromatin remodeling enzymes, which disrupt the interactions of histones and DNA (Wright, R. H. G. et al., Science, 352, 1221-1225 (2016)). In conjunction with histone acetyltransferase and deacetylase complexes, this process regulates the transcriptional activation of genes (Vicent, G. P. et al., Genes Dev, 25, 845-862 (2011), Narlikar, G. J., Sundaramoorthy, R. and Owen-Hughes, T., Cell, 154, 490-503 (2013), Mayes, K. Qiu, Z., Alhazmi, A. and Landry, J. W., Adv Cancer Res, 121, 183-233 (2014)). Blocking nuclear ATP production prevents the activation of ATP-dependent chromatin remodeling enzymes and displacement of histones H1 and H2A/H2B (Wright, R. H. G. et al., Science, 352, 1221-1225 (2016)). Histone displacement following a thirty-minute R5020 exposure in T47D.sup.WT cells treated with example compounds for two hours was analyzed. The results obtained are shown in FIG. 4d.

[0311] Without chromatin remodeling, the regulation of hormone-dependent genes and resultant cell proliferation should also be impaired (Wright, R. H. G. et al., Science, 352, 1221-1225 (2016)). Using T47D cells harboring an integrated mouse mammary tumor virus luciferase reporter (MMTV-luc; T47D.sup.M cells), mRNA expression for progesterone-dependent genes (EGFR and MMTV-luc) was compared to progesterone-independent genes (CCNB1 and RBM24) following pre-treatment with example compounds for two hours and six hours of R5020 treatment. The results obtained are shown in FIG. 4e.

[0312] It was also shown that NUDT5 inhibitor treatment using example compounds abrogated the progesterone-dependent proliferation response in T47D.sup.WT cells as measured by BrdU incorporation. Cells were pre-treated with example compounds for two hours and then stimulated with R5020 for twenty-four hours. These results are shown in FIG. 4f.

Abbreviations

[0313] The following abbreviations may be used herein.

aq aqueous
BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl
Boc tert-butoxycarbonyl
brine saturated aqueous solution of NaCl
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane

DIEA N,N-diisopropylethylamine

[0314] DMAP 4-dimethylaminopyridine
DMF dimethylformamide
DMSO dimethylsulfoxide
EDC-HCl N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride
EtOAc ethyl acetate
EtOH ethanol
Ex example
HATU O-(7-azabenzotriazolyl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate
HOBt 1-hydroxybenzotriazole
Int intermediate
LAH lithium aluminium hydride
MeCN acetonitrile
MeOH methanol

NBS N-bromosuccinimide

[0315] NMR nuclear magnetic resonance
Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium(0)
PBS phosphate buffered saline
rac racemic
rt room temperature
tBuOK potassium tert-butoxide
tBuONa sodium tert-butoxide
TBS tris-buffered saline
TFA trifluoroacetic acid
THF tetrahydrofuran
Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene