Acyl and sulfonyl derivatives of 6,9-disubstituted 2-(trans-1,4-diaminocyclohexyl)-purines and their use as antiproliferative agents

1. A compound according to the formula (I)

wherein Z is selected from the group consisting of —S(O) 2 — and —C(O)—,

when Z is —S(O) 2 —, R a is selected from the group consisting of: —R1 and —N(R1)(R3), or

when Z is —C(O)—, R a is selected from the group consisting of: —R1, —OR1, —N(R1)(R3) and —SR1,

where R1 is selected from the group consisting of:

—C 1 -C 11 alkyl, wherein each carbon may be optionally substituted with one, two or three X substituents,

—C 3 -C 10 cycloalkyl, wherein each carbon may be optionally substituted with one or two X substituents,

—(CH 2 ) n Q p (CH 2 ) n W, and

—(CH 2 ) n CHW 2 ;

wherein each carbon of —(CH 2 ) n — may be optionally substituted with one or two X substituents, Q is O, S, or NR3, n is independently an integer 0-6, p is independently an integer 0 or 1, and W is independently selected from the group consisting of hydrogen, C 3 -C 10 cycloalkyl, —(C 3 -C 10 cycloalkyl)-aromatic, and one of the following aromatic or heteroaromatic rings:

where B is selected from the group consisting of: —O—, —S—, —NR6-; where each carbon of the aromatic or heteroaromatic ring may be independently replaced by a nitrogen atom, and each carbon of the aromatic ring may be independently substituted with an X substituent;

where each X substituent is independently selected from the group consisting of: hydrogen, halogen, methylenedioxy, —C 1 -C 8 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to eight carbon atoms, —C 3 -C 10 cycloalkyl, substituted or unsubstituted phenyl, —C 1 -C 8 alkoxy, —SR3, —OH, —CY 3 , —OCY 3 , —CO 2 R3, —CN, —CO—NR4R5, —NO 2 , —COR3, —NR4R5, —NH—C(O)—R3, —NH—C(O)—(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms)-aromatic, and —NH—C(O)—(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms)-heteroaromatic;

where said phenyl when substituted is substituted with one to five substituents independently selected from the group consisting of hydrogen, halogen, methylenedioxy, —C 1 -C 8 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to eight carbon atoms, —C 3 -C 10 cycloalkyl, —C 1 -C 8 alkoxy, —OH, —CY 3 , —OCY 3 , —CO 2 R3, —CN, —NO 2 , —COR3, —SR3, and —NH—C(O)—R3;

where each Y is independently selected from the group consisting of hydrogen and halogen;

where each R3 is independently selected from the group consisting of hydrogen, and C 1 -C 8 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to eight carbon atoms, where C 1 -C 8 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to eight carbon atoms may be straight or branched, saturated or unsaturated;

where each R4 and R5 is independently selected from the group consisting of hydrogen, and C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms, where which each carbon of C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms is optionally substituted with a hydrogen, halogen, methylenedioxy, —C 1 -C 8 alkylene, —C 3 -C 10 cycloalkyl, substituted or unsubstituted phenyl, —C 1 -C 8 alkoxy, —SR3, —OH, —CY 3 , —OCY 3 , —CO 2 R3, —CN, —NO 2 , —COR3, —NH—C(O)—R3, —NH—C(O)—(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms)-aromatic, or —NH—C(O)—(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms)-heteroaromatic, or where said R4 and said R5 taken together with the nitrogen to which they are attached, form a single heterocyclic ring of three to seven atoms including the nitrogen atom as the sole heteroatom;

where —NR6- is selected from the group consisting of an N substituted with—hydrogen, —(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms), —C 3 -C 10 cycloalkyl, —S(O) 2 —(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms), —S(O) 2 —(C 3 -C 10 cycloalkyl), —C(O)R3, —C(O)—(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms)-aromatic, —C(O)-aromatic, S(O) 2 -aromatic and —S(O) 2 —(C 1 -C 6 saturated or unsaturated, straight or branched chain hydrocarbyl radical of from one to six carbon atoms)-aromatic, wherein each carbon of the aromatic ring may be optionally substituted with an X substituent; and

R2 is selected from the group consisting of cyclopentyl, cyclopentenyl, and isopropyl;

or a pharmaceutically acceptable salt, optical isomer, solvate or hydrate thereof.

2. A method of inhibiting cyclin-dependent kinases (CDKs) by administering a compound according to claim 1 wherein the CDK is selected from the group consisting of CDK1, CDK2 and CDK4.

3. The method according to claim 2 , wherein the CDK is a constituent of a complex selected from the group consisting of CDK1/cyclin B, CDK2/cyclin E, and CDK4/cyclin D wherein the CDK4/cyclin D is selected from the group consisting of CDK4/cyclin D1, CDK4/cyclin D2 and CDK4/cyclin D3 and the complex is inhibited.

4. A compound according to claim 1 of the formula

5. A compound according to claim 4 wherein 4 is —C(O)—.

6. A compound according to claim 4 wherein 4 is —S(O) 2 —.

7. A compound according to claim 5 wherein R a is selected from the group consisting of: —OR1 and —N(R1)(R3).

8. A compound according to claim 5 wherein R a is —SR1.

9. A compound according to claim 7 wherein R a is —OR1.

10. A compound according to claim 7 wherein R a is —N(R 1 )(R 3 ).

11. A compound according to claim 1 wherein R 2 is cyclopentyl.

12. A compound according to claim 1 wherein R1 is —(CH 2 ) n Q p (CH 2 ) n W.

13. A compound according to claim 10 wherein R1 is —(CH 2 ) n Q p (CH 2 ) n W.

14. A compound according to claim 13 wherein W is selected from the group consisting of:

where B is —O—, —S—, —NR6-, where each carbon of the aromatic or heteroaromatic ring may be independently replaced by a nitrogen atom, and each carbon of the aromatic ring may be independently substituted with an X substituent.

15. A compound according to claim 14 wherein W is phenyl, each carbon of which may be independently substituted with an X substituent.

16. The method according to claim 3 , wherein the cyclin D is cyclin D1.