Pyrimidine compounds
The present invention relates to substituted pyrimidines of formula I, their preparation, pharmaceutical compositions containing them and their use as inhibitors of cyclin-dependent kinases (CDKs) and hence their use in the treatment of proliferative disorders and/or viral disorders.
1. A compound of formula Ib, or a pharmaceutically acceptable Salt thereof,
wherein one of X 1 and X 2 is S, and the other of X 1 and X 2 is N;
wherein:
Z is NH, NHCO, NHSO 2 , NHCH 2 , CH 2 , CH 2 CH 2 , CH═CH, SO 2 , or SO;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, alkyl, aryl, aralkyl, halogeno, NO 2 , CN, OH, O-alkyl, O-aryl, NH 2 , NH-alkyl, NH-aryl, N-(alkyl) 2 , N-(aryl) 2 , N-(alkyl)(aryl), COOH, CONH 2 , CONH-alkyl, CONH-aryl, SO 3 H, SO 2 -alkyl, SO 2 -aryl, SO 2 NH 2 , CF 3 , CO-alkyl, CO-aryl, or R 11 , wherein alkyl, aryl, aralkyl groups may be further substituted with one or more groups selected from halogeno, NO 2 , OH, O-methyl, NH 2 , COOH, CONH 2 and CF 3 ;
wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is R 11 ;
each R 11 is:
Y, wherein Y is an alicyclic group containing one or more of the functions —O—, NH 2 , —NH—, ═N—, and wherein Y is optionally substituted by one of more substituents selected from:
SO 2 -alkyl;
alkyl optionally substituted by one or more OH groups;
CO-alkyl;
aralkyl;
COO-alkyl; and
an ether group optionally substituted by one or more OH groups.
2. A compound according to claim 1 , wherein X 1 is S and X 2 is N.
3. A compound according to claim 1 , wherein Z is NH.
4. A compound according to claim 1 , wherein R 3 is H.
5. A compound according to claim 1 , wherein at least one of R 2 , R 5 , R 6 or R 7 is R 11 .
6. A compound according to claim 1 , wherein X 1 is S, X 2 is N, Z is NH, R 1 is Me, R 2 is alkyl or amino, R 3 is H, one or two of R 5 , R 6 , and R 7 are CF 3 , OH, O-alkyl, halogeno, NO 2 , NH 2 , NH-alkyl or N-(alkyl) 2 and at least one of R 2 , R 5 , R 6 or R 7 is R 11 .
7. A compound according to claim 1 , wherein Y is a morpholine or piperazine group, each of which may be optionally substituted by one or more substituents selected from SO 2 -alkyl, alkyl optionally substituted by one or more OH groups, CO-alkyl, aralkyl, COO-alkyl, and an ether group optionally substituted by one or more OH groups.
8. A compound according to claim 1 , wherein at least one of R 2 , R 6 or R 7 is R 11 .
9. A compound according to claim 8 , wherein R 6 or R 7 is R 11 .
10. A compound according to claim 9 , wherein R 6 is R 11 and R 2 , R 4 , R 5 , R 7 and R 8 are each independently selected from alkyl, H, CF 3 , OH, O-alkyl, halogeno, NO 2 , NH 2 , NH-alkyl and N-(alkyl) 2 .
11. A compound according to claim 9 , wherein R 6 is R 11 and R 2 , R 4 , R 5 , R 7 and R 8 are each independently selected from alkyl, H, O-alkyl, halogeno, NO 2 , NH 2 and NH-alkyl.
12. A compound according to claim 9 , wherein R 6 is R 11 and R 4 , R 5 , R 7 and R 8 are all H and R 2 is selected from alkyl, O-alkyl, NH 2 and NH-alkyl.
13. A compound according to claim 9 , wherein R 11 is selected from:
14. A compound according to claim 9 , wherein R 7 is R 11 and R 4 , R 5 , R 6 , R 8 are all H, and R 2 is selected from alkyl, O-alkyl, NH 2 and NH-alkyl.
15. A compound according to claim 8 , wherein R 2 is R 11 .
16. A compound according to claim 15 , wherein R 2 is R 11 and R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from alkyl, H, CF 3 , OH, O-alkyl, halogeno, NO 2 , NH 2 , NH-alkyl and N-(alkyl) 2 .
17. A compound according to claim 15 , wherein R 2 is R 11 and R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from H, O-alkyl, halogeno, N-(alkyl) 2 , NO 2 .
18. A compound according to claim 15 , wherein R 2 is R 11 , one of R 5 or R 7 is selected from NO 2 , alkoxy, halogeno and N-(alkyl) 2 , and the remainder of R 4 , R 5 , R 6 , R 7 and R 8 are all H.
19. A compound according to claim 1 , wherein R 1 is methyl, Z is NH and R 3 is H.
20. A compound according to claim 1 which is [4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2yl]-(4-morpholin-4-yl-phenyl)-amine [1].
21. A compound selected from the following:
1
[4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-morpholin-
4-yl-phenyl)-amine
2
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-morpholin-4-yl-
phenyl)-amine
3
[4-(2-N-Methylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-
morpholinophenyl)-amine
4
[4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-
morpholin-4-yl-phenyl)-amine
5
1-(4-{4-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-
phenyl}-piperazin-1-yl)-ethanone
6
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-piperazin-1-yl-
phenyl)-amine
7
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-[4-(4′-2″-
ethoxylethanolpiperazino)-phenyl]-amine
8
3-(4-{4-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-
phenyl}-piperazin-1-yl)-propan-1-ol
9
2-(4-{4-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-
phenyl}-piperazin-1-yl)-ethanol
10
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-[4-(4-
methanesulfonyl-piperazin-1-yl)-phenyl]-amine
11
[4-(4-Benzyl-piperazin-1-yl)-phenyl]-[4-(4-methyl-2-methylamino-
thiazol-5-yl)-pyrimidin-2-yl]-amine
12
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-[4-(4-methyl-
piperazin-1-yl)-phenyl]-amine.
22. A compound according to claim 21 , which is selected from the following: [4], [8], and [12].
23. A compound according to claim 21 , which is selected from the following: [11].
24. A pharmaceutical composition comprising a compound according to any one of claims 1 , or 21 , admixed with a pharmaceutically acceptable diluent, excipient or carrier.
25. The pharmaceutical composition according to claim 24 , wherein said compound is [4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-morpholin-4-yl-phenyl)-amine [1].
26. A method of treating a proliferative disorder, said method comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 , or 21 , such that the proliferative disorder is treated, wherein the compound is administered in an amount sufficient to inhibit at least one CDK enzyme, and wherein said proliferative disorder is selected from the group consisting of bone osteosarcoma, breast cancer, cervical cancer, colon cancer, gastric adenocarcinoma, leiomyosarcoma, chronic myelogenous leukemia, lung cancer, neuroblastoma, osteogenic sarcoma, prostate cancer, and uterine cancer.
27. The method according to claim 26 , wherein said compound is administered in combination with one or more other anticancer compounds.
28. A method of treating an HIV-1 viral disorder, said method comprising administering to a mammal a therapeutically effective amount of a compound of formula Ib, or a pharmaceutically acceptable salt thereof,
wherein one of X 1 and X 2 is S, and the other of X 1 and X 2 is N;
wherein:
Z is NH, NHCO, NHSO 2 , NHCH 2 , CH 2 , CH 2 CH 2 , CH═CH, SO 2 , or SO;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, alkyl, aryl, aralkyl, halogeno, NO 2 , CN, OH, O-alkyl, O-aryl, NH 2 , NH-alkyl, NH-aryl, N-(alkyl) 2 , N-(aryl) 2 , N-(alkyl)(aryl), COOH, CONH 2 , CONH-alkyl, CONH-aryl, SO 3 H, SO 2 -alkyl, SO 2 -aryl, SO 2 NH 2 , CF 3 , CO-alkyl, CO-aryl, or R 11 , wherein alkyl, aryl, aralkyl groups may be further substituted with one or more groups selected from halogeno, NO 2 , OH, O-methyl, NH 2 , COOH, CONH 2 and CF 3 ;
wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is R 11 ;
wherein each R 11 is selected from:
Y, wherein Y is an alicyclic, group containing one or more of the functions —O—, NH 2 , —NH—, ═N—, and wherein Y is optionally substituted by one of more substituents selected from:
SO 2 -alkyl;
alkyl optionally substituted by one or more OH groups;
CO-alkyl;
aralkyl;
COO-alkyl; and
an ether group optionally substituted by one or more OH groups, such that Said HIV-1 viral disorder is treated.
29. A method of treating an HIV-1 viral disorder, said method comprising administering to a mammal a therapeutically effective amount of a compound selected from the following:
1
[4-(2-Amino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-morpholin-
4-yl-phenyl)-amine
2
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-morpholin-4-yl-
phenyl)-amine
3
[4-(2-N-Methylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-
morpholinophenyl)-amine
4
[4-(2-Ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-
morpholin-4-yl-phenyl)-amine
5
1-(4-{4-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-
phenyl}-piperazin-1-yl)-ethanone
6
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-(4-piperazin-1-yl-
phenyl)-amine
7
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-[4-(4′-2″-
ethoxylethanolpiperazino)-phenyl]-amine
8
3-(4-{4-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-
phenyl}-piperazin-1-yl)-propan-1-ol
9
2-(4-{4-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-
phenyl}-piperazin-1-yl)-ethanol
10
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-[4-(4-
methanesulfonyl-piperazin-1-yl)-phenyl]-amine
11
[4-(4-Benzyl-piperazin-1-yl)-phenyl]-[4-(4-methyl-2-methylamino-
thiazol-5-yl)-pyrimidin-2-yl]-amine
12
[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-yl]-[4-(4-methyl-
piperazin-1-yl)-phenyl]-amine.
or pharmaceutically acceptable salt thereof, such that said HIV-1 viral disorder is treated.
30. The method according to claim 29 , wherein said compound is selected from the following: [1], [3], and [4].
31. The method according to claim 26 , wherein the CDK enzyme is CDK1, CDK2, CDK3, CDK4, CDK6, CDK7, CDK8 or CDK9.
32. The method according to claim 26 , wherein said compound is [4-(2-Amino-4-methyl-thiazol-5-yl) -pyrimidin-2-yl]-(4-morpholin-4-yl-phenyl)-amine [1].
33. The method according to claim 32 , wherein said compound is administered in combination with one or more anticancer compounds.
34. The method according to claim 28 , wherein said compound is [4-(2-Amino-4-methyl-thiazol-5-yl) -pyrimidin-2-yl]-(4-morpholin-4-yl-phenyl)-amine [1].