Substituted pyrazolo[3,2-d]pyrimidines as anti-cancer agents
The present invention provides novel compounds that are antagonists of PI3 kinase, PI3 kinase and tyrosine kinase, PI3 kinase and mTOR, or PI33 kinase, mTOR and tyrosine kinase.
1. A method of treating cancer in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of an antagonist, wherein said antagonist has the formula:
wherein
X is =N—;
R 1 is hydrogen, R 3 -substituted or unsubstituted alkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, or R 3 -substituted heteroaryl; and
R 2 is R 4 -substituted heteroaryl;
R 3 is halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , —NR 10 —C(O)R 11 , —NR 12 —C(O)—OR 13 , —C(O)NR 14 R 15 , —NR 16 S(O) 2 R 17 , R 19 -substituted or unsubstituted alkyl, R 19 -substituted or unsubstituted heteroalkyl, R 19 -substituted or unsubstituted cycloalkyl, R 19 -substituted or unsubstituted heterocycloalkyl, R 19 -substituted or unsubstituted aryl, or R 19 -substituted or unsubstituted heteroaryl, wherein n is an integer from 0 to 2;
R 4 is halogen, —CN, —OR 20 , —NR 22 R 23 ;
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 and R 17 are independently hydrogen, R 35 -substituted or unsubstituted alkyl, R 35 -substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, R 35 -substituted or unsubstituted heterocycloalkyl, R 35 -substituted or unsubstituted aryl, or R 35 -substituted or unsubstituted heteroaryl;
R 19 and R 35 are independently hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl;
R 20 , R 22 , and R 23 are hydrogen;
R 36 is —NR 37 R 38 ; and
R 37 and R 38 are hydrogen.
2. The method of claim 1 , wherein R 2 has the formula:
wherein
W 1 , W 2 , W 3 , and W 4 are independently ═CH—, ═CR 4 —, or ═N-; and
ring A is a partially or fully unsaturated 6- or 7- membered ring.
3. The method of claim 1 , wherein said cancer is selected from the group consisting of liver cancer, colon cancer, breast cancer, melanoma, kidney cancer, bladder cancer, endometrial cancer, and non-small-cell lung cancer.
4. The method according to claim 1 , wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently hydrogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.
5. The method according to claim 1 , wherein R 1 is R 3 -substituted or unsubstituted alkyl, or unsubstituted heterocycloalkyl.
6. The method according to claim 1 , wherein R 1 is R 3 -substituted or unsubstituted alkyl.
7. The method according to claim 1 , wherein R 1 is R 3 -substituted or unsubstituted C 1 -C 4 alkyl.
8. The method according to claim 1 , wherein R 1 is methyl or unsubstituted C 3 -C 6 branched alkyl.
9. The method according to claim 1 , wherein R 1 is isopropyl.
10. The method according to claim 1 , wherein R 3 is R 19 -substituted or unsubstituted alkyl, R 19 -substituted or unsubstituted cycloalkyl, or R 19 -substituted or unsubstituted aryl.
11. The method according to claim 1 , wherein R 3 is R 19 -substituted or unsubstituted alkyl, or R 19 -substituted or unsubstituted cycloalkyl.
12. The method according to claim 1 , wherein R 19 is unsubstituted alkyl or unsubstituted cycloalkyl.
13. The method according to claim 1 , wherein R 19 is unsubstituted C 1 -C 4 alkyl or unsubstituted cyclopentyl.
14. The method according to claim 1 , wherein R 2 is R 4 -substituted pyridinyl, R 4 -substituted pyrimidinyl, R 4 -substituted thiophenyl, R 4 -substituted furanyl, R 4 -substituted indolyl, R 4 -substituted benzoxadiazolyl, R 4 -substituted benzodioxolyl, R 4 -substituted benzodioxanyl, R 4 -substituted thianaphthanyl, R 4 -substituted pyrrolopyridinyl, R 4 -substituted indazolyl, R 4 -substituted quinolinyl, R 4 -substituted quinoxalinyl, R 4 -substituted pyridopyrazinyl, R 4 -substituted quinazolinonyl, R 4 -substituted benzoisoxazolyl, R 4 -substituted imidazopyridinyl, R 4 -substituted benzofuranyl, or R 4 -substituted benzothiophenyl.
15. The method according to claim 1 , wherein R 2 is R 4 -substituted indolyl.
16. The method according to claim 1 , wherein R 2 is 5-hydroxy indol-2-yl and R 1 is isopropyl.
17. The method of claim 1 , wherein said cancer is a carcinoma or sarcoma.
18. The method of claim 1 , wherein said cancer is a lymphoma.
19. The method of claim 3 , wherein said cancer is acute myelogenous leukemia or chronic myelogenous leukemia.
20. The method of claim 1 , wherein said cancer is multiple myeloma.
21. The method of claim 1 , wherein said cancer is macroglobulinemia.
22. The method of claim 1 , wherein said cancer is leukemia.
23. The method of claim 1 , wherein said cancer is selected from the group consisting of bladder cancer, endometrial cancer, kidney cancer, prostate cancer, or non-Hodgkin's lymphoma.