Substituted pyrazolo[1,5-a]pyrimidines as cyclin dependent kinase inhibitors

1. A method of treating chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of at least one compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

2. A method of treating chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof, comprising administering to said patient

an amount of a first compound, which is a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof; and

an amount of at least one second compound, said second compound being an anti-cancer agent;

wherein the amounts of the first compound and said second compound result in a therapeutic effect.

3. The method of claim 2 , further comprising radiation therapy.

4. The method of claim 2 , wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, pegylated liposomal doxorubicin, liposomal doxorubicin, doxorubicin liposomal, docetaxel, paclitaxel, etoposide, irinotecan, topotecan, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, 4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide, tipifarnib, L778,123 (a farnesyl protein transferase inhibitor), BMS 214662 (a farnesyl protein transferase inhibitor), gefitinib, erlotinib, antibodies to EGFR, imatinib, interferon alfa-2b, ara-C, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, ispinesib, SB-743921, GSK-923295, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab, arsenic trioxide, Vinorelbine, Porfimer, cetuximab, Liposomal, Thiotepa, Altretamine, Melphalan, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, satriplatin, Gemtuzumab ozogamicin, pemetrexed, panitubimab, sunitinib, sorafenib, dastinib, nilotinib, lapatinib and alemtuzumab.

5. A method of treating chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof, comprising administering to said patient: a composition comprising: (i) a therapeutically effective amount of at least one compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, and (ii) temozolomide.

6. A method of treating chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof by inhibiting CDK1 or CDK2, comprising administering to said patient a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 further comprising administering radiation therapy.

8. A method of treating chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 further comprising administering radiation therapy.

10. A method of treating chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof, comprising administering to said patient a composition comprising (i) the compound:

or a pharmaceutically acceptable salt thereof, and (ii) at least one compound selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, pegylated liposomal doxorubicin, liposomal doxorubicin, doxorubicin liposomal, docetaxel, paclitaxel, etoposide, irinotecan, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, 4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide, tipifarnib, L778,123 (a farnesyl protein transferase inhibitor), BMS 214662 (a farnesyl protein transferase inhibitor), gefitinib, erlotinib, antibodies to EGFR, imatinib, interferon alfa-2b, ara-C, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, ispinesib, SB-743921, GSK-923295, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, bevacizumab, trastuzumab, tositumomab, bortezomib, ibritumomab, arsenic trioxide, Vinorelbine, Porfimer, cetuximab, Liposomal, Thiotepa, Altretamine, Melphalan, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, satriplatin, Gemtuzumab ozogamicin, pemetrexed, panitubimab, sunitinib, sorafenib, dastinib, nilotinib, lapatinib and alemtuzumab.

11. The method of claim 10 , further comprising the administration of radiation therapy.

12. A method of treating chronic lymphocytic leukemia, breast cancer, non-small cell lung cancer, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof comprising administering to said patient a composition comprising (i) the compound:

or a pharmaceutically acceptable salt thereof, and (ii) temozolomide.

13. The method of claim 12 , further comprising the administration of radiation therapy.

14. A method of treating chronic lymphocytic leukemia, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of at least one compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 wherein said cancer being treated is chronic lymphocytic leukemia.

16. The method of claim 14 wherein said cancer being treated is acute myleogenous leukemia.

17. The method of claim 14 wherein said cancer being treated is acute lymphoblastic leukemia.

18. The method of claim 14 wherein said cancer being treated is mantle cell leukemia.

19. The method of claim 14 wherein said method further comprises administering at least one anti-cancer agent.

20. The method of claim 19 wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, pegylated liposomal doxorubicin, liposomal doxorubicin, doxorubicin liposomal, docetaxel, paclitaxel, etoposide, irinotecan, topotecan, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, 4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl-]-1-piperidinyl]-2-oxoethyl]-1-piperidinecarboxamide, tipifarnib, L778,123 (a farnesyl protein transferase inhibitor), BMS 214662 (a farnesyl protein transferase inhibitor), gefitinib, erlotinib, antibodies to EGFR, imatinib, interferon alfa-2b, ara-C, cytoxan, cyclophosphamide, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, ispinesib, SB-743921, GSK-923295, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, bevacizumab, trastuzumnab, tositumomab, bortezomib, ibritumomab, arsenic trioxide, Vinorelbine, Porfimer, cetuximab, Liposomal, Thiotepa, Altretamine, Melphalan, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, satriplatin, Gemtuzumab ozogamicin, pemetrexed, panitubimab, sunitinib, sorafenib, dastinib, nilotinib, lapatinib and alemtuzumab.

21. A method of treating chronic lymphocytic leukemia, acute myleogenous leukemia, acute lymphoblastic leukemia, or mantle cell lymphoma in a patient in need thereof comprising administering to said patient a composition comprising (i) the compound:

or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 wherein said cancer is chronic lymphocytic leukemia.

23. The method of claim 21 wherein said cancer is acute myleogenous leukemia.

24. The method of claim 21 wherein said cancer is acute lymphoblastic leukemia.

25. The method of claim 21 wherein said cancer is mantle cell leukemia.