Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors

Abstract

In its many embodiments, the present invention provides a novel class of pyrazolo[1,5-a]pyrimidine compounds as inhibitors of cyclin dependent kinases, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with the CDKs using such compounds or pharmaceutical compositions.

1 . A compound of the formula:  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       2 . A method of inhibiting one or more cyclin dependent kinases comprising administering a therapeutically effective amount of at least one compound of  claim 1  to a patient in need of such inhibition.  
   
   
       3 . A method of treating one or more diseases associated with a kinase by inhibiting CDK1 or CDK2, comprising administering a therapeutically effective amount of at least one compound of  claim 1  to a patient in need of such treatment.  
   
   
       4 . The method of  claim 3 , wherein said treatment is by inhibiting CDK2.  
   
   
       5 . The method of  claim 3 , wherein said treatment is by inhibiting CDK1.  
   
   
       6 . The method of  claim 3 , wherein said cyclin dependent kinase is glycogen synthase kinase 3 beta (GSK3beta).  
   
   
       7 . The method of  claim 3 , wherein said disease is selected from the group consisting of: 
 cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;    leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma;    acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;    fibrosarcoma, rhabdomyosarcoma;    astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.    
   
   
       8 . A method of treating one or more diseases associated with cyclin dependent kinase by inhibiting CDK1 or CDK2, comprising administering to a mammal in need of such treatment 
 an amount of a first compound, which is a compound of  claim 1 , 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.    
   
   
       9 . The method of  claim 8 , further comprising radiation therapy.  
   
   
       10 . The method of  claim 8 , wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan.  
   
   
       11 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 1  in combination with at least one pharmaceutically acceptable carrier.  
   
   
       12 . The pharmaceutical composition of  claim 9 , additionally comprising one or more anti-cancer agents selected from the group consisting of cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, 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, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.  
   
   
       13 . A method of inhibiting CDK1 or CDK2, comprising administering a therapeutically effective amount of at least one compound of any of  claim 1  to a patient.  
   
   
       14 . A method of treating one or more diseases associated with a kinase, by inhibiting CDK1 or CDK2, comprising administering a therapeutically effective amount of at least one compound of any of  claim 1  to a patient.  
   
   
       15 . The method of  claim 14 , wherein said disease is selected from the group consisting of: 
 cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;    leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma;    acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;    fibrosarcoma, rhabdomyosarcoma;    astrocytoma, neuroblastoma, glioma and schwannomas;    melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.    
   
   
       16 . A method of treating one or more diseases associated with cyclin dependent kinas by inhibiting CDK1 or CDK2, comprising administering to a mammal in need of such treatment 
 an amount of a first compound, which is a compound of  claim 1 , or a pharmaceutically acceptable salt thereof;    and    an amount of temozolomide;    wherein the amounts of the first compound and said temozolomide result in a therapeutic effect.    
   
   
       17 . The method of  claim 16 , further comprising radiation therapy.  
   
   
       18 . A pharmaceutical composition comprising (i) a compound of  claim 1  or a pharmaceutically acceptable salt thereof, and (ii) temozolomide.  
   
   
       19 . A method of inhibiting one or more kinases, comprising administering the pharmaceutical composition of  claim 18 .  
   
   
       20 . The method of  claim 19  wherein said kinase is a cyclin dependent kinase.  
   
   
       21 . A method of treating one or more diseases associated with a kinase by inhibiting CDK1 or CDK2, comprising administering the pharmaceutical composition of  claim 18 .  
   
   
       22 . A method of treating a cancer, comprising administering the pharmaceutical composition of  claim 18 .  
   
   
       23 . A method of treating a cancer, comprising administering a therapeutically effective amount of at least one compound of  claim 1 .  
   
   
       24 . The method of  claim 23 , wherein said cancer is selected from the group consisting of: 
 cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma;    leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma and Burkett's lymphoma;    acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocytic leukemia;    fibrosarcoma, rhabdomyosarcoma;    astrocytoma, neuroblastoma, glioma and schwannomas;    melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.    
   
   
       25 . A method of treating a cancer, comprising administering to a mammal in need of such treatment 
 an amount of a first compound, which is a compound of  claim 1 , 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.    
   
   
       26 . The method of  claim 25 , further comprising radiation therapy.  
   
   
       27 . The method of  claim 25 , wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, ELOXATIN™, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, 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, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.  
   
   
       28 . A method of treating a cancer, comprising administering (i) a therapeutically effective amount of at least one compound of  claim 1 , and (ii) temozolomide.  
   
   
       29 . A pharmaceutical composition comprising at least one compound of  claim 1  in combination with at least one pharmaceutically acceptable carrier.  
   
   
       30 . The pharmaceutical composition of  claim 29 , additionally comprising one or more anti-cancer agents selected from the group consisting of cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, CPT-11, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5FU, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, Iressa, Tarceva, antibodies to EGFR, Gleevec, intron, ara-C, adriamycin, cytoxan, gemcitabine, Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, 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, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, CPT-11, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, or Hexamethylmelamine.