Novel imidazopyrazines as cyclin dependent kinase inhibitors

Abstract

In its many embodiments, the present invention provides a novel class of imidazo[1,2-a]pyrazine 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 represented by the structural formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R is selected from the group consisting of alkyl, CF 3 , heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl, —C(O)R 7 ,  
                     
 wherein each of said alkyl, heteroaryl, arylalkyl, cycloalkyl, heterocyclyl and the heterocyclyl moieties whose structures are shown immediately above for R can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF 3 , CN, —OCF 3 , -OR 6 , —C(O)R 7 , —NR 5 R 6 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —(CHR 5 ) n OR 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7  and —N(R 5 )C(O)NR 5 R 6 ;  
 R 1  is H, halogen or alkyl;  
 R 2  is selected from the group consisting of H, halogen, CN, cycloalkyl, heterocyclyl, alkynyl and —CF 3 ;  
 R 3  is selected from the group consisting of aryl (with the exception of phenyl), heteroaryl (with the exception of furyl), heterocyclyl, —(CHR 5 ) n -heteroaryl, —S(O 2 )R 6 , —C(O)R 6 , —S(O 2 )NR 5 R 6 , —C(O)OR 6 , —C(O)NR 5 R 6 ,  
                     
 wherein each of said aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, OCF 3 , —OR 5 , —NR 5 R 6 ,—C(O 2 )R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7  and —N(R 5 )C(O)NR 5 R 6 , with the proviso that when R 3  is —(CHR 5 ) n -heteroaryl, R 2  can additionally be alkyl;  
 R  5 is H or alkyl;  
 R6 is selected from the group consisting of H, alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7  and —N(R 5 )C(O)NR 5 R 6 ;  
 R 7  is selected from the group consisting of alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7  and —N(R 5 )C(O)NR 5 R 6 ;  
 R 8  is selected from the group consisting of R 6 , —C(O)NR 5 R 6 , —S(O 2 )NR 5 R 6 , —C(O)R 7 , —C(O 2 )R 6 , —S(O 2 )R 7  and —(CH 2 )-aryl;  
 m is 0 to 4; and  
 n is 1-4.  
 
     
     
         2 . The compound of  claim 1 , wherein R is selected from the group consisting of alkyl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, arylalkyl,  
       
         
           
           
               
               
           
         
       
       wherein each of said alkyl, heteroaryl, cycloalkyl, arylalkyl, heterocyclyl and the heterocyclyl moieties shown above for R can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, cycloalkyl, CF 3 , CN, —OCF 3 , —OR 6 , —C(O)R 7 , —NR 5 R 6 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —SR 6 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 6 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7  and —N(R 5 )C(O)N R 5 R 6 . 
 R 1  is H or halogen;  
 R 2  is selected from the group consisting of H, halogen, cycloalkyl, CN, alkynyl and —CF 3 ;  
 R 3  is selected from the group consisting of aryl, heteroaryl, heterocyclyl, —(CHR 5 ) n -heteroaryl, —S(O 2 )R 6 , —C(O)R 6 , —S(O 2 )NR 5 R 6 , —C(O)OR 6 , —C(O)NR 5 R 6 ,  
                     
 wherein each of said aryl, heteroaryl and heterocyclyl can be unsubstituted or optionally substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of halogen, alkyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —N(R 5 )C(O)R 7 , —C(O)NR 5 R 6 , —S(O 2 )R 6 , and —N(R 5 )C(O)R 7 ;  
 R5 is H or lower alkyl;  
 m is 0 to 2; and  
 n is 1 to 3.  
 
     
     
         3 . The compound of  claim 2 , wherein R is alkyl, arylalkyl or cycloalkylalkyl.  
     
     
         4 . The compound of  claim 3 , wherein R is selected from the group consisting of methyl, ethyl, t-butyl, cyclohexylmethyl, benzyl and phenethyl.  
     
     
         5 . The compound of  claim 2 , wherein R 1  is H.  
     
     
         6 . The compound of  claim 2 , wherein R 1  is methyl.  
     
     
         7 . The compound of  claim 2 , wherein R 2  is H, F, Cl, Br or 1.  
     
     
         8 . The compound of  claim 7 , wherein R 2  is Br.  
     
     
         9 . The compound of  claim 8 , wherein R 3  is (pyrid-2-yl)methyl, (pyrid-3-yl)methyl, (pyrid-4-yl)methyl, thien-2-yl or thien-3yl, wherein said pyridyl and thienyl can be unsubstituted or optionally independently substituted with one or more moieties which can be the same or different, each moiety being independently selected from the group consisting of F, Cl, Br, CF 3 , lower alkyl, methoxy and CN.  
     
     
         10 . The compound of  claim 9 , wherein R 3  is (pyrid-2-yl)methyl.  
     
     
         11 . The compound of  claim 9 , wherein R 3  is (pyrid-3-yl)methyl.  
     
     
         12 . The compound of  claim 9 , wherein R 3  is (pyrid-4-yl)methyl.  
     
     
         13 . The compound of  claim 2 , wherein m is 0.  
     
     
         14 . The compound of  claim 2 , wherein n is 1.  
     
     
         15 . (canceled)  
     
     
         16 . 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.  
     
     
         17 . A method of treating one or more diseases associated with cyclin dependent kinase, comprising administering a therapeutically effective amount of at least one compound of  claim 1  to a patient in need of such treatment.  
     
     
         18 . The method of  claim 17 , wherein said cyclin dependent kinase is CDK2.  
     
     
         19 . The method of  claim 17 , wherein said cyclin dependent kinase is mitogen activated protein kinase (MAPK/ERK).  
     
     
         20 . The method of  claim 17 , wherein said cyclin dependent kinase is glycogen synthase kinase 3 (GSK3beta).  
     
     
         21 . The method of  claim 17 , 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 pig mentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.    
     
     
         22 . A method of treating one or more diseases associated with cyclin dependent kinase, 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 or solvate 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.    
     
     
         23 . The method of  claim 22 , further comprising radiation therapy.  
     
     
         24 . The method of  claim 22 , 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.  
     
     
         25 . 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.  
     
     
         26 . The pharmaceutical composition of  claim 25 , additionally comprising one or more anti-cancer agents 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, R 115777, 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.  
     
     
         27 . A compound of  claim 1  in purified form.