NOVEL 4-CYANO, 4-AMINO, AND 4-AMINOMETHYL DERIVATIVES OF PYRAZOLO[1,5-a]PYRIDINES, PYRAZOLO[1,5-c]PYRIMIDINES AND 2H-INDAZOLE COMPOUNDS AND 5-CYANO, 5-AMINO, AND 5-AMINOMETHYL DERIVATIVES OF IMIDAZO[1,2-a]PYRIDINES, AND IMIDAZO[1,5-a]PYRAZINES AS CYCLIN DEPENDENT KINASE INHIBITORS

Abstract

In its many embodiments, the present invention provides a novel class of 4-cyano, 4-amino, and 4-aminomethyl derivatives of pyrazolo[1,5-a]pyridine, pyrazolo[1,5-c]pyrimidine, and 2H-Indazole compounds and 5-cyano, 5-amino, and 5-aminomethyl derivatives of imidazo[1,2-a]pyridine and imidazo[1,5-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:
 Y is selected from the group consisting of CN, NH 2 , and CH 2 NH 2 ; 
 R 1  is selected from the group consisting of H, halogen, R 9 , NH 2 , CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, CF 3 , heterocyclylalkyl, arylalkyl, heteroarylalkyl, heterocyclyalkylalkyl, cycloalkyl, cycloalkylalkyl, C(O)OR 4 , alkyl substituted with 1-6 R 9  groups which can be the same or different and are independently selected from the list of R 9  shown later below, 
 
       
         
           
           
               
               
           
         
       
       wherein the aryl in the above-noted definitions for R 1  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, CN, NH 2 , —OR 5 , SR S , —CH 2 OR 5 , —C(O)R 5 , —SO 3 H, —S(O 2 )R 6 , —S(O 2 )NR 5 R 6 , —NR 5 R 6 , —C(O)NR 5 R 6 , —CF 3 , and —OCF 3 ;
 R 2  is selected from the group consisting of H, halogen, —NR 5 R 6 , —C(O)OR 4 , —C(O)NR 5 R 6 , alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, 
 
       
         
           
           
               
               
           
         
       
       wherein each of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R 2  and heterocyclyl moieties whose structures are shown immediately above for R 2  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, alkenyl, alkynyl, aryl, cycloalkyl, CF 3 , CN, —OCF 3 , —(CR 4 R 5 ) n OR 5 , —OR 5 , —R 5 OR 5 , —NR 5 R 6 , —(CR 4 R 5 ) n NR 5 R 6 , —C(O 2 )R 5 , —C(O)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 ;
 R 3  is selected from the group consisting of a halogen, CN, amino, alkylamino, cycloalkylamino, arylalkylamino, heteroarylamino, heteroarylalkylamino, hydroxyalkylamino, heterocycloalkylalkylamino, wherein each of said amino, alkylamino, cycloalkylamino, arylalkylamino, heteroarylamino, heteroarylalkylamino, hydroxyalkylamino, and heterocycloalkylalkylamino 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, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 6 , —C(R 4 R 5 ) n OR 5 , —C(O 2 )R 5 , —C(O)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 4  is H, halogen, CN or alkyl; 
 R 5  is H or alkyl; 
 R 6  is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclolalkyl, heteroaryl, and heteroarylalkyl 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 10 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , 
 
       —C(O)R 5 , —C(O)NR 5 R 10 , —SO 3 H, —SR 10 , —S(O 2 )R 7 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7  and —N(R 5 )C(O)NR 5 R 10 ;
 R 10  is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and heteroarylalkyl 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 4 R 5 , —N(R 5 )Boc, —(CR 4 R 5 ) n OR 5 , —C(O 2 )R 5 , 
 
       —C(O)NR 4 R 5 , —C(O)R 5 , —SO 3 H, —SR 5 , —S(O 2 )R 7 , —S(O 2 )NR 4 R 5 , —N(R 5 )S(O 2 )R 7 , —N(R 5 )C(O)R 7  and —N(R 5 )C(O)NR 4 R 5 ; optionally (i) R 5  and R 10  in the moiety —NR 5 R 10 , or (ii) R 5  and R 6  in the moiety —NR 5 R 6 , may be joined together to form a cycloalkyl or heterocycloalkyl moiety, with each of said cycloalkyl or heterocycloalkyl moiety being unsubstituted or optionally independently being substituted with one or more R 9  groups;
 R 7  is selected from the group consisting of alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, aryl, heterocycloalkyl, heteroaryl, arylalkyl and heteroarylalkyl, for R 7  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, aryl, cycloalkyl, CF 3 , OCF 3 , CN, —OR 5 , —NR 5 R 10 , —CH 2 OR 5 , —C(O 2 )R 5 , —C(O)NR 5 R 10 , —C(O)R 5 , —SR 10 , —S(O 2 )R 10 , —S(O 2 )NR 5 R 10 , —N(R 5 )S(O 2 )R 10 , —N(R 5 )C(O)R 10  and —N(R 5 )C(O)NR 5 R 10 ; 
 R 8  is selected from the group consisting of R 6 , —C(O)NR 5 R 10 , —CH 2 OR 4 , —C(O)OR 6 , —C(O)R 7  and —S(O 2 )R 7 ; 
 R 9  is selected from the group consisting of halogen, —CN, —NR 5 R 6 , —(CH 2 ) n OR 4 , —C(O 2 )R 6 , —C(O)NR 5 R 6 , —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 ; 
 m is 0 to 4; and 
 n is 1 to 4. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is F, Cl, Br, CF 3 , CN, lower alkyl, cycloalkyl or —(CH 2 ) n OR 6 . 
     
     
         3 . The compound of  claim 1 , wherein R 2  is H, lower alkyl, cycloalkyl, —C(O)OR 4 , aryl, heteroaryl, cycloalkylalkyl, 
       
         
           
           
               
               
           
         
       
       wherein said lower alkyl, aryl, cycloalkyl, heteroaryl, and the heterocyclyl moieties shown above for R 2  are 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, CF 3 , lower alkyl, —OCH 3 , —CH 2 OH, —CH 2 CH 2 OH, and CN. 
     
     
         4 . The compound of  claim 1 , wherein R 4  is H or CN. 
     
     
         5 . The compound of  claim 1 , wherein R 3  is selected from the group consisting of (pyridin-3-ylmethyl)-amino, (pyridin-2-ylmethyl)-amino, (pyridin-4-ylmethyl)-amino, isopropylamino, phenylamino, Benzylamino, pyridin-3-ylamino, pyridin-2-ylamino, pyridin-4-ylamino, 2-amino-ethanol and 1-amino-ethanol. 
     
     
         6 . The compound of  claim 1 , wherein Y is selected from the group consisting of CN, NH 2 , and CH 2 NH 2 . 
     
     
         7 . The compound of  claim 1 , wherein Y is CN. 
     
     
         8 . The compound of  claim 1 , wherein Y is NH 2 . 
     
     
         9 . The compound of  claim 1 , wherein Y is CH 2 NH 2 . 
     
     
         10 . The compound of  claim 1 , wherein R 3  is (pyridin-3-ylmethyl)-amino. 
     
     
         11 . The compound of  claim 1 , wherein R 3  is (pyridin-2-ylmethyl)-amino. 
     
     
         12 . The compound of  claim 1 , wherein R 3  is (pyridin-4-ylmethyl)-amino. 
     
     
         13 . The compound of  claim 2 , wherein said R 1  is Br or Cl. 
     
     
         14 . The compound of  claim 2 , wherein R 1  is isopropyl or ethyl. 
     
     
         15 . The compound of  claim 2 , wherein R 1  is CH 2 OH or —CH 2 OCH 3 . 
     
     
         16 . The compound of  claim 2 , wherein R 1  is CN. 
     
     
         17 . The compound of  claim 1 , wherein R 2  is lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, —NR 5 R 6 , 
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 17 , wherein R 2  is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 17 , wherein R 2  is unsubstituted phenyl or phenyl substituted with one or more moieties selected from the group consisting of F, Br, Cl, OMe, CH 3  and CF 3 . 
     
     
         20 . The compound of  claim 17 , wherein R 2  is cyclohexylmethyl. 
     
     
         21 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         22 . 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. 
     
     
         23 . 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. 
     
     
         24 . The method of  claim 22 , wherein said cyclin dependent kinase is CDK2. 
     
     
         25 . The method of  claim 23  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, squamous cell carcinoma; leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, Burkett's lymphoma; acute and chronic myelogenous leukemia, myelodysplastic syndrome, promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. 
     
     
         26 . 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 desired therapeutic effect.   
     
     
         27 . The method of  claim 26 , further comprising radiation therapy. 
     
     
         28 . The method of  claim 26 , wherein said anti-cancer agent is selected from the group consisting of a cytostatic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan (or CPT-11), camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, 5-Fluorouracil, 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), 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, oxaliplatin, 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, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, and Hexamethylmelamine. 
     
     
         29 . 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. 
     
     
         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, 5-fluorouracil, 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, Zarnestra® (tipifarnib), L778,123 (a farnesyl protein transferase inhibitor), BMS 214662 (a farnesyl protein transferase inhibitor), 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 171-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, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, and Hexamethylmelamine. 
     
     
         31 . A compound of  claim 1  in isolated and purified form.