Claims for Patent: 7,511,049

Summary for Patent: 7,511,049

Title:	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.
Inventor(s):	Guzi; Timothy J. (Chatham, NJ), Paruch; Kamil (Garwood, NJ), Dwyer; Michael P. (Scotch Plains, NJ), Doll; Ronald J. (Convent Station, NJ), Girijavallabhan; Viyyoor M. (Parsippany, NJ), Dillard; Lawrence W. (Skillman, NJ), Tran; Vinh D. (Fountain Valle, CA), He; Zhenmin (Shanghai, CN), James; Ray Anthony (Bristol, PA), Park; Haengsoon (Plainsboro, NJ)
Assignee:	Schering Corporation (Kenilworth, NJ) Pharmacopeia, Inc. (Cranbury, NJ)
Application Number:	11/779,050
Patent Claims:	1. A method of treating breast cancer by inhibiting a cyclin dependent kinase in a patient, comprising administering a therapeutically effective amount of at least one compound represented by the structural formula III: ##STR00354## wherein: Q is --S(O.sub.2)-- or --C(O)--; R is aryl or heteroaryl, wherein said aryl or heteroaryl 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, CN, --OR.sup.5, SR.sup.5, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6, --NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, CF.sub.3, alkyl, aryl and OCF.sub.3; R.sup.2 is selected from the group consisting of CN, NR.sup.5R.sup.6, --C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.6, --OR.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.6, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.6; alkynyl, heteroaryl, CF.sub.3, heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R.sup.9 groups which can be the same or different and are independently selected from the list of R.sup.9 shown below, ##STR00355## R.sup.3 is selected from the group consisting of H, halogen, --NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6 alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, ##STR00356## wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.3 and the heterocyclyl moieties whose structures are shown immediately above for R.sup.3 can be substituted 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.sub.3, CN, --OCF.sub.3, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --OR.sup.5, --NR.sup.5R.sup.6, --(CR.sup.4R.sup.5).sub.nNR.sup.5R.sup.6, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.6; R.sup.4 is H, halo or alkyl; R.sup.5 is H or alkyl; R.sup.6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, 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, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, 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, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.4R.sup.5, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.4R.sup.5, --C(O)R.sup.5, --SO.sub.3H, --SR.sup.5, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.4R.sup.5, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.4R.sup.5; or optionally (i) R.sup.5 and R.sup.10 in the moiety --NR.sup.5R.sup.10, or (ii) R.sup.5 and R.sup.6 in the moiety --NR.sup.5R.sup.6, may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R.sup.9 groups; R.sup.7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl 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.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --CH.sub.2OR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.5R.sup.10, --C(O)R.sup.5, --SR.sup.10, --S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)R.sup.10 and --R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.8 is selected from the group consisting of R.sup.6, --C(O)NR.sup.5R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --C(O)R.sup.7 and --S(O.sub.2)R.sup.7; R.sup.9 is selected from the group consisting of halogen, CN, --NR.sup.5R.sup.10, --C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.10, --OR.sup.6, --SR.sup.6, S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; m is 0 to 4, or a pharmaceutically acceptable salt thereof to said patient, wherein said cyclin dependent kinase is CDK1 or CDK2. 2. The method of claim 1, wherein said kinase is CDK2. 3. The method of claim 1 wherein said compound is administered along with an amount of at least one second compound, said second compound being 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, oxaliplatin, leucovirin, ELOXATIN.TM., Pentostatine, Vinbiastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol, Diethyistilbestrol, 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, anti-cancer agent; wherein the amounts of the first compound and said second compound result in a therapeutic effect. 4. The method of claim 3, further comprising radiation therapy. 5. The method of claim 3, wherein said first compound is administered to said patient, together, concurrently or sequentially, with said second compound, wherein said second compound is temozolomide. 6. A method of treating breast cancer, comprising administering a therapeutically effective amount of at least one compound selected from the group consisting of ##STR00357## ##STR00358## ##STR00359## ##STR00360## ##STR00361## ##STR00362## ##STR00363## ##STR00364## ##STR00365## ##STR00366## or a pharmaceutically acceptable salt thereof. 7. A method of treating breast a cancer, comprising administering to a mammal in need of such treatment an amount of a first compound, which is a compound described in claim 6, and an amount of at least one second compound 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, oxaliplatin, leucovirin, ELOXATIN.TM., Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol, Diethyistilbestrol, 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; wherein the amounts of the first compound and said second compound result in a therapeutic effect. 8. The method of claim 7, further comprising radiation therapy. 9. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound represented by the structural formula III: ##STR00367## wherein: Q is --S(O.sub.2)-- or --C(O)--; R is aryl or heteroaryl, wherein said aryl or heteroaryl 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, CN, --OR.sup.5, SR.sup.5, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6, --NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, CF.sub.3, alkyl, aryl and OCF.sub.3; R.sup.2 is selected from the group consisting of CN, NR.sup.5R.sup.6, --C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.6, --OR.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.6, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.6; alkynyl, heteroaryl, CF.sub.3, heterocyclyl, alkynylalkyl, cycloalkyl, alkyl substituted with 1-6 R.sup.9 groups which can be the same or different and are independently selected from the list of R.sup.9 shown below, ##STR00368## R.sup.3 is selected from the group consisting of H, halogen, --NR.sup.5R.sup.6, --C(O)NR.sup.5R.sup.6, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl, ##STR00369## wherein each of said alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl and heteroarylalkyl for R.sup.3 and the heterocyclyl moieties whose structures are shown immediately above for R.sup.3 can be substituted 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.sub.3, CN, --OCF.sub.3, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --OR.sup.5, --NR.sup.5R.sup.6, --(CR.sup.4R.sup.5).sub.nNR.sup.5R.sup.6, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.6, --SR.sup.6, --S(O.sub.2)R.sup.6, --S(O.sub.2)NR.sup.5R.sup.6, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.6; R.sup.4 is H, halo or alkyl; R.sup.5 is H or alkyl; R.sup.6 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, 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, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)R.sup.5, --C(O)NR.sup.5R.sup.10, --SO.sub.3H, --SR.sup.10, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.10 is selected from the group consisting of H, alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and heteroarylalkyl, wherein each of said alkyl, aryl, arylalkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, 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, heterocyclylalkyl, CF.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.4R.sup.5, --N(R.sup.5)Boc, --(CR.sup.4R.sup.5).sub.nOR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.4R.sup.5, --C(O)R.sup.5, --SO.sub.3H, --SR.sup.5, --S(O.sub.2)R.sup.7, --S(O.sub.2)NR.sup.4R.sup.5, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.4R.sup.5; or optionally (i) R.sup.5 and R.sup.10 in the moiety --NR.sup.5R.sup.10, or (ii) R.sup.5 and R.sup.6 in the moiety --NR.sup.5R.sup.6, may be joined together to form a cycloalkyl or heterocyclyl moiety, with each of said cycloalkyl or heterocyclyl moiety being unsubstituted or optionally independently being substituted with one or more R.sup.9 groups; R.sup.7 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, wherein each of said alkyl, cycloalkyl, heteroarylalkyl, aryl, heteroaryl and arylalkyl 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.sub.3, OCF.sub.3, CN, --OR.sup.5, --NR.sup.5R.sup.10, --CH.sub.2OR.sup.5, --C(O.sub.2)R.sup.5, --C(O)NR.sup.5R.sup.10, --C(O)R.sup.5, --SR.sup.10, --S(O.sub.2)R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.10, --N(R.sup.5)C(O)NR.sup.10 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; R.sup.8 is selected from the group consisting of R.sup.6, --C(O)NR.sup.5R.sup.10, --S(O.sub.2)NR.sup.5R.sup.10, --C(O)R.sup.7 and --S(O.sub.2)R.sup.7; R.sup.9 is selected from the group consisting of halogen, CN, --NR.sup.5R.sup.10, --C(O.sub.2)R.sup.6, --C(O)NR.sup.5R.sup.10, --OR.sup.6, --SR.sup.6, --S(O.sub.2)NR.sup.7, --S(O.sub.2)NR.sup.5R.sup.10, --N(R.sup.5)S(O.sub.2)R.sup.7, --N(R.sup.5)C(O)R.sup.7 and --N(R.sup.5)C(O)NR.sup.5R.sup.10; m is 0 to 4, and n is 1 to 4 in combination with at least one pharmaceutically acceptable carrier additionally comprising temozolomide. 10. A method of breast treating cancer in a patient, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising the compound described in claim 6 in combination with at least one pharmaceutically acceptable carrier to said patient.

Details for Patent 7,511,049

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2022-09-04
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2022-09-04
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2022-09-04
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2022-09-04