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1. WO2010118207 - PYRAZOLO [1, 5-A] PYRIMIDINE DERIVATIVES AS MTOR INHIBITORS

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[ EN ]

CLAIMS

What is claimed is:

1. A compound of the formuia:


668

670

674

Ķ77





or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, in combination with at least one pharmaceutically acceptable -carrier. 3. The pharmaceutical composition according to claim 2, further comprising one or more anti-cancer agents different from the compounds of claim 1. 4. The pharmaceutical composition according to claim 3, wherein the one or more anti-cancer agents are selected from the group consisting of Adriamycin, Altretamine, Amidox, Aminoglutethimide, Amsacrine, Anastrazole, Antibodies to EGFR, 3-AP, Aphidicolon, Ara-C, Arsenic trioxide, L-Asparaginase, Bevacizumab, Bleomycin, BMS 214662, Bortezomib, Busulfan, Campath, Camptostar, Capecitabine, Carboplatin, Carmustine, Centrosome associated protein E ("CENP-E") inhibitors, Cetuximab, Cladribine, Chlorambucil, Chlormethine, Chlorotrianisene, Cisplatin, Clofarabine, cyclophosphamide, Cytarabine, a Cytostatic agent, Cytoxan, Dacarbazine, Dactinomycin, Daunorubicin, Dasatinib, Deforolimus, Deoxycoformycin, Didox,

Diethylstilbestrol, Docetaxel, Doxorubicin, Dromostanolone, Droloxafine, Epirubicin, Epothilones, ERK inhibitors, Erlotinib, Etoposide, 17α-Ethinylestradiol, Estramustine, Exemestane, Floxuridine, Fludarabine, Fludarabine phosphate, 5-Fluorouracii, Fluoxymesterone, Flutamide, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab ozogamcicin, Gosereliπ, GSK-923295, Hexamethylmelamine, Hydroxyprogesterone, Hydroxyurea, lbritumomab Tiuxetan, [darubicin, Ifosfamide, lmatinib mesylate, Intron, Irinotecan, ispinesib, KSP inhibitors, L778.123, Lapatinib, Leucovirin, Leuprolide, Lerozole, Letrazole, Levamisole, Liposomal Doxorubicin, Liposomal, Lomustine, lonafornib, Medroxyprogesteroneacetate, Megestrolacetate, Melphalan, 6-Mercaptopurine, Methoxtrexate, Methylprednisoione, Methyltestosterone, Mithramycin, Mitomycin-C, Mitotane, Mitoxantrone, Navelbene, Niiotinib, Oxaliplatin, Paclitaxel, Panitubimab, Pentostatin, Pipobroman, Porfimer, Prednisolone, Prednisone propionate, Procarbazine, Reioxafine, Rituximab, Satriplatin, SB-743921, SmII , Sorafinib, Streptozocin, Sunitinib, Tamoxifen, Taxotere, Taxol, Temozolomide, Teniposide, Testolactone, Testosterone, Tezacitabine, 6-Thioguanine, Thiotepa, Tipifarnib, Topotecan, Toremifene, Tositumomab, Trastuzumab, Triamcinolone, Triapine, Triethylenemelamine, Triethylenethiophosphoramine, Trimidox, Uracil mustard, Vinblastine, Vincristine, Vindesine, and Vinoreibine.

5. A method of treating, or slowing the progression of, a disease by inhibiting mammalian Target Of Rapamycin in a patient, said method comprising administering a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceuticaliy acceptable salt, solvate, ester or prodrug of the compound, to a patient in need thereof.

6. A method of treatment of a disease selected from the group consisting of proliferative inflammatory diseases, allergic diseases, obstructive airways diseases, diseases related to transplant rejection and diseases that respond to inhibition of mTOR, comprising administering a therapeutically effective amount of compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof to a patient in need of such treatment.

7. A method of treating a disease by inhibiting a mTOR, comprising administering to a patient in need of such treatment an amount of a first compound of claim 1 or a pharmaceutically acceptable salt, solvate, ester or prodrug 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.

8. The method according to claim 7, wherein the one or more anti-cancer agents are selected from the group consisting of Adriamycin, Altretamine, Amidox, AminogSutethimide, Amsacrine, Anastrazole, Antibodies to EGFR, 3-AP, Aphidicolon, Ara-C, Arsenic trioxide, L-Asparaginase, Bevacizumab, Bleomycin, BMS 214662, Bortezomib, Busuifan, Campath, Camptostar, Capecitabine, Carboplatin, Carmustine, Centrosome associated protein E ("CENP-E") inhibitors, Cetuximab, Cladribine, Chlorambucil, Chiormethine, Chlorotrianisene, Cisplatin, Clofarabine, cyclophosphamide, Cytarabine, a Cytostatic agent, Cytoxan, Dacarbazine, Dactinomycin, Daunorubicin, Dasatinib, Deforolimus, Deoxycoformycin, Didox, Diethylstilbestroi, Docetaxel, Doxorubicin, Dromostanolone, Droloxafine, Epirubicin, Epothilones, ERK inhibitors, Erlotinib, Etoposide, 17α-Ethiny!estradiol, Estramustine, Exemestane, Fioxuridine, Fludarabine, Fludarabine phosphate, 5-F!uorouracil, Fluoxymesterone, Flutamide, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab ozogamcicin, Goserelin, GSK-923295, Hexamethylmelamine, Hydroxyprogesterone, Hydroxyurea, lbritumomab Tiuxetan, Idarubicin, Ifosfamide, lmatinib mesylate, Intron, Irinotecan, ispinesib, KSP inhibitors, L778,123, Lapatinib, Leucovirin, Leuprolide, Lerozole, Letrazole, Levamisole, Liposomal Doxorubicin, Liposomal, Lomustine, Lonafarnib, Medroxyprogesteroneacetate, Megestrolacetate, Melphalan, 6-Mercaptopurine, Methoxtrexate, Methylprednisolone, Methyltestosterone, Mithramycin, Mitomycin-C, Mitotane, Mitoxantrone, Navelbene, Nilotinib, Oxaliplatin, Paclitaxel, Panitubimab, Pentostatin, Pipobroman, Porfimer, Prednisolone, Prednisone propionate, Procarbazine, Reloxafine, Rituximab, Satriplatin, SB-743921 , SmH , Sorafinib, Streptozocin, Sunitinib, Tamoxifen, Taxotere, Taxol, Temozoiomide, Teniposide, Testolactone, Testosterone, Tezacitabine, 6-Thioguanine, Thiotepa, Tipifarnib, Topotecan, Toremifene, Tositumomab, Trastuzumab, Triamcinolone, Triapine, Triethylenemeiamine, Triethylenethiophosphoramine, Trimidox, Uracil mustard, Vinblastine, Vincristine, Vindesine, and Vinorelbine.

9. A method of treating a cancer comprising administering a therapeutically effective amount of at least one compound of claim 1.

10. The method of claim 9, wherein said cancer is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, non-small ceil lung cancer, head and neck, 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, mantle cell lymphoma, myeloma and Burkett's lymphoma; acute and chronic myelogenous leukemia, myelodysplastic syndrome and promyelocyte leukemia; fibrosarcoma, rhabdomyosarcoma; mantle ceil lymphoma, myeloma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoctanthoma, thyroid follicular cancer, endometrial cancer, gastrointestinal tract cancer and Kaposi's sarcoma.

1 1. A method of inhibiting a mammalian Target Of Rapamycin, comprising administering a therapeutically effective amount of a compound of claim 1.

12. A method of treating a disease by inhibiting a mTOR, comprising administering to a patient in need of such treatment an amount of a first compound represented by the structural Formula I:


Formula I or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, wherein:

R is independently selected from the group consisting of halo, hydroxyl, amino, -CN, H, -(CrC6)alkyl, alkoxy, -C(=O)alkyi, heteroaryl and aryl, wherein each of said heteroaryl and aryl can be unsubstituted or substituted with one or more alkyl or halo;

R1 is independently selected from the group consisting of heterocycloalkyl, heterocycioalkylalkyl, spiroheterocycloalkyl, heterocyclenyl, -NR3R4, cycloaikyl, heteroaryl, aryl, alkynyi, heterocyclenylalkyi, cycloalkylalkyl, heteroarylaikyl heteroarylalkynyl, spiroheterocycloalkylalkyl, -N-heteroaryl, and arylalkyl, wherein each of said heterocycloalkyl, heterocycloalkyfaJkyl, spiroheterocycloaikyl, heterocycienyl, cycloaikyl, heteroaryl, aryl, alkynyi, heterocycienylalky!, cycloalkylaikyl, heteroarylaikyl, heteroarylalkynyl , -N-heteroaryi and arylalkyl can be unsubstituted or substituted with one or moieties independently selected from the group X;

X is alkoxyl, alkyl, -C(O)alkyl, -C(O)-hydroxyalkyl, -C(O)2alkyl, -C(O)2H, hydroxyalkyl, -S(O)2alkyl, hydroxyl, heterocycloalkyl, -NH-heterocycloalkyl, -trihaloalkyl, -dihaloalkyl, -monohaloaikyl, -N-S(O)2-alkyl, -C(O)-heteroaryl, -alkyl-C(O)2H, -a]kyl(CO)N(CH3)-O-CH3, -alkyl(CO)-heteroaryl, -C(O)2-alkyl, -alkyl-C(O)-NH2l -NH2, heteroaryl, -alkyl-CN, -C(O)2-arylalkyl, halo, carboxyesteralkyl, -C(O)-NH2, -alkyl-C(O)2alkyl, heteroarylaikyl, -C(O)-heteroaryl, -C(O)-alkyl-O-alkyl, -aikyl(CO)NS(O)2-cycloalkyl, -alkyl(CO)N-S(O)2-CF3, -N-aikyl, -SOa-cycloalkyl, -alkyl(CO)NS(O)2-alkyl, -alkyl-C(O)-N(alkyl)2l -alkyl-NS(O)2-alkyl, alkyl(CO)NS(O)2-cycloalkyl, -CO-CO2H1 -C(O)2-alkyl-aryl, -SO2-CF3 or -C(O)H, wherein each of said heterocycloalkyl, heteroaryl or -C(O)-heteroaryl can be unsubstituted or substituted with one or more alkyl; R2 is heteroaryl or aryl, wherein each of said heteroaryl or aryl can be unsubstituted or independently substituted with one or more moieties independently selected from the group consisting of alkyl, alkoxyl, -CN, aryloxyl, aryl, halo, hydroxyl, -C(CH3)2CN, trifiuromethyl, difluromethyl, monofluromethyl,_heterocycloalkyl, and arylalkyl; R3 is cycloaikyl or heteroaryl, wherein each of said cycloaikyl or heteroaryl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of X; and

R4 is H; 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.

13. The method according to claim 12, wherein the one or more anti-cancer agents are selected from the group consisting of Adriamycin, Altretamine, Amidox, Aminoglutethimide, Amsacrine, Anastrazole, Antibodies to EGFR, 3-AP, Aphidicolon, Ara-C, Arsenic trioxide, L-Asparaginase, Bevacizumab, Bleomycin, BMS 214662, Bortezomib, Busulfan, Campath, Camptostar, Capecitabine, Carboplatin, Carmustine, Centrosome associated protein E ("CENP-E") inhibitors, Cetuximab, Cladribine, Chlorambucil, Chlormethine, Chlorotrianisene, Cisplatin, C10farabine, cyclophosphamide, Cytarabine, a Cytostatic agent, Cytoxan, Dacarbazine, Dactinomycin, Daunorubicin, Dasatinib, Deforolimus, Deoxycoformycin, Didox, Diethylstilbestrol, Docetaxel, Doxorubicin, Dromostanoione, Droloxafine, Epirubicin, Epothilone, ERK inhibitors, Erlotinib, Etoposide, 17tx-Ethinylestradiol, Estramustine, Exemestane, Fioxuridine, Fludarabine, Fludarabine phosphate, 5-Fluorouracil, Fluoxymesterone, Flutamide, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab ozogamcicin, Goserelin, GSK-923295, Hexamethylmelamine, Hydroxyprogesterone, Hydroxyurea, lbritumomab Tiuxetan, idarubicin, Ifosfamide, lmatinib mesylate, Intron, Irinotecan, ispinesib, KSP inhibitors, L778,123, Lapatinib, Leucovirin, Leuprolide, Lerozoie, Letrazole, Levamisole, Liposomal Doxorubicin, Liposomal, Lomustine, Lonafarnib, Medroxyprogesteroneacetate, Megestrolacetate, Melphatan, 6-Mercaptopurine, Methoxtrexate, Methylprednisolone, Methyltestosterone, Mithramycin, Mitomycin-C, Mitotane, Mitoxantrone, Navelbene, Nilotinib, Oxaliplatin, Paclitaxel, Panitubimab, Pentostatin, Pipobroman, Porfimer, Prednisolone, Prednisone propionate, Procarbazine, Reloxafine, Rituximab, Satriplatin, SB-743921 , SmM , Sorafinib, Streptozocin, Sunitinib, Tamoxifen, Taxotere, Taxol, Temozolomide, Teniposide, Testolactone, Testosterone, Tezacitabine, 6-Thioguanine, Thiotepa, Tipifarnib, Topotecan, Toremifene, Tositumomab, Trastuzumab, Triamcinolone, Triapine, Triethylenemelamine, Triethylenethiophosphoramine, Trimidox, Uracil mustard, Vinblastine, Vincristine, Vindesine, and Vinorelbine. 14. A method of treating a cancer comprising administering a therapeutically effective amount of at least one compound represented by the structural Formula I:

Formula I or a pharmaceutically acceptable salt, solvate, ester, or prodrug thereof, wherein: R is independently selected from the group consisting of halo, hydroxyl, amino,

-CN, H, -(CrCβ)alkyΙ, alkoxy, -C(=O)a!kyl, heteroaryl and aryi, wherein each of said heteroaryl and aryl can be unsubstituted or substituted with one or more alkyl or halo;

R1 is independently selected from the group consisting of heterocycloalkyl, heterocycloalkylalkyl, spiroheterocycloalkyl, heterocyclenyl, -NR3R4, cycloalky!, heteroaryl, aryl, alkynyl, heterocyclenylaikyl, cycloalky I alkyl, heteroarylalky^ heteroarylalkynyl, spiroheterocycloalkylalkyi, -N-heteroaryl, and arylalkyl, wherein each of said heterocycloalkyl, heterocycloalkylalkyl, spiroheterocycloalkyl, heterocyclenyl, cycioaikyl, heteroaryl, aryl, alkynyl, heterocyclenylaikyl , cycloalkyialkyl, heteroarylalkyl, heteroaryialkynyl, -N-heteroaryl and arylalkyl can be unsubstituted or substituted with one or moieties independently selected from the group X;

X is alkoxyl, alkyl, -C(O)alkyl, -C(O)-hydroxyalkyl, -C(O)2alkyl, -C(O)2H, hydroxyalkyl, -S(O)2alkyl, hydroxyl, heterocycloalkyl, -NH-heterocycloalkyl, -trihaloalkyl, -dihaloalkyl, -monohaloalkyl, -N-S(O)2-alkyl, -C(O)-heteroaryl, -alkyl-C(O)2H, -alkyl{CO)N(CH3)-O-CH3, -alkyl(CO)-heteroaryl, -C(O)2-alkyl, -alkyl-C(O)-NH2j -NH2, heteroaryl, -alkyl-CN, -C(O)2-arylalkyi( halo, carboxyesteralkyl, -C(O)-NH2, -alkyl-C(O)2alkyl, heteroarylalkyl, -C(O)-heteroaryl, -C(O)-alkyi-O-alkyl, -alkyl(CO)NS(O)2-cycloalkyl, -alkyl(CO)N-S{O)2-CF3, -N-alkyl. -SO2-cycloalkyl, -alkyl(CO)NS(O)2-alkyl, -alkyl-C(O)-N(alkyl)2, -alkyl-NS<O)2-alkyl, alky!(CO)NS(O)2-cycloalkyl, -CO-CO2H, -C(O)2-alkyl-aryl, -SO2-CF3 or -C(O)H, wherein each of said heterocycloalkyl, heteroaryl or -C (O)- heteroaryl can be unsubstituted or substituted with one or more alkyl;

R2 is heteroaryl or aryl, wherein each of said heteroaryl or aryl can be unsubstituted or independently substituted with one or more moieties independently selected from the group consisting of alkyl, alkoxyl, -CN, aryloxyl, aryl, halo, hydroxyl, -C(CH3^CN, trifluromethyl, difluromethyl, monofluromethyl,_heterocycloalkyl and arylalkyl;

R3 is cycloalkyl or heteroaryi, wherein each of said cycloalkyl or heteroaryl can be unsubstituted or substituted with one or more moieties independently selected from the group consisting of X; and R4 is H.

15. The method of claim 14, wherein said cancer is selected from the group consisting of: cancer of the bladder, breast, colon, kidney, liver, lung, small cell lung cancer, non-smail cell lung cancer, head and neck, 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, mantle cell lymphoma, myeloma and Burkett's lymphoma; acute and chronic myelogenous leukemia, myeiodysplastic syndrome and promyelocytic leukemia; fibrosarcoma, rhabdomyosarcoma; mantle cell lymphoma, myeloma; astrocytoma, neuroblastoma, glioma and schwannomas; melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderma pigmentosum, keratoctanthoma, thyroid follicular cancer, endometrial cancer, gastrointestinal tract cancer and Kaposi's sarcoma.