Claims for Patent: 9,963,452

Summary for Patent: 9,963,452

Title:	Methods, compounds, and compositions for inhibition of ROS
Abstract:	The present invention relates to a method using some novel compounds and compositions for the inhibition of ROS tyrosine kinase. In particular, the present invention covers a method to treat abnormal cell growth, such as cancer, with ROS 10 inhibitors and compositions having ROS inhibitors. An illustrative compound of the invention is shown below Formula (I). ##STR00001##
Inventor(s):	Grueneberg; Dorre A. (Newton, MA), Kalid; Ori (Pardes-Hanna, IL), Xian; Jun (Sharon, MA), Rajur; Sharanappa B. (Andover, MA), Kim; Hwa-Ok (Lexington, MA), Neelagiri; Venugopal Rao (Acton, MA), Salgaonkar; Paresh (Medford, MA), Sethumadhavan; Divakaramenon (Waltham, MA), Moon; Chaeho (Burlington, MA), Neelagiri; Madhavi (Acton, MA)
Assignee:	AUGUSTA PHARMACEUTICALS INC. (Newton, MA)
Application Number:	14/775,825
Patent Claims:	1. A method of reducing the speed of, stopping, or reversing progression of abnormal cell growth in a mammal, the method comprising: administering to the mammal a composition comprising a therapeutically effective amount of a ROS tyrosine kinase inhibitor compound of formula I: Ar.sup.1--(CH.sub.2).sub.n--(X).sub.m--Ar.sup.2 I or a pharmaceutically acceptable salt thereof, wherein Ar' is comprised of the formula: Ar.sup.3--NH--Ar.sup.4, wherein Ar.sup.3 is aryl or heteroaryl, wherein the heteroatom of said heteroaryl independently numbers 1, 2 or 3, and is independently selected from N, S or O, wherein each of said aryl or heteroaryl is either unsubstituted or independently substituted with one or more substituent which is independently selected from the group consisting of deuterium, halo, amino, aminoalkyl-, (amino)alkoxy-, --CH.sub.zF.sub.3-z, --OCH.sub.zF.sub.3-z, C(O)(O)H, alkyl, alkenyl, alkynyl, alkoxy-, -cycloalkyl, -heterocycloalkyl, -aryl, --C(O)-alkyl, --C(O)-aryl, --C(O)cycloalkyl, --C(O)-heterocycloalkyl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms on a ring are both S or both O; and Ar.sup.4 is a six membered aryl or heteroaryl, wherein said heteroaryl independently has 1, 2, or 3 heteroatoms with each heteroatom being independently selected from N, S, or O, wherein said aryl or heteroaryl is unsubstituted or independently substituted with halo or alkyl; n is 0 or; X is N; z is 0, 1, 2, or 3; m is 1; Ar.sup.2 is aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein said heteroaryl or heteroarylalkyl independently has 1, 2 or 3 heteroatoms, with each heteroatom being independently selected from N, S or O, wherein any of said aryl, heteroaryl, arylalkyl and heteroarylalkyl is either unsubstituted or independently substituted with one substituent which is independently selected from the group consisting of cycloalkyl, -heterocycloalkyl, -aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms on a ring are both S or both O; and wherein said abnormal cell growth is caused by an elevated level of ROS or expression of fusion protein FIG-ROS. 2. The method of claim 1, wherein Ar.sup.2 is ##STR00492## 3. The method of claim 1, wherein Ar.sup.2 is ##STR00493## 4. The method of claim 1, wherein Ar.sup.3 is aryl or heteroaryl wherein the heteroatom of said heteroaryl independently numbers 1, 2 or 3, and is independently selected from N, S or O. 5. The method of claim 1, wherein Ar.sup.3 is ##STR00494## wherein R.sup.1 is cycloalkyl or heterocycloalkyl. 6. The method of claim 5, wherein R.sup.1 is ##STR00495## 7. The method of claim 5, wherein Ar.sup.2 is ##STR00496## 8. The method of claim 1, wherein Ar.sup.4 is heteroaryl wherein the heteroatom of said heteroaryl is N and independently numbers 1, 2 or 3, further wherein the atoms of said heteroaryl is unsubstituted or independently substituted with halo or alkyl. 9. The method of claim 8, wherein Ar.sup.4 is ##STR00497## 10. The method of claim 6, wherein Ar.sup.2 is ##STR00498## 11. The method of claim 6, wherein Ar.sup.2 is ##STR00499## 12. The method of claim 9, wherein Ar.sup.2 is ##STR00500## 13. The method of claim 9, wherein Ar.sup.2 is ##STR00501## 14. The method of claim 2, wherein Ar.sup.1 is ##STR00502## 15. The method of claim 14, wherein Ar.sup.2 is benzene wherein each hydrogen atom on said benzene is un-substituted or independent substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of halo, amino, aminoalkyl-, (amino)alkoxy-, --CONH.sub.2, --C(O)NH(alkyl), --C(O)N(alkyl).sub.2, --C(O)NH(aryl), --C(O)N(aryl).sub.2, --CH.sub.zF.sub.3-z, --OCH.sub.zF.sub.3-z, alkyl, alkenyl, alkynyl, alkoxy-, -aryloxy-, (alkoxyalkyl)oxy-, (alkoxyalkyl)amino-, -cycloalkyl, and -heterocycloalkyl. 16. The method of claim 1, wherein Ar.sup.1 is ##STR00503## 17. The method of claim 16, wherein Ar.sup.2 is benzene wherein each hydrogen atom on said benzene is un-substituted or independent substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of halo, amino, aminoalkyl-, (amino)alkoxy-, --CONH.sub.2, --C(O)NH(alkyl), --C(O)N(alkyl).sub.2, --C(O)NH(aryl), --C(O)N(aryl).sub.2, --CH.sub.zF.sub.3-z, --OCH.sub.zF.sub.3-z, alkyl, alkenyl, alkynyl, alkoxy-, -aryloxy-, (alkoxyalkyl)oxy-, (alkoxyalkyl)amino-, -cycloalkyl, and -heterocycloalkyl. 18. The method of claim 1, wherein the mammal is human. 19. The method of claim 1, wherein the abnormal cell growth is mediated at least in part, by a ROS tyrosine kinase or a fusion gene of the ROS tyrosine kinase with another sequence. 20. The method of claim 1, wherein the abnormal cell growth is cancer. 21. The method of claim 20, wherein said cancer is selected from the group consisting of gastric cancer, glioblastoma, cholangiocarcinoma, ovarian cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, non-small cell lung cancer (NSCLC), prostate cancer, skin cancer, and bladder cancer. 22. The method of claim 1, wherein the pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier. 23. The method of claim 22, wherein the pharmaceutical composition further comprising therapeutically effective amounts of one or more additional therapeutic agents. 24. The method of claim 23, wherein said one or more additional therapeutic agents are selected from the group consisting of cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, tipifarnib, R115777, L778,123, BMS 214662, gefitnib, erlotnib, C225, imatinib, interferon, pegylated interferon alfa-2b, aromatase combinations, 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, plicamycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin, chlorambucil, cisplatin, letrozole, megestrol, valrubicin, and vinvlastin. 25. A method of reducing the speed of, stopping, or reversing progression of abnormal cell growth in a mammal, comprising administering to the mammal a composition comprising therapeutically effective amount of a compound selected from the group consisting ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## or a pharmaceutically acceptable salt thereof, and wherein said abnormal cell growth is caused by an elevated level of ROS or expression of fusion protein FIG-ROS. 26. The method of claim 25, wherein the mammal is human. 27. A method of claim 26, wherein the composition reduces the speed of, stops, or reverses progression of abnormal cell growth through the inhibition of ROS tyrosine kinase activities. 28. The method of claim 25, wherein the abnormal cell growth is cancer. 29. The method of claim 28, wherein said cancer is selected from the group consisting of gastric cancer, glioblastoma, cholangiocarcinoma, ovarian cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, non-small cell lung cancer (NSCLC), prostate cancer, skin cancer, and bladder cancer. 30. The method of claim 25, wherein the pharmaceutical composition further comprising at least one pharmaceutically acceptable carrier. 31. The method of claim 30, wherein the pharmaceutical composition further comprising therapeutically effective amounts of one or more additional therapeutic agents. 32. The method of claim 31, wherein said one or more additional therapeutic agents are selected from the group consisting of cytotoxic agent, cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, the epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, tipifarnib, R115777, L778,123, BMS 214662, gefitnib, erlotnib, C225, imatinib, interferon, pegylated interferon alfa-2b, aromatase combinations, 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, plicamycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17.alpha.-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, Velcade, Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane, Ifosfomide, Rituximab, C225, Campath, leucovorin, and dexamethasone, bicalutamide, carboplatin, chlorambucil, cisplatin, letrozole, megestrol, valrubicin, and vinvlastin.

Details for Patent 9,963,452

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2033-03-14
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132	06/04/1986		2033-03-14
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	For Injection	103132			2033-03-14
Merck Sharp & Dohme Corp.	INTRON A	interferon alfa-2b	Injection	103132			2033-03-14
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2033-03-14
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2033-03-14