Claims for Patent: 9,956,222

Summary for Patent: 9,956,222

Title:	Quinazoline derivative as tyrosine-kinase inhibitor, preparation method therefor and application thereof
Abstract:	The invention relates to a quinazoline derivative represented by the general formula (I), a pharmaceutical acceptable salt and a stereoisomer thereof as tyrosine kinase inhibitor, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.3\', R.sup.4, R.sup.5, R.sup.6, X, L, T, Z and q are as defined in the specification. The invention also relates to a process for preparing the same, a pharmaceutical composition and a pharmaceutical formulation containing the derivative, use of the derivative for treating excessive proliferative diseases and chronic obstructive pulmonary disease and use of the derivative in the manufacture of a medicament for treating excessive proliferative diseases and chronic obstructive pulmonary disease. ##STR00001##
Inventor(s):	Wu; Frank (Jinan, CN)
Assignee:	XUANZHU PHARMA CO., LTD. (CN)
Application Number:	15/419,781
Patent Claims:	1. A method for reducing the growth of a cancer cell comprising administering to a subject in need thereof an effective amount of a compound represented by the general formula (I), and its pharmaceutically acceptable salt or stereoisomer thereof: ##STR00140## wherein: R.sup.1 is selected from the following groups that are unsubstituted or substituted by 1-3 same or different Q.sup.1: C.sub.1-6alkyl, C.sub.3-6alkenyl, C.sub.3-6alkynyl, C.sub.3-8cycloalkyl-C.sub.0-6alkyl, 6-10-membered fused ring-C.sub.0-6alkyl, 7-10-membered spiro ring-C.sub.0-6 alkyl and 7-10-membered bridged ring-C.sub.0-6alkyl, and the carbon atom in said cycloalkyl, said fused ring, said spiro ring, said bridged ring may be optionally replaced by 1-3 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), Q.sup.1 is selected from the groups consisting of halogen, hydroxy, amino, carboxyl, cyano, C.sub.1-6alkyl, C.sub.1-6alkoxyl, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, C.sub.1-6alkylcarbonyloxy, C.sub.1-4alkoxylcarbonyl, C.sub.1-6alkylacylamino, C.sub.1-6alkylsulfonyl, C.sub.1-6alkylsulfinyl, C.sub.1-6alkylsulfonylamino and C.sub.3-8cycloalkyl; R.sup.2 is selected from the following groups that are unsubstituted or substituted by 1-2 same or different Q.sup.2: C.sub.3-4cycloalkyl-C.sub.0-6alkyl, 6-10-membered fused ring-C.sub.0-6alkyl, 7-10-membered spiro ring-C.sub.0-6alkyl and 7-10-membered bridged ring-C.sub.0-6alkyl, and the carbon atom in said cycloalkyl, said fused ring, said spiro ring and said bridged ring may be replaced by 1-3 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), provided that an ester structure "--O--C(O)--" is not present in the replaced ring and when R.sup.2 is 7-10-membered bridged ring-C.sub.0-6alkyl, R.sup.1 is not C.sub.3-4cycloalkyl-C.sub.0-6alkyl or C.sub.1-6alkyl; Q.sup.2 is selected from the groups consisting of halogen, hydroxy, amino, carboxyl, cyano, nitro, trifluoromethyl, C.sub.1-6alkyl, C.sub.1-6alkoxyl, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkoxylcarbonyl, C.sub.1-6alkylacylamino, C.sub.1-6alkylsulfonyl, C.sub.1-6alkylsulfinyl and C.sub.1-6alkylsulfonylamino; R.sup.3 is selected from the group consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl, carbamoyl, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl, C.sub.1-6alkoxyl, C.sub.1-6 alkyl substituted with halogen and C.sub.1-6alkoxyl substituted with halogen, C.sub.1-6alkylamino, di(C.sub.1-6alkyl)amino, C.sub.1-6alkylthio, C.sub.1-6alkylcarbamoyl, C.sub.1-6alkylcarbonyl, C.sub.1-6alkoxylcarbonyl, C.sub.1-6alkylcarbonyloxy, C.sub.1-6alkylacylamino, C.sub.1-6alkylsulfonyl, C.sub.1-6alkylsulfinyl and C.sub.1-6alkylsulfonylamino; R.sup.3' is absent; R.sup.4, R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-6alkyl, C.sub.1-6alkoxyl, C.sub.1-6alkyl substituted with halogen and C.sub.1-6alkoxyl substituted with halogen, C.sub.1-6alkylamino and di(C.sub.1-6alkyl)amino; X is selected from the group consisting of cyano-substituted methenyl or a nitrogen atom; L is selected from the group consisting of O, S(O).sub.m, N(H), N(CH.sub.3) or C(O); T is selected from the group consisting of a covalent bond, C(O) or CH(R'), R' is selected from the group consisting of hydrogen or C.sub.1-6alkyl; Z is hydrogen; q is 2, and R.sup.3 may be identical or different; m is selected from the group consisting of 0, 1 or 2; and n is selected from the group consisting of 0 or 1, wherein the cancer cell is selected from the group consisting of cerebroma, lung cancer, squamous cell carcinoma, bladder carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, mammary cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal carcinoma, adenocarcinoma of esophagus, esophageal squamous cell cancer and prostate carcinoma. 2. The method of claim 1, wherein R.sup.1 is selected from the group consisting of the following groups that are unsubstituted or substituted by 1-3 same or different Q.sup.1: C.sub.1-4alkyl, C.sub.3-8cycloalkyl-C.sub.0-4alkyl, 6-10-membered fused ring-C.sub.0-4alkyl, 7-10-membered spiro ring-C.sub.0-4alkyl and 7-10-membered bridged ring-C.sub.0-4alkyl, the carbon atom in said cycloalkyl, said fused ring, said spiro ring or said bridged ring may be optionally replaced by 1-3 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), Q.sup.1 is selected from the group consisting of halogen, hydroxy, amino, carboxyl, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxyl, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, C.sub.1-4alkylcarbonyloxy, C.sub.1-4alkoxylcarbonyl, C.sub.1-4alkylacylamino, C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfinyl, C.sub.1-4alkylsulfonylamino and C.sub.3-8cycloalkyl; or R.sup.2 is selected from the group consisting of the following groups that are unsubstituted or substituted by 1-2 same or different Q.sup.2: cyclopropyl-C.sub.0-4alkyl, cyclobutyl-C.sub.0-4alkyl, 6-10-membered fused ring-C.sub.0-4alkyl, 7-10-membered spiro ring-C.sub.0-4alkyl or 7-10-membered bridged ring-C.sub.0-4alkyl, the carbon atom in said cyclopropyl, said cyclobutyl, said fused ring, said spiro ring or said bridged ring may be optionally replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), provided that an ester structure "--O--C(O)--" is not present in the replaced ring, and when R.sup.2 is 7-10-membered bridged ring-C.sub.0-4alkyl, R.sup.1 is not C.sub.3-4cycloalkyl-C.sub.0-4alkyl or C.sub.1-4alkyl; Q.sup.2 is selected from the group consisting of halogen, hydroxy, amino, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxyl, C.sub.1-4alkylamino, di(C.sub.1-4 alkyl)amino, C.sub.1-4alkylcarbonyloxy, C.sub.1-4alkoxylcarbonyl, C.sub.1-4alkylacylamino, C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfinyl and C.sub.1-4alkylsulfonylamino; or R.sup.3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, carbamoyl, C.sub.1-4alkyl, C.sub.2-4alkenyl, C.sub.2-4alkynyl, C.sub.1-4alkoxyl, C.sub.1-4alkyl substituted with halogen, C.sub.1-4alkoxyl substituted with halogen, C.sub.1-4alkylamino, di(C.sub.1-4alkyl)amino, C.sub.1-4alkylthio, C.sub.1-4alkylcarbamoyl, C.sub.1-4alkylcarbonyl, C.sub.1-4alkoxylcarbonyl, C.sub.1-4alkylcarbonyloxy, C.sub.1-4alkylacylamino, C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfinyl and C.sub.1-4alkylsulfonylamino; or R.sup.4, R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, C.sub.1-4alkyl, C.sub.1-4alkoxyl, C.sub.1-4alkyl substituted with halogen, C.sub.1-4alkoxyl substituted with halogen, C.sub.1-4alkylamino and di(C.sub.1-4alkyl)amino; or L is selected from the group consisting of O, S(O).sub.m or N(H); or T is selected from the group consisting of a covalent bond or CH(R'), R' is selected from the group consisting of hydrogen or methyl. 3. The method of claim 1, wherein R.sup.1 is selected from the group consisting of the following groups that are unsubstituted or substituted by 1-2 same or different Q.sup.1: (1) C.sub.1-4alkyl, cyclopropyl-C.sub.0-4alkyl, cyclobutyl-C.sub.0-4alkyl, cyclopentyl-C.sub.0-4alkyl, cyclohexyl-C.sub.0-4alkyl and cycloheptyl-C.sub.0-4alkyl, the carbon atom in said cyclopropyl, said cyclobutyl, said cyclopentyl, said cyclohexyl and said cycloheptyl may be optionally replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O); and ##STR00141## ##STR00142## the carbon atom in said ring may be optionally replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), wherein p is selected from the group consisting of 0, 1 or 2; and Q.sup.1 is selected from the group consisting of halogen, hydroxy, amino, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetoxy, acetylamino, methylsulfonyl, ethylsulfonyl, methylsulfinyl, methylsulfonylamino, ethylsulfonylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R.sup.2 is selected from the group consisting of (1) the following groups that are unsubstituted or substituted by 1-2 same or different Q.sup.2: ##STR00143## the carbon atom in said ring may be replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), provided that an ester structure "--O--C(O)--" is not present in the replaced ring; p is selected from the group consisting of 0, 1 or 2, and ##STR00144## ##STR00145## the carbon atom in said ring may be optionally replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), provided that an ester structure "--O--C(O)--" is not present in the replaced ring, wherein p is selected from the group consisting of 0, 1 or 2, and when R.sup.2 is ##STR00146## R.sup.1 is not C.sub.1-4alkyl, cyclopropyl-C.sub.0-4alkyl or cyclobutyl-C.sub.0-4alkyl; and Q.sup.2 is selected from the group consisting of halogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetoxy, acetylamino, methylsulfonyl and methylsulfonyl amino; R.sup.3 is selected from the group consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl, carbamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, methyl substituted with halogen, methoxy substituted with halogen, methylamino, ethylamino, dimethylamino, methylthio, methylcarbamoyl, acetyl, methoxycarbonyl, acetoxy, acetylamino and methyl sulfonylamino; R.sup.4, R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, methyl, methoxy, methyl substituted with halogen, methoxy substituted with halogen, methylamino or dimethylamino; X is selected from the group consisting of cyano-substituted methenyl or a nitrogen atom; L is O; T is selected from the group consisting of a covalent bond or CH(R'), R' is selected from the group consisting of hydrogen or methyl; Z is hydrogen; q is 2, and R.sup.3 may be identical or different; m is selected from the group consisting of 0, 1 or 2; and n is selected from the group consisting of 0 or 1. 4. The method of claim 3, wherein R.sup.1 is selected from the group consisting of the following groups that are unsubstituted or substituted by Q.sup.1: (1) methyl, ethyl, propyl, cyclopropyl-C.sub.0-3alkyl, cyclobutyl-C.sub.0-3alkyl, cyclopentyl-C.sub.0-3alkyl, cyclohexyl-C.sub.0-3alkyl, azetidinyl-C.sub.0-3alkyl, tetrahydrofuryl-C.sub.0-3alkyl, pyrrolidinyl-C.sub.0-3alkyl, piperidinyl-C.sub.0-3alkyl, morpholinyl-C.sub.0-3 alkyl and piperazinyl-C.sub.0-3alkyl; and ##STR00147## ##STR00148## the carbon atom in said ring may be optionally replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), wherein p is selected from the group consisting of 0, 1 or 2; and Q.sup.1 is selected from the group consisting of halogen, hydroxy, amino, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino; R.sup.2 is selected from the group consisting of ##STR00149## that is unsubstituted or substituted by Q.sup.2, the carbon atom in said ring may be replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), provided that an ester structure "--O--C(O)--" is not present in the replaced ring; wherein p is selected from the group consisting of 0, 1 or 2; and ##STR00150## ##STR00151## the carbon atom in said ring may be optionally replaced by 1-2 same or different groups consisting of O, S(O).sub.m, N(H).sub.n and/or C(O), provided that an ester structure "--O--C(O)--" is not present in the replaced ring, wherein p is selected from the group consisting of 0, 1 or 2; and when R.sup.2 is ##STR00152## R.sup.1 is not methyl, ethyl, propyl, cyclopropyl-C.sub.0-3alkyl or cyclobutyl-C.sub.0-3alkyl; and Q.sup.2 is selected from the group consisting of halogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetoxy, acetylamino, methylsulfonyl and methylsulfonyl amino; R.sup.3 is selected from the group consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl, carbamoyl, methyl, ethyl, ethenyl, ethynyl, methoxy, methyl substituted with halogen, methoxy substituted with halogen, methylamino, ethylamino, dimethylamino, methylthio, methylcarbamoyl, acetyl, methoxycarbonyl, acetoxy, acetylamino and methylsulfonylamino; R.sup.4, R.sup.5 and R.sup.6 are each independently selected from the group consisting of hydrogen, halogen, methyl, methoxy, methyl substituted with halogen, methoxy substituted with halogen, methylamino and dimethylamino; X is a nitrogen atom; L is O; T is selected from the group consisting of a covalent bond or CH(R'), R' is hydrogen; Z is hydrogen; q is 2, and R.sup.3 may be identical or different; m is selected from the group consisting of 0, 1 or 2; and n is selected from the group consisting of 0 or 1. 5. The method of claim 1, wherein said compound has a structure of the following formula (I-1): ##STR00153## 6. The method of claim 5, wherein: R.sup.1 is selected from the group consisting of the following groups that are unsubstituted or substituted by halogen, hydroxy, amino, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino: methyl, ethyl, ##STR00154## ##STR00155## R.sup.2 is selected from the group consisting of the following groups that are unsubstituted or substituted by halogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetoxy, acetylamino, methylsulfonyl, or methylsulfonylamino: ##STR00156## ##STR00157## ##STR00158## R.sup.1 is not methyl, ethyl, ##STR00159## R.sup.3 is halogen, which is selected from the group consisting of fluoro, chloro, bromo, or iodo; R.sup.4, R.sup.5 and R.sup.6 are each independently hydrogen; X is a nitrogen atom; L is O; and q is 2, and R.sup.3 may be identical or different. 7. The method of claim 6, wherein said compound has a structure of the following formula (I-2): ##STR00160## wherein R.sup.1 is selected from the group consisting of the following groups that are unsubstituted or substituted by halogen, hydroxy, amino, carboxyl, cyano, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, or diethylamino: methyl, ethyl, ##STR00161## ##STR00162## R.sup.2 is selected from the group consisting of the following groups that are unsubstituted or substituted by halogen, hydroxy, amino, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino, diethylamino, acetoxy, acetylamino, methylsulfonyl, or methylsulfonylamino: ##STR00163## ##STR00164## ##STR00165## R.sup.1 is not methyl, ethyl, ##STR00166## L is O. 8. A method for reducing the growth of a cancer cell comprising administering to a subject in need thereof an effective amount of a compound selected from the group consisting of: ##STR00167## ##STR00168## ##STR00169## ##STR00170## ##STR00171## ##STR00172## wherein the cancer cell is selected from the group consisting of cerebroma, lung cancer, squamous cell carcinoma, bladder carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, mammary cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal carcinoma, adenocarcinoma of esophagus, esophageal squamous cell cancer and prostate carcinoma. 9. A method for reducing the growth of a cancer cell comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition containing a compound according to claim 1, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the cancer cell is selected from the group consisting of cerebroma, lung cancer, squamous cell carcinoma, bladder carcinoma, gastric cancer, ovarian cancer, pancreatic cancer, mammary cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal carcinoma, adenocarcinoma of esophagus, esophageal squamous cell cancer and prostate carcinoma. 10. The method of claim 9, wherein said pharmaceutical composition further contains a second therapeutical agent selected from the group consisting of an antineoplastic agent and an immunosuppressive agent, said second therapeutical agent is selected from the group consisting of an antimetabolite, including capecitabine and gemcitabine; a growth factor inhibitor, including pazopanib and imatinib; an antibody, including herceptin and bevacizumab; a mitotic inhibitor, including paclitaxel, vinorelbine, docetaxel, and doxorubicin; an antineoplastic hormone, including letrozole, tamoxifen, and fulvestrant; an alkylating agent, including cyclophosphamide and carmustine; a metal platinum, including carboplatin, cisplatin, and oxaliplatin; a topoisomerase inhibitor, including topotecan; and an immunosuppressant, including everolimus. 11. The method of claim 9, wherein said pharmaceutical composition further contains one or more pharmaceutically acceptable carriers. 12. The method of claim 1, wherein said lung cancer is non-small cell lung cancer. 13. The method of claim 1, wherein said cerebroma is glioma. 14. The method of claim 13, wherein said glioma is glioblastoma multiforme. 15. The method of claim 8, wherein said lung cancer is non-small cell lung cancer. 16. The method of claim 8, wherein said cerebroma is glioma. 17. The method of claim 16, wherein said glioma is glioblastoma multiforme. 18. The method of claim 9, wherein said lung cancer is non-small cell lung cancer. 19. The method of claim 9, wherein said cerebroma is glioma. 20. The method of claim 19, wherein said glioma is glioblastoma multiforme. 21. A method for treating head and neck cancer or esophageal squamous cell cancer, which method comprises administering to a subject in need thereof an effective amount of ##STR00173## or its pharmaceutically acceptable salt or stereoisomer thereof.

Details for Patent 9,956,222

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2031-05-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2031-05-26
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2031-05-26