Claims for Patent: 10,300,058

Summary for Patent: 10,300,058

Title:	Tyrosine kinase inhibitor and uses thereof
Abstract:	Disclosed is a compound of Formula (I) or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers, which can be used as tyrosine kinase inhibitor. Also disclosed is a method for preparing the compound, a pharmaceutical composition and a kit comprising the compound, and uses of the compound. The compound can be used as tyrosine kinase inhibitor, or can be used to reduce or inhibit activity of EGFR or mutant thereof, such as EGFR mutant comprising T790M mutation, in a cell, or to treat and/or prevent a disease associated with overactivity of EGFR, such as cancer.
Inventor(s):	Wu; Frank (Jinan, CN)
Assignee:	Xuanzhu Pharma Co., Ltd. (Jinan, Shandong, CN)
Application Number:	15/304,708
Patent Claims:	1. A compound of Formula (I), or a pharmaceutically acceptable salt, ester, or stereoisomer thereof: ##STR00303## wherein Z.sub.1 is N; Z.sub.2 is N; X is NR.sub.5 or absent; Y is NR.sub.5; Ring A is phenyl optionally substituted by a substituent, wherein the substituent is selected from hydrogen atom, halogen atom, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy or halo-C.sub.1-4alkyl; Ring B is phenyl optionally substituted by a substituent, wherein the substituent is hydrogen atom, halogen atom, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkyl, halo-C.sub.1-4alkoxy, C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonyloxy, or C.sub.1-4alkylsulfonylC.sub.1-4alkoxy; Ring C is 7-10 membered N-containing fused heterocyclyl, 7-9 membered spiroheterocyclyl or 8 membered bridged heterocyclyl, each of which is optionally substituted by a substituent, wherein the substituent is hydrogen atom, halogen atom, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy, halo-C.sub.1-4alkyl, halo-C.sub.1-4alkoxy, C.sub.1-4alkylsulfonyl, C.sub.1-4alkylsulfonyloxy, C.sub.1-4alkylsulfonylC.sub.1-4alkoxy or 3-6 membered O-containing heterocyclyl; or Ring C is 5-6 membered N-containing heterocyclyl which is substituted by 3-6 membered O-containing heterocyclyl, and when Ring A is phenyl and Ring B is phenyl, Ring C is not piperazinyl or morpholinyl; R.sub.1 is selected from halo-methyl or halo-ethyl; R.sub.2 is selected from hydrogen atom, --N(R.sub.6)(R.sub.7), --N(R.sub.6)C(O)(R.sub.7), C.sub.1-4alkyl or 3-6 membered cycloalkyl; R.sub.3 is hydrogen atom; or R.sub.3 is C.sub.1-4alkyl, C.sub.1-4alkoxy or --C(O)--R.sub.8, each of which is optionally substituted by a substituent, wherein the substituent is selected from hydrogen atom, halogen atom or C.sub.1-4alkyl or C.sub.1-4alkylsulfonyl; R.sub.5 is selected from hydrogen atom, halogen atom or C.sub.1-4alkyl; R.sub.6 and R.sub.7 are independently selected from hydrogen atom, C.sub.1-4alkyl, halo-C.sub.1-4alkyl or C.sub.2-4alkenyl; R.sub.8 is selected from hydrogen atom, methyl, ethyl or methoxyl. 2. The compound or a pharmaceutically acceptable salt, ester, or stereoisomer thereof according to claim 1, wherein Z.sub.1 is N; Z.sub.2 is N; X and Y are independently NH; Ring A is phenyl optionally substituted by a substituent, wherein the substituent is selected from fluorine atom, chlorine atom, methyl, ethyl or trifluoromethyl; Ring B is phenyl optionally substituted by a substituent, wherein the substituent is selected from fluorine atom, chlorine atom, methyl, ethyl, methoxyl, ethoxyl, trifluoromethyl, trifluoromethoxyl, methylsulfonylpropoxy or ethyl sulfonylpropoxy; Ring C is 2-azaspiro[3.5]nonyl, 8-azabicyclo[3.2.1]octyl, octahydrocyclopenta[c]pyrrolyl, 2,7-diazaspiro[3.5]nonyl, 2,6-diazaspiro[3.3]heptyl, 2-azaspiro[3.3]heptyl, 3,8-diazabicyclo[3.2.1]octyl or hexahydropyrrolo[3,4-c]pyrrolyl, each of which is optionally substituted by a substituent, wherein the substituent is selected from fluorine atom, chlorine atom, methyl, ethyl, methoxyl, trifluoromethyl, methylsulfonyl, oxetanyl, tetrahydrofuranyl, piperidyl, piperazinyl or morpholinyl; or Ring C is azetidinyl, pyrrolidinyl, dihydropyrrolyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, piperidin-one-yl, tetrahydropyridyl, tetrahydropyridin-one-yl, dihydropiperidin-one-yl, each of which is substituted by a substituent, wherein the substituent is oxetanyl, tetrahydrofuranyl, piperidyl, piperazinyl or morpholinyl; R.sub.1 is trifluoromethyl; R.sub.2 is --NHC(O)CH.dbd.CH.sub.2; R.sub.3 is selected from hydrogen atom, methyl, ethyl, trifluoromethyl, methoxyl, 2-fluoroethyl, acetyl, propionyl, 3-fluoropropionyl or 3-methylsulfonylpropoxy. 3. The compound or a pharmaceutically acceptable salt, ester, or stereoisomer thereof according to claim 2, wherein Ring A is phenyl optionally substituted by a substituent, wherein the substituent is selected from fluorine atom, chlorine atom, methyl, ethyl or trifluoromethyl; Ring B is phenyl optionally substituted by a substituent, wherein the substituent is selected from fluorine atom, chlorine atom, methyl, ethyl, methoxyl, ethoxyl, trifluoromethyl, trifluoromethoxyl, methylsulfonylpropoxy or ethyl sulfonylpropoxy; Ring C is azetidinyl, pyrrolidinyl, dihydropyrrolyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, piperidyl, piperidin-one-yl, tetrahydropyridyl, tetrahydropyridin-one-yl or dihydropiperidin-one-yl, each of which is optionally substituted by a substituent, wherein the substituent is oxetanyl, tetrahydrofuranyl or morpholinyl. 4. The compound or a pharmaceutically acceptable salt, ester, or stereoisomer thereof wherein the compound d is selected from: ##STR00304## ##STR00305## ##STR00306## ##STR00307## ##STR00308## ##STR00309## ##STR00310## ##STR00311## 5. A pharmaceutical composition, comprising the compound, or a pharmaceutically acceptable salt, ester, or stereoisomer thereof according claim 1; optionally, the pharmaceutical composition further comprises one or more second therapeutic agents; and optionally, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carrier and/or diluent. 6. A method for reducing or inhibiting activity of EGFR or mutant thereof in a cell, comprising administering to the cell an effective amount of the compound, or a pharmaceutically acceptable salt, ester, or stereoisomer thereof according to claim 1. 7. The method of claim 6, wherein the cell is in a subject and wherein the subject has a disease associated with overactivity of EGFR. 8. A kit comprising the compound, or a pharmaceutically acceptable salt, ester, or stereoisomer thereof according to claim 1, and optionally, instructions. 9. The pharmaceutical composition of claim 5, wherein the second therapeutic agent is selected from: DNA replication inhibitors, mitotic inhibitors, angiogenesis inhibitors, growth factor inhibitors, antibodies, antimetabolites, antitumor hormone drugs, platinum drugs, immunosuppressors, additional tyrosine kinase inhibitors. 10. The pharmaceutical composition of claim 5, wherein the second therapeutic agent is selected from: methotrexate, capecitabine, gemcitabine, doxifluridine, pemetrexed disodium, pazopanib, imatinib, erlotinib, lapatinib, gefitinib, vandetanib, herceptin, bevacizumab, rituximab, trastuzumab, paclitaxel, vinorelbine, docetaxel, doxorubicin, hydroxycamptothecine, mitomycin, epirubicin, pirarubicin, bleomycin, letrozole, tamoxifen, fulvestrant, triptorelin, flutamide, leuprorelin, anastrozole, ifosfamide, busulfan, cyclophosphamide, carmustine, nimustine, semustine, mechlorethamine, melphalan, chlorambucil, carboplatin, cisplatin, oxaliplatin, lobaplatin, topotecan, camptothecin, everolimus, sirolimus, temsirolimus, 6-mercaptopurine, 6-thioguanine, azathioprine, actinomycin D, daunorubicin, adriamycin, mitoxantrone, mithramycin or aminoglutethimide. 11. The method of claim 7, wherein the disease is hyperproliferative disease or is chronic obstructive pulmonary disease. 12. The method of claim 11, wherein the hyperproliferative disease is cancer or noncancerous disease. 13. The method of claim 12, wherein the cancer is selected from: esophageal cancer, brain tumor, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, renal cancer, solid tumor, non-Hodgkin's lymphoma, central nervous system tumor, prostatic cancer and thyroid cancer. 14. The method of claim 12, wherein the noncancerous disease is benign hyperplasia of skin or prostate. 15. The method of claim 7, wherein the disease has drug resistance caused by EGFR mutant; wherein, the EGFR mutant comprises one or more of the following mutations: T790M mutation, L858R mutation, and d746-750 mutation. 16. The method of claim 6, wherein the EGFR mutant comprises one or more of the following mutations: T790M mutation, L858R mutation, and d746-750 mutation.

Details for Patent 10,300,058

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2034-04-18
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2034-04-18
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2034-04-18
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2034-04-18
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2034-04-18
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2034-04-18