Claims for Patent: 9,796,701

Summary for Patent: 9,796,701

Title:	Kinase inhibitor and use thereof
Abstract:	The invention relates to a CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers; a pharmaceutical formulation, pharmaceutical composition and kit comprising said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers, and use of said CDK4/6 kinase inhibitor, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their isomers. For example, the compounds of the invention are useful for reducing or inhibiting the activity of CDK4/6 kinase in a cell, and/or treating and/or preventing a cancer-related disease mediated by CDK4/6 kinase.
Inventor(s):	Wu; Frank (Shandong, CN), Chen; Bo (Shandong, CN)
Assignee:	XUANZHU PHARMA CO., LTD. (Jinan, Shandong, CN)
Application Number:	15/108,903
Patent Claims:	1. A compound of Formula (I'), or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers, ##STR00236## wherein: each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy, or 3-8 membered cycloalkyl optionally substituted by Q.sup.1, wherein Q.sup.1 is selected from C.sub.1-6alkyl or C.sub.1-6alkoxy; R.sup.2 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, carbamoyl or C.sub.1-6alkylcarbonylamino; R.sup.3 and R.sup.5 are independently selected from halogen or hydrogen, and at least one of R.sup.3 and R.sup.5 is halogen; R.sup.4 is selected from 3-8 membered heterocyclyl, 6-14 membered fused heterocyclyl, 5-8 membered heteroaryl, 6-14 membered fused heteroaryl, phenyl, naphthyl, 6-12 membered bridged heterocyclyl or 6-12 membered spiroheterocyclyl, each of which is optionally substituted by Q.sup.2; Q.sup.2 is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C.sub.1-6alkoxy, C.sub.1-6alkylsulfonyl, C.sub.1-6alkylsulfonylamino, or di-C.sub.1-6alkylamino; or C.sub.1-6alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocyclyl or 6-9 membered bridged heterocyclyl, each of which is optionally substituted by a substituent, wherein the substituent is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C.sub.1-6alkoxy, C.sub.1-6alkylamino, di-C.sub.1-6alkylamino, C.sub.1-6alkylsulfonyl, 3-8 membered heterocyclyl or 3-8 membered cycloalkyl; n is selected from 0, 1, 2, 3, 4 or 5. 2. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 1, wherein each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is selected from C.sub.1-4alkyl or C.sub.1-4 alkoxy; R.sup.2 is selected from C.sub.1-4alkyl, C.sub.1-4 alkoxy, cyano, carbamoyl or C.sub.1-4alkylcarbonylamino; each of R.sup.3 and R.sup.5 is a halogen; R.sup.4 is selected from a nitrogen-containing 5-6 membered heterocyclyl optionally substituted by Q.sup.2; wherein the nitrogen-containing 5-6 membered heterocyclyl is preferably a nitrogen-containing 6 membered heterocyclyl; Q.sup.2 is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C.sub.1-4 alkoxy, or di-C.sub.1-4alkylamino; or C.sub.1-4alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocyclyl, each of which is optionally substituted by a substituent, wherein the substituent is selected from amino, hydroxyl, halogen, trifluoromethyl, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, C.sub.1-4 alkylamino, di-C.sub.1-4alkylamino, or 3-6 membered cycloalkyl; n is 0. 3. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 1, wherein the compound has the structure of Formula (I), ##STR00237## wherein: each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy, or 3-8 membered cycloalkyl optionally substituted by Q.sup.1, wherein Q.sup.1 is selected from C.sub.1-6alkyl or C.sub.1-6alkoxy; R.sup.2 is selected from C.sub.1-6alkyl, C.sub.1-6alkoxy, cyano, carbamoyl or C.sub.1-6alkylcarbonylamino; R.sup.3 and R.sup.5 are independently selected from halogen or hydrogen, and at least one of R.sup.3 and R.sup.5 is halogen; R.sup.4 is selected from 3-8 membered heterocyclyl, 6-14 membered fused heterocyclyl, 5-8 membered heteroaryl, 6-14 membered fused heteroaryl, phenyl, naphthyl, 6-12 membered bridged heterocyclyl or 6-12 membered spiroheterocyclyl, each of which is optionally substituted by Q.sup.2; wherein Q.sup.2 is selected from amino, hydroxyl, halogen, trifluoromethyl, cyano, C.sub.1-6alkyl, C.sub.1-6alkoxy, 3-8 membered heterocyclyl or 6-9 membered bridged heterocyclyl. 4. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 3, wherein each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is selected from C.sub.1-4alkyl or C.sub.1-4alkoxy; R.sup.2 is selected from C.sub.1-4alkyl, C.sub.1-4alkoxy, cyano, carbamoyl or C.sub.1-4alkylcarbonylamino; each of R.sup.3 and R.sup.5 is a halogen; R.sup.4 is selected from 5-7 membered heterocyclyl, 6-11 membered fused heterocyclyl, 6-11 membered bridged heterocyclyl or 6-11 membered spiroheterocyclyl, each of which is optionally substituted by Q.sup.2; wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy, 5-6 membered heterocyclyl or 7-9 membered bridged heterocyclyl. 5. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 4, wherein each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is isopropyl; R.sup.2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino; each of R.sup.3 and R.sup.5 is F; R.sup.4 is selected from 5-6 membered heterocyclyl optionally substituted by Q.sup.2; wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C.sub.1-4alkyl, C.sub.1-4alkoxy, 6 membered heterocyclyl or 8 membered bridged heterocyclyl. 6. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 5, wherein R.sup.2 is methyl; R.sup.4 is selected from a nitrogen-containing 5-6 membered heterocyclyl optionally substituted by Q.sup.2; wherein the nitrogen-containing 5-6 membered heterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C.sub.1-4alkyl, C.sub.1-4 alkoxy, or a nitrogen-containing 8 membered bridged heterocyclyl. 7. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 6, wherein R.sup.4 is selected from ##STR00238## each of which is optionally substituted by Q.sup.2, wherein Q.sup.2 is selected from C.sub.1-4alkyl or a nitrogen-containing 8 membered bridged heterocyclyl. 8. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 4, wherein each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is isopropyl; R.sup.2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino; each of R.sup.3 and R.sup.5 is F; R.sup.4 is selected from 7-9 membered bridged heterocyclyl optionally substituted by Q.sup.2; wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C.sub.1-4alkyl, 6 membered heterocyclyl or 8 membered bridged heterocyclyl. 9. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 8, wherein R.sup.2 is methyl; R.sup.4 is selected from a nitrogen-containing 7-9 membered bridged heterocyclyl optionally substituted by Q.sup.2; wherein the nitrogen-containing 7-9 membered bridged heterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C.sub.1-4 alkyl, or a nitrogen-containing 6 membered heterocyclyl; wherein the nitrogen-containing 7-9 membered bridged heterocyclyl is preferably a nitrogen-containing 7-9 membered bridged heterocyclyl containing 1 to 2 nitrogen atoms. 10. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 9, wherein R.sup.4 is selected from ##STR00239## each of which is optionally substituted by Q.sup.2, wherein Q.sup.2 is selected from C.sub.1-4 alkyl or a nitrogen-containing 6 membered heterocyclyl. 11. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 4, wherein each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is selected from isopropyl; R.sup.2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino; each of R.sup.3 and R.sup.5 is F; R.sup.4 is selected from 6-10 membered fused heterocyclyl optionally substituted by Q.sup.2; wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C.sub.1-4alkyl, 6 membered heterocyclyl or 8 membered bridged heterocyclyl. 12. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 11, wherein R.sup.2 is methyl; R.sup.4 is selected from a 6-10 membered fused heterocyclyl that contains 1, 2 or 3 identical or different heteroatoms and is optionally substituted by Q.sup.2; wherein the heteroatoms are preferably selected from nitrogen atom and oxygen atom, and contain at least one nitrogen atom, and the 6-10 membered fused heterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, or C.sub.1-4alkyl. 13. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 12, wherein R.sup.4 is selected from ##STR00240## each of which is optionally substituted by Q.sup.2, wherein Q.sup.2 is selected from amino or C.sub.1-4alkyl. 14. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 4, wherein each of A.sup.1 and A.sup.2 is nitrogen; R.sup.1 is isopropyl; R.sup.2 is selected from methyl, methoxy, cyano, carbamoyl, or acetylamino; each of R.sup.3 and R.sup.5 is F; R.sup.4 is selected from 7-11 membered spiroheterocyclyl optionally substituted by Q.sup.2; wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, C.sub.1-4 alkyl, 6 membered heterocyclyl or 8 membered bridged heterocyclyl. 15. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 14, wherein R.sup.2 is methyl; R.sup.4 is selected from a nitrogen-containing 7-11 membered spiroheterocyclyl optionally substituted by Q.sup.2; wherein the nitrogen-containing 7-11 membered spiroheterocyclyl is linked to the methylene of Formula (I) via a nitrogen atom, wherein Q.sup.2 is selected from amino, hydroxyl, trifluoromethyl, cyano, or C.sub.1-4alkyl; wherein the nitrogen-containing 7-11 membered spiroheterocyclyl is preferably a nitrogen-containing 7-11 membered spiroheterocyclyl containing 1 to 2 nitrogen atoms. 16. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 15, wherein R.sup.4 is selected from ##STR00241## each of which is optionally substituted by Q.sup.2, wherein Q.sup.2 is selected from C.sub.1-4 alkyl. 17. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 1, wherein the compound is selected from: ##STR00242## ##STR00243## ##STR00244## ##STR00245## ##STR00246## ##STR00247## 18. A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 1, and optionally one or more pharmaceutically acceptable carriers. 19. The pharmaceutical composition according to claim 18, further comprising one or more additional anti-tumor agents and/or immunosuppressors. 20. The pharmaceutical composition according to claim 19, wherein the additional anti-tumor agents and/or immunosuppressors are selected from one or more of the following: 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 and aminoglutethimide. 21. A method for treating colon cancer, breast cancer, melanoma, or glioma, comprising the step of administering to a subject in need thereof a therapeutically effective amount of the compound, or a pharmaceutically acceptable salt, ester, or solvate thereof, or their stereoisomers according to claim 1. 22. The compound, or a pharmaceutically acceptable salt, ester, or solvate thereof or their stereoisomers according to claim 6, wherein the nitrogen-containing 5-6 membered heterocyclyl is a nitrogen-containing 5-6 membered heterocyclyl containing 1 to 2 nitrogen atoms.

Details for Patent 9,796,701

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2033-12-31
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2033-12-31
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2033-12-31
Genentech, Inc.	AVASTIN	bevacizumab	Injection	125085	02/26/2004		2033-12-31
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2033-12-31
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2033-12-31