Claims for Patent: 10,085,983

Summary for Patent: 10,085,983

Title:	Azabicyclo derivatives, process for preparation thereof and medical use thereof
Abstract:	Azabicyclo derivatives, a preparation process, and medical use thereof are provided. In particular, azabicyclo derivatives of formula (I), pharmaceutically acceptable salts, stereoisomers, solvates and prodrugs thereof are described. The azabicyclo derivatives of formula (I) are useful as Epidermal Growth Factor Receptor (EGFR) inhibitors. The definitions of the variable R groups in the azabicyclo derivatives of formula (I) are described in the specification. ##STR00001##
Inventor(s):	Jin; Yunzhou (Pudong New Area Shanghai, CN), Bu; Ping (Pudong New Area Shanghai, CN), He; Qi (Pudong New Area Shanghai, CN), Lan; Jiong (Pudong New Area Shanghai, CN), Zhou; Fusheng (Pudong New Area Shanghai, CN), Zhang; Liang (Pudong New Area Shanghai, CN), He; Xiangyu (Pudong New Area Shanghai, CN)
Assignee:	Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN)
Application Number:	15/515,767
Patent Claims:	1. A compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ##STR00126## wherein; each of Z.sub.1 and Z.sub.2 is independently N or CR.sub.0, wherein R.sub.0 is selected from the group consisting of H, halogen, C.sub.1-10 alkyl, and C.sub.1-10 haloalkyl; each of R.sub.1 and R.sub.2 is independently H, halogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, C.sub.1-10 alkoxy, or C.sub.3-8 cycloalkoxy; R.sub.3 is C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.6-10 aromatic ring, or substituted or unsubstituted C.sub.4-10 cycloalkenyl, ##STR00127## wherein "substituted" means 1-6 hydrogen atoms on a ring atom are substituted with a substituent selected from the group consisting of hydroxy, CN, NO.sub.2, halogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, --CON(C.sub.1-10 alkyl).sub.2, --C(O)OC.sub.1-10 alkyl, --OC(O)C.sub.1-10 alkyl, --COC.sub.1-10 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-10 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-10 alkyl, and --S(O)-phenyl, --N(C.sub.1-10 alkyl).sub.2 and wherein the phenyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen and C.sub.1-10 alkyl; Z.sub.11 is CR.sub.15 or N; Z.sub.21 is CR.sub.26 or N; Z.sub.31 is CR.sub.37 or N; Z.sub.41 is CR.sub.44 or N; n.sub.1 is 1, 2 or 3; n.sub.2 is 1 or 2; each of R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.22, R.sub.23, R.sub.24, R.sub.25, R.sub.26, R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, R.sub.36, R.sub.37, R.sub.42, R.sub.43, R.sub.44, R.sub.51, R.sub.52, R.sub.53, R.sub.54, and R.sub.61 is independently H, hydroxy, CN, NO, halogen, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, --CON(C.sub.1-10 alkyl).sub.2, --N(C.sub.1-10 alkyl).sub.2, --C(O)OC.sub.1-10 alkyl, --OC(O)C.sub.1-10 alkyl, --COC.sub.1-10 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-10 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-10 alkyl, or --S(O)-phenyl, wherein the alkyl or phenyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, C1, and methyl; each of R.sub.11, R.sub.21, and R.sub.41 is independently H, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, --COC.sub.1-10 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-10 alkyl, or --SO.sub.2-phenyl, wherein the phenyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, and methyl; R.sub.4 is selected from the group consisting of: ##STR00128## R.sub.5 is methoxy; and each of R.sub.6 and R.sub.7. 2. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, wherein R.sub.3 is methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted C.sub.4-8 cycloalkenyl, ##STR00129## 3. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, wherein, Z.sub.11 is N; each of R.sub.12, R.sub.13, and R.sub.14 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; R.sub.11 is H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl; Z.sub.21 is CR.sub.26; each of R.sub.22, R.sub.23, R.sub.24, R.sub.25, and R.sub.26 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; R.sub.21 is H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl; Z.sub.31 is N; each of R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, and R.sub.36 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; Z.sub.41 is N or CR.sub.44; each of R.sub.42, R.sub.43, and R.sub.44 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; R.sub.41 is H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl; each of R.sub.51, R.sub.52, R.sub.53, and R.sub.54 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; n.sub.1 is 2; n.sub.2 is 2; and R.sub.61 is H, halogen, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl. 4. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 3, wherein, Z.sub.11 is N; each of R.sub.12, R.sub.13, and R.sub.14 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; R.sub.11 is H, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3; Z.sub.21 is CR.sub.26; each of R.sub.22, R.sub.23, R.sub.24, R.sub.25, and R.sub.26 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; R.sub.21 is H, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3; Z.sub.31 is N; each of R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, and R.sub.36 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; Z.sub.41 is N or CR.sub.44; each of R.sub.42, R.sub.43, and R.sub.44 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; R.sub.41 is H, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3; each of R.sub.51, R.sub.52, R.sub.53, and R.sub.54 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; n.sub.1 is 2; n.sub.2 is 2; and R.sub.61 is H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3. 5. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), or formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ##STR00130## wherein R.sub.11, R.sub.12, R.sub.13, R.sub.14, Z.sub.11, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00131## wherein R.sub.21, R.sub.22, R.sub.23, R.sub.24, R.sub.25, Z.sub.21, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00132## wherein R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, R.sub.36, Z.sub.31, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00133## wherein R.sub.41, R.sub.42, R.sub.43, Z.sub.41, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00134## wherein R.sub.51, R.sub.52, R.sub.53, R.sub.54, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00135## wherein R.sub.61, n.sub.1, n.sub.2, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00136## wherein R.sub.41, R.sub.42, R.sub.43, Z.sub.41, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00137## wherein R.sub.51, R.sub.52, R.sub.53, R.sub.54, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1. 6. A compound selected from the group consisting of: ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. 7. A pharmaceutical composition comprising the compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, and a pharmaceutically acceptable carrier. 8. A method for treating an EGFR-related disease in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 7, wherein the EGFR-related disease is non-small cell lung cancer. 9. A medicinal composition comprising the compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1 and an additional medicament, wherein the additional medicament is at least one medicament selected from the group consisting of gefitinib, erlotinib, icotinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, vandetanib, PF00299804, WZ4002, cetuximab, trastuzumab, panitumumab, matuzumab, nimotuzumab, zalutumumab, pertuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccine PX 1041, HSP90 inhibitors, CNF2024, tanespimycin, alvespimycin, IPI-504, SNX-5422, and NVP-AUY922. 10. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 6, and a pharmaceutically acceptable carrier. 11. A method for treating an EGFR-related disease in a subject, the method comprising administering to the subject the pharmaceutical composition according to claim 10, wherein the EGFR-related disease is non-small cell lung cancer. 12. The method according to claim 8, wherein the non-small cell lung cancer is caused by mutations of EFGR comprising L858R and T790M. 13. The method according to claim 11, wherein the non-small cell lung cancer is caused by mutations of EGFR comprising L858R and T790M.

Details for Patent 10,085,983

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2034-09-30
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2034-09-30
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2034-09-30
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2034-09-30
Amgen, Inc.	VECTIBIX	panitumumab	Injection	125147	09/27/2006		2034-09-30