Claims for Patent: 9,890,168

Summary for Patent: 9,890,168

Title:	2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, preparation method and medicinal use thereof
Abstract:	The present invention relates to a 2,4-disubstituted 7H-pyrrolo[2,3-d]pyrimidine derivative, a preparation method and a medicinal use thereof. In particular, the present invention discloses a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, and a preparation method and use thereof. For the definition of each group in formula (I), see the description tbr details. ##STR00001##
Inventor(s):	Lan; Jiong (Shanghai, CN), Jin; Yunzhou (Shanghai, CN), Zhou; Fusheng (Shanghai, CN), Lei; Jing (Shanghai, CN), Wen; Chong (Shanghai, CN), Zhang; Zhiyuan (Shanghai, CN), He; Xiangyu (Shanghai, CN)
Assignee:	Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN)
Application Number:	15/329,183
Patent Claims:	1. A compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ##STR00119## wherein, ring A is a substituted or unsubstituted C.sub.3-10 heterocyclic ring, substituted or unsubstituted C.sub.6-10 aryl ring or substituted or unsubstituted C.sub.4-10 cycloalkenyl ring; when substituted, 1-6 hydrogen atoms of the heterocyclic, aryl or cycloalkenyl ring are substituted with a substituent selected from the group consisting of hydroxy, CN, NO.sub.2, halogen, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, --CON (C.sub.1-3 alkyl).sub.2, --C(O)OC.sub.1-3 alkyl, --OC(O)C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-3 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-3 alkyl, --S(O)-phenyl, and --N(C.sub.1-3 alkyl).sub.2; X is a covalent bond, or NH, O or S; R.sub.0 is H, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, C.sub.3-6 cycloalkyl, C.sub.3-6 halocycloalkyl, --CHO, --COC.sub.1-3 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-3 alkyl, or --SO.sub.2-phenyl; R.sub.1 and R.sub.2 are each independently H, halogen, C.sub.1-3 alkyl, or C.sub.1-3 haloalkyl; and R.sub.3 is selected from the group consisting of: ##STR00120## ##STR00121## wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of halogen and C.sub.1-3 alkyl. 2. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein R.sub.3 is selected from the group consisting of: ##STR00122## 3. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein R.sub.0 is H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, --CO-phenyl, --SO.sub.2CH.sub.3 or --SO.sub.2-phenyl; wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: fluorine, chlorine, bromine, methyl, and ethyl; and R.sub.1 and R.sub.2 are each independently H, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl. 4. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein the substituted or unsubstituted C.sub.3 -10 heterocyclic ring is a substituted or unsubstituted 9-10 membered bicyclic heteroaryl ring containing 1, 2 or 3 nitrogen atoms and is selected from the group consisting of: ##STR00123## wherein Z.sub.11 is CR.sub.15 or N; Z.sub.12 is CR.sub.16 or N; Z.sub.21 is CR.sub.26 or N; R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.16, R.sub.22, R.sub.23, R.sub.24, R.sub.25, and R.sub.26 are each independently H, hydroxy, CN, NO.sub.2, halogen, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --CON (C.sub.1-3 alkyl).sub.2, --N(C.sub.1-3 alkyl).sub.2, --C(O)OC.sub.1-3 alkyl, --OC(O)C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-3 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-3 alkyl, or --S(O)-phenyl; wherein phenyl are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, and methyl; and R.sub.11 and R.sub.21 are each independently H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-3 alkyl, or --SO.sub.2-phenyl; wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of: fluorine, chlorine, and methyl. 5. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein the substituted or unsubstituted C.sub.3-10 heterocyclic ring is a substituted or unsubstituted 5-6 membered monocyclic heteroaryl ring containing 1-2 nitrogen atoms and is selected from the group consisting of: ##STR00124## wherein Z.sub.31 is CR.sub.34 or N; R.sub.32, R.sub.33, R.sub.34, R.sub.35, R.sub.36, R.sub.37, and R.sub.38 are each independently H, hydroxy, CN, NO.sub.2, halogen, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --CON(C.sub.1-3 alkyl).sub.2, --N(C.sub.1-3 alkyl).sub.2, --C(O)OC.sub.1-3 alkyl, --OC(O)C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-3 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-3 alkyl, or --S(O)-phenyl; wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, and methyl; and R.sub.31 is H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-3 alkyl, or --SO.sub.2-phenyl; wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, and methyl. 6. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein the substituted or unsubstituted C.sub.3-10 heterocyclic ring is a substituted or unsubstituted 4-7 membered saturated monocyclic heterocyclic ring containing one nitrogen atom and is selected from the group consisting of: ##STR00125## wherein n.sub.1 is 1, 2 or 3; n.sub.2 is 1 or 2; and R.sub.41 is H, C.sub.1-3 alkyl, C.sub.1-3 haloalkyl, --COC.sub.1-3 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-3 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-3 alkyl, or --S(O)-phenyl; wherein phenyl is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of fluorine, chlorine, and methyl. 7. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 4, wherein, the compound of formula (I) is a compound of formula (II) or formula (III): ##STR00126## wherein R.sub.11, R.sub.12, R.sub.13, R.sub.14, R.sub.0, R.sub.1, R.sub.2, R.sub.3, Z.sub.11, and Z.sub.12 are defined as in claim 4; ##STR00127## wherein R.sub.21, R.sub.22, R.sub.23, R.sub.24, R.sub.25, R.sub.0, R.sub.1, R.sub.2, R.sub.3, and Z.sub.21 are defined as in claim 4. 8. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein the substituted or unsubstituted C.sub.3-10 heterocyclic ring is: ##STR00128## 9. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein the substituted or unsubstituted C.sub.6-10 aryl ring is: ##STR00129## 10. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 1, wherein the compound of formula (I) is a compound of formula (VII) or formula (VIII): ##STR00130## wherein R.sub.0, R.sub.1, R.sub.2, and R.sub.3 are defined as in claim 1. 11. A compound selected from the group consisting of: ##STR00131## ##STR00132## ##STR00133## ##STR00134## ##STR00135## or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. 12. A pharmaceutical composition comprising the compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, and a pharmaceutically acceptable carrier. 13. A medicinal composition comprising the compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1; and one or more medicaments selected from the group consisting of gefitinib, erlotinib, erlotinib, 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 inhibitor, CNF2024, tanespimycin, alvespimycin, IPI-504, SNX-5422, and NVP-AUY922. 14. A method for preparing the compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, wherein the method comprises the following steps: (i) subjecting a compound of formula I-f to a reduction reaction to form a compound of formula I-g; and (ii) subjecting the compound of formula I-g and acryloyl chloride to a condensation reaction to form the compound of formula (I); ##STR00136## or the method comprises step (i'): allowing a compound of formula I-c to react with a compound of formula I-h in an inert solvent to form the compound of formula (I); ##STR00137## wherein in each of the above formulas, R.sub.0, R.sub.1, R.sub.2, R.sub.3, X, and A ring are defined as in claim 1; and L.sub.1 is a leaving group. 15. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 5, wherein the compound of formula (I) is a compound of formula (IV) or formula (V): ##STR00138## wherein R.sub.31, R.sub.32, R.sub.33, R.sub.0, R.sub.1, R.sub.2, R.sub.3, and Z.sub.31 are defined as in claim 5; ##STR00139## wherein R.sub.35, R.sub.36, R.sub.37, R.sub.38, R.sub.0, R.sub.1, R.sub.2, and R.sub.3 are defined as in claim 5. 16. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof of claim 6, wherein, the compound of formula (I) is a compound of formula (VI): ##STR00140## wherein R.sub.41, R.sub.0, R.sub.1, R.sub.2, R.sub.3, X, n.sub.1, and n.sub.2 are defined as in claim 6. 17. A method of inhibiting EGFR tyrosine kinase activity in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 12. 18. A method of treating an EGFR-related disease in a subject in need thereof, the method comprising administering to the subject the pharmaceutical composition of claim 12, wherein the EGFR-related disease is a cancer selected from the group consisting of gastric cancer, non-small cell lung cancer, esophageal cancer, and pancreatic cancer. 19. The method of claim 17, wherein the EGFR tyrosine kinase comprises a T790M mutation. 20. A pharmaceutical composition comprising the compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 11, and a pharmaceutically acceptable carrier.

Details for Patent 9,890,168

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2034-07-25
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2034-07-25
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2034-07-25