Claims for Patent: 11,504,375

Summary for Patent: 11,504,375

Title:	ErbB/BTK inhibitors
Abstract:	Disclosed are compounds inhibiting ErbBs (e.g., EGFR or Her 2), especially mutant forms of ErbBs, and BTK, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof and pharmaceutical compositions comprising the compounds. The compound and the pharmaceutical composition can effectively treat ErbBs (especially mutant forms of ErbBs) or BTK associated diseases, including cancer.
Inventor(s):	Zhengtao LI, Hao Zou, Wei Zhu, Changmao Shen, Rumin WANG, Wengeng LIU, Xiang Chen, Honchung Tsui, Zhenfan YANG, Xiaolin Zhang
Assignee:	Dizal Jiangsu Pharmaceutical Co Ltd
Application Number:	US17/224,121
Patent Claims:	1. A compound of Formula (I): or a pharmaceutically acceptable salt, hydrate, solvate or stereoisomer thereof, wherein, A1 is N or CR8; A2, A3, A4 and A5 are each independently N or CR9, wherein no more than one of A2, A3, A4 and A5 is N; R1 and R2 are each independently hydrogen or C1-12, alkyl optionally mono- or independently multi-substituted by one or more of halogen, hydroxyl, —NRaRb, C1-12 alkyl, C1-12 alkoxy, 3-10 membered saturated or unsaturated carbocyclyl, 3-10 membered saturated or unsaturated heterocyclyl, wherein each of C1-12 alkyl, C1-12 alkoxy, 3-10 membered saturated or unsaturated carbocyclyl, 3-10 membered saturated or unsaturated heterocyclyl can be unsubstituted or mono- or multi-substituted by C1-12 alkyl, wherein, Ra and Rb are each independently selected from hydrogen or C1-12 alkyl, which can be optionally mono- or independently multi-substituted by deuterium, tritium, halogen, hydroxyl, or C1-12 alkoxy, or Ra and Rb taken together with the nitrogen atom to which they are bound to form a 3-10 membered saturated or unsaturated heterocyclyl optionally mono- or multi-substituted by halogen, hydroxyl, or C1-12 alkyl; or, R1 and R2 taken together with the nitrogen atom to which they are bound to form a 3-12 membered monocyclic or polycyclic ring optionally comprising one or more additional heteroatoms selected from N, O, and S, which can be optionally mono- or independently multi-substituted by halogen, hydroxyl, C1-12 alkyl, C1-12 alkoxy, —NRaRb, or —C1-12 alkyl-NRaRb; R3 is H, C1-12 alkyl, or —C1-12 alkyl-NRaRb; R4 and R5 are each independently C1-6 alkyl optionally mono- or independently multi-substituted by one or more of deuterium, tritium, halogen, hydroxyl, C1-12, alkyl, or C1-12 alkoxy, or, R4 and R5 taken together with the carbon atom to which they are bound to form a 3-10 membered monocyclic or polycyclic ring optionally comprising one or more heteroatoms selected from N, O, and S, which can be optionally mono- or independently multi-substituted by one or more of deuterium, tritium, halogen, hydroxyl, C1-12 alkyl, or C1-12 alkoxy, R6 is hydrogen, or C1-12 alkyl, which can be optionally mono- or independently multi-substituted by deuterium, tritium, halogen, hydroxyl, C1-12 alkyl or C1-12 alkoxy, R7 is hydrogen, or C1-12 alkyl, which can be optionally mono- or multi-substituted by deuterium, tritium, halogen, or hydroxyl, R8 is hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C1-12 alkyl C1-12 alkoxyl, which can be optionally mono- or independently multi-substituted by one or more of deuterium, tritium, halogen, or C1-12 alkyl; R9 is null, hydrogen, deuterium, tritium, halogen, cyano, hydroxyl, C1-12 alkyl, or C1-12 alkoxyl which can be optionally mono- or independently multi-substituted by one or more of deuterium, tritium, halogen, or C1-12 alkyl; n is 0, 1, 2, 3, or 4; each R is independently hydrogen, deuterium, tritium; halogen, cyano, hydroxyl, C1-12 alkyl, C1-12 alkoxy, 3-10 membered saturated or unsaturated carbocyclyl, or 3-10 membered saturated or unsaturated heterocyclyl which is fused with the ring to which it is bound, which can be optionally mono- or independently multi-substituted by one or more of deuterium, tritium, halogen, or C1-12 alkyl. 2. The compound of claim 1, wherein A1 is N. 3. The compound of claim 1, wherein A1 is CH. 4. The compound of claim 1, wherein A2, A3, A4 and A5 are each independently CR9. 5. The compound of claim 1, wherein R1 and R2 are each independently selected from: 6. The compound of claim 1, wherein R1 and R2 are taken together with the nitrogen atom to which they are hound to form a 3-12 membered monocyclic or polycyclic ring selected from: which is optionally mono- or independently multi-substituted by halogen, hydroxy C1-12 alkyl, C1-12 alkoxy, —NRaRb, or —C1-12 alkyl-NRaRb. 7. The compound of claim 1, wherein RI and R2 are taken together with the nitrogen atom to which they are bound to form: 8. The compound of claim 1, wherein n is 2, A2 and A5 are CH, A3 and A4 are each independently CH substituted by R, R is each independently halogen, and R4 and R5 are each independently unsubstituted C1-6 alkyl. 9. The compound of claim 1, selected from the group consisting of 10. A pharmaceutical composition comprising one or more compounds of Formula (I), pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof according to claim 1 as a first active ingredient, and a pharmaceutically acceptable diluent, excipient or carrier. 11. A method of inhibiting EGFR, Her2 or BTK by using one or more compounds, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof of claim 1. 12. A method of treating an ErbB associated disease or BTK associated diseases in a subject, comprising administering to the subject an effective amount of one or more compounds, pharmaceutically acceptable salts, hydrates, solvates or stereoisomers thereof of claim 1, wherein the ErbB associated disease is selected from the group consisting of: lung cancer, colorectal cancer, head and neck cancer, pancreatic cancer, breast cancer, cervix cancer, colon cancer and esophageal cancer; wherein the BTK associated disease is selected from the group consisting of: lymphoma, leukemia and autoimmune disease. 13. The method according to claim 12, wherein the subject is a warm blooded-animal. 14. The method according to claim 12, wherein the lung cancer is non-small cell lung cancer. 15. The method according to claim 12, wherein the lymphoma is non-Hodgkin's lymphoma (NHL), mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLBCL). 16. The method according to claim 12, wherein the leukemia is chronic lymphocytic leukemia (CLL). 17. The method according to claim 12, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus or Sjogren's syndrome. 18. The method according to claim 11, wherein the EGFR or Her2 is mutant EGFR or mutant Her2. 19. The method according to claim 18, wherein the mutant EGFR selected from the group consisting of EGFR D761_E762insEAFQ, EGER A763_Y764insHH, EGFR M766_A767instAI, EGFR A767_V769dupASV, EGFR A767_S768insTLA, EGFR S768_D770 dupSVD, EGFR S768_V769insVAS, EGER S768_V769insAWT, EGFR V769_D770insASV, EGFR V769_D770insGV, EGFR V769_D770insCV, EGER V769_D770insDNV, EGFR V769_D770insGSV, EGFR V769_D770insGVV, EGER V769_D770insMASVD, EGER D770_N771insSVD, EGFR D770_N771insNPG, EGFR D770_N771insAPW, EGFR D770_N771insD, EGFR D770_N771insDG, EGFR D770_N771insG, EGFR D770_N771_insGL, EGFR D770_N771insN, EGER D770_N771insNPH, EGFR D770_N771insSVP, EGFR D770_N771insSVQ, EGER D770_N771insMATP, EGFR delD770insGY, EGER N771_P772insH, EGFR N771_P772insN, EGFR N771_H773dupNPH, EGFR delN771insGY, EGFR delN771insGF, EGFR P772_H773insPR, EGFR P772_H773insYNP, EGFR P772_H773insX, EGFR P772_H773insDPH, EGFR P772_H773insDNP, EGFR P772_H773insQV, EGFR P772_H773insTPH, EGFR P772_H773insN, EGFR P772_H773insV, EGFR H773_V774insNPH, EGFR H773_V774insH, EGFR H773_V774insPH, EGFR H773_V774insGNPH, EGFR H773_V774dupHV, EGFR H773_V774insG, EGFR H773_V774insGH, EGFR V774_C775insHV, EGFR exon19 deletion, EGFR L858R, EGFR T790M, EGFR L858R/T790M, EGFR exon 19 deletion/T790M, EGFR S768I, EGER, G719S, EGFR G719A, EGFR G719C, EGFR E709A/G719S, EGFR E709A/G719A, EGFR E709A/G719C, and EGFR L861Q. 20. The method according to claim 18, wherein the mutant Her2 is selected from the group consisting of Her2 A775 G776insYVMA, Her2 delG776insVC, Her2 V777_G778insCG and Her2 P780_Y781insGSP. 21. A composition comprising compound of Formula (I), or pharmaceutically acceptable salt, hydrates, solvates or stereoisomers thereof, as claimed in claim 1 and a second therapeutic agent. 22. The method according to claim 13, wherein the warm blooded-animal is man. 23. The composition according to claim 21, wherein the second therapeutic agent is an anti-tumour agent.