Heteroaryl ester derivatives as sodium channel inhibitors

Abstract

This invention generally relates to compounds of formula (I) that inhibit sodium channel (NaV) activity; more specifically, it relates to compounds that are heteroaryl ester derivatives, including zwitterionic forms and pharmaceutically acceptable salts thereof, as well as methods for preparing such compounds and their therapeutic uses. The compounds of this invention can, for example, be used to treat a variety of NaV-related diseases, such as respiratory diseases.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480075314.X (22) Application Date 2024.10.30 (30) Priority Data 23207539.0 2023.11.02 EP (85) PCT International Application Entering National Phase Date 2026.05.28 (86) PCT International Application Application Data PCT / EP2024 / 080664 2024.10.30 (87) PCT International Application Publication Data WO2025 / 093590 EN 2025.05.08 (71) Applicant: Chis Pharmaceuticals Co., Ltd. Address: Italy (72) Inventors: C. Fiorelli, G. Fussati, L. Mengozchi, S. Crotti, A. Riz, G. Bourgio, S. Battagrioli (74) Patent Agency: China Council for the Promotion of International Trade Patent & Trademark Office Co., Ltd. 11038 Patent Attorney: Wang Guijie (51) Int.Cl. C07D 217 / 22 (2006.01) C07D 223 / 04 (2006.01) C07D 239 / 42 (2006.01) C07D 241 / 20 (2006.01) C07D 261 / 14 (2006.01) C07D 261 / 18 (2006.01) C07D 275 / 03 (2006.01) C07D 305 / 08(2006.01) C07D 333 / 36(2006.01) C07D 333 / 38(2006.01) C07D 333 / 68(2006.01) C07D 333 / 70(2006.01) C07D 333 / 78(2006.01) C07D 401 / 12(2006.01) C07D 405 / 12(2006.01) C07D 409 / 12(2006.01) C07D 409 / 14(2006.01) C07D 413 / 12(2006.01) C07D 413 / 14(2006.01) C07D 417 / 12(2006.01) C07D 417 / 14(2006.01) C07D 491 / 107(2006.01) C07D 495 / 04(2006.01) C07D 498 / 04(2006.01) A61P 11 / 00(2006.01) A61P 11 / 14(2006.01) A61K 31 / 55(2006.01) A61K 31 / 381(2006.01) A61K 31 / 506(2006.01) A61K31 / 4725(2006.01) A61K 31 / 422(2006.01) A61K 31 / 4535(2006.01) A61K 31 / 5377(2006.01) A61K 31 / 541(2006.01) A61K 31 / 438(2006.01) A61K 31 / 4025(2006.01) A61K 31 / 497(2006.01) (continued) (54) Invention Title Heteroaryl Ester Derivatives as Sodium Channel Inhibitors (57) Abstract This invention generally relates to compounds of formula (I) that inhibit sodium channel (NaV) activity; more specifically, this invention relates to compounds that are heteroaryl ester derivatives, including zwitterionic forms and pharmaceutically acceptable salts thereof, as well as methods for preparing such compounds and their therapeutic uses. The compounds of this invention can be used, for example, to treat a variety of diseases associated with NaV, such as respiratory diseases. [Continued on page] Claims: 8 pages; Description: 129 pages; CN 122374293 A; 2026.07.10; CN 1 22 37 42 93 A (51)Int.Cl. A61K 31 / 42(2006.01) A61K 31 / 4965(2006.01) A61K 31 / 472(2006.01) A61K 31 / 505(2006.01) A61K 31 / 4365(2006.01) A61K 31 / 425(2006.01) A61K 31 / 454(2006.01) A61K 31 / 5365(2006.01) A61K 31 / 4545(2006.01) A61K 31 / 4523(2006.01) 2 / 2 Page 2 [Continued from previous page] CN 122374293 A 1. Compound (I) of formula (I) wherein at least one of Y and Z is S, and the other is CR4; R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C10)heteroalkyl, wherein the -(C3-C10)heteroalkyl is optionally substituted by one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl; R3 and R4 are independently H or selected from CN, -(C1-C6)alkyl and aryl, or wherein Y is CR4, and R3 and R4 are fused together to form aryl; R5 is selected from -(C1-C6)alkyl, -(C1-C6)alkyl-NR6R7, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-C(O)NR6R7, -(C3-C10)heterocyclic alkyl and -(C3-C7)cycloalkyl;R6 and R7 are independently H or selected from -(C1-C6)alkyl and -(C1-C6)alkyl-aryl; L1 is a bond or selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic-ene-, and -(C1-C6)cycloalkylene-; and A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl, and -(C3-C10)heterocyclic alkyl, wherein any such aryl, heteroaryl, -(C3-C10)cycloalkyl, or -(C3-C10)heterocyclic alkyl is optionally substituted by one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and - (C1-C6)alkyl-NR6R7; provided that when L1 is a bond, no such aryl group is substituted with -(C1-C6)alkyl; it is in zwitterionic form or pharmaceutically acceptable salt form. 2. The compound of formula (I) according to claim 1, wherein Z, Y, R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1; L1 is selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic- and -(C1-C6)cycloalkylene-; and A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl and -(C3-C10)heterocyclic-, wherein any such aryl, heteroaryl, -(C3-C10)cycloalkyl or -(C3-C10)heterocyclic- is optionally substituted by one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; It is in zwitterionic form or pharmaceutically acceptable salt form. 3. The compound of formula (I) according to claim 1, wherein L1 is a bond, the compound being represented by formula (Ia). Claim 1 / 8 page 2 CN 122374293 A 3 (Ia) wherein Z, Y, R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1; and A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl and -(C3-C10)heterocycloalkyl, wherein any such heteroaryl, -(C3-C10)cycloalkyl or -(C3-C10)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1- C6)alkyl-NR6R7; and wherein any such aryl group is optionally substituted by one or more groups selected from halogens.The compounds are: -C(O)OR6, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; which are either zwitterionic or pharmaceutically acceptable salts. 4. The compound according to any one of the preceding claims, wherein R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C10)heterocyclic alkyl, wherein the -(C3-C10)heterocyclic alkyl is optionally substituted by one or more groups selected from halogens, -OR6, -(C1-C6)alkyl and -C(O)OR6-; R3 and R4 are independently H or -(C1-C6)alkyl, or, wherein Y is CR4, R3 and R4 fused together to form an aryl group; R5 is selected from -(C1-C6)alkyl and -(C3-C6)cycloalkyl; and it is in zwitterionic form or pharmaceutically acceptable salt form. 5. The compound according to any one of the preceding claims, wherein R1 and R2 are fused together to form a -(C3-C10) heterocyclic alkyl group, wherein the -(C3-C10) heterocyclic alkyl group is optionally substituted by one or more groups selected from -OR6, -C(O)OR6, -(C1-C6) alkyl, and -(C1-C6) haloalkyl; which is in zwitterionic form or pharmaceutically acceptable salt form. 6. The compound according to any one of the preceding claims, wherein R3 and R4 are independently H or -(C1-C6) alkyl; which is in zwitterionic form or pharmaceutically acceptable salt form. 7. The compound according to any one of the preceding claims, wherein Z is S and Y is CH or Z is CH and Y is S, and R3 is H or methyl; which is in zwitterionic form or pharmaceutically acceptable salt form. 8. The compound according to any one of the preceding claims, wherein A is a heteroaryl group, optionally substituted with one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-NR6R7 and -(C1-C6)alkyl-C(O)NR6R7. 9. The compound according to claim 1, wherein the compound is selected from: Claims 2 / 8, page 3, CN 122374293 A 4 1,1-bis(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 1); 2-((3-carbamoyl-5,6-dihydro-4H-cyclopentadien[b]thiophen-2-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3 ...(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 2); 2-((3-(methoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 3); 2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-N,N-dimethyl-2-oxo-N-(2-oxo-2-(pyrimidin-5-ylamino)ethyl)ethyl-1-ammonium (Example 4); 2-(isoquinoline-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 5); 2-(benzylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 6); 2-(isoxazo-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 7); 2-((cyclohexylmethyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 8); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 9); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 10); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N,N-dimethyl-2-oxo-N-(2-oxo-2-((2-(trifluoromethyl)benzyl)amino)ethyl)ethyl-1-ammonium (Example 11); 2-(benzylamino)-N,N-dimethyl-N-(2-((4-methyl-2-(propoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-2-oxoethyl-1-ammonium (Example 12); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 13);2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N,N-dimethyl-N-(2-((2-methylbenzyl)amino)-2-oxoethyl)-2-oxoethyl-1-ammonium (Example 14); 2-(benzylamino)-N-(2-((2-(isopropoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 15); 2-((2,6-dimethylbenzyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 16); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 19); 2-(((2,3-dihydro-1H-indene-2-yl)methyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 20); 1-(2-((2,3-dihydro-1H-indene-2-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 22); 1-(2-(benzylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)- Claims 3 / 8 Page 4 CN 122374293 A 5 2-oxoethyl)azacycloheptane-1-onium (Example 23); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-(((5-(methoxycarbonyl)thiophen-3-yl) (Methyl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 24); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 25); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-((2-(methoxymethyl)benzyl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 26); 1-(2-((2-((2-(benzylamino)-2-oxoethoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(benzylamino)-2-oxoethyl)azacycloheptane-1-onium (Example 27);1-(2-(benzylamino)-2-oxoethyl)-1-(2-((2-(tert-butoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 28); 1,1-bis(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 29); 2-((2-(isopropoxycarbonyl)benzyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 30); 1 1-Bis(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 31); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 32); 1-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazo-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 33); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 34); 1,1-bis(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 35); 1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazo-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 36); (R)-1-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azacycloheptane-1-onium (Example 37); (R)-1-(2-((2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azacycloheptane-1-onium (Example 38); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 39); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)(Amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 40); 1-(2-((2-(tert-butoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)azacycloheptane-1-onium (Example 41); 4-hydroxy-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 42); Claims 4 / 8 pages 5 CN 122374293 A 6 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4-methoxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 43); 4-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)morpholine-4-onium (Example 44); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-5-phenylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 45); (R)-1-(2-((5-(tert-butyl)-2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azacycloheptane-1-onium (Example 46); 4-(2-(benzylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)thiomorpholine-4-onium (Example 47); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylcyclopropyl)amino)ethyl)azacycloheptane-1-onium (Example 50); 7-(2-(benzylamino)-2-oxoethyl)-7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-2-oxa-7-azaspiro[3.5]nonane-7-onium (Example 51); (S)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)pyrrolidine-1-onium (Example 52); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisooxa)(Example 53) 7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-7-(2-(((4-methylisooxazol-3-yl)amino)-2-oxoethyl)-2-oxa-7-azaspiro[3.5]nonane-7-on-(Example 55) 4-(ethoxycarbonyl)-1-(2-(isooxazol-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazine-1-on-(Example 56) 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N,N-dimethyl-N-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)-2-oxoethyl-1-ammonium (Example 57); 4-(tert-butoxycarbonyl)-1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazine-1-onium (Example 58); 2-(isoxazol-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-bis(2-methoxyethyl)-2-oxoethyl-1-ammonium (Example 59); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazine-1-onium (Example 60); 4-methoxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazo-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 62); 4-hydroxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazo-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 63); 1-(2-((2-(cyclopropoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 64); 4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-methyl-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 65); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((3-methylisothiophene) (Claims)Page 5 / 8, CN 122374293 A 7 (Azolium-5-yl)amino)-2-oxoethyl)azacycloheptan-1-onium (Example 66); (2-((1r,4r)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-methylpiperidin-1-onium-1-yl)acetyl)(4-methylisooxazolium-3-yl)amide (Example 67); 1-(2-(isooxazolium-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidin-1-onium (Example 68); 2,2-Difluoro-7-(2-(isoxazo-3-ylamino)-2-oxoethyl)-7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonane-7-onthium (Example 69); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((3-phenyloxetane-3-yl)amino)ethyl)piperidine-1-onthium (Example 70); 4,4-Difluoro-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 71); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 72); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((4-methyl-2-((piperidine-4-yloxy)carbonyl)thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 73); 1-(2-((2-((2-hydroxyethoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 74); (1s,4s)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidine-1-onium (Example 75); 1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2- 2-(pyrazin-2-ylamino)ethyl)piperidine-1-onium (Example 76);1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 77); 2-(2-(2-(isoxazo-3-ylamino)-2-oxoethyl)-2-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)isoindoline-2-onium (Example 78); 1-(2-((4-cyano-2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 79); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-((2-methoxyethoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 80); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-((oxetane-3-yloxy)carbonyl)thiophene-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 81); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-(((tetrahydro-2H-) 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 82); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-((1-(pyridin-2-yl)cyclopropyl)amino)ethyl)piperidine-1-onium (Example 83); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-(pyrimidin-5-ylamino)ethyl)piperidine-1-onium (Example 84); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-((methylamino)methyl)thiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 85); Claims 6 / 8 pages 7 CN 122374293 A 8 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-((3-methylpyrazin-2-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 86);1-(2-((4-chloroisoxazo-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 87); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((3-phenyloxetane-3-yl)amino)ethyl)azacycloheptane-1-onium (Example 88); 6-(2-(isoxazo-3-ylamino)-2-oxoethyl)-6-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl) (Amino)-2-oxoethyl)-6-azaspiro[2.5]octane-6-onium (Example 89); 1-(2-(benzylamino)-2-oxoethyl)-4,4-bis(hydroxymethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 90); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-((1-(pyrimidin-2-yl)cyclopropyl)amino)ethyl)piperidine-1-onium (Example 91); 1-(2-((5-(methoxycarbonyl)-3-methylisoxazol-4-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 92); 1-(2-((3,4-dimethylisoxazol-5-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 93); 1-(2-((2-(hydroxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 94); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((6-methoxypyrazin-2-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 95); 1-(2-((2-((4-aminobutoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)azacycloheptane-1-onium (Example 96); 1-(2-((2-((4-aminobutoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(benzyl)(1r,4r)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)azonylheptane-1-onium (Example 97); (2-((1s,4s)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-methylpiperidin-1-onium-1-yl)acetyl)(4-methylisoxazo-3-yl)amide (Example 98); and (1r,4r)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidin-1-onium (Example 99); which are in zwitterionic form or pharmaceutically acceptable salt form. 10. Use of an intermediate compound selected from compounds (III), (V), (VII), and (X) for the preparation of a compound of formula (I) according to any one of claims 1 to 9, wherein R1, R2, R3, R5, L1, and A are as defined in claims 1 to 9, and X2 is a halogen, preferably chlorine or bromine. 11. A pharmaceutical composition comprising a compound of any one of claims 1 to 9 mixed with one or more pharmaceutically acceptable carriers or excipients. Claims 7 / 8 pages 8 CN 122374293 A 9 12. The pharmaceutical composition according to claim 11, formulated for inhalation administration. 13. A compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 11 or 12, used as a medicament. 14. A compound of formula (I) or a pharmaceutical composition for the use according to claim 13, for the prevention and / or treatment of diseases, disorders, or conditions related to sodium channel receptor mechanisms. 15. A compound or pharmaceutical composition of formula (I) for use according to claim 13 or 14, for the prevention and / or treatment of respiratory diseases selected from cough, subacute or chronic cough, refractory cough, intractable chronic cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm. 16. A compound or pharmaceutical composition of formula (I) for use according to claim 15, for the prevention and / or treatment of chronic cough. Claims 8 / 8 Page 9 CN 122374293 A 10 Heteroaryl ester derivatives as sodium channel inhibitors

[0001] Field of the Invention

[0002] The present invention generally relates to compounds that inhibit the activity of voltage-gated sodium channels (NaV) (hereinafter referred to as NaV inhibitors); the present invention relates to compounds that are heteroaryl ester derivatives, including pharmaceutically acceptable salts thereof, and methods for preparing such compounds and their therapeutic uses.

[0003] The compounds of this invention can be used, for example, to treat a variety of diseases associated with sodium channel receptor mechanisms, such as respiratory diseases.

[0004] Background of the Invention

[0005] Sensory afferent nerves transmit impulses caused by various stimuli (heat, cold, thermal, mechanical, and chemical) and also mediate the cough reflex.

[0006] Coughing is a defensive reflex designed to protect the airways from foreign objects and help clear debris from the lumen. Chronic cough is defined as a cough lasting more than 8 weeks. Hypersensitive cough states and atypical cough states are generally chronic, lasting more than three months, and can be seen in a variety of airway disease states, including asthma, chronic obstructive pulmonary disease (COPD), asthma-COPD overlap syndrome (ACOS), cough variant asthma, gastroesophageal reflux disease (GERD), idiopathic pulmonary fibrosis (IPF), and lung cancer. In addition, acute or chronic inappropriate cough reflexes may also occur after viral infections. Finally, chronic cough may be idiopathic in nature, with unknown etiology (Dicpinigaitis, PV et al, Pharmacol Rev, 2014, 66, 468-512; Patil, MJ et al, Pulmonary Pharmacology & Therapeutics, 2019, 56, 15-19).

[0007] Due to the poor efficacy of many cough suppression treatment strategies in clinical practice, there has been increasing interest in potential inhibitors of voltage-gated sodium channels (NaV) in recent years. These NaV channels are crucial for the conduction of action potentials generated by nerve endings in response to a variety of stimuli, including various inflammatory mediators. At least nine members of the NaV α subunit family are currently known. Based on phylogenetic relationships, the NaV family is divided into two subfamilies: NaV 1.x (excluding SCN6A) and NaV 2.x (SCN6A). The NaV 1.x subfamily can be further divided into two groups based on function: a subfamily sensitive to tetrodotoxin (TTX-sensitive or TTX-s) and a subfamily insensitive to tetrodotoxin (TTX-tolerant or TTX-r). Coughing is a complex physiological process triggered and regulated by two independent neural pathways that may interfere with each other: mechanosensitive Aδ fibers of the nodal ganglion of the vagus nerve and chemosensitive C fibers of the jugular vein of the vagus nerve. Among the many known NaV 1.x subunits, only a few are expressed in the airway jugular vein C fibers, including TTX-sensitive NaV 1.7 and TTX-tolerant NaV 1.8 and NaV 1.9 (Kollarik, M., et al, J Physiol, 2018, 596, 1419–1432).1.7 (PN1, SCN9A) is sensitive to tetrodotoxin blockade and is preferentially expressed in peripheral sympathetic and sensory neurons.

[0008] The cough reflex can be eliminated by effective sodium channel blockers, of which lidocaine is an example. Lidocaine blocks all sensory inputs (e.g., local anesthesia) and mechanoreceptors and motor neurons, resulting in numbness and paralysis. Lidocaine inhalers are often used to suppress the cough reflex before bronchoscopy. The use of inhaled lidocaine to relieve intractable cough was first reported in 1977 (C Fletcher et al, Br Med J, 1977 1(6077), 1645-8). Its efficacy was subsequently confirmed in a recent clinical trial for patients with refractory chronic cough (RCC) in the form of a throat spray (Abdulqawi, R. et al., The Journal of Allergy and Clinical Immunology: In Practice, 2021, 9, 4, 1640-1647). However, lidocaine has a short duration of action, poor selectivity, weak potency, and off-target effects (causing burns upon injection). Due to its poor risk / benefit ratio (blocking the cardiac NaV 1.5 channel), its use (as an antitussive) is limited.

[0009] Sensory neurons express a variety of channels (TRPV1, TRPA1, ASICS, P2X3, etc.), which have macropores. Upon activation, these channels allow charged molecules that normally cannot penetrate the neuronal membrane to permeate, unlike neutral molecules such as lidocaine, which can enter the NaV binding site in the channel pore and penetrate the lipid membrane surrounding the channel (Frazier et al, JPET, 2015; 171, 1.; Brenneis et al, J Neuroscience, 2013, 33(1):315-26).

[0010] In 1999, Nortran Pharmaceutical filed a patent application (WO99 / 63985) relating to a pharmaceutical composition with antitussive activity and a method for treating warm-blooded animals affected by cough or bronchoconstriction by administering an effective amount of the pharmaceutical composition of the invention. One of the exemplary active antitussives reported is a charged quaternary ammonium compound, namely N,N-bis(phenylcarbamoylmethyl)dimethylammonium chloride (also known as carcainium chloride).

[0011] Carcainium chloride was first disclosed by Astra in 1962 for the treatment of arrhythmias (US3255207). Carcainium chlorideThe antitussive effect of carcaine has been studied in various animal models: in a guinea pig model, carcaine chloride showed higher antitussive potency than lidocaine, with a slightly different mechanism of action (J.J. Adcock, British Journal of Pharmacology, 2003, 138, 407-416). In 2013, Verona Pharma filed a patent application (WO2013 / 03490) relating to a salt form of carcaine chloride with an anion of a pharmaceutically acceptable acid, for the treatment and / or suppression of cough, cough attacks, or cough-related events in patients. A preliminary study in patients with chronic cough and idiopathic interstitial pneumonia found the compound to be effective (Lavorini et al., Pulmonary Pharmacology & Therapeutics, 2016, 40, 91-94), but it was never marketed because it failed to reduce the frequency and severity of cough in a subsequent, larger study (Satia et al., Thorax, 2015;70 (Suppl 3): A1-A254).

[0012] Currently available cough medications often have limited efficacy. Cough can significantly impact a patient's quality of life, causing physiological (including fatigue, dyspnea, sleep disturbances, and incontinence), psychological (including anger, frustration, depression, and anxiety), and social consequences. Therefore, continued exploration of promising cough treatments and targets is crucial, as chronic cough remains an unmet medical need.

[0013] The prior art has not described or proposed ester derivative compounds of the present invention (I), which may represent solutions to the aforementioned unmet medical needs.

[0014] Summary of the Invention

[0015] In a first aspect, the present invention relates to compounds of formula (I)

[0016]

[0017] (I) Specification 2 / 129 pages 11 CN 122374293 A 2

[0018] It is in zwitterionic form or pharmaceutically acceptable salt form,

[0019] wherein at least one of Y and Z is S, and the other is CR4;

[0020] R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C10)heterocyclic alkyl, wherein the -(C3-C10)heterocyclic alkyl is optionally substituted by one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0021] R3 and R4 are independently H or selected from CN, -(C1-C6)alkyl and aryl, or, where Y is CR4, R3 and R4 are fused together.Together they form an aryl group;

[0022] R5 is selected from -(C1-C6)alkyl, -(C1-C6)alkyl-NR6R7, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-C(O)NR6R7, -(C3-C10)heterocyclic alkyl and -(C3-C7)cycloalkyl;

[0023] R6 and R7 are independently H or selected from -(C1-C6)alkyl and -(C1-C6)alkyl-aryl;

[0024] L1 is a bond or selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic alkylene- and -(C1-C6)cycloalkylene-; and

[0025] A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl, and -(C3-C10)heteroalkyl, wherein any such aryl, heteroaryl, -(C3-C10)cycloalkyl, or -(C3-C10)heteroalkyl is optionally substituted by one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7; provided that when L1 is a bond, any such aryl group is not substituted by -(C1-C6)alkyl.

[0026] In a second aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) mixed with one or more pharmaceutically acceptable carriers or excipients.

[0027] In a third aspect, the present invention relates to compounds of formula (I) used as pharmaceuticals.

[0028] In another aspect, the present invention relates to compounds of formula (I) for treating diseases, disorders, or conditions associated with voltage-gated sodium channels (NaV) dysregulation.

[0029] In another aspect, the present invention relates to compounds of formula (I) for preventing and / or treating respiratory diseases selected from cough, subacute or chronic cough, refractory cough, intractable chronic cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm.

[0030] Detailed Description of the Invention

[0031] Unless otherwise specified, the term “compound of formula (I)” includes stereoisomers, tautomers, pharmaceutically acceptable salts, zwitterionic forms, or solvates.

[0032] The term “stereoisomer” refers to isomers having the same structure but different atomic spatial arrangements. Enantiomers and diastereomers are examples of stereoisomers.

[0033] The term "enantiomer" refers to one of a pair of molecules that are mirror images of each other and cannot be superimposed.

[0034] The term "diastereomer" refers to a stereoisomer that is not a mirror image of another.

[0035] The term “racemic mixture” or “racemic mixture” refers to a composition consisting of two enantiomers in equimolar amounts, wherein the composition is not optically active.

[0036] The symbols “R” and “S” denote the configuration of the substituents around the chiral carbon atom and are intended to be used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied Chemistry, 68:2193-2222 (1996)).

[0037] The term “tautomer” refers to each of two or more isomers of a compound that coexist in equilibrium and can readily interconvert by migration of intramolecular atoms or groups.

[0038] The compound of formula (I) is a quaternary ammonium compound. The term “pharmaceutically acceptable salt” as used herein refers to the compound of formula (I) 3 / 129 page 12 CN 122374293 A 3, wherein the compound is provided in the form of an addition salt formed with any acid generally considered pharmaceutically acceptable. Therefore, suitable examples of the salt may include salts of inorganic or organic acid additions of the quaternary ammonium moiety, such as salts of hydrochloric acid, hydrobromic acid, iodate, formic acid, benzoic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, 2-naphthoic acid, tartaric acid, 1-hydroxy-2-naphthoic acid, naphthalene-2,7-disulfonic acid, and citric acid.

[0039] Alternatively, according to the invention, the compound of formula (I) may be provided in a “zwitterionic form,” also known as an internal salt or dipolar ion, which is a form in which both a positive and a negative charge are present.

[0040] The term “solvent” refers to a physical bond formed between the compound of the invention and one or more solvent molecules, whether organic or inorganic. This physical bond includes hydrogen bonds. In some cases, the solvate may be separated by crystallization, for example, when one or more solvent molecules are incorporated into the lattice of a crystalline solid. The solvate may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

[0041] The terms “halogen” or “halogen atom” or “halogenated” as used herein include fluorine, chlorine, bromine, and iodine atoms.

[0042] The term “-(Cx-Cy)alkyl”, where x and y are integers, refers to a straight-chain or branched alkyl group having x to y carbon atoms. Thus, for example, when x is 1 and y is 6, “-(C1-C6)alkyl” includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. When x is 1 and y is 4, the term “-(C1-C4)alkyl” includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.

[0043] The term “-(Cx-Cy)alkylene-”, where x and y are integers, refers to a (Cx-Cy)alkylene group having a total of two unsatisfied valence bonds.Cy)alkyl groups. Examples of such "-(Cx-Cy)alkylene-" groups may include, for example, dimethyl groups -CH2- and -CH(CH3)-.

[0044] The term "-(Cx-Cy)haloalkyl", where x and y are integers, refers to the "(Cx-Cy)alkyl" group as defined above, wherein one or more hydrogen atoms are replaced by one or more halogen atoms, which may be the same or different. Examples of the "-(Cx-Cy)haloalkyl" groups include "(C1-C6)haloalkyl" and "(C1-C4)haloalkyl". The "-(Cx-Cy)haloalkyl" group may include haloalkyl, polyhaloalkyl, and perhaloalkyl in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl.

[0045] The term “-(Cx-Cy)aminoalkyl”, where x and y are integers, refers to the “-(Cx-Cy)alkyl” group as defined above, wherein one or more hydrogen atoms are replaced by one or more amino groups, which may be the same or different. For example, examples of “-(Cx-Cy)aminoalkyl” include, for example, aminomethyl.

[0046] The term “-(Cx-Cy)hydroxyalkyl”, where x and y are integers, refers to the “-(Cx-Cy)alkyl” group as defined above, wherein one or more hydrogen atoms are replaced by one or more hydroxyl (OH) groups. Examples of “-(Cx-Cy)hydroxyalkyl” include hydroxymethyl.

[0047] The term “partially unsaturated” refers to a ring moiety comprising at least one double or triple bond. The term “partially unsaturated” is intended to cover rings having multiple unsaturated sites, but does not include aryl or heteroaryl moiety as defined herein.

[0048] The term “-(Cx-Cy)cycloalkyl,” where x and y are integers, refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group containing a specified number of cyclic carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0049] The term “-(Cx-Cy)cycloalkylene,” where x and y are integers, refers to a saturated or partially unsaturated (Cx-Cy) monocyclic or polycyclic alkyl group containing a specified number of cyclic carbon atoms, having a total of two unsatisfied valence bonds on the same carbon atom. For example, examples of “-(Cx-Cy)cycloalkylene” include “-(C1-C4)cycloalkylene” and “-(C1-C6)cycloalkylene,” such as cyclopropylene.

[0050] The term "(C3-C10) heterocyclic alkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic or polycyclic spirocyclic compound containing a specified number of ring carbon atoms, wherein at least one ring carbon atom is replaced by at least one heteroatom or heterogroup (e.g., N, NH, S, or O), or has an oxo (=O) substituent. The heterocyclic alkyl (i.e., heterocyclic group or group) may optionally have a ring-dependent...The carbon atom (i.e., a heteroatom or heterogroup that can be substituted) is further substituted by one or more specific groups. When more than one substituent is present, these substituents can be located at the same or adjacent positions on the ring; for example, "(C3-C10)heterocyclic alkyl" can be 1,1-, 1,2-, or 1,3-disubstituted. Substitution on the carbon atom includes spirocyclic disubstituted, wherein an additional spirocyclic fused 3- to 6-membered ring is formed. Such spirocyclic disubstituted is included in the meaning of "(C3-C10)heterocyclic alkyl" as a polycyclic spirocyclic group. Non-limiting examples of "(C3-C10)heterocyclic alkyl" are represented as pyrrolidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, dihydropyridinyl or tetrahydropyridinyl, oxeherabutyl, tetrahydropyranyl, isoindolyl, pyranyl, dihydrofuranyl or tetrahydrofuranyl, 7-azaspirononyl, and 7-azaspirooctyl.

[0051] The term “-(Cx-Cy)heterocyclic alkyl-”, where x and y are integers, refers to a saturated or partially unsaturated mono- or poly-(Cx-Cy)heterocyclic alkyl group containing a specified number of cyclic carbon atoms, wherein there are a total of two unsatisfied valence bonds on the same carbon atom. Examples include divalent oxetanes or oxetanes, such as: . Examples of “-(Cx-Cy)heterocyclic alkyl-” include “-(C1-C4)heterocyclic alkyl-” and “-(C1-C6)heterocyclic alkyl-”.

[0052] The group may be optionally substituted, where “optionally substituted” means substituted or unsubstituted. When the term “one or more” refers to any atom or group that is a substituent of a group in a compound of formula (I), it means that 1 to 3 (preferably 1 to 2, more preferably 1) of such substituents may replace the hydrogen atoms on these variables.

[0053] The term “aryl” refers to a monocyclic or bicyclic unsaturated or partially unsaturated carbocyclic system, wherein at least one ring is an aromatic ring. Examples of suitable aryl ring systems include, for example, phenyl, dihydro-1H-indenyl, and naphthyl.

[0054] The term “heteroaryl” refers to a monocyclic, bicyclic, or tricyclic system having 5 to 20 (preferably 5 to 15) ring atoms, wherein at least one ring is an aromatic ring and wherein at least one ring atom is a heteroatom (e.g., N, NH, S, or O). Examples of “heteroaryl” include thiophene, benzothiophene, pyrrole, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrazinyl, and triazinyl.

[0055] Bonds pointing to wavy or meandering lines (e.g., as used in the structural formulas herein) represent bonds that serve as the connection points between the part or substituent and the core or backbone structure.

[0056] The term "bond" used to define a substituent refers to a situation where the two functional groups to which the substituent is attached are directly connected to each other without any other atoms in between.

[0057] A dash ("-") not between two letters or symbols indicates the connection point of the substituent.

[0058] The terms “sodium channel receptor” or “voltage-gated sodium channel receptor” or “NaV receptor” used to refer to the inhibitory activity of the compounds of the present invention are intended to include members of the voltage-gated sodium channel (NaV) α subunit family expressed in the C fibers of the vagus nerve in the airway, namely NaV 1.7, NaV 1.8 and NaV 1.9.

[0059] The term “NaV inhibitor” refers to the compounds of the present invention as inhibitors of NaV receptors, particularly but not limited to inhibitors of NaV 1.7 receptors.

[0060] The term “IC50” refers to the half-maximal inhibitory concentration, used as an indicator of the efficacy of a substance in inhibiting a specific biological or biochemical function. Specification 5 / 129 pages 14 CN 122374293 A 5

[0061] The term “pIC50” refers to the negative logarithm of the IC50 value expressed as molar concentration.

[0062] When other basic amino or quaternary ammonium groups are present in the compounds of formula (I), pharmaceutically acceptable anions may be present, selected from chlorides, bromides, iodides, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, emipamoate, sine, and naphthalenedisulfonate. Similarly, when acidic groups such as COOH groups are present, corresponding pharmaceutically acceptable cations may be present, including alkali metal or alkaline earth metal ions, including sodium, potassium, calcium, etc.

[0063] As described above, the present invention relates to a series of compounds represented by formula (I), which, as described in detail below, have inhibitory activity against voltage-gated sodium channel receptors.

[0064] In the automated patch-clamp assay described in the Experimental Section, the inhibitory activity of the compound of formula (I) was tested on CHO cells stably expressing the human NaV 1.7 channel.

[0065] For some of the compounds of the present invention, pIC50 values ​​were calculated, demonstrating the intracellular inhibitory effect of the test compounds on the NaV 1.7 receptor (see Qian, Binbin et al, Current protocols in pharmacology, 2020, 89, 1).

[0066] Indeed, the compounds of formula (I) of the present invention can act as inhibitors of NaV 1.7 in a substantial and effective manner. In particular, as noted in the Experimental Section, the compounds of formula (I) of the present invention exhibit intracellular inhibition of NaV 1.7, as shown in Table 2.

[0067] The compounds of formula (I) are heteroaryl quaternary ammonium ester derivatives in salt or zwitterionic form, and exhibit particularly good inhibitory activity against NaV 1.7.

[0068] As indicated in the experimental section, the comparative compound section, especially Table 3, compares it with carcaine chloride (which is considered to be...In contrast to the comparative compound C1), the presence of an ester-substituted thiophene or benzothiophene ring in the compounds of the present invention unexpectedly and significantly increases the intracellular inhibitory activity against the NaV 1.7 receptor.

[0069] Furthermore, as noted in the same experimental section, the reported data indicate that, in contrast to the comparative compound C2, which is characterized by a different heteroaryl ring, the presence of an ester-substituted thiophene or benzothiophene ring in the compounds of the present invention unexpectedly and significantly determines a corresponding increase in inhibitory activity against the NaV receptor.

[0070] The pharmaceutically acceptable salt form or zwitterionic form of the compounds of formula (I), hereinafter also referred to as the compounds of the present invention, can be used as a medicament. Therefore, the present invention also provides compounds of formula (I) present in a pharmaceutically acceptable salt form or zwitterionic form for use as a medicament.

[0071] The compounds of formula (I) of the present invention are capable of acting as inhibitors of the NaV 1.7 receptor in a substantial and effective manner, which is particularly important to those skilled in the art in the search for compounds that can be used to treat respiratory diseases such as cough, asthma, IPF, and COPD, and especially chronic cough.

[0072] Therefore, when it comes to NaV receptors, compounds of formula (I) can be used to treat respiratory diseases such as cough, asthma, IPF, and COPD, and especially chronic cough.

[0073] It is understood that the compounds of the present invention according to Table 2 show their efficacy in inhibiting intracellular activity against NaV 1.7 receptors, expressed as pIC50 values, equal to or greater than 5, preferably between 5 and 5.5, more preferably equal to or greater than 5.5.

[0074] More advantageously, compounds represented by formula (I) are able to inhibit one or more voltage-gated ion channels when exposed or applied intracellularly, but have little or no inhibitory effect when applied extracellularly.

[0075] Compounds of formula (I) were also tested in an automated patch-clamp assay using a similar extracellular inhibition protocol, i.e., after exchanging the external solution with a solution containing the test compound: the experimental values ​​obtained were used to calculate pIC50 values ​​representing extracellular inhibition of NaV 1.7 receptors (6 / 129 pages, 15 CN 122374293 A 6).

[0076] As shown in the experimental section, the compounds of formula (I) of the present invention exhibit lower extracellular inhibition of NaV 1.7 than intracellular inhibition, as shown in Table 2.

[0077] Therefore, the compounds of the present invention, according to Table 2, show a difference between intracellular and extracellular potency in NaV 1.7 inhibition, defined as DELTA, which is equal to or greater than 0.5, preferably between 0.5 and 1, more preferably equal to or greater than 1.

[0078] This difference between intracellular and extracellular inhibition may result in higher safety of the compounds for sensory neurons.

[0079] The compounds of the present invention have also been tested in safety pharmacology studies, particularly in human Ether-a-go-go phases.In vitro assays of hERG channels. Safety pharmacology studies are non-clinical studies designed to test the safety of new drugs in humans from a pharmacological perspective. The Guideline on Safety Pharmacology Studies, designed to examine the safety of test substances in humans and predict their adverse reactions, has been established by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) between Europe, Japan, and the United States. According to this guideline, safety pharmacology studies must include testing for the arrhythmogenic effects of the test substance, particularly the presence of QT interval prolongation on an electrocardiogram. The QT interval is a measurement on an electrocardiogram used to assess certain electrophysiological characteristics of the heart; it approximates the time required for the ventricles to begin contraction and fully relax. To protect patients from ventricular tachycardia, torsades de pointes, and fatal arrhythmias caused by drug-induced QT interval prolongation, it is crucial to detect QT interval prolongation effects that may cause such serious adverse reactions during drug development.

[0080] To date, it is known that many drugs with QT interval prolongation effects inhibit delayed rectifier potassium channels in cardiomyocytes. hERG channels are considered to be the main constituent proteins of delayed rectifier potassium channels. Therefore, in the draft guidelines for non-clinical evaluation of the potential effects of human drugs on delayed ventricular repolarization (QT interval prolongation), an hERG channel ion channel detection method was adopted. Channel transfer cells are recommended for non-clinical studies.

[0081] In addition to having significant inhibitory activity against NaV receptors, the compound of formula (I) of the present invention has also undergone in vitro hERG channel inhibition assays, which showed low toxicity to hERG channels, thereby reducing the likelihood of adverse events being observed in clinical studies.

[0082] Therefore, in one aspect, the present invention relates to compounds of formula (I)

[0083]

[0084] (I)

[0085] which are zwitterionic or pharmaceutically acceptable salt forms,

[0086] wherein at least one of Y and Z is S, and the other is CR4;

[0087] R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C10)heterocyclic alkyl, wherein the -(C3-C10)heterocyclic alkyl is optionally substituted by one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl;

[0088] R3 and R4 are independently H or selected from C, -(C1-C6)alkyl and aryl, or, wherein Y is CR4, R3 and R4 are fused together to form an aryl, preferably phenyl;

[0089] R5 is selected from -(C1-C6)alkyl, -(C1-C6)alkyl-NR6R7, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-C(O)NR6R7, -(C3-C10)heterocyclic alkyl and -(C3-C7)cycloalkyl;

[0090] R6 and R7 are independently H or selected from -(C1-C6)alkyl and -(C1-C6)alkyl-aryl;

[0091] L1 is a bond or selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic alkylene- and -(C1-C6)cyclic alkylene-; and

[0092] A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl, and -(C3-C10)heteroalkyl, wherein any such aryl, heteroaryl, -(C3-C10)cycloalkyl, or -(C3-C10)heteroalkyl is optionally substituted by one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7; provided that when L1 is a bond, any such aryl group is not substituted by -(C1-C6)alkyl.

[0093] All listed groups of the variable portions Y, Z, R1, R2, R3, R4, R5, R6, R7, L1, and A in the compounds of the present invention should be considered as interchangeable, and in embodiments within the scope of the present invention, these groups can be combined with each other.

[0094] The 5-membered ring containing Y and Z is an aromatic ring, i.e., a thiophene ring, which is substituted with a COOR5 group.

[0095] In a preferred embodiment, Z is S and Y is CR4. In a more preferred embodiment, Z is S and Y is CH.

[0096] In another embodiment, Y is S and Z is CR4, wherein R4 is preferably hydrogen.

[0097] In one embodiment, R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C10)heterocyclic alkyl, wherein the -(C3-C10)heterocyclic alkyl is optionally substituted with one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl, and -(C1-C6)haloalkyl. In a preferred embodiment, R1 and R2 are independently selected from -(C1-C6)alkyl, -(C1-C6)alkyl-OR6, or fused together to form -(C3-C10)heterocyclic alkyl, wherein the -(C3-C10)heterocyclic alkyl is optionally substituted with one or more groups selected from -OR6, -(C1-C6)alkyl and -C(O)OR6.

[0098] In another preferred embodiment, R1 and R2 are independently -(C1-C6)alkyl. In a more preferred embodiment, R1 and R2 are independently -(C1-C4)alkyl. In an even more preferred embodiment, R1 and R2 are methyl. In another preferred embodiment, R1 and R2 are fused together to form -(C3-C10)heteroalkyl, wherein the -(C3-C10)heteroalkyl is optionally substituted by one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl. In a more preferred embodiment, R1 and R2 are fused together to form a -(C3-C10) heterocyclic alkyl group, wherein the -(C3-C10) heterocyclic alkyl group is optionally substituted with one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C4) alkyl, and -(C1-C4) haloalkyl. In a most preferred embodiment, R1 and R2 are fused together to form a piperidinyl or aziridine-heptyl ring, wherein the piperidinyl or aziridine-heptyl ring is optionally substituted with one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C4) alkyl, and -(C1-C4) haloalkyl.

[0099] In one embodiment, R3 and R4 are independently H or selected from CN, -(C1-C6) alkyl, and aryl, or, wherein Y is CR4, R3 and R4 are fused together to form an aryl group.

[0100] In a preferred embodiment, R3 and R4 are independently selected from H and -(C1-C6)alkyl, or, wherein Y is CR4, R3 and R4 are fused together to form an aryl group. In another embodiment, R3 and R4 are independently -(C1-C6)alkyl. In a preferred embodiment, R3 and R4 are independently -(C1-C4)alkyl. In another embodiment, R3 and R4 are hydrogen. In a more preferred embodiment, R3 and R4 are independently hydrogen or methyl, most preferably R3 is methyl and R4 is hydrogen. In another preferred embodiment, R3 and R4 are fused together to form an optionally substituted phenyl ring, which is fused with a five-membered ring to form an optionally substituted benzothiophene ring system.

[0101] In one embodiment, R5 is selected from -(C1-C6)alkyl, -(C1-C6)alkyl-NR6R7, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-C(O)NR6R7, -(C3-C10)heterocyclic alkyl, and -(C3-C7)cycloalkyl. In a preferred embodiment,R5 is selected from -(C1-C4)alkyl, -(C1-C4)alkyl-NR6R7, -(C1-C4)alkyl-OR6, and -(C1-C4)alkyl-C(O)NR6R7. In another embodiment, R5 is -(C1-C6)alkyl-NR6R7. In a preferred embodiment, R5 is -(C1-C4)alkyl-NR6R7. In another embodiment, R5 is -(C1-C6)alkyl. In a preferred embodiment, R5 is -(C1-C4)alkyl. In a more preferred embodiment, R5 is methyl, ethyl, isopropyl, or tert-butyl. In another embodiment, R5 is -(C3-C7)cycloalkyl. In a preferred embodiment, R5 is cyclopropyl. In another embodiment, R5 is -(C3-C10)heterocyclic alkyl. In another preferred embodiment, R5 is selected from piperidine and oxetane. In another preferred embodiment, R5 is selected from -(C1-C6)alkyl and -(C3-C6)cycloalkyl. In one embodiment, R6 and R7 are independently H or selected from -(C1-C6)alkyl and -(C1-C6)alkyl-aryl. In a preferred embodiment, R6 and R7 are independently H or -(C1-C4)alkyl. In another embodiment, R6 and R7 are -(C1-C4)alkyl. In a preferred embodiment, R6 and R7 are independently H or methyl. In a preferred embodiment, R6 and R7 are H. In a more preferred embodiment, R6 and R7 are methyl. In another embodiment, R6 and R7 are independently H or -(C1-C6)alkyl-aryl. In a preferred embodiment, R6 and R7 are independently -(C1-C4)alkyl-aryl. In a more preferred embodiment, R6 and R7 are independently H or benzyl.

[0102] In one embodiment, L1 is a bond or selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic alkylene-, and -(C1-C6)cycloalkylene-. In a preferred embodiment, L1 is a bond or selected from -(C1-C4)alkylene-, -(C1-C4)heterocyclic alkylene-, and -(C1-C4)cycloalkylene-. In a more preferred embodiment, L1 is a bond. In another more preferred embodiment, L1 is selected from methylene, cyclopropylene, oxetane, and -CH(CH3)-.

[0103] In one embodiment, A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl, and -(C3-C10)heterocycloalkyl, wherein any such aryl, heteroaryl, -(C3-C10)cycloalkyl, or -(C3-C10)heterocycloalkyl is optionally substituted by one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, and -(C1-C6)haloalkyl.The aryl group is selected from aryl and heteroaryl groups, wherein any such aryl and heteroaryl group is optionally substituted by one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7; wherein any such aryl group is not substituted by -(C1-C6)alkyl when L1 is a bond. In a preferred embodiment, A is a heteroaryl group, optionally substituted with one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-NR6R7, and -(C1-C6)alkyl-C(O)NR6R7. In another preferred embodiment, A is a heteroaryl group selected from optionally substituted thiophene, benzothiophene, pyrrole, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and triazinyl. In another preferred embodiment, A is an aryl group, optionally substituted with one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7. In another preferred embodiment, A is an aryl group, optionally substituted with one or more groups selected from -OR6, -C(O)OR6, and -C(O)NR6R7. In a more preferred embodiment, A is a phenyl group, optionally substituted with one or more groups selected from -OR6, -C(O)OR6, and -C(O)NR6R7.

[0104] For each variable part Y, Z, R1, R2, R3, R4, R5, R6, R7, L1 and A in the compounds of the present invention, all the preferred groups listed above can be combined with each other in embodiments of the present invention, and such embodiments are included within the scope of the present invention on pages 9 / 129 of this specification, CN 122374293 A 9.

[0105] Preferred halogens, either themselves or in -(Cx-Cy) haloalkyl substituents, are fluorine and bromine, wherein fluorine is more preferred.

[0106] In another preferred embodiment, the present invention relates to compounds of formula (I) as defined above

[0107]

[0108] (I)

[0109] wherein

[0110] Z, Y, R1,R2, R3, R4, R5, R6 and R7 are as defined above;

[0111] L1 is selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic- and -(C1-C6)cycloalkylene-; and

[0112] A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl and -(C3-C10)heterocyclic-, wherein any such aryl, heteroaryl, -(C3-C10)cycloalkyl or -(C3-C10)heterocyclic- is optionally substituted by one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7.

[0113] In a preferred embodiment, L1 is selected from -(C1-C4)alkylene-, -(C1-C4)heterocyclic-, and -(C1-C4)cycloalkylene-. In an even more preferred embodiment, L1 is selected from methylene, cyclopropylene, oxetane, and -CH(CH3)-.

[0114] In another preferred embodiment, A is a ring selected from aryl and heteroaryl groups, wherein any such aryl and heteroaryl groups are optionally substituted by one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7. In a more preferred embodiment, A is a heteroaryl group, wherein any such heteroaryl group is optionally substituted with one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7. In another more preferred embodiment, A is an aryl group, wherein any such aryl group is optionally substituted with one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, and -(C1-C6)alkyl-NR6R7. In an even more preferred embodiment, A is an aryl group, wherein any such aryl group is optionally substituted with one or more groups selected from -OR6, -C(O)OR6, and -C(O)NR6R7.

[0115] In another embodiment, the present invention relates to a compound of formula (I) wherein L1 is a bond, which is represented by formula (Ia): Specification 10 / 129 pages 19 CN 122374293 A 20

[0116]

[0117] (Ia)

[0118] It is in zwitterionic form or pharmaceutically acceptable salt form,

[0119] Wherein

[0120] Z, Y, R1, R2, R3, R4, R5, R6 and R7 are as defined above; and

[0121] A is a ring selected from aryl, heteroaryl, -(C3-C10)cycloalkyl and -(C3-C10)heterocycloalkyl, wherein any such heteroaryl, -(C3-C10)cycloalkyl or -(C3-C10)heterocycloalkyl is optionally substituted by one or more groups selected from halogen, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and - (C1-C6)alkyl-NR6R7; and wherein any such aryl group is optionally substituted with one or more groups selected from halogens, -C(O)OR6, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7.

[0122] In a preferred embodiment, A is a heteroaryl group, which is optionally substituted with one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7. In a more preferred embodiment, A is a heteroaryl group, optionally substituted with one or more groups selected from halogens, -C(O)OR6, -C(O)NR6R7, -(C1-C4)alkyl, and -(C1-C4)alkyl-OR6. In an even more preferred embodiment, A is a heteroaryl group selected from optionally substituted thiophene, pyrrole, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and triazinyl groups, and optionally substituted with one or more methyl, ethyl, isopropyl, or tert-butyl groups.

[0123] In another preferred embodiment, the present invention relates to a compound of formula (I) as defined above,

[0124]

[0125] (I)

[0126] wherein

[0127] at least one of Y and Z is S, and the other is CR4;

[0128] R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C4)alkyl-OR6, or fused together to form -(C3-C10)heterocyclic alkyl, wherein the -(C3-C10)heterocyclic alkyl is optionally substituted by one or more groups selected from halogens, -OR6, -(C1-C6)alkyl and -C(O)OR6-;

[0129] R3 and R4 are independently H or -(C1-C6)alkyl, or, wherein Y is CR4, R3 and R4 fused together to form an aryl;

[0130] R5 is selected from -(C1-C6)alkyl and -(C3-C6)cycloalkyl;

[0131] R6 and R7 are independently H or selected from -(C1-C4)alkyl and -(C1-C4)alkyl-aryl;

[0132] L1 is a bond or selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic- and -(C1-C6)cycloalkylene-; and

[0133] A is a ring selected from aryl, heteroaryl and -(C3-C10)cycloalkyl, wherein any such aryl, heteroaryl or -(C3-C10)cycloalkyl is optionally substituted by one or more groups selected from -OR6, -C(O)OR6, -C(O). NR6R7, -(C1-C6)alkyl and -(C1-C6)haloalkyl; provided that when L1 is a bond, any such aryl group is not substituted with -(C1-C6)alkyl.

[0134] In another preferred embodiment, the invention relates to compounds of formula (I) as defined above, wherein Z is S and Y is CH or Z is CH and Y is S; R3 is H or methyl, and R1, R2, R4, R5, R6, R7, L1 and A are as defined above.

[0135] In a preferred embodiment, the invention relates to at least one of the compounds listed in Table 1 below, in zwitterionic form or in a pharmaceutically acceptable salt form thereof.

[0136] Table 1 - List of Preferred Compounds Specification 12 / 129 pages 21 CN 122374293 A 2

[0137] Specification 13 / 129 pages 22 CN 122374293 A 3

[0138] Specification 14 / 129 pages 23 CN 122374293 A 4

[0139] Specification 15 / 129 pages 24 CN 122374293 A 5

[0140] Specification 16 / 129 pages 25 CN 122374293 A 6

[0141] Specification 17 / 129 pages 26 CN 122374293 A 7

[0142] Specification 18 / 129 pages 27 CN 122374293 A 8

[0143] Specification 19 / 129 pages 28 CN 122374293 A 9

[0144] Specification 20 / 129 pages 29 CN 122374293 A 30

[0145] Specification 21 / 129 pages 30 CN 122374293 A 1

[0146] Specification 22 / 129 pages 31 CN 122374293 A 2

[0147] Specification 23 / 129 pages 32 CN 122374293 A 3

[0148] Specification24 / 129 Page 33 CN 122374293 A 4

[0149] Specification 25 / 129 Page 34 CN 122374293 A 5

[0150] Specification 26 / 129 Page 35 CN 122374293 A 6

[0151] Specification 27 / 129 Page 36 CN 122374293 A 7

[0152] Specification 28 / 129 Page 37 CN 122374293 A 8

[0153] Specification 29 / 129 Page 38 CN 122374293 A 9

[0154]

[0155] It should be understood that all single enantiomers, diastereomers and mixtures thereof of the compounds of formula (I) of the present invention, regardless of proportion, are included within the scope of the present invention.

[0156] In a preferred embodiment, the compounds of formula (I) of the present invention are referred to as NaV inhibitors. In this respect, it has been found that the inhibitory pharmacological efficacy (expressed as pIC50) of the compound of formula (I) of the present invention against the NaV 1.7 receptor is equal to or greater than 5.

[0157] Preferably, the pIC50 of the compound of the present invention against NaV 1.7 is 5 to 5.5. More preferably, the pIC50 of the compound of the present invention against NaV 1.7 is equal to or greater than 5.5. Even more preferably, the pIC50 of the compound of the present invention against NaV 1.7 is 5.5 to 6. Specification 30 / 129 pages 39 CN 122374293 A 40

[0158] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) mixed with at least one or more pharmaceutically acceptable carriers and / or excipients, said compound being in zwitterionic form or pharmaceutically acceptable salt form.

[0159] As used herein, “effective amount” in the context of a zwitterionic or pharmaceutically acceptable salt form of a compound of formula (I) or other pharmaceutically active agents means an amount of compound sufficient to treat a patient’s condition but low enough to avoid serious side effects, and such amount can still be routinely determined by those skilled in the art.

[0160] Compounds of formula (I) may be administered as a single dose or according to a dosing regimen, i.e., multiple doses at different time intervals over a given period of time. Typical daily doses may vary depending on the chosen route of administration.

[0161] In one embodiment, the present invention relates to pharmaceutical compositions of compounds of formula (I) mixed with one or more pharmaceutically acceptable carriers or excipients (e.g., those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., NY, USA).

[0162] In therapeutic applications, compounds of formula (I) may be administered via any convenient, suitable, or effective route. The route of administration of the compounds of the present invention and their pharmaceutical compositions may be determined according to the patient's needs, for example, oral, nasal, parenteral (subcutaneous, intravenous, intramuscular, intrasternal, and infusion), and inhalation administration.

[0163] Preferably, the compounds of the present invention are administered orally or by inhalation.

[0164] In a more preferred embodiment, the compounds of the present invention or their pharmaceutical compositions are administered by inhalation.

[0165] In another preferred embodiment, the compounds of the present invention or their pharmaceutical compositions are administered orally.

[0166] In a preferred embodiment, the pharmaceutical composition comprising a compound of formula (I) in zwitterionic form or a pharmaceutically acceptable salt form is a solid oral dosage form, such as tablets, gel capsules, capsules, pouches, granules, lozenges, and bulk powders.

[0167] The compounds of the present invention can be used alone or in combination with a variety of pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starch) and known excipients (including suspending agents, solubilizers, buffers, binders, disintegrants, preservatives, colorants, flavorings, lubricants, etc.).

[0168] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is a liquid oral dosage form, such as an aqueous and non-aqueous solution, an emulsion, a suspension, or a syrup. The liquid dosage form may also contain a suitable known inert diluent (e.g., water) and suitable known excipients (e.g., preservatives, wetting agents, sweeteners, flavorings), as well as agents for emulsifying and / or suspending the compounds of the present invention.

[0169] In another embodiment, the pharmaceutical composition comprising the compound of formula (I) is an inhalation formulation, such as an inhaled powder, a metered-dose aerosol containing a propellant, or an inhalation formulation without a propellant. The inhalation formulation can be administered via a suitable inhalation device, such as a dry powder inhaler, a pressurized metered-dose inhaler, or a nebulizer.

[0170] In another embodiment, the invention also relates to a device comprising a pharmaceutical composition of a compound according to formula (I) of the invention, the compound being in a zwitterionic form or a pharmaceutically acceptable salt form, obtained according to the invention as described above, the device being a single-dose or multi-dose dry powder inhaler or a metered-dose inhaler.

[0171] If administered in dry powder form, single-dose or multi-dose inhalers known in the art can be used. In this case, the powder can be filled in capsules, cartridges, blister packs, or reservoirs made of gelatin, plastic, or other materials.

[0172] A diluent or carrier (e.g., lactose or any other additive suitable for enhancing the inhalable portion) that is chemically inert to the compounds of the invention can be added to the powdered compounds of the invention.

[0173] Inhalation aerosols containing propellant gases (e.g., hydrofluorocarbons) can contain compounds of the invention, these compounds...The compound may be present in solution or dispersion form. Propellant-driven formulations may also contain other components, such as solubilizers, stabilizers, and optional excipients.

[0174] Propellant-free inhalation formulations containing the compounds of the present invention may be in the form of aqueous solutions, alcoholic solutions or aqueous-alcoholic solutions or suspensions, and may be delivered by jet nebulizers or ultrasonic nebulizers or soft fog nebulizers known in the art.

[0175] The compounds of the present invention may be used alone as active ingredients or in combination with other pharmaceutical active ingredients.

[0176] The dosage of the compounds of the present invention depends on a variety of factors, including the specific disease to be treated, the severity of symptoms, the route of administration, etc.

[0177] In another aspect, the present invention relates to the use of compounds of formula (I) in the preparation of pharmaceuticals. In another aspect, the present invention relates to the use of compounds of formula (I) as pharmaceuticals.

[0178] Therefore, the present invention relates to a compound of formula (I) for the preparation of a medicament, preferably for the treatment of diseases associated with voltage-gated sodium channel (NaV) receptor mechanisms.

[0179] In another embodiment, the present invention relates to a compound of formula (I) for the prevention and / or treatment of diseases, disorders, or conditions associated with voltage-gated sodium channel (NaV) dysregulation.

[0180] In one aspect, the present invention also relates to a method for the prevention and / or treatment of diseases associated with NaV receptor mechanisms, the method comprising administering a therapeutically effective amount of a compound of formula (I) to a patient requiring such treatment.

[0181] Preferably, the compounds of the present invention can be used for the treatment and / or prevention of respiratory diseases.

[0182] In a preferred embodiment, the present invention provides a method for the prevention and / or treatment of respiratory diseases, the method comprising administering a compound of formula (I).

[0183] In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients for the prevention and / or treatment of respiratory diseases.

[0184] In another embodiment, the present invention provides a method for preventing and / or treating respiratory diseases, the method comprising administering a pharmaceutical composition comprising a compound of formula (I).

[0185] In another aspect, the above-mentioned respiratory diseases are selected from cough, subacute or chronic cough, refractory cough, idiopathic chronic cough, persistent chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD, and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm.

[0186] In one embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for treating and / or preventing cough, subacute or chronic cough, refractory cough, idiopathic chronic cough,Intractable chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD, and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm.

[0187] In another embodiment, the present invention relates to a compound or pharmaceutical composition of formula (I) for the prevention and / or treatment of respiratory diseases, wherein the respiratory disease is selected from: cough, subacute or chronic cough, refractory cough, idiopathic chronic cough, intractable chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD, and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm.

[0188] In another embodiment, the present invention relates to a method for treating and / or preventing respiratory diseases selected from cough, subacute or chronic cough, refractory cough, idiopathic chronic cough, intractable chronic cough, post-viral cough, iatrogenic cough, asthma, IPF, COPD, and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

[0189] In a preferred embodiment, the above-mentioned respiratory disease is chronic cough. Specification 32 / 129 pages 41 CN 122374293 A 2

[0190] In another preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutical composition thereof for the prevention and / or treatment of chronic cough.

[0191] In another preferred embodiment, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof for the preparation of a medicament for the treatment and / or prevention of chronic cough.

[0192] In another preferred embodiment, the present invention relates to a method for treating and / or preventing chronic cough, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and / or excipients.

[0193] Any suitable route of administration may be used to provide an effective dose of the compound of formula (I) to mammals, particularly humans.

[0194] The preventive or therapeutic dose of the compound of formula (I) will, of course, vary depending on the severity of the disease to be treated and the route of administration, and generally needs to be determined through clinical trials in accordance with the requirements of the pharmaceutical field. Furthermore, the dose may also vary depending on the patient's age, weight, and individual response.

[0195] All preferred groups or embodiments described above for the compound of formula (I) may be combined with each other and may be adapted accordingly.

[0196] The compounds of the present invention can be prepared by a variety of methods of organic synthesis known to those skilled in the art. It should be understood that the functional groups on the molecule should be consistent with the proposed transformation. Sometimes, in order to obtain the compounds required by the present invention, it may be necessary to...The order of the synthetic steps needs to be adjusted. Although the optimal reaction conditions may vary depending on the reactants or solvents used, those skilled in the art can easily determine these conditions using conventional optimization methods. Therefore, the methods described below should not be considered as a limitation on the range of synthetic methods that can be used to prepare the compounds of the present invention. In some cases, according to general principles of chemistry (Protective group in organic syntheses, 3rd ed. TW Greene, P. G. M. Wuts), a generally known protecting group (PG) may be used to mask or protect the sensitive or active moiety when necessary.

[0197] Compounds of formula (I), including all the compounds listed above, can generally be prepared according to the methods outlined in Schemes 1 to 4 below, wherein at least one non-limiting synthetic route is provided for the preparation of exemplary compounds (i.e., examples).

[0198] Scheme 1

[0199]

[0200] In one embodiment of the invention, the intermediate compound for preparing the compounds of the present invention may be prepared according to Scheme 33 / 129, page 42, CN 122374293 A 3 1.

[0201] Compound (III) may be prepared from compound (II), and compound (VII) may be prepared from compound (IV). Compound (III) may be prepared from compound (II) by acylation with a suitable haloacetyl halide (IX), wherein X1 and X2 are halogens, preferably and independently chlorine or bromine.

[0202] Similarly, compound (V) may be prepared from compound (IV) by acylation with a suitable haloacetyl halide (IX), wherein X1 and X2 are halogens, preferably and independently chlorine or bromine. Compound (VII) may be prepared from compound (V) by alkylation with a suitable amine NHR1R2 (VI). Alternatively, compound (VII) may be prepared directly from compound (IV) by acylation with a suitable amino acid (VIII) using a coupling agent such as TCFH or the like.

[0203] Scheme 2

[0204]

[0205] According to Scheme 2, the intermediate compound (X) can be prepared from compound (II) or compound (III). Compound (X) can be prepared from compound (III) by alkylation reaction with a suitable amine NHR1R2 (VI). Alternatively, compound (X) can be prepared from compound (II) by acylation reaction with a suitable amino acid (VIII) using a coupling agent such as TCFH or the like.

[0206] Scheme 3 Specification 34 / 129 pages 43 CN 122374293 A 4

[0207]

[0208] In one embodiment of the invention, according to Scheme 3, compound (Xa) (wherein R5 is not methyl) can be prepared from a compoundCompound (Xb) is prepared as described in Scheme 2 for compound (X) (where R5 is methyl). Compound (XI) can be prepared from compound (Xb) by hydrolysis of a methyl ester in the presence of a base (e.g., NaOH or KOH) or an acid (e.g., HCl or H2SO4). Compound (XII) can be prepared from compound (XI) by a cyclization reaction mediated by a reagent such as TCFH or the like. Then, compound (Xa) can be prepared from compound (XII) by a ring-opening reaction in the presence of a suitable alcohol R5-OH (XIII).

[0209] Scheme 4

[0210]

[0211] According to Scheme 4, the compound of formula (I) of the present invention can be prepared by coupling of compounds (III) and (VII) or compounds (V) and (X), respectively, wherein compound (X) can be a compound of formula (Xa) or (Xb).

[0212] Compound (I) can be prepared by a nitrogen quaternization reaction (Menshutkin reaction) of compound (III) and compound (VII). Alternatively, the Menshutkin reaction can also be used with compound (V) and compound (X) to obtain compound (I).

[0213] Therefore, the present invention provides intermediate compounds (III), (V), (VII), (VIII), (X), (XI) and (XII) as described above, and their use in the preparation of compound (I).

[0214] In another aspect, the present invention provides the use of intermediate compounds selected from those defined above, particularly those in scheme 4, specifically (III), (V), (VII) and (X) in the specification 35 / 129 pages 44 CN 122374293 A 5, for the preparation of compound (I) as defined above.

[0215] When compounds of formula (I) are separated from the reaction mixture by precipitation and then ground or crystallized, they are typically obtained in salt form with an anion of chloride or bromide, depending on the meaning of X2 in the alkylating agent (i.e., the compound (III) or (V) used to form the quaternary ammonium salt) (see Scheme 4). Compounds of formula (I) in salt form can be obtained in zwitterionic form by subsequent treatment under basic conditions, for example by purification on an amino-functionalized silica gel chromatography. Compounds of formula (I) in zwitterionic form can be treated with an acid (such as hydrochloric acid, etc.) to obtain the corresponding salt form of compound of formula (I).

[0216] Exemplary preparation procedures are given in the Experimental section below.

[0217] Preparation of Intermediates and Examples

[0218] The chemical names of the compounds were generated by the "Structure-Name" tool of the PerkinElmer ChemDraw® Professional application (v. 20.0.0.41.) or by common chemical names. Their synthesis methods are not described in the Experimental section.All reagents used in this method are either commercially available, or are known compounds, or can be formed from known compounds by known methods by those skilled in the art.

[0219] In the following methods, some starting materials will be indicated by “intermediate” or “example” numbers, and the step numbers will be noted. This is provided only to assist chemists skilled in the art.

[0220] When “similar” or “similar” methods are mentioned, those skilled in the art should understand that such methods may involve some minor differences, such as reaction temperature, reagent / solvent volume, reaction time, post-treatment conditions, or chromatographic purification conditions. Unless otherwise stated, all final compounds were obtained in pharmaceutically acceptable salt form.

[0221] All intermediates and examples reported have been analyzed and characterized by LC-MS and / or 1H-NMR as described herein. Optimal proton frequencies and solvent conditions may vary and can be easily determined by those skilled in the art using conventional optimization methods.

[0222] Abbreviations

[0223] ACN = Acetonitrile; AMU = Atomic mass unit; CDCl3 = Deuterated chloroform; CyHex = Cyclohexane; DCM = Dichloromethane; DIPEA = Diisopropylethylamine; DMF = Dimethylformamide; Diasteresome excess = d.e.; DMSO = Dimethyl sulfoxide; DMSO-d6 = Deuterated dimethyl sulfoxide; EGTA = Ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid; Et2O = Diethyl ether; EtOAc = Ethyl acetate; eq. = Equivalent; FCC = Fast column chromatography; h = Hour; HATU = 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HEPES = N-2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid; HCOOH = formic acid; HPLC = High performance liquid chromatography; MeOH = methanol; min = minutes; NMR = Nuclear magnetic resonance; RT / rt = room temperature; s.s. = saturated solution; tR = retention time; TCFH = chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; T3P = (2s,4s,6s)-2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphine-2,4,6-trioxide; LC-MS = Liquid chromatography / mass spectrometry; v / v = volume / volume; w / w = weight / weight; XPhos Pd G3 = (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate; NMDG =N-methyl-D-glucosamine.

[0224] Analytical methods

[0225] NMR characterization:

[0226] 1H-NMR spectra were performed on a 400 Agilent INOVA, 500 Agilent VNMRS, or 600 Agilent INOVA spectrometer (operated at 400, 500, or 600 MHz (proton frequency)) or a Bruker Avance III 400 or Avance III HD 600 spectrometer.

[0227] Chemical shifts are expressed as δ values ​​in ppm, with tetramethylsilane (TMS) as an internal standard. Coupling constants (J values) are expressed in Hz, and multiplicity is reported using the following abbreviations (s = singlet, d = doublet, t = triplet, quin = quintet, m = multiplet, br = broad peak).

[0228] Information on the zwitterionic or salt forms of the compound of formula (I) was obtained by 1H-NMR spectroscopy: the zwitterionic form typically shows a missing amide NH signal. HBr or HCl salts typically show all amide NH signals. Formate (i.e., formate salt) was detected and quantified by the 1H-NMR signal of formic acid.

[0229] LC-MS:

[0230] LC-MS can be recorded under the following conditions: diode array (DAD) chromatograms, mass spectrometry chromatograms, and mass spectra can be acquired on a Waters LC / PDA / MS Acquity™ system coupled to a Micromass ZQ™ or Waters SQD single quadrupole mass spectrometer, operated in positive and / or negative ion electrospray ES ionization mode.

[0231] LC / UV / MS characterization:

[0232] The LC / MS retention time (tR) estimate is affected by an experimental error of ±0.5 min.

[0233] LC-MS Method 1: Column: Acquity CSH C18 2.1 x 50 mm 1.7 μm, column temperature: 40℃; mobile phase solvent A: milliQ water + 0.1% HCOOH, mobile phase solvent B: ACN + 0.1% HCOOH. Flow rate: 1 mL / min.

[0234] Gradient table: t=0 min 97% A 3% B, t=1.5 min 0.1% A 99.9% B, t=1.9 min 0.1% A 99.9% B, and t=2 min 97% A 3% B. UV detection range: 210–350 nm, and ES+ / ES- range: 100–1000 AMU.

[0235] LC-MS Method 2: Chromatographic column: Kinetex EVO C18 2.1 x 50 mm 1.7 μm, column temperature: 40 °C; mobile phase: solubleAgent A is a 10 mM NH4HCO3 aqueous solution, with pH adjusted to 10 using ammonia. Mobile phase solvent B is ACN. The flow rate is 1 mL / min. The gradient table is as follows: t=0 min 97%A 3%B, t=1.5 min 0.1%A 99.9%B, t=1.9 min 0.1%A 99.9%B, and t=2 min 97%A 3%B. The UV detection range is 210–350 nm, and the ES+ / ES- range is 100–1200 AMU.

[0236] LC-MS Method 3: The chromatographic column is an Acquity CSH C18 2.1 x 50 mm 1.7 μm column, with a column temperature of 40 °C; mobile phase solvent A is milliQ water + 0.1% HCOOH, and mobile phase solvent B is ACN + 0.1% HCOOH. The flow rate is 1 mL / min. The gradient table is as follows: t=0 min 97%A 3%B, t=3.5 min 0.1%A 99.9%B, t=3.9 min 0.1%A 99.9%B and t=4.0 min 97%A 3%B. The UV detection range is 210-350 nm, and the ES+ / ES- range is 100 to 1000 AMU.

[0237] Purification Method

[0238] Some compounds were purified by semi-preparative HPLC (HPLC semi-preparative method) using a Waters MDAP instrument equipped with mass spectrometry detection (MS: ZQ2000) and DAD detection 220, and a CSH C18 (30 x 100 mm, 5 μm) and a 1 mL injection loop. The ACN gradient in H2O + 0.1% HCOOH (flow rate = 40.00 mL / min) was used as the mobile phase: gradient conditions are detailed in the respective examples. Other compounds were purified by FCC using Biotage® columns, with conditions detailed in the examples. The Biotage® columns used herein and their abbreviations used in the synthesis steps are described below:

[0239] Sfär silica: Biotage® Sfär silica D Duo 60 μM

[0240] Sfär amino: Biotage® Sfär KP-amino D Duo 50 μM

[0241] Sfär C18: Biotage® Sfär C18 D Duo 100 Å 30 μM

[0242] The separation of some diastereomer mixtures was achieved by semi-preparative chiral HPLC using the following method.

[0243] Chiral HPLC Method 1: Column: Chiralcel OD-H (25 x 2.0 cm), 5 μL mobile phase: n-hexane / (ethanol + 0.1% isopropylamine) 60 / 40% v / v. Flow rate (mL / min)17 mL / min. DAD detection 220 nm. Injection loop 1000 μL.

[0244] Chiral HPLC method 2: Column Chiralcel OD-H (25 x 3.0 cm), 5 μL. Mobile phase n-hexane / (ethanol / methanol 1 / 1 + 0.1% isopropylamine) 75 / 25% v / v. Flow rate (mL / min) 40 mL / min. DAD detection 220 nm. Injection loop 500 μL.

[0245] General Synthesis Procedure Instructions 37 / 129 Page 46 CN 122374293 A 7

[0246] Intermediate 1: Methyl 3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2-carboxylate

[0247]

[0248] A solution of methyl 3-amino-4-methylthiophene-2-carboxylate (500 mg, 2.92 mmol), N,N-dimethyl-4-pyridinium chloride (570 mg, 4.67 mmol), ditert-butyl dicarbonate (1.91 g, 8.76 mmol) and TEA (0.85 mL, 6.13 mmol) in DCM (12 mL) was stirred overnight at RT. The reaction mixture was diluted with DCM, washed with 0.1 M HCl, and the separated organic layer was washed with water and brine, dried by a phase separator, and concentrated under high vacuum. The crude product was purified by Sfär silica gel FCC (CyHex 100% to CyHex / EtOAc 9:1) to give the title compound (intermediate 1, 720 mg, 1.94 mmol, 66% yield) as a white oil.

[0249] LC-MS method 1: tR = 1.23 min, m / z = 394.1 [M+Na]+

[0250] Intermediate 2: 3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2-carboxylic acid

[0251]

[0252] The solution of intermediate 1 (700 mg, 1.88 mmol) in MeOH (25 mL) was treated with an aqueous sodium hydroxide solution (2.19 mL, 1.31 mmol), and the reaction mixture was heated to 50 °C and stirred vigorously overnight. The mixture was diluted with water and the MeOH was evaporated under reduced pressure. The aqueous layer was washed with EtOAc and then acidified with sulfuric acid (10% v / v) to pH = 3. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried by a phase separator, and concentrated under vacuum to give the title compound (intermediate 2, 510 mg, 1.427 mmol, 76% yield) as an off-white solid, which was used in the next step without further purification.

[0253] LC-MS Method 1: tR = 1.09 min, m / z = 356.3 [M-H]-

[0254] Intermediate 3:3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2-carboxylic acid isopropyl ester specification 38 / 129 pages 47 CN 122374293 A 8

[0255]

[0256] The solution of intermediate 2 (180 mg, 0.50 mmol) in acetone (5 mL) was treated with potassium carbonate (83 mg, 0.60 mmol). 2-Iodopropane (94 mg, 0.55 mmol) was added at RT, and the mixture was stirred at 70 °C for 30 h. The reaction mixture was cooled to RT and concentrated under vacuum. The residue was dissolved with EtOAc and washed with water. The aqueous layer was separated and extracted with EtOAc, the organic layer was washed with brine, dried by a phase separator, and concentrated under high vacuum to give the title compound (intermediate 3, 202 mg, 0.506 mmol, crude product) as a yellow oil, which was used in the next step without further purification.

[0257] LC-MS Method 1: tR = 1.38 min, m / z = 422.4 [M+Na]+

[0258] Intermediate 4: (3-(bis(tert-butoxycarbonyl)amino)-4-methylthiophene-2-carboxylic acid propyl ester)

[0259]

[0260] Intermediate 4 was prepared from intermediate 2 using 1-iodopropane, following the same method as intermediate 3. The title compound was used in the next step without further purification (intermediate 4, 210 mg, 0.526 mmol).

[0261] LC-MS Method 1: tR = 1.39 min, m / z = 422.4 [M+Na]+

[0262] Intermediate 5: Isopropyl 3-amino-4-methylthiophene-2-carboxylate

[0263]

[0264] TFA (0.39 mL, 5.10 mmol) was slowly added to a solution of intermediate 3 (202 mg, 0.51 mmol) dissolved in DCM (5.0 mL) on ice. The reaction mixture was heated to RT and stirred for 4 h, diluted with DCM, and washed with a saturated solution of NaHCO3. The aqueous layer was separated and extracted with DCM, the organic layer was dried by a phase separator and concentrated under vacuum to give the title compound (intermediate 5, 108 mg, 0.542 mmol, quantitative yield) as a yellow oil, which was used in the next step without further purification.

[0265] LC-MS Method 1: tR = 1.07 min, m / z = 200.3 [M+H]+

[0266] Intermediate 6: (3-amino-4-methylthiophene-2-propionic acid ester) Specification 39 / 129 pages 48 CN 122374293 A 9

[0267]

[0268] Intermediate 6 was prepared from intermediate 4 using the same method as intermediate 5, and was used in the next step without further purification (intermediate 6,108 mg, 0.526 mmol, quantitative yield).

[0269] LC-MS Method 1: tR = 1.09 min, m / z = 200.3 [M+H]+

[0270] Intermediate 7: Isopropyl 2-aminobenzoate

[0271]

[0272] Tripotassium phosphate (351 mg, 1.65 mmol) and triethyl-(phenylmethyl)ammonium chloride (75 mg, 0.33 mmol) were added to a solution of methyl 2-aminobenzoate (0.43 mL, 3.31 mmol) in anhydrous propion-2-ol (7 mL, 86.64 mmol) in a microwave-safe vial. The vial was sealed and the reaction mixture was shaken overnight at 90 °C. After cooling to RT, the solvent was removed under reduced pressure, and the crude product was purified by Sfär silica gel FCC (CyHex / EtOAc from 100:0 to 85:15) to give the title compound (intermediate 7, 460 mg, 2.57 mmol, 78% yield).

[0273] LC-MS Method 1: tR = 1.10 min, m / z = 180.3 [M+H]+

[0274] Intermediate 8: methyl 3-cyano-4-methylthiophene-2-carboxylate

[0275]

[0276] 0.1N potassium hexacyanoferrate (II) solution (64.1 mL, 6.41 mmol) and tert-butanol (85.1 mL) were added to methyl 3-iodo-4-methylthiophene-2-carboxylate (3.1 g, 11.0 mmol), potassium acetate (215.7 mg, 2.2 mmol), dicyclohexyl-[2-[2,4,6-tris(propyl-2-yl)phenyl]phenyl]phosphine (1.05 g, 2.2 mmol) and XPhos PD G3 (930.2 mg, 1.1 mmol). Three N2-vacuum cycles were performed, and the mixture was stirred at 100 °C for 3 h. Further XPhos PD G3 (460 mg, 0.55 mmol) and 0.1N potassium hexacyanoferrate(II) solution (27 mL, 2.7 mmol) were added under N2 at RT, and the reaction mixture was stirred at 100 °C for an additional 5 h. EtOAc was added to the cooled reaction mixture, and the organic layer was concentrated under vacuum. The crude product was purified by Sfär silica gel FCC (CyHex 100% to CyHex / EtOAc 9:1) to give the title compound (intermediate 8, 850 mg, 4.7 mmol, 43% yield), as per specification page 49 of CN 122374293 A 50 (40 / 129 pages).

[0277] LC-MS Method 1: tR = 0.82 min, m / z = 182.1 [M+H]+

[0278] Intermediate 9:3-(aminomethyl)-4-methylthiophene-2-carboxylate

[0279]

[0280] A suspension of intermediate 8 (850.0 mg, 4.69 mmol), Raney nickel (50% in water slurry) (27.5 mg, 0.47 mmol), and ammonia (7N MeOH solution, 2.0 mL, 14.0 mmol) in MeOH (47 mL) was stirred at RT in a hydrogen atmosphere at 1 atm for 36 h. The catalyst was filtered and washed with MeOH, DCM, and DCM / MeOH (8:2). The organic phase was evaporated under reduced pressure, and the crude product was purified by Sfär silica gel FCC (DCM 100% to DCM / MEOH 9:1) to give the title compound (intermediate 9, 150 mg, 0.810 mmol, 17% yield).

[0281] LC-MS Method 2: tR = 0.66 min, m / z = 186.4 [M+H]+

[0282] Intermediate 80: (3-amino-4-methylthiophene-2-yl)methanol

[0283]

[0284] A solution of methyl 3-amino-4-methylthiophene-2-carboxylate (6.8 g, 40 mmol) in THF (48 mL) was added dropwise to a flask containing a 2M lithium aluminum hydride THF solution (20 mL, 40 mmol) over 30 min at -15 °C, while maintaining the temperature between -15 °C and -10 °C. After 2 h, another 2M lithium aluminum hydride THF solution (10 mL, 20 mmol) was added dropwise, and the reaction mixture was stirred for another 2 h while maintaining the temperature between -15 °C and -10 °C. The reaction was quenched dropwise by adding 18 mL of water at -10 °C. After 5 min, 9 mL of 15% (w / w) NaOH aqueous solution was added. The cooling bath was removed, and the mixture was stirred at RT for 30 min. The suspension was then filtered through a diatomaceous earth mat, and the mat was washed with THF. The organic layer was evaporated under reduced pressure to obtain a solid, which was then ground with Et₂O to give the title compound (intermediate 80, 4.0 g, 28 mmol, 70% yield).

[0285] LC-MS Method 1: tR = 0.44 min, MS (ESI) m / z = 126.0 [M-H2O+H]+

[0286] Intermediate 81: 2-bromo-N-(2-(hydroxymethyl)-4-methylthiophene-3-yl)acetamide

[0287]

[0288] TEA (0.48 mL, 3.49 mmol) was added to a solution of intermediate 80 (200.0 mg, 1.4 mmol) in DCM (7 mL) at 0 °C, followed by the addition of 2-bromoacetyl bromide (0.26 mL, 2.79 mmol). After stirring at 0 °C for 1 hour,The reaction was concentrated to half its volume and then purified by Sfär silica gel FCC (from 80:20 to 50:50 CyHex / EtOAc) to give the title compound (intermediate 81, 142 mg, 0.54 mmol, 38% yield).

[0289] LC-MS Method 1: tR = 0.57 min, MS (ESI) m / z = 246.3 / 248.3 [M-H2O]+

[0290] 1H NMR (400 MHz , DMSO-d6) δ ppm 9.67 (br s , 1H) , 7 .02 (s , 1H) , 5 .34 (br s , 1H) , 4.43 (s , 2H) , 4.01 (s , 2H) , 2.00 (br s , 3H)

[0291] Intermediate 82: 2-(methoxymethyl)-4-methylthiophene-3-amine

[0292]

[0293] Sodium hydride (60% suspension, 602 mg, 15 mmol) was added to a solution of intermediate 80 (1.96 g, 14 mmol) in THF (91 mL) at 0 °C. The mixture was stirred at the same temperature for 15 min, and then methyl iodide (0.94 mL, 16 mmol) was added. The mixture was stirred at 0 °C for 2 h. Water was added, and the mixture was extracted with EtOAc (3x). The combined organic fractions were washed with water and brine and concentrated under reduced pressure. The crude product was purified by Sfär silica gel FCC (from 100% CyHex to 40:60 CyHex / EtOAc) to give the title compound (intermediate 82, 365 mg, 3.32 mmol, 17% yield).

[0294] LC-MS Method 2: tR = 0.50 min, MS (ESI) m / z = 158.0 [M+H]+

[0295] Intermediate 83: 2-bromo-N-(2-(methoxymethyl)-4-methylthiophene-3-yl)acetamide

[0296]

[0297] 2-bromoacetyl bromide (0.224 mL, 2.55 mmol) was added dropwise to a suspension of potassium carbonate (641 mg, 4.63 mmol) and intermediate 82 (365 mg, 2.32 mmol) in ACN (13 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h, then filtered and concentrated under reduced pressure. The residue was stored at -5°C for one week, and then purified by Sfär silica gel FCC (from 100% CyHex to 40:60 CyHex / EtOAc) to give the title compound (intermediate 83, 375 mg, 1.35 mmol, 58% yield).

[0298] LC-MS method 1: tR = 0.74 min, MS (ESI)m / z = 246.0 / 248.0 [M-31]+

[0299] 1H NMR (400MHz, CDCl3) δ 7.88 (s, 1H), 6.90 (q, J = 1.10 Hz, 1H), 4.48 (s, 2H), 4.04 (s, 2H), 3.39 (s, 3H), 2.12 (d, J = 1.09 Hz, 3H)

[0300] Intermediate 84: 3-amino-4-methylthiophene-2-carboxylic acid 2-((tert-butyldimethylsilyl)oxy)ethyl ester Specification 42 / 129 pages 51 CN 122374293 A 2

[0301]

[0302] Methyl 3-amino-4-methylthiophene-2-carboxylate (3.00 g, 17.5 mmol) was slowly added to a stirred suspension of 2-((tert-butyldimethylsilyl)oxy)ethanol (10.5 mL, 52.5 mmol) and sodium hydride (60% suspension, 2.10 g, 52.6 mmol) in THF (35 mL) at 0 °C. The reaction mixture was stirred at RT for 2 h. The reaction mixture was neutralized by dropwise addition of glacial acetic acid. The resulting mixture was filtered through a Gooch funnel and the solid was washed with EtOAc. The liquid organic phase was concentrated under reduced pressure to give a crude product, which was purified by Sfär silica gel FCC (from CyHex 100% to 6:4 CyHex / EtOAc) to give the title compound (intermediate 84, 1.80 g, 5.70 mmol, 33% yield).

[0303] LC-MS Method 1: tR = 1.43 min, MS (ESI) m / z = 316.2 [M+H]+

[0304] Intermediate 85: 4-((3-amino-4-methylthiophene-2-carbonyl)oxy)piperidine-1-carboxylate tert-butyl ester

[0305]

[0306] 3-amino-4-methylthiophene-2-carboxylate (2.00 g, 11.7 mmol) was added to a stirred suspension of 4-hydroxypiperidine-1-carboxylate (6.11 g, 30.4 mmol) and sodium hydride (60% suspension, 1.17 g, 29.2 mmol) in THF (44 mL) at 0 °C, and the reaction mixture was stirred at RT for 5 h. The resulting mixture was filtered through a Gooch funnel, and the solids were washed with EtOAc. The liquid organic phase was concentrated under reduced pressure to obtain a crude product, which was then purified by Sfär silica gel FCC (from DCM 100% to 75:25 DCM / ACN) to give the title compound (intermediate 85, 500 mg, 1.46 mmol, 13% yield).

[0307] LC-MS method 1: tR = 1.19 min,MS (ESI) m / z = 285.1 [M-57]+

[0308] Intermediate 86: 2-methoxyethyl 3-amino-4-methylthiophen-2-carboxylic acid

[0309]

[0310] Potassium carbonate (1.58 mg, 11.5 mmol) was added to a solution of 3-amino-4-methylthiophen-2-carboxylic acid (900 mg, 5.73 mmol) in DMF (20 mL), followed by the addition of 1-bromo-2-methoxyethane (0.54 mL, 5.7 mmol) at RT. Water was added after 4 h, and the mixture was extracted with EtOAc (3x). The collected organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure according to the specification 43 / 129 pages 52 CN 122374293 A 3. The residue was purified by Sfär silica gel FCC (from 100% CyHex to CyHex / EtOAc 90:10) to give the title compound (intermediate 86, 824 mg, 3.83 mmol, 67% yield).

[0311] LC-MS method 1: tR = 0.85 min, MS (m / z) = 216.0 [M+H]+

[0312] Intermediate 10: methyl 3-(2-bromoacetamido)-4-methylthiophene-2-carboxylate

[0313]

[0314] 2-bromoacetamido (6.1 mL, 70.90 mmol) was added dropwise to a stirred suspension (235 mL) of methyl 3-amino-4-methylthiophene-2-carboxylate (10.0 g, 58.4 mmol) cooled to 0 °C in water, and the reaction was heated to rt and stirred overnight. Add 5.08 mL of 2-bromoacetyl bromide (58.40 mmol) at 0 °C and stir the reaction mixture at rt for 5 h. Filter the resulting solid, wash with water, and dry under high vacuum to give the title compound (intermediate 10, 15 g, 51.34 mmol, 88% yield) as an off-white powder.

[0315] LC-MS Method 1: tR = 0.82 min, m / z = 292.1–294.1 [M+H]+

[0316] The following intermediates were prepared from suitable starting materials according to a method similar to that used for intermediate 10. Specification page 44 / 129, page 53, CN 122374293 A 4

[0317] Specification page 45 / 129, page 54, CN 122374293 A 5

[0318] Specification page 46 / 129, page 55, CN 122374293 A 6

[0319] Specification page 47 / 129, page 56, CN 122374293 A 7

[0320] Specification page 48 / 129, page 57, CN122374293 A 8

[0321]

[0322] Specification 49 / 129 pages 58 CN 122374293 A 9

[0323] Intermediate 27: methyl 2-(2-chloroacetamido)4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate

[0324]

[0325] 2-chloroacetyl chloride (0.17 mL, 2.19 mmol) was added dropwise to a solution of methyl 2-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylate (420 mg, 1.99 mmol) and TEA (0.31 mL, 2.19 mmol) in DCM (15.78 mL) cooled to 0 °C, and the reaction was then heated to rt. After stirring at rt for 1 h, the reaction mixture was washed with water, the layers were separated, and the combined aqueous phase was washed with DCM. The organic phases were combined, dried in a phase separator, and concentrated under high vacuum to obtain the crude title compound (intermediate 27, 585 mg, 2.03 mmol, quantitative yield) as a yellow powder. This product was used in the next step without further purification.

[0326] LC-MS method 2: tR = 1.13 min, m / z = 288.03 [M+H]+

[0327] The following intermediates were prepared from suitable starting materials according to a method similar to that used for intermediate 27. Instruction manual 50 / 129 pages 59 CN 122374293 A 60

[0328] Instruction manual 51 / 129 pages 60 CN 122374293 A 1

[0329] Instruction manual 52 / 129 pages 61 CN 122374293 A 2

[0330] Instruction manual 53 / 129 pages 62 CN 122374293 A 3

[0331]

[0332] Intermediate 95: Methyl 4-(2-chloroacetamido)-5-cyanothiophene-3-carboxylate

[0333]

[0334] 2-chloroacetyl chloride (0.13 mL, 1.65 mmol) was added to a suspension of methyl 4-amino-5-cyanothiophene-3-carboxylate (300 mg, 1.65 mmol) in 1,4-dioxane (3 mL). The reaction was stirred at 100 °C for 16 h. The resulting solution was diluted with water and extracted with EtOAc (3x). The organic phase was dried using a phase separator and concentrated under reduced pressure to give a crude product, which was purified by Sfär amino FCC (CyHex 100% to CyHex / EtOAc 70:30) to give the title compound (intermediate 95, 322 mg, 1.24 mmol, 76% yield).

[0335] LC-MS method 1: tR = 0.75 min, m / z = 259.4 [M+H]+

[0336] Intermediate 39: methyl 3-(2-(azacycloheptane-1-yl)acetamido)-4-methylthiophene-2-carboxylate, specification 54 / 129 pages, 63 CN 122374293 A 4

[0337]

[0338] Perpiperidine (3.5 mL, 30.8 mmol) was added to a stirred solution of intermediate 10 (3.03 g, 10.3 mmol) in ACN (34 mL), and the mixture was stirred for 2 h. The solvent was concentrated under high vacuum, and the crude mixture was purified by Sfär amino FCC (CyHex 100% to CyHex / EtOAc 1:9) to give the title compound (intermediate 39, 2.6 g, 8.38 mmol, 82% yield) as a colorless oil.

[0339] LC-MS method 1: tR = 0.48min, m / z = 311.3[M+H]+

[0340] The following intermediates were prepared from suitable starting materials according to a method similar to that of intermediate 39. Specification page 55 / 129, page 64, CN 122374293 A 5

[0341] Specification page 56 / 129, page 65, CN 122374293 A 6

[0342] Specification page 57 / 129, page 66, CN 122374293 A 7

[0343] Specification page 58 / 129, page 67, CN 122374293 A 8

[0344] Specification page 59 / 129, page 68, CN 122374293 A 9

[0345] Specification page 60 / 129, page 69, CN 122374293 A 70

[0346] Specification page 61 / 129, page 70, CN 122374293 A 1

[0347] Specification page 62 / 129, page 71, CN 122374293 A 2

[0348] Specification 63 / 129 pages 72 CN 122374293 A 3

[0349] Specification 64 / 129 pages 73 CN 122374293 A 4

[0350] Specification 65 / 129 pages 74 CN 122374293 A 5

[0351] Specification 66 / 129 pages 75 CN 122374293 A 6

[0352]

[0353]

[0354] Intermediate 66: 2-(dimethylamino)-N-(2-(methoxymethyl)benzyl)acetamide Specification 67 / 129 pages 76 CN 122374293 A 7

[0355]

[0356] To 2-(dimethylamino)acetic acid (273mg,3-(ethyliminomethyleneamino)-N,N-dimethyl-1-propylamine hydrochloride (761 mg, 3.97 mmol) and 1-hydroxybenzotriazole hydrate (405 mg, 2.65 mmol) were added to a solution of 2.65 mmol in DMF (4 mL). The mixture was stirred for 15 min, then [2-(methoxymethyl)phenyl]methylamine (400 mg, 2.65 mmol) was added, and the reaction was stirred overnight at RT. The reaction mixture was diluted with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was separated, dried using a phase separator, and concentrated under reduced pressure. The crude product was purified by Sfär amino FCC (EtOAc 100% to EtOAc:MeOH 90:10), and then purified by Sfär C18 reverse-phase FCC (water / NH4OH 0.1%) 100% to (water / NH4OH 0.1%) / ACN 7:3 to give the title compound (intermediate 66, 176 mg, 0.745 mmol, 28% yield).

[0357] LC-MS Method 2: tR = 0.69 min, m / z = 237.3 [M+H]+

[0358] Intermediate 67: Methyl 3-(2-(azacycloheptane-1-yl)acetamido)thiophene-2-carboxylate

[0359]

[0360] 2-Bromoacetyl bromide (0.83 mL, 9.54 mmol) was slowly added to a suspension of methyl 3-amino-2-thiophene carboxylate (1.5 g, 9.54 mmol) and potassium carbonate (3.9 g, 28.63 mmol) in ACN (29 mL) at 0 °C. The reaction was stirred at RT for 2 h, then perpiperidine (1.1 mL, 9.54 mmol) was added, and the reaction mixture was continued to be stirred at RT for 45 min. The volatiles were removed under reduced pressure, and the crude product was purified by Sfär amino FCC (CyHex 100% to CyHex / EtOAc 1:1) to give the title compound (intermediate 67, 1.8 g, 6.07 mmol, 64% yield).

[0361] LC-MS Method 1: tR = 0.54 min, m / z = 297.2 [M+H]+

[0362] Intermediate 113: 4-((3-(2-(azacycloheptane-1-yl)acetamido)-4-methylthiophene-2-carbonyl)oxy)piperidine-1-carboxylic acid tert-butyl ester

[0363]

[0364] 2-bromoacetyl bromide (0.14 mL, 1.62 mmol) was added dropwise to intermediate 85 (515 mg, 1.47 mmol) and potassium carbonate (405 mg, 2.94 mmol) in a stirred suspension in ACN (8 mL) at 0 °C, and then the reaction was heated to RT and stirred for 2 h. Then azacycloheptane (0.17 mL,The solid was removed by filtration and the liquid phase was concentrated to give the title compound (intermediate 113, 600 mg, 1.25 mmol, 85% yield). Instructions for Use 68 / 129, Page 77, CN 122374293 A 8

[0365] LC-MS Method 1: tR = 0.75 min, m / z = 480.2 [M+H]+

[0366] Intermediate 68: methyl 3-(2-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)acetamido)-4-methylthiophene-2-carboxylate

[0367]

[0368] Tert-butyl-chloro-dimethylsilane (597 mg, 3.96 mmol) was added to a stirred solution of intermediate 54 (825 mg, 2.64 mmol) in DCM (21 mL) at 0 °C, and the mixture was stirred overnight at rt. Water and EtOAc were added to the reaction mixture, the organic layer was separated, and the aqueous layer was extracted with EtOAc. The solvent was removed under reduced pressure, and the crude product was purified by Sfär amino FCC (100% CyHex to CyHex / EtOAc 2:8) to give the title compound (intermediate 68, 470 mg, 1.10 mmol, 42% yield) as a colorless oil.

[0369] LC-MS method 1: tR = 0.85 min, m / z = 427.2 [M+H]+

[0370] Intermediate 69: methyl 4-methyl-3-(2-(piperazin-1-yl)acetamido)thiophene-2-carboxylate hydrochloride

[0371]

[0372] 4M HCl in 1,4-dioxane solution (3.1 mL, 12.4 mmol) was added dropwise to a stirred solution of intermediate 64 (490 mg, 1.23 mmol) in 1,4-dioxane (3 mL) under rt. After 6 hours, another 4M HCl solution of 1,4-dioxane (1.2 mL, 4.8 mmol) was added dropwise. The reaction mixture was stirred overnight, the volatiles were removed under reduced pressure, and the crude product was ground with DCM to give the title compound (intermediate 69, 241 mg, 0.722 mmol, 58% yield).

[0373] LC-MS method 1: tR = 0.42 min, m / z = 298.2 [M+H]+

[0374] Intermediate 70: 4-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperazine-1-carboxylic acid ethyl ester

[0375]

[0376] Sodium carbonate (267.8 mg, 0.72 mmol) was added to the stirred solution of intermediate 69 (241.0 mg, 0.72 mmol) in ethanol (6.0 mL).2.53 mmol) and ethyl chloroformate (0.08 mL, 0.80 mmol) were added, and the reaction mixture was stirred at rt for 4 h. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The collected organic layer was dried over Na2SO4, filtered, and concentrated to give the crude title compound (intermediate 70, 200 mg, 0.54 mmol, 75% yield), which was used in the next step without further purification.

[0377] LC-MS Method 1: tR = 0.64 min, m / z = 370.3 [M+H]+

[0378] Intermediate 71: 3-(2-(azacycloheptane-1-yl)acetamido)-4-methylthiophene-2-carboxylic acid

[0379]

[0380] Intermediate 39 (4.5 g, 14.5 mmol) was dissolved in THF (50 mL), water (9 mL) and 2 M sodium hydroxide aqueous solution (8.7 mL, 17.4 mmol) were added, and the reaction mixture was heated at 50 °C overnight. The pH was adjusted to pH = 7 with 2 M HCl aqueous solution at 0 °C, and the volatiles were removed under reduced pressure to give the title compound (intermediate 71, 5.0 g, 14.1 mmol, 97% yield) as an orange solid.

[0381] LC-MS Method 1: tR = 0.43 min, m / z = 297.1 [M+H]+

[0382] Intermediate 72: 2-(azacycloheptane-1-ylmethyl)-7-methyl-4H-thieno[3,2-d][1,3]oxazin-4-one

[0383]

[0384] 1-methylimidazolium (0.34 mL, 4.23 mmol) was added to a suspension of intermediate 71 (500.0 mg, 1.41 mmol) in anhydrous ACN (13 mL). The suspension was cooled to 0 °C, TCFH (435 mg, 1.55 mmol) was added, and the reaction mixture was heated to RT and stirred for 1 h. The solid was filtered and washed with ACN to give the title compound (intermediate 72, 450 mg, 1.617 mmol) as a white solid, which was used in the next step without further purification.

[0385] LC-MS Method 1: tR = 0.49 min, m / z = 279.1 [M+H]+

[0386] Intermediate 73: 3-(2-(azacycloheptane-1-yl)acetamido)-4-methylthiophene-2-carboxylic acid tert-butyl ester

[0387]

[0388] The stirred suspension of intermediate 71 (6.30 g, 16.0 mmol) in toluene (113 mL) was refluxed for 15 min. 1,1-di-tert-butoxy-N,N-dimethylmethylamine (7.66 mL,32.0 mmol). The reaction was stirred under reflux for 24 h. The solvent was evaporated to give a crude mixture, which was purified by Sfär amino FCC (100% CyHex to CyHex / (DCM / EtOAc 80 1:1) 8:2) to give the title compound (intermediate 73, 3.15 g, 8.9 mmol, 56% yield).

[0389] LC-MS Method 1: tR = 0.65 min, MS (ESI) m / z = 353.2 [M+H]+

[0390] Intermediate 74: 3-(2-(azacycloheptane-1-yl)acetamido)-4-methylthiophene-2-carboxylic acid cyclopropyl ester

[0391]

[0392] Sodium hydride (60% suspension, 19 mg, 0.47 mmol) was added to a solution of cyclopropanol (27 mg, 0.47 mmol) in THF (2 mL) at 0 °C under a nitrogen atmosphere. After 2 min, intermediate 72 (100 mg, 0.36 mmol) was added, and the reaction mixture was stirred at 0 °C for 1 h. Water (5 mL) was added, and the reaction mixture was extracted with EtOAc. The collected organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Sfär amino FCC (CyHex:EtOAc from 8:2 to 100% EtOAc) to give the title compound (intermediate 74, 50 mg, 0.15 mmol, 41% yield).

[0393] LC-MS method 1: tR = 0.55 min, m / z = 337.3 [M+H]+

[0394] Intermediate 114: 3-(2-(azacycloheptane-1-yl)acetamido)-4-methylthiophene-2-carboxylic acid 4-((tert-butoxycarbonyl)amino)butyl ester

[0395]

[0396] Sodium hydride (60% suspension, 86 mg, 2.16 mmol) was added to a solution of (4-hydroxybutyl)carbamate tert-butyl ester (0.40 mL, 2.16 mmol) in ACN (7 mL) at 0 °C under a nitrogen atmosphere. After 5 min, intermediate 72 (606 mg, 2.16 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 12 h. Volatiles were removed under reduced pressure, and the residue was purified by Sfär silica gel FCC (CyHex:(EtOAc / EtOH 3:1 v / v) from 100:0 to 40:60) to give the title compound (intermediate 114, 530 mg, 1.13 mmol, 53% yield).

[0397] LC-MS Method 1: tR = 0.69 min, m / z = 468.4 [M+H]+

[0398] Intermediate 115:3-(2-(4,4-dimethylpiperidin-1-yl)acetamido)-4-methylthiophene-2-carboxylic acid specification 71 / 129 pages 80 CN 122374293 A 1

[0399]

[0400] The title compound (intermediate 115, 2.40 g, quantitative yield) was obtained by following the method described in intermediate 71 and starting from intermediate 52 (2.20 g, 6.30 mmol).

[0401] LC-MS method 1: tR = 0.52 min, MS (ESI) m / z = 311.2 [M+H]+

[0402] Intermediate 116: 2-((4,4-dimethylpiperidin-1-yl)methyl)-7-methyl-4H-thieno[3,2-d][1,3]oxazine-4-one

[0403]

[0404] The title compound (intermediate 116, 1.70 g, 8.65 mmol, 82% yield) was obtained by following the method described for intermediate 72 and starting from intermediate 115 (2.20 g, 7.09 mmol).

[0405] LC-MS Method 1: tR = 0.51 min, MS (ESI) m / z = 293.3 [M+H]+

[0406] Intermediate 117: 3-(2-(4,4-dimethylpiperidin-1-yl)acetamido)-4-methylthiophene-2-carboxylic acid oxetane-3-yl ester

[0407]

[0408] Sodium hydride (60% suspension, 45 mg, 1.13 mmol) was added to a solution of oxetane-3-ol (84 mg, 1.13 mmol) in ACN (1 mL) at 0 °C under N2 atmosphere. After 5 min, intermediate 116 (300 mg, 1.03 mmol) was added, and the reaction mixture was stirred at 0 °C for 15 min, and then heated to RT. After 4 hours, 10 mL of phosphate buffer (pH = 7) was added, and the reaction mixture was extracted with EtOAc. The collected organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The crude product was purified by Sfär amino FCC (CyHex:EtOAc from 9:1 to 7:3) to give the title compound (intermediate 117, 120 mg, 0.33 mmol, 32% yield).

[0409] LC-MS Method 1: tR = 0.51 min, m / z = 367.2 [M+H]+

[0410] Intermediate 118: 3-(2-(4,4-dimethylpiperidin-1-yl)acetamido)-4-methylthiophene-2-carboxylic acid tetrahydro-2H-pyran-4-yl ester Specification 72 / 129 pages 81 CN 122374293 A 2

[0411]

[0412] Following the method described for intermediate 117, and starting from intermediate 116 (300 mg, 1.03 mmol) and tetrahydro-2H-pyran-4-ol (115 mg, 1.13 mmol), the title compound (intermediate 118, 191 mg, 0.48 mmol, 47% yield) was obtained.

[0413] LC-MS Method 1: tR = 0.58 min, MS (ESI) m / z = 395.4 [M+H]+

[0414] Intermediate 75: 4-((tert-butyldimethylsilyl)oxy)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium

[0415]

[0416] Intermediate 18 (123 mg, 0.56 mmol) was added to the stirred solution of intermediate 68 (240 mg, 0.56 mmol) in ACN (4 mL). The mixture was stirred at 55 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by Sfär amino FCC (from 0% to 5% DCM / MeOH) to give the title compound (intermediate 75, zwitterion, a mixture of diastereomers, 90 mg, 0.163 mmol, 29% yield) as a colorless oil.

[0417] LC-MS Method 2: tR = 1.10 min, m / z = 551.3 [M+H]+

[0418] Intermediate 76: 4-((tert-butyldimethylsilyl)oxy)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onthionyl carbamate Specification 73 / 129 pages 82 CN 122374293 A 3

[0419]

[0420] Intermediate 16 (120.2 mg, 0.52 mmol) was added to the stirred solution of intermediate 68 (200 mg, 0.47 mmol) in ACN (3 mL). The mixture was stirred overnight at 80°C and then concentrated under reduced pressure. The residue was purified by Sfär amino FCC (100% DCM to DCM:MeOH 96:4). The resulting impure compound was further purified by Sfär C18 FCC (water + 0.1% HCOOH / ACN 95:5 to water + 0.1% HCOOH / ACN 6:4) to give the title compound (intermediate 76, formate, a mixture of diastereomers, 51 mg, 0.082 mmol, 17% yield).

[0421] LC-MS method 1: tR = 0.88 min,m / z = 565.4 [M+H]+

[0422] Intermediate 77: methyl 3-((2-(azacycloheptane-1-yl)acetamido)methyl)-4-methylthiophene-2-carboxylate

[0423]

[0424] 2-bromoacetyl bromide (0.07 mL, 0.81 mmol) was added dropwise to a suspension of intermediate 9 (150 mg, 0.81 mmol) and TEA (0.12 mL, 0.89 mmol) in ACN (4.5 mL) at 0 °C. The reaction mixture was then heated to RT and stirred for 20 min. Perpiperidine (0.46 mL, 4.05 mmol) was added to the reaction mixture at RT, and the volatiles were removed under reduced pressure after stirring for 3 h. The crude product was purified by Sfär silica gel FCC (100% DCM to DCM / MeOH 95:5) to give the title compound (intermediate 77, 170 mg, 0.52 mmol, 65% yield).

[0425] LC-MS method 2: tR = 1.05 min, m / z = 325.5 [M+H]+

[0426] Intermediate 119: 2-(4,4-dimethylpiperidin-1-yl)tert-butyl acetate

[0427]

[0428] In a double-necked round-bottom flask, potassium carbonate (1.42 g, 10.3 mmol) was added to a stirred solution of 4,4-dimethylpiperidin hydrochloride (0.77 g, 5.13 mmol) in anhydrous DCM (25 mL), followed by 2-bromoacetic acid tert-butyl ester (0.76 mL, 5.1 mmol), and the mixture was stirred overnight at RT. Subsequently, a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with DCM (3x). The combined organic layers were filtered through a phase separator and concentrated under reduced pressure to give the title compound (intermediate specification 74 / 129 pages 83 CN 122374293 A 4 119, 1.0 g, 4.40 mmol, 86% yield).

[0429] 1H NMR (400MHz, DMSO) δ 3.09 (s, 2H), 2.46 (dd, J = 6.6, 4.7 Hz, 4H), 1.41 (s, 9H), 1.34–1.26 (m, 4H), 0.89 (s, 6H)

[0430] Intermediate 120: 2-(4,4-dimethylpiperidin-1-yl)acetic acid hydrochloride

[0431]

[0432] Intermediate 119 (1.0 g, 4.4 mmol) was dissolved in HCl (4M 1,4-dioxane solution, 22 mL, 88 mmol), and the resulting solution was stirred overnight at RT. The mixture was concentrated under reduced pressure to give the title compound (intermediate 120, 913 mg, 4.39 mmol).99% yield).

[0433] 1H NMR (400MHz, DMSO) δ 4.11 (s, 2H), 3.26 (s, 4H), 1.79–1.43 (m, 4H), 0.98 (s, 6H)

[0434] Intermediate 121: 2-(4,4-dimethylpiperidin-1-yl)-N-(1-(pyrimidin-2-yl)cyclopropyl)acetamide

[0435]

[0436] TEA (0.27mL, 1.93mmol) and T3P (50% EtOAc solution, 0.290mL, 0.48mmol) were added to the suspension of intermediate 120 (100mg, 0.48mmol) in EtOAc (5mL). After stirring for 5 min, 1-(pyrimidin-2-yl)cyclopropyl-1-amine hydrochloride (99 mg, 0.58 mmol) was added, and the mixture was stirred at RT for 3 h. Then, T3P (50% EtOAc solution, 0.290 mL, 0.48 mmol) was added, and the mixture was stirred at RT overnight. Then, T3P (50% EtOAc solution, 0.29 mL, 0.48 mmol) was added. After stirring at RT for 3 hours, the mixture was heated to 50 °C and held for 2 h. The mixture was cooled to RT and diluted with EtOAc and water. The two phases were separated, and the organic phase was washed with brine. The aqueous phase was extracted with DCM:iPrOH (2 / 1 v / v) (x3). The collected organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by Sfär amino FCC (CyHex from 100% to CyHex / EtOAc 40:60) to give the title compound (intermediate 121, 76 mg, 0.26 mmol, 55% yield) as a white solid.

[0437] LC-MS Method 2: tR = 0.75 min, MS (ESI) m / z = 289.2 [M+H]+

[0438] Intermediate 122: 2-(azacycloheptan-1-yl)-N-(3-phenyloxetane-3-yl)acetamide

[0439]

[0440] T3P (50% EtOAc solution, 1.92 mL, 3.23 mmol) was added dropwise to a suspension of 2-(azacycloheptan-1-yl)acetic acid hydrochloride (573 mg, 2.96 mmol) and TEA (1.31 mL, 9.43 mmol) in EtOAc (25 mL) at RT, followed by the dropwise addition of 3-phenyloxetane-3-amine hydrochloride (500 mg, 2.69 mmol), and the reaction mixture was stirred at RT for 22 h. The reaction mixture was then partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The phases were separated, and the organic composition was described.Page 75 / 129, 84 CN 122374293 A 5. The phase was washed with saturated NaHCO3 aqueous solution and concentrated under reduced pressure. The residue was purified by Sfär silica gel FCC (from CyHex 100% to 3:7 CyHex / EtOAc) to give the title compound (intermediate 122, 277 mg, 0.96 mmol, 36% yield).

[0441] LC-MS Method 1: tR = 0.40 min, MS (ESI) (m / z) = 289.6 [M+H]+

[0442] Intermediate 123: 2-(4,4-dimethylpiperidin-1-yl)-N-(1-(pyridin-2-yl)cyclopropyl)acetamide

[0443]

[0444] HATU (1.10 g, 2.91 mmol) was added to a solution of intermediate 120 (511 mg, 2.46 mmol) in DMF (9 mL). After 5 min, a solution of 1-(pyridin-2-yl)cyclopropyl-1-amine (300 mg, 2.24 mmol) in DMF (2 mL) was added, followed by DIPEA (0.233 mL, 1.34 mmol), and the mixture was stirred overnight at RT. The reaction mixture was diluted with EtOAc and water, the phases were separated, and the organic phase was washed first with a saturated aqueous solution of NaHCO3, then with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by Sfär amino FCC (from CyHex 100% to 60:40 CyHex / EtOAc) to give the title compound (intermediate 123, 487 mg, 1.69 mmol, 76% yield).

[0445] LC-MS Method 2: tR = 0.82 min, MS (ESI) m / z = 288.1 [M+H]+

[0446] Intermediate 124: N-(3-phenyloxetane-3-yl)-2-(piperidin-1-yl)acetamide

[0447]

[0448] 1-methylimidazolium (0.20 mL, 2.5 mmol) and DIPEA (0.28 mL, 1.62 mmol) were added to a suspension of 2-(piperidin-1-yl)acetate hydrochloride (145 mg, 0.81 mmol) in ACN (7 mL). The suspension became a homogeneous solution. Then TCFH (249 mg, 0.89 mmol) was added at 0 °C, and the reaction mixture was stirred at RT for 15 min. 3-Phenyrocyclobutane-3-amine hydrochloride (150 mg, 0.81 mmol) was then added, and the reaction mixture was stirred overnight at RT. Volatile substances were removed by evaporation, water was added, and the mixture was extracted with DCM. The collected organic phase was filtered through a phase separator and subjected to further treatment.Concentrate under pressure. The residue was purified by Sfär silica gel FCC (from 100% CyHex60 to 4:6 CyHex / EtOAc) to give the title compound (intermediate 124, 163 mg, 0.59 mmol, 74% yield). H NMR (400MHz, DMSO-d6) δ 1.34-1.47 (m, 2H), 1.57 (p, J=5.6 Hz, 4H), 2.42 (t, J=5.4 Hz, 4H), 2.94 (s, 2H), 4.69 (d, J= 6.8 Hz, 2H), 4.89 (d, J = 6.8 Hz, 2H), 7.24-7.33 (m, 1H), 7.34-7.44 (m, 2H), 7.48-7.57 (m, 2H), 8.77 (s, 1H)

[0450] Intermediate 125: 2-Chloroacetic acid (3-(2-chloroacetamido)-4-methylthiophene-2-yl) methyl ester, specification 76 / 129 pages, 85 CN 122374293 A 6

[0451]

[0452] TEA (2.14 mL, 15.4 mmol) was added to a solution of intermediate 80 (1.0 g, 7.0 mmol) in DCM (28 mL) at 0 °C, followed by the addition of 2-chloroacetyl chloride (1.17 mL, 14.7 mmol), and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with DCM and water, the two phases were separated, and the organic phase was washed with saturated NaHCO3 aqueous solution and concentrated. The residue was purified by Sfär silica gel FCC (from CyHex 100% to 60:40 CyHex / EtOAc) to give the title compound (intermediate 125, 1.54 g, 5.2 mmol, 75% yield).

[0453] LC-MS Method 1: tR = 0.88 min, MS (ESI) m / z = 294.1 / 296.1 [M-H]-

[0454] Intermediate 126: 2-(4,4-dimethylpiperidin-1-yl)-N-(2-(hydroxymethyl)-4-methylthiophene-3-yl)acetamide

[0455]

[0456] Potassium carbonate (1.44 g, 10.4 mmol) and 4,4-dimethylpiperidin hydrochloride (856 mg, 5.72 mmol) were added to a suspension of intermediate 125 (770 mg, 2.60 mmol) in ACN (25 mL) at RT. The reaction mixture was stirred overnight at RT. The mixture was evaporated to dryness, the residue was dissolved in MeOH (25 mL), and then potassium carbonate (1.44 mg, 10.4 mmol) was added.10.4 mmol), and the mixture was stirred overnight at RT. The solid was then removed by filtration and the organic phase was concentrated to give a crude product, which was purified by Sfär amino FCC (from CyHex 100% to 60:40 CyHex / EtOAc) to give the title compound (intermediate 126, 423 mg, 1.43 mmol, 55% yield).

[0457] LC-MS Method 2: tR = 0.92 min, MS (ESI) m / z = 297.4 [M+H]+

[0458] Intermediate 127: 2-(4,4-dimethylpiperidin-1-yl)-N-(2-formyl-4-methylthiophen-3-yl)acetamide

[0459]

[0460] Manganese(IV) oxide (1.20 g, 13.8 mmol) was added to a stirred solution of intermediate 126 (820 mg, 2.77 mmol) in DCM (16 mL) at 0 °C. The mixture was stirred at RT for 8 h. Additional manganese(IV) oxide (721 mg, 8.30 mmol) was added and the mixture was stirred at RT overnight. It was then filtered through a diatomaceous earth pad and the diatomaceous earth pad was washed with DCM. The filtered organic phase was concentrated to give the title compound (intermediate 127, 700 mg, 2.38 mmol, 88% yield).

[0461] LC-MS Method 2: tR = 1.01 min, MS (ESI) m / z = 295.1 [M+H]+ Specification 77 / 129 pages 86 CN 122374293 A 7

[0462] Intermediate 128: 2-(4,4-dimethylpiperidin-1-yl)-N-(4-methyl-2-((methylamino)methyl)thiophen-3-yl)acetamide

[0463]

[0464] TEA (0.21 mL, 1.53 mmol) and methylamine hydrochloride (103 mg, 1.53 mmol) were added to a stirred solution of intermediate 127 (300 mg, 1.02 mmol) in MeOH (3.0 mL), and the mixture was stirred overnight at RT. The reaction mixture was then concentrated under reduced pressure, and the residue was dissolved in MeOH (4.0 mL). Sodium borohydride (51 mg, 1.35 mmol) was then added at 0 °C, and the reaction mixture was stirred at RT for 2 h. Water and DCM were then added. The organic phase was separated, dried over Na2SO4, and concentrated under reduced pressure to give the title compound (intermediate 128, 180 mg, 0.58 mmol, 43% yield).

[0465] LC-MS Method 2: tR = 0.92 min, MS (ESI) m / z = 310.2 [M+H]+

[0466] Intermediate 129: ((3-(2-(44-Dimethylpiperidin-1-yl)acetamido)-4-methylthiophene-2-yl)methyl)methyl)tert-butyl carbamate

[0467]

[0468] Triethylamine (0.162 mL, 1.16 mmol), N,N-dimethyl-4-pyridinamine (7 mg, 0.06 mmol) and ditert-butyl dicarbonate (152 mg, 0.67 mmol) were added to a stirred solution of intermediate 128 (180 mg, 0.582 mmol) in MeOH (3.0 mL). The mixture was stirred at RT for 3 h. Water was then added and the reaction was extracted with DCM. The collected organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by Sfär amino FCC (from CyHex 100% to 60:40 CyHex / EtOAc) to give the title compound (intermediate 129, 118 mg, 0.044 mmol, 50% yield).

[0469] LC-MS method 1 tR = 0.75min, MS (ESI) m / z = 410.3[M+H]+

[0470] Intermediate 130: 1-(2-((2-((4-((tert-butoxycarbonyl)amino)butoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazol-3-ylamino)-2-oxoethyl)azacycloheptane-1-onium Specification 78 / 129 pages 87 CN 122374293 A 8

[0471]

[0472] Intermediate 18 (117mg, 0.57mmol) was added to the stirred solution of intermediate 114 (265mg, 0.57mmol) in ACN (1.4mL). The mixture was stirred in a sealed vial at 70°C for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Sfär amino FFC (0% to 40% EtOAc / EtOH (3:1 v / v) in DCM) to give the title compound (intermediate 130, zwitterionic, 117 mg, 0.20 mmol, 35% yield) as a white solid.

[0473] LC-MS method 1: tR = 0.70 min, m / z = 592.8 [M]+

[0474] The following intermediates were prepared from suitable starting materials according to a method similar to that used for intermediate 130. Specification 79 / 129 pages 88 CN 122374293 A 9

[0475] Specification 80 / 129 pages 89 CN 122374293 A 90

[0476]

[0477] Example 1: 1,1-bis(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium bromide

[0478] Intermediate 39 (200.0 mg, 0.640 mmol) was added to a stirred solution of intermediate 10 (190.14 mg, 0.640 mmol) in ACN (2 mL). The mixture was stirred in a sealed vial at 80 °C for 24 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Sfär C18 FFC (from 0% to 100% ACN / water) to give the title compound (Example 1, 131 mg, 0.217 mmol, 34% yield) as a white solid.

[0479] LC-MS Method 2: tR = 1.06 min, m / z = 522.3 [M]+

[0480] 1H NMR (400 MHz, DMSO-d6) δ ppm 13.01-15.38 (m, 2 H), 7.38 (s, 2 H), 4.47 (s, 4 H), 3.71-3.90 (m, 4 H), 3.68 (s, 6 H), 1.92-2.11 (m, 4 H), 1.89 (s, 6 H), 1.57-1.76 (m, 4 H).

[0481] The following examples were prepared from suitable starting materials according to the method described in similar to Example 1.

[0482] Specification page 81 / 129, page 90, CN 122374293 A 1

[0483] Specification page 82 / 129, page 91, CN 122374293 A 2

[0484] Specification page 83 / 129, page 92, CN 122374293 A 3

[0485] Specification page 84 / 129, page 93, CN 122374293 A 4

[0486] Specification page 85 / 129, page 94, CN 122374293 A 5

[0487] Specification page 86 / 129, page 95, CN 122374293 A 6

[0488] Specification page 87 / 129, page 96, CN 122374293 A 7

[0489] Specification page 88 / 129, page 97, CN 122374293 A 8

[0490] Specification 89 / 129 pages 98 CN 122374293 A 9

[0491] Specification 90 / 129 pages 99 CN 122374293 A 100

[0492] Specification 91 / 129 pages 100 CN 122374293 A 1

[0493] Specification 92 / 129 pages 101 CN 122374293 A 2

[0494] Specification 93 / 129 pages 102 CN 122374293 A 3

[0495] Specification 94 / 129 pages 103 CN 122374293 A 4

[0496] Specification 95 / 129 pages 104 CN 122374293 A 5

[0497] Specification 96 / 129 pages 105 CN 122374293 A 6

[0498] Specification 97 / 129 pages 106 CN 122374293 A 7

[0499] Specification 98 / 129 pages 107 CN 122374293 A 8

[0500] Specification 99 / 129 pages 108 CN 122374293 A 9

[0501] Specification 100 / 129 pages 109 CN 122374293 A 10

[0502] Specification 101 / 129 pages 110 CN 122374293 A 1

[0503] Specification 102 / 129 pages 111 CN 122374293 A 2

[0504] Specification 103 / 129 pages 112 CN 122374293 A 3

[0505]

[0506] Example 67 is a zwitterion: (1r,4r)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-methyl-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium (diasteretropic 1 trans)

[0507]

[0508] Example 68 is a zwitterion: (1s, 4s)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-methyl-1-(2-(((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium

[0509] Example 65 (a mixture of diastereomers, 43 mg, 0.092 mmol) was separated by chiral preparative HPLC (Chiral HPLC manual 104 / 129 pages 113 CN 122374293 A 4 Method 1) to obtain diastereomer 1 and diastereomer 2.

[0510] Example 67, diastereomer 1, trans, zwitterion: 23 mg, 0.049 mmol, 54% yield, 100% d.e., as a white solid.

[0511] LC-MS method 1: tR = 0.56 min, m / z = 467.4 [M]+

[0512] 1H NMR (500 MHz, DMSO-d6)δ ppm 12.47 (br s, 1 H) , 8.25 (s, 1 H) , 7.50 (s, 1 H) , 4.61 (s, 2 H) , 4.42 (s, 2 H) , 3.84 ‑ 3.98 (m, 3 H) , 3.74 (s, 3 H) , 3.64 - 3.79 (m, 1 H) , 2.25 - 2.41 (m, 2 H) , 2.04 (s, 3 H) , 1.98 - 2.09 (m, 2 H) , 1.78 (d, J=1.0 Hz, 3 H) , 1.46 (d, J=21.6 Hz, 3 H)

[0513] Example 98, diastereomer 2, cis, zwitterion: 7 mg, 0.015 mmol, 16% yield, 100% d.e., is an off-white solid. LC-MS method 1: tR = 0.59min, m / z = 467.3 [M]+

[0515] 1H NMR (400MHz, DMSO-d6) δ 12.12 (br s, 1H), 8.21 (s, 1H), 7.54 (s, 1H), 4.68 (s , 2H) , 4.34 (s , 2H) , 3.97 (br d , J = 12.2 Hz, 2H) , 3.78 ‑ 3.64 (m , 5H) , 2.47‑ 2.23 (m , 2H) , 2.05 (s , 3H) , 2.11 - 1.96 (m, 2H), 1.79 (s, 3H), 1.45 (d, J = 21.7 Hz, 3H)

[0516] Example 75 is a zwitterion: (1s, 4s)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidine-1-onium

[0517] and

[0518] Example 99 is a zwitterion: (1r, 4r)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2- ((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidine-1-onium

[0519] Intermediate 10 (1.37 g, 4.69 mmol) was added to a stirred solution of intermediate 98 (1.30 g, 4.69 mmol) in ACN (23 mL). The mixture was stirred at 80 °C for 36 h. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to SfThe α-amino FFC was purified (from 0% to 5% MeOH in DCM) to give the desired product, a mixture of diastereomers (299 mg, 0.61 mmol). The mixture was separated by chiral preparative HPLC (Method 2) to give diastereomer 1 and diastereomer 2.

[0520] Diastereomer 1 was purified by α-amino FFC (from 0% to 5% MeOH in DCM) to give the title compound, an amphoteric ion (Example 75, diastereomer 1, cis, amphoteric ion, 85 mg, 0.17 mmol, 4% yield, 100% d.e.), as a white solid. LC-MS method 1: tR=0.61min, m / z=489.2 [M]+

[0522] H NMR (500MHz, CDC13) δ ppm 8.20 (d, J=1.6 Hz, 1 H), 7.15 (d, J=1.0 Hz, 1 H), 6.85 (d , J=1.6 Hz, 1 H) , 4.63 (br s, 2 H) , 4.53 (br s, 2 H) , 4.21 (br d , J=13.2 Hz, 2 H) , 3.80 (s, 3 H) , 3.65 ‑ 3.76 (m, 2 H) , 2.52 ‑ 2.64 (m, 1 H) , 2.14–2.30 (m, 7 H)

[0523] The diastereomer 2 was purified by recrystallization in DCM to obtain the title compound, which is an amphoteric ion (Example 99, diastereomer 2, trans, amphoteric ion, 75 mg, 0.15 mmol, 3% yield, 100% de), and is an off-white solid. LC-MS method 1: tR=0.58min, m / z=489.2 [M]+

[0525] H NMR (500MHz, CDC13) δ ppm 8.20 (d, J=1.6 Hz, 1 H), 7.13 (d, J=1.0 Hz, 1 H), 6.85 (d , J=1.5 Hz, 1 H) , 4.58 (s, 2 H) , 4.47 (s, 2 H) , 4.34 (br d , J=12.9 Hz, 2 H) , 3.79 (s, 3 H) , 3.45 ‑ 3.56 (m, 2 H) , 2.48 (d , J=11.4 Hz, 1 H) , 2.30–2.42 (m, 2H), 2.22 (s, 3H), 2.15–2.24 (m, 2H) (Explanation)Book 105 / 129 Page 114 CN 122374293 A 5

[0526] Example 94: 1-(2-((2-(hydroxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium chloride

[0527] Intermediate 39 (130 mg, 0.38 mmol) was added to a stirred solution of intermediate 81 (100 mg, 0.38 mmol) in ACN (1.9 mL). The mixture was stirred in a sealed vial at 80 °C for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by Sfär amino FFC (from 0% to 3% MeOH in DCM) to give the desired product, which is zwitterionic. It was dissolved in DCM (1.0 mL), and a solution of Et2O in 2 M HCl (0.5 mL, 1 mmol) was added while stirring at RT. After 5 min, the volatiles were removed under reduced pressure to give the title compound, a chloride salt (Example 94, 146 mg, 0.28 mmol, 73% yield), as an off-white solid. LC-MS method 1: tR = 0.85min, m / z = 494.4 [M]+

[0529] H NMR (500MHz, DMSO-d6) δ ppm 10.58 (br s, 1H), 10.14 (br s, 1H), 7.58 (br s, 1H) , 7.04 (d , J = 0.8 Hz, 1H) , 5.39 (br t, J = 5.3 Hz, 1H) , 4.67 (br s, 4H) , 4.46 (d, J = 4.9 Hz, 2H) , 4.00 ‑ 3.82 (m, 4H) , 3.75 (s, 3H) , 2.07 (br s, 3H), 2.04 - 1.98 (m, 7H), 1.77 - 1.60 (m, 4H)

[0530] The following examples were prepared from suitable starting materials according to a method similar to that in Example 94, and have been isolated as chloride salts. Specification 106 / 129 pages 115 CN 122374293 A 6

[0531] Specification 107 / 129 pages 116 CN 122374293 A 7

[0532]

[0533] Specification 108 / 129 pages 117 CN 122374293 A 8

[0534]

[0535] Example 3:2-((3-(methoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium carboxylate

[0536] Intermediate 10 (79 mg, 0.27 mmol) was added to a stirred solution of potassium iodide (5 mg, 0.03 mmol) and intermediate 40 (80 mg, 0.27 mmol) in ACN (1 mL). The resulting solution was stirred overnight at 55 °C in a sealed vial. After concentration of the reaction mixture, the residue was purified by Sfär C18 FCC (from (H2O + 0.1% HCOOH) 100% to (H2O + 0.1% HCOOH) / ACN 6:4). The pure fractions were combined and concentrated under reduced pressure at 30°C. The residue was dissolved in H₂O + ACN 1:1 and freeze-dried overnight to give the title compound (Example 3: 53 mg, 0.09 mmol, 35% yield) as a pale yellow powder. LC-MS method 3: tR = 2.62min, m / z = 508.4 [M]+

[0538] H NMR (500MHz, DMSO-d6) δ ppm 10.71 (br s, 1 H), 8.32 (s, 1 H), 7.58 (s, 1 H), 4.84 (br s, 2 H) , 4.45 (br s, 2 H) , 3.74 (s, 3 H) , 3.69 (s, 3 H) , 3.46 (s, 6 H) , 2.51 ‑ 2.70 (m, 4 H) , 2.03 (s, 3 H) , 1.60 ‑ 1.80 (m, 4H).

[0539] The following examples were prepared from suitable starting materials according to the method described in similar to Example 3. Specification 109 / 129 pages 118 CN 122374293 A 9

[0540] Specification 110 / 129 pages 119 CN 122374293 A 20

[0541] Specification 111 / 129 pages 120 CN 122374293 A 1

[0542] Specification 112 / 129 pages 121 CN 122374293 A 2

[0543] Specification 113 / 129 pages 122 CN 122374293 A 3

[0544]

[0545] Example 42: 4-hydroxy-1-(2-(isoxazol-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxy)Carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)piperidine-1-onium chloride

[0546] Intermediate 75 (36 mg, 0.065 mmol) was dissolved in DCM (1 mL), and a solution of Et2O in 2 M HCl (0.7 mL, 1.4 mmol) was added dropwise under RT. After stirring under RT for 24 h, the volatiles were evaporated to give the title compound (Example 42, mixture of diastereomers, 19 mg, 0.04 mmol, 62% yield). LC-MS method 1: tR = 0.52min, m / z = 437.1 [M]+

[0548] 1H NMR (500MHz, DMSO-d6) δ ppm 11.76 (br s, 1H), 10.84-10.31 (m, 1H), 8.88 , 3.88 (br s, 3H), 3.76-3.68 (m, 3H), 2.26-2.06 (m, 2H), 2.01 (s, 3H), 1.94-1.78 (m, 2H).

[0549] Example 63: 4-hydroxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium chloride

[0550] Intermediate 76 (51 mg, 0.08 mmol) was dissolved in DCM (1.5 mL), and 2 M HCl Et2O solution (1.8 mL, 1.8 mmol) was added dropwise at RT. After reacting for 24 h, the volatiles were evaporated to remove the solid residue, which was then redissolved in a DCM / MeOH mixed solvent. The solvent was then removed under reduced pressure to obtain the title compound (Example 63, a mixture of diastereomers, 24 mg, 0.05 mmol, 60% yield), a pale yellow solid.

[0551] LC-MS Method 1: tR = 0.51 min, m / z = 451.3 [M]+

[0552] 1H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (brd, J=4.4 Hz,1 H) , 10.50 (s, 1 H) , 8.68 (s , 1 H) , 7.60 (s , 1 H) , 5.24 (dd , J=12.8, 3.0 Hz, 1 H) , 4.65 ‑ 4.89 (m, 4 H) , 3.79 ‑ 4.09 (m, 5 H), 3.75 (d, J=1.0 Hz, 3 H), 2.05 (s, 3 H), 1.91 (s, 3 H), 1.77 - 2.28 (m, 4 H).

[0553] Example 44: 4-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)morpholine-4-onthionate

[0554] The activated molecular sieve was added to a mixture of intermediate 55 (100 mg, 0.34 mmol), intermediate 18 (78.8 mg, 0.34 mmol) and 2,6-bis(1,1-dimethylethyl)pyridine (26 mg, 0.15 mmol) in ACN (2 mL), and the reaction mixture was stirred at 60 °C for 24 h. The mixture was then concentrated under reduced pressure, and the residue was purified by Sfär amino FCC (from 100% DCM to DCM / (DCM / MeOH 9:1) 5:95), and then by Sfär C18 FCC (H2O + HCOOH 0.1% / ACN 95:5 to H2O + HCOOH 0.1% / ACN 60:30) to give the title compound (Example 44, 8 mg, 0.016 mmol, 10% yield) as a white solid. LC-MS method 1: tR = 0.49min, m / z = 423.2 [M]+

[0556] H NMR (500MHz, DMSO-d6) δ ppm 8.75 (s, 1 H), 8.40 (s, 1 H), 7.56 (s, 1 H), 6.90 (s, 1 H) , 4.88 (br s , 2 H) , 4.80 (br s , 2 H) , 4.01 ‑ 4.15 (m , 4 H) , 3.90 ‑ 3.99 (m, 4 H) , 3.70 (s, 3 H) , 2.03 (s, 3 H).

[0557] Example 60: 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazine-1-onium chloride hydrochloride

[0558] The compound from Example 58 (35 mg, 0.067 mmol) was dissolved in 1,4-dioxane (0.116 mL), and a solution of 1,4-dioxane containing 4 M HCl (0.145 mL, 0.581 mmol) was added dropwise under constant temperature and humidity (rt). After 24 h under constant temperature and humidity, the evaporation was evaporated, and the solid residue was dissolved in DCM / MeOH and then dried to give the title compound (Example 60, 20 mg, 0.04 mmol, 60% yield) as a pale yellow solid. LC-MS method 2: tR = 0.63min, m / z = 422.2 [M]+

[0560] 1H NMR (400MHz, DMSO-d6) δ ppm 11.89 (s, 1H), 10.80 (s, 1H), 9.14-10.30 (m, 2H), 8.90 (d , J=1.5 Hz, 1 H) , 7.59 (s, 1 H) , 6.92 (s, 1 H) , 4.97 (s, 2 H) , 4.92 (s, 2 H) , 4.09 ‑ 4.33 (m, 4 H) , 3.71 (s, 3 H) , 3.57 - 3.83 (m, 4 H), 2.05 (s, 3 H).

[0561] Example 96: 1-(2-((2-((4-aminobutoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazol-3-ylamino)-2-oxoethyl)azacycloheptane-1-onium chloride hydrochloride

[0562] Intermediate 130 (117 mg, 0.174 mmol) was dissolved in DCM (3.0 mL), and 2 M HCl in Et2O solution (1.7 mL, 3.48 mmol) was added dropwise at RT. After 16 h, a solid was formed. The liquid phase was removed, and the solid was ground with DCM to give the title compound (Example 96, 92 mg, 0.163 mmol, 94% yield), as a colorless solid.

[0563] LC-MS Method 1: tR = 0.38 min, m / z = 246.9 [(M+H) / 2]+; 492.4 [M]+ Specification 115 / 129 pages 124 CN 122374293 A 5

[0564] 1H NMR (400MHz, DMSO-d6) δ ppm 8.89 (d, J = 1.8 Hz, 1H), 7.58 (s, 1H), 13.16-7.12 (m, 5H), 6.91 (d, J = 1.5 Hz, 1H), 4.87–4.67 (m, 4H), 4.16 (t, J = 6.0 Hz, 2H), 4.07–3.75 (m, 4H), 2.81 (t, J = 7.2 Hz, 2H), 2.21–1.90 (m, 7H), 1.79–1.52 (m, 8H).

[0565] The following examples were prepared from suitable starting materials according to a method similar to that described in Example 96.

[0566] Specification 116 / 129 pages 125 CN 122374293 A 6

[0567]

[0568] The salt form of the compounds of the present invention can be desalted to obtain the corresponding zwitterionic form as described in Example 89 below.

[0569] Example 89 is a zwitterion: 6-(2-(isoxazo-3-ylamino)-2-oxoethyl)-6-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-6-azaspiro[2.5]octane-6-onium

[0570] The formate of Example 89 (37 mg, 0.070 mmol) was purified by Sfär amino FCC (from DCM 100% to DCM / MeOH 95:5) to give the title compound (Example 89, zwitterion, 25 mg, 0.052 mmol, 74% yield) as a white powder. LC-MS method 1: tR = 0.66min, m / z = 483.4 [M]+

[0572] H NMR (400MHz, DMSO-d6) δ ppm 13.00 (s, 1H), 8.65 (d, J = 1.8 Hz, 1H), 7.89 (d , J = 8.1 Hz, 1H) , 7.81 (d , J = 7.9 Hz, 1H) , 7.48 (ddd , J = 1.3, 7.1, 8.1 Hz, 1H) , 7.33 (ddd , J = 1.0, 7.1, 8.0 Hz, 1H) , 6.91 (d , J = 1.8 Hz, 1H), 4.67 (s, 2H), 4.48 (s, 2H), 3.98–3.79 (m, 4H), 3.75 (s, 3H), 1.95–1.64 (m, 4H), 0.47 (s, 4H)

[0573] The zwitterionic form of the compounds of the present invention can be converted into the corresponding salt form according to the chloride salt form in Example 89 below.

[0574] Example 89 is a chloride salt:6-(2-(isoxazo-3-ylamino)-2-oxoethyl)-6-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-6-azaspiro[2.5]octane-6-onium chloride

[0575] The zwitterion (18 mg, 0.037 mmol) of Example 89 was dissolved in DCM (2.0 mL), and a solution of Et2O in 2 M HCl (28 μL, 0.056 mmol) was added dropwise under RT. After 5 min, the volatiles were removed under reduced pressure to give the title compound, page 117 / 129, CN 122374293 A7 (Example 89, chloride salt, 20 mg, 0.037 mmol, quantitative yield), as a white powder. LC-MS method 1: tR = 0.65min, m / z = 483.4 [M]+

[0577] H NMR (400MHz, DMSO-d6) δ ppm 12.45-10.43 (m, 2H), 8.90 (d, J = 1.8 Hz, 1H), 8.06 (d, J = 8.1 Hz, 1H) , 7.84 (d, J = 8.1 Hz, 1H) , 7.58 (ddd, J = 1.1, 7.1, 8.2 Hz, 1H) , 7.49 ‑ 7.35 (m, 1H) , 6.96 (d , J = 1.2 Hz, 1H) , 4.93 (s, 2H), 4.84 (s, 2H), 4.11–3.88 (m, 4H), 3.80 (s, 3H), 2.04–1.67 (m, 4H), 0.51 (br s, 4H)

[0578] The following examples are prepared as chloride salts according to a method similar to that described in Example 89, starting from suitable examples (e.g.) in zwitterionic form. Instruction manual 118 / 129 pages 127 CN 122374293 A 8

[0579] Instruction manual 119 / 129 pages 128 CN 122374293 A 9

[0580] Instruction manual 120 / 129 pages 129 CN 122374293 A 30

[0581]

[0582] Example 40 is a bromide salt: 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium bromide

[0583] The zwitterion (65mg,0.15 mmol) was dissolved in DCM (2.0 mL), and 2 M HBr aqueous solution (400 μL, 0.8 mmol) was added dropwise under RT. After 4 h, the volatiles were removed under reduced pressure to give the title compound (Example 40, bromide salt, 77 mg, 0.15 mmol, quantitative yield), as a white powder. LC-MS method 1: tR = 0.60min, m / z = 449.2 [M]+

[0585] 1H NMR (600MHz, DMSO-d6) δ ppm 11.76 (1H, s), 10.53 (1H, br s), 8.89 (1H, d, , 1.75 (4H, br s), 1.10 (3 H, s), 1.07 (3 H, s)

[0586] Comparative compounds C1 and C2 were prepared as follows.

[0587] C1 is characterized by replacing the ester-substituted thiophene or benzothiophene ring of the compound of the present invention with a benzene ring.

[0588] C2 is characterized by replacing the ester-substituted thiophene or benzothiophene ring of the compound of the present invention with different heteroaromatic rings.

[0589] The preparation method of compound C1: N,N-bis(phenylcarbamoylmethyl)dimethylammonium chloride (also known as carcaine chloride) is as described on page 6 of WO99 / 63985.

[0590] Compound C2: 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((5-((methoxycarbonyl))-3-methylisoxazo-4-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (zwitterion)

[0591] Intermediate 46 (50 mg, 0.180 mmol) was added to a stirred solution of intermediate 79 (40 mg, 0.180 mmol) in ACN (1.2 mL). The mixture was stirred at RT for 24 h. The mixture was then concentrated under reduced pressure, and the residue was purified by Sfär amino FCC (0-5% MeOH in DCM) to give the title compound (compound C2: 57 mg, 0.114 mmol, 75% yield).

[0592] LC-MS Method 2: tR = 0.52 min, MS (ESI) m / z = 420.1 [M]+

[0593] 1H NMR (500 MHz, DMSO-d6) δ ppm 12.25- 14.42 (m, 1 H), 8.76 (d, J=1.6 Hz, 1 H), 6.92 (d, J=1.6 Hz, 1 H), 4.61 (s, 2 H), 4.14 (s, 2 H), 3.74 (s, 3 H), 3.68 - 3.85 (m, 4 H), 2.11 (s, 3 H), 1.93 (br s, 4 H), 1.63 (br s, 4 H)

[0594] Pharmacological activity of the compounds of the present invention

[0595] hNav 1.7 cell assay protocol

[0596] In the automated patch-clamp assay described herein, the intracellular and extracellular inhibition of NaV 1.7 by representative embodiments of the present invention was tested.

[0597] Cell Culture

[0598] CHO cells stably expressing the human NaV 1.7 channel were purchased from B'SYS GmbH, Switzerland. Cells were cultured in F12 Nutmix (Gibco, Carlsbad CA) supplemented with 10% fetal bovine serum (Invitrogen, Waltham MA), 1% penicillin-streptomycin (Gibco, Carlsbad CA), and 200 μg / ml hygromycin B (Invitrogen, Waltham MA). Cells were cultured and maintained at 37°C in a humidified atmosphere with 5% CO2. At passage, cells were removed from the culture flask and collected using TrypLE Express (Sigma-Aldrich, St. Louis, MO). Experimental flasks were prepared with cells cultured for 2–4 days without antibiotics and used at ~80% confluence. Before the experiment, cells were washed with Ca²⁺- and Mg²⁺-free PBS and separated with preheated TrypLE Express. After a brief centrifugation step, the cells were resuspended in CHO-S- serum-free medium II (Life Technologies, Carlsbad CA). Cells were counted, and the final concentration was set at 3-4 million cells per mL.

[0599] Patch-clamp solution and drugs

[0600] The intracellular solution (or internal solution) contained the following components: 140 mM CsF, 10 mM NaCl, 1 mM EGTA and 10 mM HEPES, adjusted to pH 7.2 with CsOH, and adjusted to osmolarity 325 with sucrose. The extracellular solution (or external solution) contained the following components: 40 mM NMDG, 100 mM NaCl, 4 mM KCl, 1 mM MgCl₂,2 mM CaCl2, 10 mM HEPES, 10 mM glucose, adjusted to pH 7.4 with HCl, and osmotic pressure adjusted to 310 with sucrose. All chemicals were purchased from Sigma-Aldrich, St. Louis, MO.

[0601] For intracellular and extracellular applications of the test compounds, the spotted compounds were dissolved in intracellular and extracellular solutions, respectively, and tested at up to 60 μM, resulting in a pIC50 of not less than 4.2.

[0602] Automated Patch-Clamp Test Protocol

[0603] Automated patch-clamp experiments were performed on a Qube 384 (Sophion Bioscience A / S, Ballerup, Denmark) equipped with a porous Qchip at a temperature set at 22 °C. A whole-cell clamp configuration was formed using the default Qube sealing and rupture parameters. The membrane potential was maintained at -100 mV before the voltage protocol was started. The voltage protocol consisted of 20 pulses, with 30 scans for intracellular applications and 55 scans for extracellular applications before and after compound administration. Cells were maintained at -100 mV, and a depolarization pulse lasting 10 ms was applied to -20 mV. The scan interval was set to 9 s while the holding potential was -100 mV.

[0604] Testing the internal blockade (intracellular inhibition) induced by the compound

[0605] For intracellular applications of the compound, the QChip was removed from the recording chamber. The intracellular solution was replaced with a solution containing the test compound. After the intracellular solution exchange, the QChip was returned to the recording chamber, and a voltage pulse was applied.

[0606] Data filtering was performed using Sophion Analyzer software. Only orifices with a minimum sealing resistance of 40 MΩ and a premixed current of 1 nA were used for subsequent Aplus software analysis. The average peak current amplitude of the 20th pulse in the last three pulse sequences under both premixed and postmixed conditions was calculated. Calculate the post-mixed / premixed ratio for each well.

[0607] The results were then normalized to the 0.3% DMSO control group (which was considered 0%) and the complete blockade group (100 μM N-(2,6-dimethylphenylcarbamoylmethyl)triethylammonium chloride, also known as QX314, for internal use) (which was considered 100% inhibition). The percentage of activity was plotted and the concentration-response curve was fitted using a four-parameter logistic Hill equation. Based on the fitted curve, the IC50 value was estimated and the intracellular pIC50 value was calculated.

[0608] Test for external blockade (extracellular inhibition) caused by the compound

[0609] To apply the compound extracellularly, the original extracellular solution was replaced with a solution containing the test compound. After the extracellular solution was replaced, a voltage pulse was applied.

[0610] Data filtering was performed using Sophion Analyzer software. Only data with a minimum 50 MΩ sealing resistance and 1 nA pre-...The wells of the mixed-liquid current were subsequently analyzed using Aplus software. The average value of the peak current amplitude of the 20th pulse in the last three pulse sequences under both premixed and postmixed conditions was calculated. The postmixed / premixed ratio for each well was calculated.

[0611] The results were then standardized to: a baseline of 0.3% DMSO control group (which was considered 0%) and a baseline of complete blockade group (300 μM tetracaine topical) (which was considered 100% inhibition). The percentage of activity was plotted and the concentration-response curve was fitted using the four-parameter logistic Hill equation. Based on the fitted curve, the IC50 value was estimated and the extracellular pIC50 value was calculated.

[0612] When the inhibition rate was less than or equal to 50% at the highest compound concentration tested (60 μM), the obtained pIC50 value was ≤ 4.2. (Pages 122 / 129 of the specification, CN 122374293 A 2).

[0613] Table 2 lists the intracellular and extracellular inhibition data of representative examples.

[0614] Table 2 - Intracellular and extracellular inhibition of representative embodiments, hNav 1.7 Specification 123 / 129 pages 132 CN 122374293 A 3

[0615] Specification 124 / 129 pages 133 CN 122374293 A 4

[0616] Specification 125 / 129 pages 134 CN 122374293 A 5

[0617]

[0618] As previously stated, the compounds in Table 2, i.e. the compounds of the present invention, exhibit high intracellular inhibitory activity against the NaV 1.7 receptor. Conversely, the compounds in Table 2 exhibit low extracellular inhibitory activity against the NaV 1.7 receptor.

[0619] Table 3 lists the inhibition data of the selected compounds tested in zwitterionic and salt (chloride) forms. It can be seen that both forms have high intracellular inhibitory activity against the NaV 1.7 receptor. In some cases, the difference between the corresponding zwitterionic and salt forms can be ignored, which can be considered to be within the experimental error range.

[0620] Table 3 - Comparison of intracellular and extracellular inhibition of representative examples in zwitterionic or salt forms, hNav 1.7 Specification 126 / 129 pages 135 CN 122374293 A 6

[0621]

[0622] Therefore, the compounds of the present invention, whether in zwitterionic or salt forms, can be used to treat respiratory diseases, such as cough, asthma, idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD), especially chronic cough.

[0623] Comparative Compounds

[0624] Compounds C1 and C2 were tested in the same binding assays described above, and their intracellular and extracellular pIC50 are listed in Table 4.

[0625] Table 4 - Intracellular and extracellular inhibition of comparative compoundsPages 127 / 129, 136 CN 122374293 A 7

[0626]

[0627] As shown in Tables 2, 3 and 4 (Example 25), the compounds of formula (I) of the present invention exhibit intracellular inhibitory activity against NaV 1.7, expressed as pIC50 values ​​greater than 5, 5 to 5.5, greater than 5.5, or 5.5 to 6.

[0628] These data indicate that, unlike the comparative compound C1, the presence of an ester-substituted thiophene or benzothiophene ring in the compounds of the present invention unexpectedly and significantly increases the intracellular inhibitory activity against NaV 1.7 and increases the difference between intracellular and extracellular inhibition of NaV 1.7, as shown in the DELTA reported in Tables 2, 3 and 4.

[0629] Furthermore, as described in the same section of the Experimental section, the reported data indicate that, compared to the comparative compound C2, the presence of an ester-substituted thiophene ring in the compounds of the present invention (particularly Example 25) unexpectedly and significantly increased the intracellular inhibitory activity of the NaV 1.7 receptor and increased the difference between intracellular and extracellular inhibition of NaV 1.7 (DELTA).

[0630] hERG Assay Protocol

[0631] The effect of the test substance on the tail current of the human Ether-à-go-go-related gene (hERG) was evaluated in an automated patch-clamp protocol using a QPatch instrument (Sophion Bioscience A / S, Ballerup, Denmark).

[0632] Cell Culture

[0633] hERG was expressed in HEK293 cells after induction with tetracycline.

[0634] Cells were cultured in minimum essential medium (MEM) supplemented with 10% heat-inactivated fetal bovine serum, 1% non-essential amino acids, 1% sodium pyruvate, 2 mM L-glutamine, 1% penicillin-streptomycin, 15 μg / ml blastomycin, and 100 μg / ml hygromycin. hERG cells were induced with 10 μg / ml tetracycline for 24 to 72 h prior to recording.

[0635] Before the experiment, cells were washed with calcium- and magnesium-free Dulbecco phosphate-buffered saline (DPBS), peeled with TrypLE, and then ground in serum-free medium containing 25 mM HEPES and soybean trypsin inhibitor to resuspend the cells and disperse cell clumps. After cell counting, the final cell concentration was set at 4–6 million cells / mL. All chemical reagents used for cell culture were purchased from Life Technologies Italia Srl, Monza, Italy. Instructions for Use, pages 128 / 129, 137 CN 122374293 A 8

[0636] Patch-clamp solution and drug

[0637] The intracellular solution contains the following components (unit: mM): KCl 130, MgCl2 1EGTA 5, MgATP 5, HEPES 10, pH adjusted to 7.2 with 1M KOH.

[0638] The external solution contained the following components (in mM): NaCl 137; KCl 4; CaCl2 1.8; MgCl2 1; d-glucose 10; HEPES 10; pH adjusted to 7.4 with NaOH.

[0639] All chemicals used in the patch-clamp solution were from Merck Life Science Srl, Milano, Italy.

[0640] To assess the degree of external blockade, the compounds were first dissolved in DMSO and then diluted with extracellular buffer to achieve final test concentrations of 0.6 μM, 6 μM, and 60 μM in 0.3% DMSO.

[0641] Voltage Protocol

[0642] Voltage clamp experiments were performed using a single-well QPlate chip (Sophion Bioscience, Denmark). The membrane potential was maintained at -80 mV before the voltage protocol was started. The voltage scheme consisted of the following sequential steps: -50 mV for 200 ms, +20 mV for 4.8 s, -50 mV for 5 s, and then a return to the holding potential. The hERG tail current was measured during the repolarization from +20 mV to -50 mV. Each voltage scheme scan lasted 15 s and was continuously repeated at a frequency of 0.066 Hz during the experiment.

[0643] Liquid Scheme

[0644] An external solution was applied first, followed by a solvent solution (equivalent to an external solution of 0.3% DMSO), each lasting 3 min 45 s to achieve a stable current recording. Then, three increasing concentrations (0.6, 6, and 60 μM, dissolved in 0.3% DMSO) of the test compound were applied, each lasting 5 min.

[0645] Data Analysis

[0646] In each compound dosing regimen, the average tail current obtained from the last four voltage scans was measured; subsequently, using Sophion Analyser software (Sophion Bioscience, Denmark), the percentage of inhibition relative to solvent pretreatment was calculated for each cell at each test concentration. The IC50 value was estimated using the Hill fitting equation in Sophion Analyser software. Specification 129 / 129 pages 138 CN 122374293 A 9

Claims

1. Compound of formula (I) (I) At least one of Y and Z is S, and the other is CR4; R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C6)alkyl-OR6. 10 Heterocyclic alkyl groups, wherein -(C3-C 10 The heterocyclic alkyl group is optionally substituted with one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl; R3 and R4 are independently H or selected from CN, -(C1-C6) alkyl and aryl, or, where Y is CR4, R3 and R4 are fused together to form an aryl group; R5 is selected from -(C1-C6)alkyl, -(C1-C6)alkyl-NR6R7, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-C(O)NR6R7, -(C3-C 10 Heterocyclic alkyl groups and -(C3-C7)cycloalkyl groups; R6 and R7 are independently H or selected from -(C1-C6)alkyl and -(C1-C6)alkyl-aryl; L1 is a bond or selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic- and -(C1-C6)cycloalkylene-; and A is a ring, selected from aryl, heteroaryl, and -(C3-C) rings. 10 )cycloalkyl and -(C3-C 10 Heterocyclic alkyl groups, wherein any such aryl group, heteroaryl group, -(C3-C 10 )cycloalkyl or -(C3-C 10 The heterocyclic alkyl group may optionally be substituted with one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; provided that when L1 is a bond, any such aryl group is not substituted with -(C1-C6)alkyl. It is in zwitterionic form or pharmaceutically acceptable salt form.

2. The compound of formula (I) according to claim 1, wherein Z, Y, R1, R2, R3, R4, R5, R6 and R7 as defined in claim 1; L1 is selected from -(C1-C6)alkylene-, -(C1-C6)heterocyclic- and -(C1-C6)cycloalkylene-; and A is a ring, selected from aryl, heteroaryl, and -(C3-C) rings. 10 )cycloalkyl and -(C3-C 10 Heterocyclic alkyl groups, wherein any such aryl group, heteroaryl group, -(C3-C 10 )cycloalkyl or -(C3-C 10 The heterocyclic alkyl group is optionally substituted with one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; It is in zwitterionic form or pharmaceutically acceptable salt form.

3. The compound of formula (I) according to claim 1, wherein L1 is a bond, and the compound is represented by formula (Ia). (Ia) in Z, Y, R1, R2, R3, R4, R5, R6, and R7 as defined in claim 1; and A is a ring, wherein the ring is selected from aryl, heteroaryl, -(C3-C 10 )cycloalkyl and -(C3-C 10 Heterocyclic alkyl groups, wherein any such heteroaryl group, -(C3-C 10 )cycloalkyl or -(C3-C 10 The heterocyclic alkyl group is optionally substituted with one or more groups selected from halogens, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; and any such aryl group is optionally substituted with one or more groups selected from halogens, -C(O)OR6, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6 and -(C1-C6)alkyl-NR6R7; It is in zwitterionic form or pharmaceutically acceptable salt form.

4. The compound according to any one of the preceding claims, wherein R1 and R2 are independently selected from -(C1-C6)alkyl and -(C1-C6)alkyl-OR6, or fused together to form -(C3-C6)alkyl-OR6. 10 Heterocyclic alkyl groups, wherein -(C3-C 10 The heterocyclic alkyl group is optionally substituted with one or more groups selected from halogens, -OR6, -(C1-C6)alkyl and -C(O)OR6-; R3 and R4 are independently H or -(C1-C6)alkyl, or, where Y is CR4, R3 and R4 are fused together to form an aryl group; R5 is selected from -(C1-C6)alkyl and -(C3-C6)cycloalkyl; It is in zwitterionic form or pharmaceutically acceptable salt form.

5. The compound according to any one of the preceding claims, wherein R1 and R2 fused together to form -(C3-C 10 Heterocyclic alkyl groups, wherein -(C3-C 10 The heterocyclic alkyl group is optionally substituted with one or more groups selected from -OR6, -C(O)OR6, -(C1-C6)alkyl and -(C1-C6)haloalkyl; It is in zwitterionic form or pharmaceutically acceptable salt form.

6. The compound according to any one of the preceding claims, wherein R3 and R4 are independently H or -(C1-C6) alkyl; It is in zwitterionic form or pharmaceutically acceptable salt form.

7. The compound according to any one of the preceding claims, wherein Z is S and Y is CH or Z is CH and Y is S, and R3 is H or methyl; It is in zwitterionic form or pharmaceutically acceptable salt form.

8. The compound according to any one of the preceding claims, wherein A is a heteroaryl group, which is optionally substituted by one or more groups selected from halogens, -OR6, -C(O)OR6, -(C1-C6)alkyl, -C(O)NR6R7, -(C1-C6)haloalkyl, -(C1-C6)alkyl-OR6, -(C1-C6)alkyl-NR6R7 and -(C1-C6)alkyl-C(O)NR6R7.

9. The compound according to claim 1, wherein the compound is selected from: 1,1-Bis(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 1); 2-((3-carbamoyl-5,6-dihydro-4H-cyclopentadien[b]thiophen-2-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 2); 2-((3-(methoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 3); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N,N-dimethyl-2-oxo-N-(2-oxo-2-(pyrimidin-5-ylamino)ethyl)ethyl-1-ammonium (Example 4); 2-(isoquinoline-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 5); 2-(benzylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 6); 2-(isoxazo-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 7); 2-((cyclohexylmethyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 8); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 9); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 10); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N,N-dimethyl-2-oxo-N-(2-oxo-2-((2-(trifluoromethyl)benzyl)amino)ethyl)ethyl-1-ammonium (Example 11); 2-(benzylamino)-N,N-dimethyl-N-(2-((4-methyl-2-(propoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-2-oxoethyl-1-ammonium (Example 12); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 13); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N,N-dimethyl-N-(2-((2-methylbenzyl)amino)-2-oxoethyl)-2-oxoethyl-1-ammonium (Example 14); 2-(benzylamino)-N-(2-((2-(isopropoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 15); 2-((2,6-dimethylbenzyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 16); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 19); 2-(((2,3-dihydro-1H-inden-2-yl)methyl)amino)-N-(2-((2-((methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 20); 1-(2-((2,3-dihydro-1H-inden-2-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 22); 1-(2-(benzylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 23); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-(((5-(methoxycarbonyl)thiophen-3-yl)methyl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 24); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 25); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N-(2-((2-(methoxymethyl)benzyl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 26); 1-(2-((2-((2-(benzylamino)-2-oxoethoxy)carbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-(benzylamino)-2-oxoethyl)azacycloheptane-1-onium (Example 27); 1-(2-(benzylamino)-2-oxoethyl)-1-(2-((2-(tert-butoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 28); 1,1-Bis(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 29); 2-((2-(isopropoxycarbonyl)benzyl)amino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-dimethyl-2-oxoethyl-1-ammonium (Example 30); 1,1-Bis(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 31); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 32); 1-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 33); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 34); 1,1-Bis(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 35); 1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 36); (R)-1-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azacycloheptane-1-onium (Example 37); (R)-1-(2-((2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azacycloheptane-1-onium (Example 38); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 39); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 40); 1-(2-((2-(tert-butoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)azacycloheptane-1-onium (Example 41); 4-Hydroxy-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 42); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4-methoxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 43); 4-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)morpholine-4-onium (Example 44); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-5-phenylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 45); (R)-1-(2-((5-(tert-butyl)-2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)azacycloheptane-1-onium (Example 46); 4-(2-(benzylamino)-2-oxoethyl)-4-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)thiomorpholine-4-onium (Example 47); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylcyclopropyl)amino)ethyl)azacycloheptane-1-onium (Example 50); 7-(2-(benzylamino)-2-oxoethyl)-7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-2-oxa-7-azaspiro[3.5]nonane-7-onium (Example 51); (S)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((1-phenylethyl)amino)ethyl)pyrrolidine-1-onium (Example 52); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)pyrrolidine-1-onium (Example 53); 7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-7-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)-2-oxa-7-azaspiro[3.5]nonane-7-onthium (Example 55); 4-(ethoxycarbonyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazine-1-onium (Example 56); 2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-N,N-dimethyl-N-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)-2-oxoethyl-1-ammonium (Example 57); 4-(tert-butoxycarbonyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazine-1-onium (Example 58); 2-(isoxazo-3-ylamino)-N-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-N,N-bis(2-methoxyethyl)-2-oxoethyl-1-ammonium (Example 59); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperazine-1-onium (Example 60); 4-Methoxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 62); 4-Hydroxy-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 63); 1-(2-((2-(cyclopropoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 64); 4-Fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-methyl-1-(2-((4-methylisoxazol-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 65); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((3-methylisothiazo-5-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 66); (2-((1r,4r)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-methylpiperidin-1-onthium-1-yl)acetyl)(4-methylisoxazol-3-yl)amide (Example 67); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidine-1-onium (Example 68); 2,2-Difluoro-7-(2-(isoxazo-3-ylamino)-2-oxoethyl)-7-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-7-azaspiro[3.5]nonane-7-onthium (Example 69); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((3-phenyloxetane-3-yl)amino)ethyl)piperidine-1-onium (Example 70); 4,4-Difluoro-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 71); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((4-(methoxycarbonyl)-2-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 72); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((4-methyl-2-((piperidin-4-yloxy)carbonyl)thiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 73); 1-(2-((2-((2-hydroxyethoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 74); (1s,4s)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidine-1-onium (Example 75); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-(pyrazin-2-ylamino)ethyl)piperidine-1-onium (Example 76); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 77); 2-(2-(isoxazo-3-ylamino)-2-oxoethyl)-2-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)isoindoline-2-onium (Example 78); 1-(2-((4-cyano-2-(methoxycarbonyl)thiophen-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 79); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-((2-methoxyethoxy)carbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 80); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-((oxecyclobutane-3-yloxy)carbonyl)thiophene-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 81); 1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-(((tetrahydro-2H-pyran-4-yl)oxy)carbonyl)thiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 82); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-((1-(pyridin-2-yl)cyclopropyl)amino)ethyl)piperidine-1-onium (Example 83); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-(pyrimidin-5-ylamino)ethyl)piperidine-1-onium (Example 84); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-((4-methyl-2-((methylamino)methyl)thiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 85); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-((3-methylpyrazin-2-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 86); 1-(2-((4-chloroisoxazo-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 87); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-oxo-2-((3-phenyloxetane-3-yl)amino)ethyl)azacycloheptane-1-onium (Example 88); 6-(2-(isoxazo-3-ylamino)-2-oxoethyl)-6-(2-((2-(methoxycarbonyl)benzo[b]thiophen-3-yl)amino)-2-oxoethyl)-6-azaspiro[2.5]octane-6-onium (Example 89); 1-(2-(benzylamino)-2-oxoethyl)-4,4-bis(hydroxymethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)piperidine-1-onium (Example 90); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethyl-1-(2-oxo-2-((1-(pyrimidin-2-yl)cyclopropyl)amino)ethyl)piperidine-1-onium (Example 91); 1-(2-((5-(methoxycarbonyl)-3-methylisoxazol-4-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 92); 1-(2-((3,4-dimethylisoxazo-5-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 93); 1-(2-((2-(hydroxymethyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)azacycloheptane-1-onium (Example 94); 1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-1-(2-((6-methoxypyrazin-2-yl)amino)-2-oxoethyl)-4,4-dimethylpiperidine-1-onium (Example 95); 1-(2-((2-((4-aminobutoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)azacycloheptane-1-onium (Example 96); 1-(2-((2-((4-aminobutoxy)carbonyl)-4-methylthiophene-3-yl)amino)-2-oxoethyl)-1-(2-(benzylamino)-2-oxoethyl)azacycloheptane-1-onium (Example 97); (2-((1s,4s)-4-fluoro-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-methylpiperidin-1-onthien-1-yl)acetyl)(4-methylisoxazol-3-yl)amide (Example 98); and (1r,4r)-1-(2-(isoxazo-3-ylamino)-2-oxoethyl)-1-(2-((2-(methoxycarbonyl)-4-methylthiophen-3-yl)amino)-2-oxoethyl)-4-(trifluoromethyl)piperidine-1-onium (Example 99); It is in zwitterionic form or pharmaceutically acceptable salt form.

10. Use of an intermediate compound selected from compounds (III), (V), (VII) and (X) for the preparation of a compound of formula (I) according to any one of claims 1 to 9, R1, R2, R3, R5, L1 and A are as defined in claims 1 to 9, and X2 is a halogen, preferably chlorine or bromine.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9, which is mixed with one or more pharmaceutically acceptable carriers or excipients.

12. The pharmaceutical composition according to claim 11, which is formulated for inhalation administration.

13. The compound of formula (I) according to any one of claims 1 to 9 or the pharmaceutical composition according to claim 11 or 12, used as a medicine.

14. The compound or pharmaceutical composition of formula (I) according to claim 13, for the prevention and / or treatment of diseases, disorders or conditions related to sodium channel receptor mechanisms.

15. The compound or pharmaceutical composition of formula (I) according to claim 13 or 14 for the prevention and / or treatment of respiratory diseases selected from cough, subacute or chronic cough, refractory cough, intractable chronic cough, idiopathic chronic cough, post-viral cough, iatrogenic cough, asthma, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and cough associated with respiratory diseases such as COPD, asthma, and bronchospasm.

16. The compound or pharmaceutical composition of formula (I) according to claim 15, for the prevention and / or treatment of chronic cough.