Novel compounds as α4β7 inhibitors

Abstract

Novel compounds that act as inhibitors of alpha4beta7 integrin are disclosed. Pharmaceutical compositions and methods of use of inhibitors of [alpha] 4 [beta] 7 integrin are disclosed. In particular, methods of using the [alpha] 4 [beta] 7 inhibitors in the treatment of diseases or conditions associated with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480040048.7 (22) Application Date 2024.04.16 (30) Priority Data 23168190.9 2023.04.17 EP (85) PCT International Application Entering National Phase Date 2025.12.15 (86) PCT International Application Application Data PCT / EP2024 / 060235 2024.04.16 (87) PCT International Application Publication Data WO2024 / 218058 EN 2024.10.24 (71) Applicant: Evotek International GmbH Address: Hamburg, Germany (72) Inventors: M. Bizarro, G.F. Ruda, M. Saba, C.V. Miduturu (74) Patent Agency: China Patent Agency (Hong Kong) Limited 72001 Patent Attorneys: Xu Houcai, Peng Chang (51) Int.Cl. C07D 207 / 416 (2006.01) C07D 211 / 60 (2006.01) C07D 213 / 81 (2006.01) C07D 213 / 82 (2006.01) C07D 215 / 48 (2006.01) C07D 231 / 14 (2006.01) C07D 231 / 56 (2006.01) C07D 401 / 04 (2006.01) C07D 401 / 12 (2006.01) C07D 471 / 04 (2006.01) C07D 487 / 04 (2006.01) A61P 29 / 00 (2006.01) C07C 235 / 34 (2006.01) C07K 5 / 06 (2006.01) A61K 38 / 05 (2006.01) (54) Novel Compounds with Invention Title as α4β7 Integrin Inhibitors (57) Abstract: Novel compounds that act as inhibitors of α4β7 integrins are disclosed. Pharmaceutical compositions and methods of use of α4β7 integrins inhibitors are disclosed. In particular, methods of using the α4β7 inhibitors in the treatment of diseases or conditions associated with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. Claims 48 pages, Description 484 pages, CN 121335883 A 2026.01.13 CN 1 21 33 58 83 A 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: wherein: Ry is -CH(CH3)2, -CF3, -CH2F, CHF2, -CH(CF3)2, cyclopropyl or cyclobutyl; Rx is hydrogen or methyl; R1 is -C(O)-R7;Wherein R7 is a -C1-6 alkyl group substituted with 0 or 1 pyridine, phenyl, or cyclopropyl groups; or R7 is a phenyl or 5-10 membered heterocyclic group, each independently substituted with 0, 1, 2, 3, or 4 instances of R9; each R9 is independently selected from halogens, =O, -C1-6 alkyl, -C(O)-R10, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, -O-R11, phenyl, and 4-10 membered heterocycles; and each R9 is independently substituted with 0, 1, 2, or 3 groups independently selected from R17; R17 is selected from halogens, -C1-6 alkyl, -O-R15, -C(O)-N(C1-4 alkyl)2, -N(R 12R13), cyclopropyl and 4 to 10 membered heterocycles, wherein when R17 is a heterocycle, it is further substituted by 0, 1, 2 or 4 groups independently selected from halogen, -C1-6 alkyl, =O, -C(O)-R14, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, -O-R18; R10 is independently selected from -C1-6 alkyl, -C1-6 alkyl-C3-6 cycloalkyl and C3-6 cycloalkyl; R11 is -C1-6 alkyl, -C1-6 haloalkyl, 4 to 10 membered heterocycles or -C1-6 alkyl-N(C1-6 alkyl)2, wherein the 4 to 10 membered heterocycles are substituted by 0 or 1 -C1-6 alkyl; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein the C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl are substituted with 0, 1, 2, or 3 F atoms; R14 is independently selected from -C1-6 alkyl and C3-6 cycloalkyl; R15 is H, -C1-6 alkyl, -C1-6 haloalkyl, 4- to 10-membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2, wherein when R15 is a 4- to 10-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl; R18 is -C1-6 alkyl or -C1-6 haloalkyl; In each of the -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2 groups, the two alkyl groups attached to N can be the same or different; R2 is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 heteroaryl groups, each of which can be independently substituted by 0, 1, 2, 3, or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6 haloalkyl, -O-C1-6 alkyl, phenyl, 5- to 6-heteroaryl, -O-C3-6 cycloalkyl, -O-phenyl, and -O-(5- to 6-heterocycloalkyl); Y is -N= or -C(R3)=; R3 is halogen, -C1-6 haloalkyl, -C1-4 alkyl, or -C3-6 cycloalkyl; R4 is halogen or hydrogen; R5 is halogen or hydrogen;R6 is -C(O)-O-R8, claim 1 / 48 page 2 CN 121335883 A wherein R8 is hydrogen or -C1-4 alkyl, -C1-4 alkyl-R16, -C1-4 alkyl-C(O)N(Me)-R16, -C1-4 alkyl-R16, -C1-4 alkyl-C(O)N(R16,R16a)- or -C1-4 alkyl-O-C(O)-R16; R16 and R16a are independently selected from -C1-6 alkyl, 3 to 6 cycloalkyl, 4 to 6 membered heterocycles, 4 to 6 membered partially saturated heterocycles, wherein the partially saturated heterocycle is further substituted by one or two groups independently selected from =O or -C1-4 alkyl. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, having formula Ia wherein R1 to R6, Rx, Ry and Y are as defined in claim 1. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: Rx is hydrogen. 4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Rx is methyl. 5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Ry is -CH(CH3)2, -CF3, cyclopropyl, or cyclobutyl. 6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ry is -CH(CH3)2, cyclopropyl, or cyclobutyl. 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Ry is -CH(CH3)2. 8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Ry is cyclopropyl. 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Ry is cyclobutyl. 10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl, wherein C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F. 11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R17 is selected from halogens, -C1-6 alkyl, -O-R15, -C(O)-N(C1-4 alkyl)2, -N(R12R13) and 4 to 10 membered heterocycles, and when R17 is a heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogens, -C1-6 alkyl, =O, -C(O)-R14, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl and -O-R18.12. The compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, wherein R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, and cyclopropyl. 13. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R15 is -C1-6 alkyl, -C1-6 haloalkyl, a 4- to 10-membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2, wherein when R15 is a 4- to 10-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl group. 14. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R2 is independently substituted with 0, 1, 2, or 3 groups. 15. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen or -C1-4 alkyl or -C1-4 alkyl-O-C(O)-R16. Claims 2 / 48 pages 3 CN 121335883 A 16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein R8 is hydrogen or -C1-4 alkyl-C1-4 alkyl-R16, -C1-4 alkyl-C(O)N(Me)-R16- or -C1-4 alkyl-O-C(O)-R16, and R16 is independently selected from -C1-6 alkyl, 3 to 6 cycloalkyl, 4 to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycle is further substituted by one or two groups independently selected from =O or -C1-4 alkyl. 17. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein: R2 is phenyl or 5-10-membered heteroaryl, each of the groups being substituted by 1, 2, 3 or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6 haloalkyl. 18. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein: R2 is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, and -C1-6 haloalkyl, and selected from [specific groups]. 19. The compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, wherein: R2 is substituted with 1, 2, 3 or 4 groups independently selected from -CN, methyl, F, Cl, and -CF3, and selected from [specific groups]. 20. The compound of any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, wherein: R2 is substituted with 1, 2, 3 or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, and -C1-6 haloalkyl, and selected from [specific groups]. 21. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Y is -C(R3)=. 22. The compound of any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, wherein Y is -N=.23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R3)= and R3 is a halogen, -CF3, methyl, ethyl, or cyclopropyl. 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R4 is a halogen or hydrogen. 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein R4 is a halogen. 26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R4 is fluorine. 27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R5 is fluorine or hydrogen. 28. The compound of claim 27, wherein R5 is hydrogen. 29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R6 is -C(O)-R8, wherein R8 is hydrogen, methyl, CF3, ethyl, isopropyl, –CH2-(5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl) or –CH2-C(O)N(Me)2. 30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R6 is -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl, or isopropyl. 31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R8 is hydrogen. 32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R7 is a -C1-6 alkyl group substituted with 0 or 1 pyridine. 33. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R7 is a phenyl group substituted with 0, 1, 2, 3, or 4 groups selected from -C1-6 alkyl, halogen, or -O-C1-6 alkyl groups. 34. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R7 is a phenyl group substituted with 0, 1, 2, or 3 groups selected from -C1-6 alkyl, halogen, or -O-C1-6 alkyl groups. 35. The compound according to any one of claims 1 to 31 or a pharmaceutically acceptable salt thereof, wherein R7 is a 5-10 membered heterocyclic group substituted with 0, 1, 2, 3 or 4 groups independently selected from R9, and each R9 is independently selected from halogen, =O, -C1-6 alkyl, -C(O)-R10, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R11; each R9 is independently substituted with 0, 1 or 2 groups independently selected from R17; R10 is independently selected from -C1-6 alkyl, C3-6 cycloalkyl and -C1-6 alkyl-C3-6 cycloalkyl;R11 is a -C1-6 alkyl, -C1-6 alkyl-N(-C1-6 alkyl)2, -C1-6 haloalkyl, or a 4- to 7-membered heterocycle; R17 is selected from halogens, -O-R15, -C(O)N(C1-4 alkyl)2, -N(R12R13), and 4- to 10-membered heterocycles, wherein when R17 is a 4- to 10-membered heterocycle, it is substituted by 0, 1, 2, or 4 independently selected halogens, -C1-6 alkyl, or -C1-6 haloalkyl; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, and cyclopropyl; R15 is a -C1-6 alkyl, -C1-6 haloalkyl, or a 4- to 7-membered heterocycle, wherein when R15 is a 4- to 7-membered heterocycle, it is substituted by 0 or 1 -C1-6 alkyl. Furthermore, in each of the -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2 groups, the two alkyl groups connected to the N group may be the same or different. 36. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein R7 is a 5-10 membered heterocyclic group substituted with 0, 1, 2, or 3 groups, and R17 is a 4- to 10 membered heterocyclic ring, wherein R17 is substituted with 0, 1, or 2 groups. 37. The compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, wherein R9 is a -C1-6 alkyl group substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C1-4 alkyl)2, -O-R15, -N(R12R13), 4 to 10-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is further substituted with 0, 1 or 2 groups independently selected from halogen or -C1-6 alkyl groups; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl and cyclopropyl; R15 is a -C1-6 alkyl, -C1-6 haloalkyl or 4 to 7-membered heterocycle, and when R15 is a 4 to 7-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl group, and wherein in each -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups connected to N may be the same or different. 38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from the group consisting of: (Claims 4 / 48, page 5, CN 121335883 A), each substituted by 0, 1, or 2 independently selected substituents from: –F, –Cl, oxo, –Me, –isobutyl, –isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –CF3, –OMe, –OCF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, 3-N(Me)2-3-Me-azacyclobutane-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl1-Isopropyl-piperidin-4-yl, 4-N(Me)2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-Me-1,4-diazacycloheptane-1-yl, 4-isopropyl-1,4-diazacycloheptane-1-yl, 4-cyclopropyl-1,4-diazacycloheptane-1-yl, 5-methyl-2,4,6,7-tetrahydropyrazole[4,3-c]pyridin-2-yl, 2-methyl-2,7-diazaspiro[3.5]nonane-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonane-2-yl, 1-methyl-1 ,7-diazaspiro[3.5]nonane-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptane-6-yl, 3-(3-azabicyclo[3.1.1]heptane-3-yl)-azacyclobutane-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-azacyclobutane-1-yl) –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3-OCF3-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-azacyclobutane-1-yl), –CH2-CH2-(3-OCHF2-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(2,2-diMe-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe- Azahexacyclic butane-1-yl), –CH2-CH2-(3-MeO-3-Me-azahexacyclic butane-1-yl), –CH2-CH2-(3-CHF2-3-Me-azahexacyclic butane-1-yl), –CH2-CH2-(3-F-3-Me-azahexacyclic butane-1-yl), –CH2-CH2-CH2-(3-F-3-Me-azahexacyclic butane-1-yl), –C H2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2-(3-CF3-pyrrolidine-1-yl), –CH2CH2-(3,3-diF-pyrrolidine-1-yl), oxacyclobutane-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, –CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N(Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me)2N(Me)2, –CH2CH2C(Me)2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)CH(Me)2, –CH2CH2N(Me)C(Me)3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl, –CH2CH2-(2-azaspiro[3] .4]octan-2-yl), –CH2CH2CH2-(2-azaspiro[3.4]octan-2-yl), –CH2CH2CH2CH2-(2-azaspiro[3.4]octan-2-yl), –CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(6-MeO-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2CH2-(7-azaspiro[3.4]octan-2-yl), –CH2CH2-(7-azaspiro[3.4]octan-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2CH2-(7-azaspiro[3.4]octan-2-yl), –CH2CH2-(2 ... [3.5]nonane-7-yl), –CH2CH2-(6-azaspiro[3.5]nonane-6-yl), –CH2CH2-(2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(5-oxa-8-azaspiro[3.5] Nonane-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(6,6-diF-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(8-azabicyclo[3.2.1]octane-8-yl), –CH2CH2-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octane-2-yl), –CH2CH2CH2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2- (7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane-3-yl), –CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2-(2-azabicyclo[2.2.1]heptane-2-yl), CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(2-azabicyclo[2.1.1]hexane-2-yl), –CH2CH2-(6,6-diMe-3-azabicyclo[3.1.0]hexane-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe- Piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2,6,6-tetra-Me-morpholin-4-yl), –CH2-CH2-CH2-(2,2-diMe-morpholin-4-yl), –CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxazaza ... 39. The compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, wherein R7 is selected from the group consisting of: , each being substituted by 0, 1 or 2 independently selected from: –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, –C(O)CH2cyclopropyl, – CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl)–CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, –CH2CH2CH2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl, and –S(O)2Me. 40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, wherein each R2 is independently selected from the group consisting of: -Br, -CF3, . 41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein each R2 is independently selected from the group consisting of: (Claims 7 / 48, page 8, CN 121335883 A). 42. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 41, wherein each R2 is independently selected from the group consisting of: -Br, -CF3, . 43. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein each R2 is independently selected from the group consisting of: (Claims 8 / 48, page 9, CN 121335883 A). 44. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein R1 is selected from: -C(O)-CH3, (Claims 9 / 48, page 10, CN 121335883 A, Claims 10 / 48, page 11, CN 121335883 A). 45. The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: Claims 11 / 48, page 12, CN 121335883 A; Claims 12 / 48, page 13, CN 121335883 A; Claims 13 / 48, page 14, CN 121335883 A; Claims 14 / 48, page 15, CN 121335883 A. 46. ​​The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from claims 15 / 48, page 16, CN 121335883 A, page 16 / 48, page 17, CN 121335883 A, page 17 / 48, page 18, CN 121335883 A, page 18 / 48, page 19, CN 121335883 A, page 19 / 48, page 20, CN 121335883 A, page 20 / 48, page 21, CN 121335883 A, page 21 / 48, page 22, CN.121335883 A Claims 22 / 48 pages 23 CN 121335883 A Claims 23 / 48 pages 24 CN 121335883 A Claims 24 / 48 pages 25 CN 121335883 A Claims 25 / 48 pages 26 CN 121335883 A Claims 26 / 48 pages 27 CN 121335883 A . 47. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from claims 27 / 48, page 28, CN 121335883 A, page 29, CN 121335883 A, page 29 / 48, page 30, CN 121335883 A, page 30 / 48, page 31, CN 121335883 A, page 31 / 48, page 32, CN 121335883 A, page 32 / 48, page 33, CN 121335883 A, page 33 / 48, page 34, CN 121335883 A, page 34 / 48, page 35, CN 121335883 A, page 35 / 48, page 36, CN 121335883 A, page 36 / 48, page 37, CN 121335883 A. Claims 37 / 48, page 38, CN 121335883 A; Claims 38 / 48, page 39, CN 121335883 A; Claims 39 / 48, page 40, CN 121335883 A; Claims 40 / 48, page 41, CN 121335883 A; Claims 41 / 48, page 42, CN 121335883 A; Claims 42 / 48, page 43, CN 121335883 A; Claims 43 / 48, page 44, CN 121335883 A; Claims 44 / 48, page 45, CN 121335883 A; Claims 45 / 48, page 46, CN 121335883 A; Claims 46 / 48, page 47, CN 121335883 A. 48. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or thereof.49. Use of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical preparation. 50. The compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, used as a pharmaceutical preparation. 51. A method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, the method comprising administering to a subject in need a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof. 52. A method for treating inflammatory bowel disease in a person in need, the method comprising administering to a person a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof. 53. A compound selected from any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, used for treating inflammatory bowel disease. 54. The method of claim 52 or 53, wherein the inflammatory bowel disease is ulcerative colitis. 55. The method of claim 52 or 53, wherein the inflammatory bowel disease is Crohn's disease. 56. A method of treating ulcerative colitis in a person, the method comprising administering to a person in need a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof. 57. The compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, for treating ulcerative colitis. 58. The method of claim 56, wherein the ulcerative colitis is ulcerative colitis. Claims 47 / 48 Page 48 CN 121335883 A 59. The method of claim 56, wherein the ulcerative colitis is Crohn's disease. 60. A kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and b) instructions for administering said one or more compositions to a person in need. Claims 48 / 48 Page 49 CN 121335883 A Novel Compounds as α4β7 Inhibitors Technical Field

[0001] This disclosure relates to novel compounds that act as inhibitors of integrins, particularly α4β7 integrins. Additionally, this disclosure relates to pharmaceutical compositions and methods for using α4β7 inhibitors in the treatment of diseases or conditions associated with inflammatory bowel diseases, including ulcerative colitis and Crohn's disease. Background Art

[0002] Integrins are involved in many cellular processes, including cell-cell and cell-extracellular matrix interactions. Following binding to extracellular ligands, integrins mediate intracellular signal transduction leading to lymphocyte capture, adhesion, and infiltration into tissues. In fact, integrins are heterodimeric cell surface glycoprotein receptors composed of non-covalently bound α (alpha) and β (beta) subunits.

[0003] Twenty-four human integrins have been identified using molecular biology and protein chemistry, and they are known to act on a variety of human diseases, including platelet dysfunction, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic nephropathy, macular degeneration, and autoimmune and chronic inflammatory diseases.

[0004] α4-integrins α4β1 and α4β7 play important roles in lymphocyte migration on most leukocytes, including B and T lymphocytes. α4β1 and α4β7 integrins specifically adhere to VCAM-1 (vascular cell adhesion molecule 1) and MAdCAM-1 (mucosal addressin cell adhesion molecule 1), respectively. MAdCAM-1 is an immunoglobulin superfamily adhesion receptor for lymphocytes and a selective ligand for the α4β7 receptor. MAdCAM-1 is involved in the selective homing of lymphocytes to normal mucosal tissues. In humans, MAdCAM-1 expression is associated with lymphoid tissue and related lymphoid tissues in the gastrointestinal tract. Lymphocyte integrin α4β7 has been shown to mediate the adhesion of memory T cells to MAdCAM-1. MAdCAM-1 is upregulated in the gut during inflammation and is thought to play a significant role in inflammatory bowel disease (IBD) (a group of diseases such as ulcerative colitis (UC) and Crohn's disease (CD)). Inhibiting the interaction between integrins and their respective ligands has been proposed as an effective approach to treating various autoimmune and inflammatory diseases, and blocking AdCAM-1 interactions has shown therapeutic benefits in inflammatory bowel diseases such as ulcerative colitis and Crohn's disease (Hao Li et al., α4β7integrin inhibitors: a patent review (2018), Vol. 28, No. 12, 903-917).

[0005] Currently, injectable monoclonal antibodies as integrin inhibitors are available on the market, see, for example, nastatinumab (Tysabri®) approved for the treatment of highly active relapsing and remission multiple sclerosis, or vedolizumab (Entyvio®) approved for Crohn's disease and ulcerative colitis. However, orally bioavailable integrin inhibitors have not yet been approved.

[0006] Therefore, there is a need to provide integrin inhibitors, preferably α4β7 selective inhibitors, that can be used for the prevention and / or treatment of diseases characterized by MAdCAM-1 upregulation, such as inflammatory bowel disease.

[0007] This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein R1 to R6, Rx, Ry and Y are defined below. Summary of the Invention

[0008] This invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein:Ry is -CH(CH3)2, -CF3, -CH2F, CHF2, -CH(CF3)2, cyclopropyl, or cyclobutyl; Rx is hydrogen or methyl; R1 is -C(O)-R7; wherein R7 is a -C1-6 alkyl group substituted with 0 or 1 pyridine, phenyl, or cyclopropyl; or R7 is a phenyl or 5-10 membered heterocyclic group, each independently substituted with 0, 1, 2, 3, or 4 instances of R9; each R9 is independently selected from halogens, =O, -C1-6 alkyl, -C(O)-R10, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, -O-R11, phenyl, and 4-10 membered heterocycles; and each R9 is independently substituted with 0, 1, 2, or 3 groups independently selected from R17; R17 is selected from halogens, -C1-6 alkyl, -O-R15, -C(O)-N(C1-4 alkyl)2, -N(R12R13), cyclopropyl, and 4 to 10-membered heterocycles. When R17 is a heterocycle, it is further substituted by 0, 1, 2, or 4 groups independently selected from halogens, -C1-6 alkyl, =O, -C(O)-R14, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, and -O-R18. R10 is independently selected from -C1-6 alkyl, -C1-6 alkyl-C3-6 cycloalkyl, and C3-6 cycloalkyl. R11 is a -C1-6 alkyl, -C1-6 haloalkyl, 4- to 10-membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2, wherein the 4- to 10-membered heterocycle is substituted with 0 or 1 -C1-6 alkyl; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein the C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl are substituted with 0, 1, 2, or 3 F; R14 is independently selected from -C1-6 alkyl and C3-6 cycloalkyl; R15 is H, -C1-6 alkyl, -C1-6 haloalkyl, 4- to 10-membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2. When R15 is a 4- to 10-membered heterocycle, it is substituted by 0 or 1 -C1-6 alkyl group. R18 is -C1-6 alkyl or -C1-6 haloalkyl; wherein in each -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups attached to N can be the same or different; R2 is selected from the group consisting of Br, phenyl, naphthyl, and 5- to 10-membered heteroaryl groups, each of which can be independently substituted by 0, 1, 2, 3, or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6 haloalkyl, -O-C1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, -O-C3-6 cycloalkyl, -O-phenyl, and -O- (5- to 6-membered heterocyclic alkyl) groups are substituted; Y is -N= or -C(R3)=; R3 is halogen, -C1-6 haloalkyl, -C1-4 alkyl, or -C3-6 cycloalkyl; R4 is halogen or hydrogen; R5 is halogen or hydrogen; R6 is -C(O)-O-R8, wherein R8 is hydrogen or -C1-4 alkyl, -C1-4 alkyl-R16, -C1-4 alkyl-C(O)N(Me)-R16-C1-4 alkyl-R16, -C1-4 alkyl-C(O)N(R16,R16a)- or -C1-4 alkyl-O-C(O)-R16; R16 and R16a are independently selected from -C1-6 alkyl, 3 to 6 cycloalkyl, 4 to 6-membered heterocycle, and 4 to 6-membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted by one or two groups independently selected from =O or -C1-4 alkyl.

[0009] The present invention also relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein: Ry is -CH(CH3)2, cyclopropyl, or cyclobutyl; Rx is hydrogen or methyl; R1 is -C(O)-R7; wherein R7 is a -C1-6 alkyl group substituted with 0 or 1 pyridine, phenyl, or cyclopropyl; or R7 is a phenyl or 5-10-membered heterocyclic group, each independently substituted with 0, 1, 2, or 3 instances of R9; each R9 is independently selected from halogens, =O, -C1-6 alkyl, -C(O)-R10, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, -O-R11, phenyl, and 4-10-membered heterocycles; and each R9 is independently substituted with 0, 1, 2, or 3 groups independently selected from R17; R17 is selected from halogens, -C1-6 alkyl, -O-R15, -C(O)-N(C1-4 alkyl)2, -N(R12R13), and 4 to 10-membered heterocycles. When R17 is a heterocycle, it is further substituted by 0, 1, or 2 groups independently selected from halogens, -C1-6 alkyl, =O, -C(O)-R14, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, and -O-R18. R10 is independently selected from -C1-6 alkyl, -C1-6 alkyl-C3-6 cycloalkyl, and C3-6 cycloalkyl. R11 is a -C1-6 alkyl, -C1-6 haloalkyl, 4- to 10-membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2, wherein the 4- to 10-membered heterocycle is substituted with 0 or 1 -C1-6 alkyl; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, and cyclopropyl; R14 is independently selected from -C1-6 alkyl and C3-6 cycloalkyl; Specification 3 / 484 pages 52 CN 121335883 AR15 is a -C1-6 alkyl, -C1-6 haloalkyl, 4- to 10-membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2. When R15 is a 4- to 7-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl group. R18 is a -C1-6 alkyl or -C1-6 haloalkyl group. In each -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups attached to N can be the same or different. R2 is selected from the group consisting of Br, phenyl, naphthyl, and 5- to 10-membered heteroaryl groups, each of which can be independently substituted with 0, 1, 2, or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1-6 haloalkyl, -O-C1-6 alkyl, phenyl, 5- to 6-membered heteroaryl, -O-C3-6 cycloalkyl, -O-phenyl, and -O-(5- to 6-membered heterocycloalkyl). Y is -N= or -C(R3)=; R3 is a halogen, -C1-6 haloalkyl, -C1-4 alkyl, -C3-6 cycloalkyl; R4 is a halogen or hydrogen; R5 is a halogen or hydrogen; R6 is -C(O)-O-R8, wherein R8 is hydrogen or -C1-4 alkyl, -C1-4 alkyl-O-C(O)-R16; R16 is -C1-6 alkyl, 3 to 6 cycloalkyl, 4 to 6-membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted by one or two groups independently selected from =O or -C1-4 alkyl.

[0010] In one embodiment, the present invention relates to a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, wherein R1 to R6, Rx, Ry and Y are as defined herein.

[0011] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Rx is hydrogen.

[0012] In other embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Rx is methyl.

[0013] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Ry is -CH(CH3)2, -CF3, cyclopropyl, or cyclobutyl.

[0014] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Ry is -CH(CH3)2, cyclopropyl, or cyclobutyl.

[0015] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, Ry is -CH(CH3)2.

[0016] In a further embodiment of the compounds of the present invention or pharmaceutically acceptable salts thereof, Ry is cyclopropyl.

[0017] In a further embodiment of the compounds of the present invention or pharmaceutically acceptable salts thereof, Ry is cyclobutyl.

[0018] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, wherein R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl.In the C1-6 alkyl-cyclopropyl, C1-6 alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl groups, 0, 1, 2, or 3 F groups are substituted.

[0019] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R17 is selected from halogens, -C1-6 alkyl, -O-R15, -C(O)-N(C1-4 alkyl)2, -N(R12R13), and 4 to 10 membered heterocycles, and when R17 is a heterocycle, it is further substituted with 0, 1, or 2 groups independently selected from halogens, -C1-6 alkyl, =O, -C(O)-R14, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, and -O-R18. Specification 4 / 484 pages 53 CN 121335883 A

[0020] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, and cyclopropyl.

[0021] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R15 is -C1-6 alkyl, -C1-6 haloalkyl, 4 to 10-membered heterocycle, or -C1-6 alkyl-N(C1-6 alkyl)2, wherein when R15 is a 4 to 10-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl.

[0022] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R8 is hydrogen or -C1-4 alkyl or -C1-4 alkyl-O-C(O)-R16.

[0023] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R8 is hydrogen or -C1-4 alkyl-C1-4 alkyl-R16, -C1-4 alkyl-C(O)N(Me)-R16-, or -C1-4 alkyl-O-C(O)-R16, and R16 is independently selected from -C1-6 alkyl, 3 to 6 cycloalkyl, 4 to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycle is further substituted by one or two groups independently selected from =O or -C1-4 alkyl.

[0024] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is independently substituted by 0, 1, 2, 3, or 4 groups.

[0025] In further embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is independently substituted by 0, 1, 2, or 3 groups.

[0026] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is a phenyl or a 5-10 heteroaryl group, each of which is substituted by one, two, three, or four groups independently selected from -CN, -C1-6 alkyl, halogen, and -C1-6 haloalkyl groups.

[0027] In further embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is a phenyl or a 5-10 heteroaryl group.The heteroaryl group is substituted with 1, 2, or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, and -C1-6 haloalkyl.

[0028] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is substituted with 1, 2, 3, or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, and -C1-6 haloalkyl, and selected from

[0029] In further embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is substituted with 1, 2, 3, or 4 groups independently selected from -CN, -C1-6 alkyl, halogen, and -C1-6 haloalkyl, and selected from

[0030] In further embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is substituted with 1, 2, or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, and -C1-6 haloalkyl, and selected from [5 / 484 pages, CN 121335883 A].

[0031] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R2 is substituted by 1, 2, 3 or 4 groups independently selected from -CN, methyl, F, Cl and -CF3, and selected from

[0032] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R2 is substituted by 1, 2 or 3 groups independently selected from -methyl, fluorine or -CF3, and selected from

[0033] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, Y is -C(R3)=.

[0034] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, R3 is halogen, -CF3, methyl, ethyl, cyclopropyl.

[0035] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, Y is -N=.

[0036] In some embodiments of the compound of the present invention or a pharmaceutically acceptable salt thereof, Y is -C(R3)= and R3 is halogen, -CF3, methyl, ethyl, cyclopropyl.

[0037] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R4 is a halogen or hydrogen.

[0038] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R4 is a halogen.

[0039] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R4 is fluorine.

[0040] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R5 is fluorine or hydrogen.

[0041] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R5 is hydrogen.

[0042] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R6 is -C(O)-O-R8, which...R8 is hydrogen, methyl, CF3, ethyl, isopropyl, –CH2-(5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl) or –CH2-C(O)N(Me)2.

[0043] In a further embodiment of the compound of the present invention or a pharmaceutically acceptable salt thereof, R6 is –C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl or isopropyl, –O-CH2-O-C(O)-R16 or –O-C(CH3)-O-C(O)-R16, wherein R16 is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl or (5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl)methyl.

[0044] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R6 is -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl, or isopropyl.

[0045] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R6 is -C(O)-O-R8, and R8 is hydrogen, as described on page 6 / 484 of CN 121335883 A.

[0046] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is a -C1-6 alkyl group substituted with 0 or 1 pyridine, or R7 is a phenyl group substituted with 0, 1, 2 or 3 groups selected from -C1-6 alkyl, halogen or -O-C1-6 alkyl, or R7 is a 5-10 membered heterocyclic group substituted with 0, 1, 2 or 3 groups independently selected from R9, and each R9 is independently selected from halogen, =O, -C1-6 alkyl, -C(O)-R10, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R11; each R9 is independently substituted with 0, 1 or 2 groups independently selected from R17; R10 is independently selected from -C1-6 alkyl, C3-6 cycloalkyl, and -C1-6 alkyl-C3-6 cycloalkyl; R11 is -C1-6 alkyl, -C1-6 alkyl-N(-C1-6 alkyl)2, -C1-6 haloalkyl, or a 4- to 7-membered heterocycle; R17 is selected from halogens, -O-R15, -C(O)N(C1-4 alkyl)2, -N(R12R13), and 4- to 10-membered heterocycles, wherein when R17 is a 4- to 10-membered heterocycle, it is substituted by 0, 1, or 2 independently selected halogens, -C1-6 alkyl, or -C1-6 haloalkyl; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, and cyclopropyl; R15 is -C1-6 alkyl, -C1-6 haloalkyl, or a 4- to 7-membered heterocycle, and wherein when R15 is a 4- to 7-membered heterocycle, it is substituted by 0 or 1... α-C1-6 alkyl substitution;Furthermore, in each of the -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups connected to N may be the same or different.

[0047] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is a -C1-6 alkyl group substituted with 0 or 1 pyridine.

[0048] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is a phenyl group substituted with 0, 1, 2, 3 or 4 groups selected from -C1-6 alkyl, halogen or -O-C1-6 alkyl.

[0049] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is a phenyl group substituted with 0, 1, 2 or 3 groups selected from -C1-6 alkyl, halogen or -O-C1-6 alkyl.

[0050] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is a 5-10 membered heterocyclic group substituted with 0, 1, 2, 3 or 4 groups independently selected from R9, and each R9 is independently selected from halogen, =O, -C1-6 alkyl, -C(O)-R10, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, phenyl, 4 to 7 membered heterocycles, -O-R11; each R9 is independently substituted with 0, 1 or 2 groups independently selected from R17; R10 is independently selected from -C1-6 alkyl, C3-6 cycloalkyl and -C1-6 alkyl-C3-6 cycloalkyl; R11 is -C1-6 alkyl, -C1-6 alkyl-N(-C1-6 alkyl)2, -C1-6 haloalkyl or 4 to 7 membered heterocycles; R17 is selected from halogens, -O-R15, -C(O)N(C1-4 alkyl)2, -N(R12R13), and 4- to 10-membered heterocycles. When R17 is a 4- to 10-membered heterocycle, it is substituted by 0, 1, 2, or 4 independently selected halogens, -C1-6 alkyl, or -C1-6 haloalkyl. R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, and cyclopropyl. R15 is a -C1-6 alkyl, -C1-6 haloalkyl, or 4- to 7-membered heterocycle, and when R15 is a 4- to 7-membered heterocycle, it is substituted by 0 or 1 -C1-6 alkyl. In each -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups connected to N can be the same or different.

[0051] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is a 5-10 membered heterocyclic group substituted with 0, 1, 2, or 3 groups, and R17 is a 4- to 10-membered heterocycle, wherein R17 is substituted with 0, 1, or 2 groups.

[0052] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is a 5-10 membered heterocyclic group substituted with 0, 1, 2, or 3 groups independently selected from R9, and each R9 is independently selected from halogens, -O, -C1-6 alkyl, -C(O)-Specification 7 / 484 pages 56 CN 121335883 A R10, -C1-6 haloalkyl, -SO2-C1-6 alkyl, -NH-C1-4 alkyl, -N(C1-4 alkyl)2, -C3-6 cycloalkyl, phenyl, 4 to 7 membered heterocycles, -O-R11; each R9 is independently substituted by 0, 1 or 2 R17s; R17 is selected from halogens, -O-R15, -C(O)N(C1-4 alkyl)2, -N(R12R13) and 4 to 10 membered heterocycles, when R17 is a 4 to 10 membered heterocycle, it is substituted by 0, 1 or 2 halogens, -C1-6 alkyl or -C1-6 haloalkyl; R10 is independently selected from -C1-6 alkyl, -C3-6 cycloalkyl and -C1-6 alkyl-C3-6 cycloalkyl; R11 is a -C1-6 alkyl group, which, when R11 is a -C1-6 alkyl group, is substituted with 0 or 1 -N(C1-4 alkyl)2, or R11 is a -C1-6 haloalkyl group or a 4- to 7-membered heterocycle; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl, and cyclopropyl groups; R15 is a -C1-6 alkyl group, a -C1-6 haloalkyl group, or a 4- to 7-membered heterocycle, and, when R15 is a 4- to 7-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl group.

[0053] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R9 is a -C1-6 alkyl group substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C1-4 alkyl)2, -O-R15, -N(R12R13), 4 to 10-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is further substituted with 0, 1 or 2 groups independently selected from halogen or -C1-6 alkyl groups; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl and cyclopropyl; R15 is a -C1-6 alkyl, -C1-6 haloalkyl or 4 to 7-membered heterocycle, and when R15 is a 4 to 7-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl group; and wherein in each -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups connected to N may be the same or different.

[0054] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R9 is a -C1-6 alkyl group substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C1-4 alkyl)2, -N(R12R13), -O-R15, 4 to 7-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is further substituted with 0, 1 or 2 groups independently selected from halogen or -C1-6 alkyl groups; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl and cyclopropyl; R15 is a -C1-6 alkyl, -C1-6 haloalkyl or 4 to 7-membered heterocycle, and when R15 is a 4 to 7-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl group;Furthermore, in each of the -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups connected to N can be the same or different.

[0055] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R9 is a -C1-6 alkyl group substituted with 0, 1, 2 or 3 groups independently selected from -C(O)-N(C1-4 alkyl)2, -O-R15, -N(R12R13), 4 to 10-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl group is further substituted with 0, 1 or 2 groups independently selected from halogen or -C1-6 alkyl groups; R12 and R13 are independently selected from -C1-6 alkyl, -C1-6 haloalkyl and cyclopropyl; R15 is a -C1-6 alkyl, -C1-6 haloalkyl or 4 to 7-membered heterocycle, and when R15 is a 4 to 7-membered heterocycle, it is substituted with 0 or 1 -C1-6 alkyl group, and wherein in each -N(C1-6 alkyl)2 or -N(C1-4 alkyl)2, the two alkyl groups connected to N may be the same or different.

[0056] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, wherein R7 is selected from the group consisting of substituted or unsubstituted compounds: (See specification 8 / 484, page 57, CN 121335883 A).

[0057] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, wherein R7 is selected from the group consisting of substituted or unsubstituted compounds:

[0058] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is selected from the group consisting of: (Specification 9 / 484 pages 58 CN 121335883 A), each substituted by 0, 1, or 2 substituents independently selected from: –F, –Cl, oxo, –Me, –isobutyl, –isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –CF3, –OMe, –OCF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, 3-N(Me)2-3-Me-azacyclobutane-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidine-1-yl 1-Me-piperidin-4-yl, 1-isopropyl-piperidin-4-yl, 4-N(Me)2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-Me-1,4-diazacycloheptane-1-yl, 4-isopropyl-1,4-diazacycloheptane-1-yl, 4-cyclopropyl-1,4-diazacycloheptane-1-yl, 5-methyl-2,4,6,7-tetrahydropyrazole[4,3-c]pyridin-2-yl, 2-methyl-2,7-diazaspiro[3.5]nonane-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonane-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonane-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptane-6-yl, 3-(3-azabicyclo[3.1] .1]Heptane-3-yl)-azacyclobutane-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1]Heptane-5-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3-OCF3-azacyclobutane-1-yl) –CH2-CH2-(3-CHF2-azacyclobutane-1-yl), –CH2-CH2-(3-OCHF2-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(2,2-diMe-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-CH2-(3-MeO-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-3-Me-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl) Me-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2-(3-CF3-pyrrolidine-1-yl), –CH2CH2-(3,3-diF-pyrrolidine-1-yl), oxacyclobutane-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, –CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N (Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me)2N(Me)2, –CH2CH2C(Me)2N(Me)2、–CH2CH2N(Me)CH2CF3、–CH2CH2N(Me)CH(Me)2、–CH2CH2N(Me)C(Me)3、–CH2CH2N(Me)cyclopropyl、4-F-phenyl、–CH2CH2-(2-azaspiro[3.4]octane-2-yl),–CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl),–CH2CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl),–CH2CH2-(6-azaspiro[3.4]octane-6-yl),– Specification 10 / 484 pages 59 CN 121335883 A CH2CH2CH2-(6-azaspiro[3.4]octane-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octane-6-yl), –CH2CH2-(2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(6-MeO-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2CH2-(7-azaspiro[3.5]nonane-7-yl), –CH2CH2-(6-azaspiro[3.5]nonane-6-yl), –CH2CH2-(2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(5-oxa-8-azaspiro[3.5] Nonane-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(6,6-diF-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(8-azabicyclo[3.2.1]octane-8-yl), –CH2CH2-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octane-2-yl), –CH2CH2CH2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2- (7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane-3-yl), –CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2-(2-azabicyclo[2.2.1]heptane-2-yl), CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(2-azabicyclo[2.1.1]hexane-2-yl), –CH2CH2-(6,6-diMe-3-azabicyclo[3.1.1]heptane-3-yl),.0] hexane-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2,6,6-tetratetraMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2-diMe-morpholin-4-yl), –CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1 ,4-oxaza-4-yl), –CH2CH2-CH2- (1,4-oxaza-4-yl) and –S(O)2Me.

[0059] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is selected from the group consisting of: , each substituted by 0, 1 or 2 independently selected from: –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F- Azacyclic butane-1-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclic butane-1-yl, –CH2-CH2-(3-F-azacyclic butane-1-yl), –CH2-CH2-(3-CF3-azacyclic butane-1-yl), –CH2-CH2-(3,3-diF-azacyclic butane-1-yl), –CH2-CH2-(3,3-diMe-azacyclic butane-1-yl), –CH2-azacyclic butane-1-yl, –CH2-(3-F-azacyclic butane-1-yl), –CH2-(1-Me-azacyclic butane-3-yl), –CH2-azacyclic butane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl) –CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, –CH2CH2CH2N(Me)2, –CH2CH2N(Me)CH2CF3, – CH2CH2N(Me)cyclopropyl, 4-F-phenyl and –S(O)2Me.

[0060] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is selected from the group consisting of: , each independently selected from 0, 1 or 2.The following substituents are allowed: –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl). 1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, –CH2CH2CH2N(Me)2, –CH2CH2N(Me) CH2CF3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl and –S(O)2Me.

[0061] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R7 is selected from the group consisting of: , each being substituted by 0, 1 or 2 independently selected from: –F, –Cl, oxo, –Me, –isobutyl, –isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –CF3, –OMe, –OCF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, 3-N(Me)2-3-Me-azacyclobutane-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4- Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1-isopropyl-piperidin-4-yl, 4-N(Me)2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-Me-1,4-diazacycloheptane-1-yl, 4-isopropyl-1,4-diazacycloheptane-1-yl, 4-cyclopropyl-1,4-diazacycloheptane-1-yl, 5-methyl-2,4,6,7-tetrahydropyrazole[4,3-c]pyridin-2-yl, 2-methyl-2,7-diazaspiro[3.5]nonane-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonane-2-yl, 1-methyl2-methyl-2,6-diazaspiro[3.5]nonane-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptane-6-yl, 3-(3-azabicyclo[3.1.1]heptane-3-yl)-azacyclobutane-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1]heptane-5-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-... Specification 12 / 484 pages 61 CN 121335883 A OMe-aza-butane-1-yl), –CH2-CH2-CH2-(3-OMe-aza-butane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-aza-butane-1-yl), –CH2-CH2-(3-CF3-aza-butane-1-yl), –CH2-CH2-(3-OCF3-aza-butane-1-yl), –CH2-CH2-(3-CHF2-aza-butane-1-yl), –CH2-CH2-(3-OCHF2-aza-butane-1-yl), –CH2-CH2-(3,3-diF-aza-butane-1-yl), –CH2-CH2-(2,2-diMe-aza-butane-1-yl), –CH2-CH2- (3,3-DiMe-azacyclobutane-1-yl), –CH2-CH2-(3-MeO-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2- (3-CF3-pyrrolidine-1-yl), –CH2CH2-(3,3-diF-pyrrolidine-1-yl), oxacyclobutane-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, –CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N(Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me)2N(Me)2, –CH2CH2C(Me)2N(Me)2、–CH2CH2N(Me)CH2CF3、–CH2CH2N(Me)CH(Me)2、–CH2CH2N(Me)C(Me)3、–CH2CH2N(Me)cyclopropyl、4-F-phenyl、–CH2CH2-(2-azaspiro[3.4]octan-2-yl),–CH2CH2CH2-(2-azaspiro[3.4]octan-2-yl),–CH2CH2CH2CH2-(2-azaspiro[3.4]octan-2-yl),–CH2CH2-(6-azaspiro[3.4]octan-6-yl),–CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl),–CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6-yl),– CH2CH2-(2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(6-MeO-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2CH2-(7-azaspiro[3.5]nonane-7-yl), –CH2CH2-(6-azaspiro[3.5]nonane-6-yl), –CH2CH2-(2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(5-oxa-8-azaspiro[3.5] Nonane-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(6,6-diF-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(8-azabicyclo[3.2.1]octane-8-yl), –CH2CH2-(8-oxa-3-azabicyclo[3.2.1]octane-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octane-2-yl), –CH2CH2CH2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2- (7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane-3-yl), –CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2-(2-azabicyclo[2.2.1]heptane-2-yl), CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2CH2CH2-(3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(2-azabicyclo[2.1.1]hexane-2-yl), –CH2CH2-(6,6-diMe-3-azabicyclo[3.1.0]hexane-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2,6,6-tetra-Me-morpholin-4-yl), –CH2-CH2-CH2-(2,2-diMe-morpholin-4-yl), –CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxaza-4-yl), –CH2CH2-CH2- (1,4-oxaza-4-yl) and –S(O)2Me.

[0062] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R1 is selected from: -C(O)-CH3, (See page 13 / 484, CN 121335883 A, page 14 / 484, CN 121335883 A).

[0063] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R1 is selected from: -C(O)-CH3, (See page 15 / 484, CN 121335883 A, page 16 / 484, CN 121335883 A, page 17 / 484, CN 121335883 A).

[0064] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R1 is selected from: (Specification 18 / 484 page 67 CN 121335883 A, Specification 19 / 484 page 68 CN 121335883 A, Specification 20 / 484 page 69 CN 121335883 A, Specification 21 / 484 page 70 CN 121335883 A).

[0065] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R1 is selected from: -C(O)-CH3.

[0066] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is independently selected from the group consisting of: -Br, -CF3, (Specification 22 / 484 page 71 CN 121335883 A).

[0067] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is independently selected from the group consisting of:

[0068] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is independently selected from the group consisting of:-Br, -CF3, Specification 23 / 484 pages 72 CN 121335883 A.

[0069] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is independently selected from the group consisting of: -Br, -CF3, .

[0070] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, R2 is independently selected from the group consisting of: .

[0071] In some embodiments of the compounds of the present invention or pharmaceutically acceptable salts thereof, wherein R3 is independently selected from the group consisting of -F, -CF3 and -CH3.

[0072] In another embodiment, the present invention relates to compounds selected from any one of Examples 1 to 122 described herein or pharmaceutically acceptable salts thereof. Specification 24 / 484 pages 73 CN 121335883 A

[0073] In a further embodiment, the present invention relates to a compound selected from any one of Examples 200 to 359, 359A, 360 to 402, 404, 405, 407, 410, 411 described herein, or a pharmaceutically acceptable salt thereof.

[0074] In one embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0075] In one embodiment, the present invention relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical formulation.

[0076] In one embodiment, the present invention relates to a compound of the present invention or a pharmaceutically acceptable salt thereof, used as a pharmaceutical formulation.

[0077] In some embodiments, the present invention relates to a compound that inhibits α4β7-integrin.

[0078] In some embodiments, the present invention relates to a prodrug of a compound that inhibits α4β7-integrin (i.e., a compound that is converted to an α4β7-integrin inhibitor under physiological conditions or by enzymatic activity in a mammalian host).

[0079] This compound can be used to treat inflammatory bowel disease, ulcerative colitis, Crohn's disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathy, intestinal flora imbalance, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, inflammatory gastrointestinal cancer associated with familial adenomatous polyposis (FAP), intestinal graft-versus-host disease (GVHD), celiac disease, chronic pouchitis, and checkpoint inhibitor-associated colitis.

[0080] In one embodiment, the present invention relates to a method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, the method comprising administering to a subject in need a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0081] In another embodiment, the present invention relates to a method of treating inflammatory bowel disease in a person in need, the method comprising administering to a person a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0082] In another embodiment, the present invention relates to the compound of the present invention or a pharmaceutically acceptable salt of any of the foregoing for the treatment of inflammatory bowel disease.

[0083] In another embodiment, the present invention relates to the compound of the present invention or a pharmaceutically acceptable salt of any of the foregoing for the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is ulcerative colitis.

[0084] In another embodiment, the present invention relates to the compound of the present invention or a pharmaceutically acceptable salt of any of the foregoing for the treatment of inflammatory bowel disease, wherein the inflammatory bowel disease is Crohn's disease.

[0085] In another embodiment, the present invention relates to a method of treating ulcerative colitis in a person, the method comprising administering to a person in need a pharmaceutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0086] In another embodiment, the present invention relates to the compound of the present invention or a pharmaceutically acceptable salt of any of the foregoing for the treatment of ulcerative colitis.

[0087] In another embodiment, the present invention relates to the compounds of the present invention, or pharmaceutically acceptable salts of any of the foregoing, for the treatment of ulcerative colitis, wherein the ulcerative colitis is ulcerative colitis.

[0088] In another embodiment, the present invention relates to the compounds of the present invention, or pharmaceutically acceptable salts of any of the foregoing, for the treatment of ulcerative colitis, wherein the ulcerative colitis is Crohn's disease.

[0089] In another embodiment, the present invention relates to a kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of the compounds of the present invention or pharmaceutically acceptable salts of any of the foregoing, and a pharmaceutically acceptable carrier or excipient; and specification 25 / 484 pages 74 CN 121335883 A b) a specification relating to the administration of the one or more compositions to a person in need.

[0090] The terms used in the specification, description, examples and claims are compiled herein. These definitions should be interpreted in accordance with the remainder of this disclosure and as understood by those skilled in the art. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0091] Unless otherwise stated, terms and phrases are defined below and apply throughout the specification.

[0092] Unless the context clearly indicates otherwise, the articles “a,” “an,” and “the” include plural objects and are used herein to refer to one or more (i.e., at least one) grammatical object of the article. For example, “an element” means one element or more elements.

[0093] The phrase “and / or” as used in the specification and claims should be understood to mean “any one or both” of the elements so connected.

[0094] In the claims and in the foregoing specification, all conjunctions such as “comprising,” “including,” “with,” “having,” “containing,” “involving,” “owning,” “composed of,” etc., are understood to be open-ended, meaning including but not limited to. As described in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03, only the conjunctions “consisting of” and “consistently composed of” should be closed or semi-closed conjunctions, respectively.

[0095] Certain compounds contained in the compositions of the present invention may be present in specific geometric or stereoisomer forms. The present invention contemplates all such compounds falling within the scope of the present invention, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Additional asymmetric carbon atoms may be present in the substituents, such as alkyl groups. All such isomers and mixtures thereof are intended to be included in this invention. Unless the stereochemistry is explicitly specified in the structure, the structure is intended to include all possible stereoisomers of the described compound. If the stereochemistry is explicitly specified for one or more parts of the molecule but not for another one or more parts of the molecule, the structure is intended to include all possible stereoisomers for one or more parts for which the stereochemistry is not explicitly specified. If, for example, a specific enantiomer of the compound of this invention is required, the desired enantiomer can be separated from the racemic mixture using chiral separation methods known in the art, such as chiral chromatography. Alternatively, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino group, or an acidic functional group, such as a carboxyl group, it can form a diastereomeric salt with a suitable optically active acid or base, followed by resolution of the resulting diastereomeric isomer by fractional crystallization or chromatographic means known in the art, and then recovery of the pure enantiomer.

[0096] Stereochemistry / solvate / hydrate: Unless otherwise stated, the structural formula or chemical name given in the specification or claims refers to the corresponding compound itself, mixtures of the forms mentioned above (if such forms exist), and salts thereof, particularly pharmaceutically acceptable salts. Compounds and salts according to the invention may exist in a solvated form (e.g., with a pharmaceutically acceptable solvent, such as water, ethanol, etc.) or a non-solvated form. Generally, for the purposes of this invention, the solvated form...Formulas, such as hydrates, are considered to have equivalent value to unsolvated forms.

[0097] Aliphatic chains include the alkyl, alkenyl, and alkynyl classes as defined below. As used herein, the term "aliphatic group" refers to an unbranched or straight-chain, branched or cyclic aliphatic hydrocarbon group, and includes saturated and unsaturated aliphatic groups such as alkyl, alkenyl, or alkynyl.

[0098] The term "alkyl" refers to a straight-chain or branched hydrocarbon. For example, an alkyl group may have a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkyl or C1-6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1-pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)) CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2) and 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3).

[0099] As used herein, the term "alkylene" refers to a compound containing two atoms on its longest carbon chain that are similar to the rest of the compound.Alkyl groups having a specified number of carbon atoms, such as 2 to 12 carbon atoms, are used as the connecting points. Non-limiting examples of alkylene groups include methylene-(CH2)-, ethylene-(CH2CH2)-, n-propylene-(CH2CH2CH2)-, isopropylene-(CH2CH(CH3))-, etc. Alkylene groups can be cyclic or acyclic, branched or straight-chain carbon chain moieties and can optionally be substituted with one or more substituents.

[0100] "Alkenyl" means any cyclic or acyclic, branched or straight-chain unsaturated carbon chain moieties having a specified number of carbon atoms, or, if no limit is specified, a maximum of 26 carbon atoms; and having one or more double bonds in the moieties. Examples of alkenyl groups with 6 to 26 carbon atoms are hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, heptadecanenyl, octadecenyl, nonadecanenyl, eicosene, icosene, icosene, icosene, and icosene, in their various isomers, wherein the unsaturated bond may be located at any position in the moiety and may have a (Z) or (E) configuration surrounding the double bond.

[0101] "Alkynyl" refers to a hydrocarbon moiety within the alkenyl range, but having one or more triple bonds in the moiety.

[0102] The term "alkoxy" refers to a group having the formula "-O-alkyl", wherein the alkyl group as defined above is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group may have a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., C1-C6 alkoxy or C1-6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), tert-butoxy (-O-C(CH3)3 or -OtBu), etc.

[0103] The term "haloalkyl" refers to a group in which one or more hydrogen atoms of the alkyl group as defined above are replaced by halogen atoms. The alkyl portion of a haloalkyl group may have a specified number of carbon atoms, such as 1 to 6 carbon atoms (i.e., -C1-C6 haloalkyl or -C1-6 haloalkyl). Examples include: -CFH2, -CF2H, -CF3, -CF2CF3, -CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3, etc.

[0104] The term “carbonyl” refers to C=O, where a carbon atom is bonded to oxygen via a double bond and further to two other atoms. It is represented herein as -CO- or -C(O)-.

[0105] The term “carbocyclic” or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated, unsaturated, partially saturated, and aromatic rings. For clarity, “carbocyclic” includes “cycloalkyl” and “aryl” as defined herein.

[0106] “Cycloalkyl” refers to a monocyclic, bicyclic, bridged, spirocyclic, or polycyclic saturated carbon ring having 3 to 12 carbon atoms. Similarly, and unless otherwise stated, preferred cycloalkyl groups have 3 to 10 carbon atoms in their ring structure, more preferably 3 to 6 carbon atoms. Cycloalkyl groups can be substituted or unsubstituted. In some embodiments, preferred cycloalkyl groups are monocyclic rings having 3 to 6 carbon atoms.

[0107] The term “aryl” as used herein includes 6 to 12-membered substituted or unsubstituted monocyclic aromatic groups, wherein each atom of the ring is carbon. Preferably, aryl groups comprise 5 to 12-membered rings, more preferably 6 to 10-membered rings. The term "aryl" also includes, as described on page 27 / 484 of the specification, CN 121335883 A, a polycyclic system having two or more cyclic rings, wherein two or more carbons are common to two adjacent rings, wherein at least one ring is aromatic, for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloynyl, aryl and / or heterocyclic, wherein the connecting point is on an aromatic ring. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Aryl groups also include dihydrobenzofuran, indoline, isoindoline, quinoline, isoquinoline, etc., wherein the connecting point is on a phenyl ring.

[0108] The terms "heterocyclic group," "heterocycle," or "heterocyclic group" refer to a 3- to 12-membered ring structure, more preferably a 4- to 12-membered ring, more preferably a 5- to 10-membered ring, whose ring structure includes 1 to 4 heteroatoms selected from N, O, S, and their oxidized forms. Heterocyclic groups may be saturated, partially saturated, unsaturated, and / or aromatic. Heterocyclic rings can be monocyclic, bicyclic, spirocyclic, or multicyclic. Heterocyclic groups include, for example, aziridine, thiophene, thiathrone, furan, pyran, isobenzofuran, benzopyran, xanthan, phenoxthia, pyrrole, imidazole, pyrazole, isothiazol, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indazine, isoindole, indole, indazole, purine, quinazine, isoquinoline, quinoline, phthalazine, naphthidine, quinoxaline, quinazoline, cyclophosphine, pteridine, carbazole, caroline, phenanthridine, acridine, pyrimidine, phenanthroxaline, phenazine, phenpyrazine, phenothiazine, furazan, phenothiazine, pyrrole, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactone, lactam such as aziridine, pyridinone and pyrrolidone, sulfonamide, sulfonyl lactone, etc.

[0109] For clarity, "heterocyclic group" includes "heteroaryl" and "heterocyclic alkyl".

[0110] The heterocyclic ring may be substituted at one or more positions with substituents as described above, such as halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, mercapto, imino, amide, phosphate ester, phosphonate ester, phosphonite ester, carbonyl, carboxyl, silyl, aminosulfonyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclic group, aromatic or heteroaromatic moiety, -CF3, -CN, etc.

[0111] It is to be understood that the generic term for heterocycles used herein includes every isomer of the heterocycle, such that the term “dithiaalkyl” includes 1,2-dithiaalkyl, 1,3-dithiaalkyl, and 1,4-dithiaalkyl; the term “thiadiazinyl” includes 1,2,5-thiadiazinyl and 1,3,4-thiadiazinyl; the term “azaindolyl” includes 4-azaindolyl, 5-azaindolyl, 6-azaindolyl, and 7-azaindolyl; and “benzothiophenyl” includes benzo[b]thiophenyl and benzo[c]thiophenyl.

[0112] Similarly, generic heterocycle names include each variation of one or more unsaturation points. For example, the term “dihydropyrroleyl” refers to both the “2,3-dihydro-1H-pyrroleyl” and “2,5-dihydro-1H-pyrroleyl” groups.

[0113] "Heterocyclic alkyl" refers to a saturated heterocyclic ring having 3 to 12 ring member atoms, more preferably 4 to 10 members, more preferably 4 to 7 members, whose ring structure includes 1 to 4 heteroatoms selected from N, O, S and their oxidized forms. The heterocycle can be monocyclic, bicyclic, spirocyclic or polycyclic. Heterocyclic groups include, for example, azirrobutane, oxobutane, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, dioxacyclohexane, azirroheptane, etc.

[0114] Heterocyclic alkyl can be substituted or unsubstituted. In some embodiments, preferred heterocyclic alkyl is a monocyclic ring having 4 to 6 ring members, including 1 or 2 heteroatoms.

[0115] A partially saturated heterocycle refers to a heterocyclic ring having at least one carbon-carbon double bond, preferably one, two or three carbon-carbon double bonds, preferably one or two carbon-carbon double bonds, preferably one carbon-carbon double bond.

[0116] Heteroaryl groups include substituted or unsubstituted aromatic 5- to 12-membered ring structures, more preferably 5- to 10-membered rings, whose ring structure includes 1 to 4 heteroatoms selected from N, O, S, and their oxidized forms. The term "heteroaryl" also includes polycyclic systems having two or more cyclic rings, wherein two or more atoms are common to two adjacent rings, wherein at least one ring is aromatic, for example, other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclic groups, wherein the connecting point is on an aromatic ring. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups also include benzofuran, benzothiophene, indole, benzothiazole, etc., regardless of the position of the connecting point. Aryl and heteroaryl groups may be monocyclic, bicyclic, or polycyclic. Instruction manual 28 / 484 pages 77 CN 121335883 A

[0117] The term “halogen” refers to an atom selected from the elements chlorine, fluorine, bromine and iodine, i.e. -F, -Cl, -Br or -I.

[0118] The term “oxo” refers to a double bond oxygen “=O”.

[0119] As used herein, the term “nitro” refers to -NO2; the term “thiol” refers to -SH; the term “hydroxyl” refers to -OH;The term "sulfonyl" refers to -SO2-; the term "azido" refers to -N3; ​​the term "cyano" refers to -CN; the term "isocyanate" refers to -NCO; the term "thiocyanate" refers to -SCN; the term "isothiocyanate" refers to -NCS; and the term "cyanoxy" refers to -OCN.

[0120] As used herein, the term "substituted" is intended to include all permissible substituents of an organic compound. In a broad sense, permissible substituents include acyclic and cyclic, branched and linear, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. Exemplary substituents include, for example, those described above. For a suitable organic compound, permissible substituents may be one or more and may be the same or different. For the purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents that satisfy the valence of the heteroatom and / or any permissible substituents of the organic compound described herein. This invention is not intended to be limited in any way to the permissible substituents of an organic compound. It is to be understood that “substitution” or “being substituted” includes the implicit premise that such substitution conforms to the permissible valence of the substituted atom and the substituent, and that the substitution yields a stable compound, for example, which does not spontaneously transform, such as through rearrangement, cyclization, elimination, etc.

[0121] The term “prodrug” as used herein encompasses compounds that are converted into a therapeutically active agent under physiological conditions. A common method of manufacturing a prodrug involves hydrolysis under physiological conditions to present a selected portion of the desired molecule. In other embodiments, the prodrug is converted by the enzymatic activity of a mammalian host. Examples of hydrolysis under physiological conditions to present a portion of the desired molecule include functionalized carboxyl groups and carboxylic acid esters, which can be converted into the corresponding active molecule under physiological conditions. Examples of hydrolysis under physiological conditions to present a portion of the desired molecule are shown below.

[0122] For the purposes of this invention, chemical elements are identified according to the periodic table, CAS version, Handbook of Chemistry and Physics, 67th edition, 1986-87, inner cover.

[0123] The terms “therapeutic effective amount” and “pharmaceutical effective amount” refer to an amount sufficient to achieve the treatment as defined below when administered to a subject (e.g., a mammal, such as a human) requiring such treatment. Therapeutic or pharmaceutically effective amounts will vary depending on the subject being treated and the disease condition, the subject's weight and age, the severity of the disease condition, the method of administration, etc., which can be readily determined by those skilled in the art. For example, a “therapeutic effective amount” or “pharmaceutical effective amount” of a compound of formula (I) or a pharmaceutically acceptable salt or cocrystal thereof is an amount sufficient to inhibit and thereby treat a subject (e.g., a human) with the indication or to improve or alleviate existing symptoms of the indication.

[0124] “Treatment” or “treating” is used to obtain beneficial or desired results (including clinical...)The method of (results). Beneficial or desired clinical results may include one or more of the following: (i) suppressing a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition, and / or reducing the severity of the disease or condition); (ii) slowing or preventing the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the deterioration or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or (iii) alleviating the disease, i.e. causing the remission of clinical symptoms (e.g., improving the disease state, providing partial or complete remission of the disease or condition, enhancing the effect of another agent, delaying disease progression, improving quality of life and / or prolonging survival).

[0125] The term "inhibitor" refers to the compound of the present invention that selectively binds to α4β7 integrin to prevent the interaction between α4β7 integrin and MAdCAM-1 protein. Therefore, “inhibition” or “inhibition” refers to a reduction in the baseline activity of a biological activity or process regulated by the interaction between α4β7 integrin and MAdCAM-1 protein. In some embodiments, the inhibition of α4β7 integrin activity can be compared in the same subject before treatment or in other untreated subjects. The term “inhibitor” is understood to mean a compound or agent that provides the desired inhibitory activity after administration to a person in need at a pharmaceutically or therapeutically effective dose.

[0126] Numerical values ​​in the specification and claims of this application should be understood to include the same numerical value when simplified to the same number of significant figures, and numerical values ​​that differ from the specified numerical value by less than the experimental error of conventional measurement techniques of the type used to determine the numerical value as described in this application.

[0127] All scopes disclosed and / or claimed herein include the enumerated endpoints and can be combined independently (e.g., the ranges “2 to 10” and “2–10” include endpoints 2 and 10, and all intermediate values ​​3, 4, 5, 6, 7, 8, and 9).

[0128] "Significant" means any detectable change that is statistically significant in a standard parametric test of statistical significance, such as a Student's t-test, where p < 0.05.

[0129] Salt: The term "pharmaceutically acceptable" is used herein to mean a compound, material, composition, and / or formulation that, according to accepted medical opinion, is suitable for use in combination with human and / or animal tissues and does not have or produce any excessive toxicity, irritation, or immune response or cause other problems or complications, i.e., corresponds to an acceptable risk / benefit ratio overall. The term "pharmaceutically acceptable salt" refers to a derivative of the disclosed chemical compound wherein the parent compound is disposed of by means of an acid or base.Addition modification. Examples of pharmaceutically acceptable salts include (but are not limited to): salts of inorganic or organic acids with a basic functional group, such as amines, or salts of acidic functional groups, such as carboxylic acids, such as alkali metal or organic salts. These salts particularly include acetates, ascorbic acid salts, benzenesulfonates, benzoates, benzenesulfonates, bicarbonates, tartrates, bromides / hydrobromides, calcium EDTA / EDTA, camphorsulfonates, carbonates, chlorides / hydrochlorides, citrates, ethanedisulfonates, ethanedisulfonates, propionate, estolate, esylate, fumarate, gluconate, gluconate, glutamate, glycolate, glycolyllarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthylcarboxylate, iodides, isothiona te, lactate, lacturonate, malate, maleate, mandelate, methanesulphonate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucilage, naphthalene sulfonate, nitrate, oxalate, dihydroxynaphthalate, pantothenate, phenylacetate, phosphate / hydrogen phosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfonamide, sulfate, tannin, tartrate, teoclate, toluene sulfonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, and procaine. Other pharmaceutically acceptable salts can be formed from cations of metals such as aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci., (1977), 66, 1-19).

[0130] As used herein, the terms “isotope” and “isotopic” with respect to the compounds disclosed herein mean that one or more atoms of the compound are replaced by isotopes of such one or more atoms. “Isotope” means any of two or more forms of chemical elements having the same number of protons in the nucleus but different numbers of neutrons in the nucleus. For example, isotopic compounds include compounds in which one or more hydrogen atoms (H) have been replaced by one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and replacing hydrogen atoms (at one or more positions) with deuterium makes the resulting compound isotopic. Specification 30 / 484 pages 79 CN 121335883 ACompounds. For example, and referring to formula (I), the two methyl groups of the isopropyl moiety (-CH(CH3)2) replaced by a fully deuterated methyl group (-CH(CD3)2) would become an isotopic compound of formula (I). Other stable (non-radioactive) isotopic substitutions, besides replacing hydrogen with deuterium, include replacing carbon-12 with carbon-13, while unstable (radioactive) isotopes include replacing hydrogen with tritium, replacing carbon-12 with carbon-14, replacing iodine-127 with iodine-123 or iodine-125, etc. Therefore, all references herein to isotopic compounds of formula (I) and to all various embodiments thereof relate to compounds having one or more isotopic substitutions, including (but not limited to) one or more hydrogen atoms replaced by one or more deuterium atoms and any occurrence thereof in the compound. For this purpose, the isotopic compounds disclosed herein offer advantages relative to their non-isotopic forms. For this purpose, isotopic modification provides a means of improving existing drugs and / or serves as a tool in new drug design. For example, isotopic drug design has already proven successful in the case of deuterium (D) kinetic isotope effects. Because D has twice the mass of H, the C-D bond is much more resistant to oxidation processes (such as its ability to be catalyzed by CYP450 or other enzymes involved in metabolism) while maintaining very similar steric properties. Therefore, H-D isochoric substitution generally preserves the pharmacodynamics of the compound while improving its pharmacokinetics, thereby affecting the half-life and / or area under the curve, and ultimately the dosage and / or dosing regimen. For example, drug exposure can be enhanced by isotopic modification and / or clearance reduction. These benefits are provided to the compounds disclosed herein through their isotopic derivatization.

[0131] Terms such as “subject” and “patient” refer to animals, such as mammals, that are already or will be the subject of treatment, observation, or experimentation. The methods described herein can be used for human treatment and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments, the subject is a human; and in some embodiments, the subject is selected from cats and dogs. "Subjects in need" or "persons in need" means subjects, such as humans, who may have or are suspected of having a disease or condition that would benefit from a particular treatment (e.g., treatment with a compound of formula (I) as described herein or a pharmaceutically acceptable salt or cocrystal thereof). This includes subjects who may be identified as being at risk or susceptible to such a disease or condition so that treatment would prevent the development of the disease or condition.

[0132] The pharmaceutically acceptable salts of the present invention can be prepared from parent compounds carrying basic or acidic functional groups by conventional chemical methods. Typically, such salts can be synthesized by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent, such as ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof). Salts of acids other than those described above that can be used, for example, to purify or isolate the compound from the reaction mixture (e.g., trifluoroacetate)Salts (acid salts) are also considered part of this invention.

[0133] As used herein, the phrase “pharmaceuticalally acceptable excipient” or “pharmaceuticalally acceptable carrier” means a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in carrying or transporting the chemical in question from one organ or site of the body to another organ or site of the body. Each carrier must be “acceptable” in the sense of compatibility with other components of the formulation, harmlessness to the patient, and substantially pyrogen-free. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) (18) Isotonic saline; (19) Ringer's solution; (20) Ethanol; (21) Phosphate buffer solution; and (22) Other non-toxic and compatible substances used in pharmaceutical preparations. In some embodiments, the pharmaceutical compositions of the present invention are pyrogen-free, i.e., do not induce a significant increase in temperature when administered to a patient.

[0134] The compounds of the present invention may optionally be present as racemic compounds, but may also be obtained as pure enantiomers, i.e., in the form of (R) specification 31 / 484 pages 80 CN 121335883 A or (S). Preferably, compounds having a specific stereochemistry of formula Ia are preferred.

[0135] This invention relates to the compounds discussed, optionally in the form of individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of individual enantiomers, or racemic compounds, in the form of tautomers, and in the form of free bases or corresponding acid addition salts with pharmacologically acceptable acids, such as acid addition salts with hydrohalic acids (e.g., hydrochloric acid or hydrobromic acid) or organic acids (e.g., oxalic acid, fumaric acid, diethylene glycol, or methanesulfonic acid).

[0136] This invention relates to the compounds of formula I in their pharmacologically acceptable salt forms. These pharmacologically acceptable salts of the compounds of formulas I and Ia may also exist in the form of their respective hydrates (e.g., monohydrates, dihydrates, etc.) and in the form of their respective solvates.

[0137] For the purposes of this invention, a hydrate of a compound according to formula I refers to a crystalline salt of a compound according to formula I containing water of crystallization.

[0138] For the purposes of this invention, a solvate of a compound according to Formula I refers to a crystalline salt of a compound according to Formula I containing solvent molecules (e.g., ethanol, methanol, etc.) in a crystal lattice.

[0139] Compounds of Formula I can be used alone or in combination with other active substances of Formula I according to the invention. Compounds of Formula I can also optionally be used in combination with other pharmacologically active substances. Preferably, the active substances used herein can be selected from, for example, anti-IL17, bispecific antibody IL23p19 / TNF, fecal grafts, aminosalicylate (5-ASA), cox-2 inhibitors, corticosteroids, azathioprine, cyclosporine, tacrolimus, 6-mercaptopurine and / or antibiotics (e.g., ciprofloxacin, metronidazole, ampicillin).

[0140] Formulations of compounds of Formula I according to the invention also possess the properties required for the manufacture of suitable pharmaceutical dosage forms. These properties include, for example, properties related to sufficient bioavailability of the active ingredient, particularly its sufficiently high solubility, such as a solubility of >2 µg / ml measured in an aqueous solution at pH 6.8.

[0141] Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions, or inhalable powders or aerosols. In each case, the amount of the pharmaceutically effective compound should be in the range of 0.1 to 90% by weight of the total composition, preferably 0.5 to 50% by weight, i.e., an amount sufficient to achieve the dosage range specified below.

[0142] The formulation can be administered orally in the form of tablets, powders, powders in capsules (e.g., hard gelatin capsules), solutions, or suspensions. When administered by inhalation, the active substance combination can be administered as a powder, as an aqueous solution or a water-ethanol solution, or using a propellant gas formulation.

[0143] Thus, preferably, the pharmaceutical formulation is characterized by an amount of one or more compounds of Formula I according to the preferred embodiments described above.

[0144] Particularly preferred are the compounds of Formula I administered orally, and equally particularly preferred are they administered once or twice daily. Suitable tablets can be obtained, for example, by mixing the active substance with known excipients, such as inert diluents like calcium carbonate, calcium phosphate, or lactose, disintegrants like corn starch or alginic acid, binders like starch or gelatin, lubricants like magnesium stearate or talc, and / or delay-release agents like carboxymethyl cellulose, cellulose phthalate acetate, or polyvinyl acetate. Tablets may also comprise several layers.

[0145] Correspondingly, coated tablets can be prepared by coating a core similar to that used in tablet coatings with substances commonly used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide, or sugar. To achieve delayed release or prevent incompatibility, the core may also consist of multiple layers. Similarly, tablet coatings may consist of multiple layers to achieve delayed release, possibly using the excipients mentioned above for tablets. Specification 32 / 484 pages 81 CN 121335883 A

[0146] Syrups containing the active substances or combinations thereof according to the invention may additionally contain sweeteners such as saccharin, cyclamate, glycerin, or sugar, and flavor enhancers such as flavoring agents like vanillin or orange extract. They may also contain suspending agents or thickeners such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols and ethylene oxide, or preservatives such as parabens.

[0147] Capsules containing one or more active substances or combinations thereof can be prepared, for example, by mixing the active substances with an inert carrier such as lactose or sorbitol and packaging them into gelatin capsules. Suitable suppositories can be manufactured, for example, by mixing with a carrier provided for this purpose, such as neutral fats or polyethylene glycol or derivatives thereof.

[0148] Excipients that may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffin (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), monofunctional or polyfunctional alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicates and silicates), sugars (e.g., sucrose, lactose, and glucose), emulsifiers (e.g., lignin, sulfite waste, methylcellulose, starch, and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

[0149] For oral administration, in addition to the carriers described above, tablets may of course contain additives such as sodium citrate, calcium carbonate, and dicalcium phosphate, as well as various additives such as starch, preferably potato starch, gelatin, etc. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc may also be used in the tableting process. In the case of aqueous suspensions, in addition to the excipients mentioned above, the active substance can also be combined with various flavor enhancers or colorants.

[0150] It is also preferred that the compounds of Formula I be administered by inhalation, particularly preferably once or twice daily. For this purpose, the compounds of Formula I must be supplied in a form suitable for inhalation. Inhalable formulations include inhalable powders, propellant-containing metered aerosols, or propellant-free inhalable solutions, optionally mixed with excipients that are conventionally physiologically acceptable.

[0151] Within the scope of the invention, the term propellant-free inhalable solution also includes concentrates or sterile ready-to-use inhalable solutions. Formulations that can be used according to the invention are described in more detail in the next part of the specification.

[0152] Exemplary Method – Indications In some embodiments, the present invention relates to a treatment for inflammation selected from inflammatory bowel disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathy, intestinal flora imbalance, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, and familial adenomatous polyposis (FAP)-related inflammation.A method for diagnosing a disease or condition comprising the group consisting of symptomatic gastrointestinal cancer, intestinal graft-versus-host disease (GVHD), celiac disease, chronic pouchitis, and checkpoint inhibitor-associated colitis, comprising the step of administering a therapeutically effective amount of any of the above-mentioned compounds to a subject in need.

[0153] In some embodiments, the disease or condition is inflammatory bowel disease. In some embodiments, the inflammatory bowel disease is colitis, Crohn's disease, ileitis, celiac disease, nontropical stomatitis, enteropathy associated with seronegative arthropathy, gastroenteritis, or pouchitis.

[0154] In some embodiments, the disease or condition is Crohn's disease.

[0155] In some embodiments, the disease or condition is colitis.

[0156] In some embodiments, the disease or condition is ulcerative colitis.

[0157] In some embodiments, the invention relates to any of the foregoing methods, wherein the subject is a mammal. In some embodiments, the invention relates to any of the foregoing methods, wherein the subject is a human.

[0158] The compounds described herein can be prepared by methods known in the art and are illustrated by way of example in the following non-limiting description (pages 33 / 484, CN 121335883 A).

[0159] Unless otherwise stated, all reactions are generally carried out under an inert atmosphere (e.g., under nitrogen). The following abbreviations are used in this document: ss = saturated solution ON = overnight Abbreviation list ACN or MeCN CH3CN, acetonitrile AcOH Acetic acid aq. Aqueous 9-BBN 9-boronabicyclo[3.3.1]nonane BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) Boc tert-butoxycarbonyl nBuLi n-butyllithium CDCl3 Deuterated chloroform C6H5N Pyridine CO2 Carbon dioxide Cs2CO3 Cesium carbonate CuCl Cuprous chloride CuI Cuprous iodide CV Column volume DCM Dichloromethane DCE 1,2-dichloroethane DIPEA Diisopropylethylamine DMAP Dimethyl-pyridin-4-yl-amine DMF N,N-dimethylformamide DMSO Dimethyl sulfoxide EDTA Ethylenediaminetetraacetic acid EtOAc or EA Ethyl acetate EtOH Ethanol Et2O Diethyl ether FA Formic acid FC or FCC Rapid chromatography (h or hr) H2 Hydrogen H2O2 Hydrogen peroxide HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide HCl Hydrogen chloride HPLC High performance liquid chromatography KF Potassium fluoride Instructions 34 / 484 pages 83 CN 121335883 A KOAc Potassium acetate K2CO3 Potassium carbonate K3PO4 Potassium phosphate LCMSLiquid Chromatography-Mass Spectrometry (LC-MS) LiHMDS Hexamethyldisilamide LiOH Lithium hydroxide M MgSO4 Magnesium sulfate MnO2 Manganese dioxide Min min mL milliliters MS Mass Spectrometry MW Microwave N Standard (concentration) N2 Nitrogen NaBH3CN Sodium cyanoborohydride NaBH4 Sodium borohydride NaH Sodium hydride NaOH Sodium hydroxide Na2SO3 Sodium sulfite Na2SO4 Sodium sulfate NH3 Ammonia NH4Cl Ammonium chloride NH4OH Ammonium hydroxide NaHCO3 Sodium bicarbonate Na2CO3 Sodium carbonate NMR Nuclear Resonance Spectroscopy ON or ON Overnight PD / C Palladium / Carbon Pd(dppf)Cl2 Cyclopentyl(diphenyl)phosphine Dichloromethane Dichloropalladium iron Pd(OAc)2 Palladium acetate PE Petroleum ether pin Pinalol PPh3 Triphenylphosphine MeOH Methanol IPA Isopropanol Int. Intermediate THF Tetrahydrofuran DIBAL Diisobutylaluminum hydride instruction manual 35 / 484 pages 84 CN 121335883 A rac racemic RP reversed phase Rpm revolutions per minute RT or rt room temperature RTP room temperature and atmospheric pressure SFC supercritical fluid chromatography SCX strong cation exchange resin STAB sodium triacetoxyborohydride TBAB tetrabutylammonium bromide TBME tert-butylmethyl ether TEA triethylamine T3P propionic anhydride tert tert-TFA trifluoroacetic acid THF tetrahydrofuran Ti(OEt)4 tetraethoxytitanium Rt retention time [min] TRIS tris(hydroxymethyl)aminomethane tBuXPhos 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl weight % weight percentage sat. saturated uPLC ultra-high performance liquid chromatography uL microliter Ar aromatics.

[0160] Other features and advantages of the invention will become apparent from the following more detailed embodiments, which exemplify the principles of the invention without limiting its scope.

[0161] General Unless otherwise stated, all reactions were carried out in commercially available apparatus using methods commonly used in chemical laboratories. Starting materials sensitive to air and / or moisture were stored under a protective gas and their respective reactions and operations were carried out under a protective gas (nitrogen or argon).

[0162] Analytical methods LCMS conditions were as follows: System 1 (S1): Acidic IPC method using a Waters UPLC® BEHTM C18 column (2.1 mm × 50 mm, 1.7 µm; temperature 40 °C) on a Waters Acquity uPLC system and a gradient of 5–100% B over 1.1 min (A = 0.1% formic acid / H2O2-H: B = 0.1% formic acid / MeCN), followed by 100% B for 0.25 min for analytical (MET / uPLC / 1704) uHPLC-MS. A second gradient of 100-5% B was then applied for 0.05 min and held for 0.1 min, with an injection volume of 1 µL and a flow rate of 0.9 mL / min. UV spectra were recorded at 215 nm on a Waters Acquity PDA, with a spectral range of 200-400 nm. Mass spectra were obtained using a Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software, with retention times (Rt) reported in minutes. (Instructions 36 / 484 pages 85 CN 121335883 A)

[0163] System 2 (S2): The alkaline IPC method was performed using a Waters UPLC™ BEH™ C18 column (2.1 mm × 30 mm, 1.7 μm; temperature 55 °C) reversed-phase analytical (MET / uPLC / AB2010) (M15) UHPLC-MS with an injection volume of 1 µL, a flow rate of 1.0 mL / min, and a gradient of 1–100% B for 1.10 min, followed by 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate / water, buffered to pH 10, and B = acetonitrile. A second gradient of 100–1% B was then applied for 0.05 min and held for 0.40 min. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. Mass spectra were obtained using a Waters QuattroPremier XE or SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software, with retention times (Rt) reported in minutes.

[0164] System 3 (S3): Acidic final method was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm × 100 mm, 1.7 µM; temperature 40 °C) and a gradient of 5–100% B (A = 0.1% formic acid / H2O; B = 0.1% formic acid / MeCN) for 5.3 min, followed by 0.25 min of 100% B for analytical (MET / uPLC / AB101) uHPLC-MS. A second gradient of 100–5% B was then applied for 0.02 min and held for 1.18 min, with an injection volume of 1 µL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector, with a spectral range of 200–400 nm. Waters SQD or Waters...Mass spectrometry was obtained using Acquity QDA. Data were integrated and reported using Waters MassLynx and OpenLynx software, with retention times (Rt) reported in minutes.

[0165] System 4 (S4): The alkaline final method was performed on a Waters Acquity uPLC system using a Waters UPLC® BEHTM C18 column (2.1 mm × 100 mm, 1.7 µm column; temperature 40 °C) and an analytical (MET / uHPLC / AB105) uPLC-MS step of 5–100% (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = MeCN) for 5.3 min, followed by 0.5 min of 100% B. A second gradient of 100–5% B was then applied for 0.02 min and held for 1.18 min at an injection volume of 1 µL and a flow rate of 0.6 mL / min. UV spectra were recorded at 215 nm using a Waters Acquity photodiode array detector, with a spectral range of 200–400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software, with retention times (Rt) reported in minutes.

[0166] System 5 (S5): Neutral final method Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 1.9 µm; temperature 50 °C) in binary gradient mode (A = 10 mM NH4OAc / H2O: B = ACN) at 0.8 mL / min for 4.5 min (1% B 0.25 min, then linearly increased to 100% B over 2.25 min, then 100% B 0.40 min, then back to initial conditions over 0.1 min). The default injection volume was 0.2 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA, with a spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6490A QQQ (Agilent Jet Stream source) with positive or negative electrospray ionization. Data were utilized using the Agilent MassHunter software suite, and retention times (Rt) were reported in minutes.

[0167] System 6 (S6): Neutral IPC Method 1 An Agilent Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 1.9 μm) was used on an Agilent 1260 system.Analytical UHPLC-MS was performed at 0.8 mL / min for 4.2 min (1% B for 0.25 min, then linearly increased to 100% B over 2.25 min, then 100% B for 0.40 min, then back to initial conditions over 0.1 min) in binary gradient mode (A = 10 mM NH4OAc / H2O; temperature 50 °C). The default injection volume was 1 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA, with a spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization (see instruction manual page 37 / 484, 86 CN 121335883 A). Data were utilized using Agilent OpenLab software, and retention times (Rt) were reported in minutes.

[0168] System 7 (S7): Neutral IPC Method 2 Analytical UHPLC-MS was performed on an Agilent 1260 system using an Agilent Poroshell 120 EC-C18 column (2.1 mm × 50 mm, 2.7 µm; temperature 50 °C) in binary gradient mode (A = 10 mM NH4OAc / H2O: B = ACN) at 1.0 mL / min for 3.8 min (0.5% B 0.10 min, then linearly increased to 100% B over 1.6 min, then 100% B 0.40 min, then back to initial conditions over 0.1 min). The default injection volume was 1 µL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA, with a spectral range of 190–400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionization. Data were utilized using Agilent OpenLab software, and retention times (Rt) were reported in minutes.

[0169] System 8 (S8): Acidic delayed elution IPC method was performed using a Waters UPLC™ CORTECS™ C8 column (2.1 mm × 50 mm, 1.6 µm; temperature 40 °C) in reverse phase with an injection volume of 1 μL at a flow rate of 0.9 mL / min, and a gradient of 5% to 100% B for 1.10 min, followed by 100% B for 0.30 min, where A = 0.1% formic acid aqueous solution and B = 0.1% formic acid acetonitrile solution. A second gradient of 100% to 5% B was then applied for 0.02 min and held for 0.28 min. UV spectra were recorded at 215 nm; spectral range: 200–400 nm. Reports were made using Waters UPLC™ CORTECS™ C8 column (2.1 mm × 50 mm, 1.6 µm; temperature 40 °C).ELS data were collected using an ELS detector. Mass spectra were obtained using a Waters SQD2 or QDa; ionization mode: electrospray positive or negative ion. Data were integrated and reported using Waters MassLynx and OpenLynx software, with retention times (Rt) reported in minutes.

[0170] Purification methods were as follows: Compounds were purified using one of the following methods: normal-phase or reversed-phase automated rapid column chromatography on silica gel or C-18 silica gel (e.g., Biotage™ Isolera or Selekt instruments); open-access reversed-phase preparative HPLC (methods detailed below, P1-4); and custom-developed reversed-phase preparative HPLC methods.

[0171] Method 1: Acidic Early Elution Method (P1) Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: RT) with a gradient of 10–95% B for 14.44 min (A = 0.1% formic acid / H2O; B = 0.1% formic acid / MeCN), followed by 95% B for 2.11 min (P1) LC. A second gradient of 95–10% B was then applied for 0.2 min at an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0172] Method 2: Acidic Standard Method (P2) Purification was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm × 100 mm, 10 μM; temperature: RT) with a gradient of 30–95% B for 11.00 min (A = 0.1% formic acid / water; B = 0.1% formic acid / MeCN), followed by 95% B for 2.10 min (P2) LC. A second gradient of 95–30% B was then applied for 0.2 min at an injection volume of 1500 μL and a flow rate of 40 mL / min. UV spectra were recorded at 215 nm using a Gilson detector.

[0173] Method 3: Alkaline Early Elution Method (P3) Purification (P3) was performed using a Waters XBridge™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) in reverse phase (P3) LC. The injection volume was 1500 μL, the flow rate was 40 mL / min, and the solution was eluted at 10% B for 2.00 min, followed by a 10-95% B gradient for 14.00 min and a hold for 2.00 min, where A = 0.2% NH4OH / water and B = MeCN. Then a second gradient of 95-10% B was applied for 0.20 min and a hold for 1.25 min. The UV spectrum was recorded at 215 nm.

[0174] Method 4: Alkaline Standard Method (P4) Purification was performed using a Waters XBridge™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) in reverse phase (P3) LC.XBridge™ C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature) reverse-phase pure (P4) LC was performed. Injection volume was 1500 μL, flow rate was 40 mL / min, and incubation was performed at 30% B for 2.00 min, followed by a 9.50 min gradient of 30–95% B and a hold for 1.97 min, where A = 0.2% NH4OH / water and B = MeCN. A second gradient of 95–30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.

[0175] Chiral separation methods: LC method: Chiral separation on Gilson LC [column at room temperature; isocratic eluent; flow rate: 18 mL / min; detector wavelength: 215 / 254 nm; dilution solvent: IPA; injection volume: 100-1000 µL] SFC method: Chiral separation on Waters Thar SFC [column at 40 °C; isocratic eluent; back pressure: 120 bar; flow rate: 15 mL / min; dilution solvent: MeOH / acetonitrile; injection volume: 250 µL] NMR method as follows: Method 1, NMR (N1) Unless otherwise specified, 1H NMR spectra are recorded at 500 MHz, 400 MHz or 250 MHz on a Bruker Avance III HD 500 MHz spectrometer, a Bruker Avance III HD 400 MHz spectrometer or a Bruker Avance III HD 250 MHz spectrometer. Chemical shift δ is expressed in parts per million (ppm) and referenced to the residual solvent peak. The following abbreviations are used to denote multiplicity and general assignments: s (singleton), d (doublet), t (triplet), q (quartet), dd (doublet), ddd (doublet of doublets), dt (doublet of doublets), dq (doublet of quartets), hep (septet), m (multipleton), pent (quintet), td (triple doublet), qd (quartet), app. (apparent), and br. (broadness). The coupling constant J is given accurate to 0.1 Hz.

[0176] Method 2, NMR: (N2) Unless otherwise stated, 1H is recorded at 300 K on a Bruker 300 MHz Fourier spectrometer with dual z-grad 1H / 13C probes, or at 298 K on a Bruker 500 MHz AVIII HD spectrometer with a z-grad broadband CPP BBO probe cooled by N2, at 300 MHz or 500 MHz.NMR spectra. Chemical shifts δ are expressed in parts per million (ppm) and referenced to residual solvent peaks. The following abbreviations are used to denote multiplicity and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet), ddd (doublet of doublets), dt (doublet of doublets), dq (doublet of quartets), hep (septet), m (multiplet), pent (pentet), td (triple doublet), qd (quartet), app. (apparent), and br. (broad). Coupling constant J is given accurate to 0.1 Hz.

[0177] General Synthesis Unless otherwise stated, all compounds are synthesized with a purity greater than 95%.

[0178] Schematic diagram of general route 1a, 39 / 484 pages, 88 CN 121335883 A Synthesis of intermediate A1 (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylene]-2-methylpropane-2-sulfinamide (Step B) Titanium ethoxide (IV) (35 mL, 0.170 mol) was added dropwise to a stirred solution of 5-bromo-2,3-difluorobenzaldehyde (25.00 g, 0.113 mol) and (R)-2-methylpropane-2-sulfinamide (15.08 g, 0.124 mol) in anhydrous THF (300 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 hour, followed by stirring at 40 °C for 1.5 hours. The reaction mixture was poured into a mixture of water (300 mL) and EtOAc (200 mL) and stirred vigorously for 10 minutes. The suspension was then sonicated and filtered, and washed with EtOAc (200 mL). The organic layer was separated, and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over MgSO4, and concentrated under vacuum to give the title product as a white solid (33.74 g, 87% yield). LCMS m / z: 323.9 / 325.9 [M+H]+, (ESI+), Rt=1.08 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.61 (s, 1H), 8.09 (ddd, J=9.8, 7.1, 2.5 Hz,1H), 7.95 (dt, J = 5.3, 2.2 Hz, 1H), 1.20 (s, 9H).

[0180] Synthesis of Intermediate A2: Ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (Step C) Condition A: Activated zinc powder (26.91 g,A stirred suspension of 0.411 mol of ethyl 2-bromoacetic acid (29 mL, 0.257 mol) in anhydrous THF (350 mL) was treated dropwise over 20 minutes at 65 °C under N2. The solution was stirred at 65 °C for 1.5 hours, then cooled to room temperature and allowed to settle for 30 minutes. This organozinc solution was added over 5 minutes at 65 °C under N2 to a stirred suspension of 35.10 g, 0.103 mol of ethyl 2-bromoacetic acid (29 mL, 0.257 mol) in anhydrous THF (350 mL). The reaction was stirred at 65 °C for 1.5 hours, then cooled and poured into a mixture of TBME (400 mL) and 10% citric acid (600 mL). The organic layer was separated, and the aqueous layer was extracted with TBME (3 × 150 mL). The combined organic layers were washed with brine (2 × 150 mL), dried over MgSO4, and concentrated under vacuum to give the crude product. Purification was performed by column chromatography (approximately 300 g silica, 0–70% EtOAc / heptane) to give the title product as orange oil (29.40 g, 55% yield).

[0181] Condition B: Copper chloride (1+) (7.54 g, 76.2 mmol) was added to a stirred suspension of activated zinc powder (39.87 g, 0.610 mol) in THF (400 mL) at room temperature under N2 at 65 °C. The suspension was heated at 65 °C for 30 min. Heating was stopped, and ethyl 2-bromoacetate (34 mL, 0.305 mol) was added dropwise over 15 min to achieve reflux (note: very exothermic). After the addition, the reaction mixture was stirred at 65°C for another hour. The reaction was cooled to -5°C, and a solution of (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylene]-2-methylpropane-2-sulfinamide (95%, 52.00 g, 0.152 mol) in THF (200 mL) was added dropwise over 10 minutes. The reaction was stirred at -5°C for 30 minutes, and then at 0°C for 45 minutes. The reaction mixture was filtered through diatomaceous earth and washed with TBME (~200 mL). The filtrate was poured into 10% citric acid (300 mL) to separate the organic layer. The aqueous layer was extracted with TBME (2 × 150 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, and concentrated under vacuum. Purified by column chromatography (340 g silica, 20-35% acetone / heptane), the title product (63.26 g, 84% pure, 55% yield) was obtained as the yellow oil.

[0182] LCMS m / z: 412.4 / 414.2 [M+H]+,(ESI+) , Rt = 0.98 (S1) 1H NMR (400 MHz, DMSO‑d6) δ [ppm]: 7.74 (ddd , J = 9.6, 6.9, 2.4 Hz, 1H) , 7.57(dt, J = 5.4 , 2.1 Hz, 1H) , 5.85 (d , J = 7.0 Hz, 1H) , 4.95 (d , J = 7.2 Hz, 1H) , 4.07 – 3.97 (m, 2H) , 3.02 (dd, J = 15.8, 7.2Hz, 1H) , 2.90 (dd, J = 15.8, 7.5 Hz, 1H) , 1.13 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H).

[0183] Synthesis of intermediate A3: Ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (step D) Ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (20.00 g, 38.3 mmol), (2,6-dimethylphenyl)boronic acid (11.50 g, 76.6 mmol) and K2CO3 (15.89 g, 0.115 mol) in a solution of 1,4-dioxane (110 mL) and water (8 mL) was degassed for 10 min. Pd(dppf)Cl2 (1.57 g, 1.92 mmol) was added, and the reaction was stirred at 100 °C for 4 hours under N2. The reaction was cooled, poured into water (400 mL), and extracted with EtOAc (4 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over MgSO4, and concentrated to give the crude product. Purification was performed by column chromatography (350 g silica; 10%–100% EtOAc / heptane, then 0–20% MeOH / EtOAc) to give the title product (8.25 g, 44% yield) as the brown oil.

[0184] LCMS m / z: 438.4 [M+H]+, (ESI+), Rt = 1.14 (S1).

[0185] Synthesis instructions for intermediate A4, pages 41 / 484, 90 CN 121335883 A Step E: (3S)-3-amino-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionate ethyl hydrochloride (Step E)Ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate (9.63 g, 18.3 mmol) in a stirred solution in DCM (100 mL) was treated with HCl (4 M in dioxane, 9.1 mL, 36.5 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. Purification by column chromatography on silica gel (50 g silica, 0%–40% MeOH / EtOAc) gave the title product (7.38 g, 94% yield) as an orange solid.

[0186] LCMS m / z: 334.1 [M+H]+, (ESI+), Rt=0.71 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.80 (s, 3H), 7.42 – 7.35 (m, 1H), 7.35 – 7.27 (m, 1H), 7.22-7.17 (m, 1H), 7.17-7.09 (m, 2H), 4.95-4.81 (m, 1H), 4.08-3.94 (m, 2H), 3.25-3.17 (m, 1H), 3.17 – 3.03 (m, 1H), 2.03 (s, 3H), 1.95 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H). (N1).

[0187] Synthesis of intermediate A5 5-bromo-2-fluoro-3-(trifluoromethyl)benzaldehyde (step A) At -78°C, LDA (1M in THF, 31 mL, 30.9 mmol) was added dropwise over 1 hour to a solution of 4-bromo-1-fluoro-2-(trifluoromethyl)benzene (5.00 g, 20.6 mmol) in THF (39 mL). After 1 hour at -78°C, DMF (1.6 mL, 20.6 mmol) was added dropwise, and the reaction mixture was stirred at -78°C for another 2 hours. The reaction was quenched at 0°C with NH4Cl (saturated aqueous solution, 50 mL) and extracted with EtOAc (3 × 60 mL). The combined organic layers were washed with brine (80 mL), dried over MgSO4, and concentrated under vacuum to obtain a crude residue. Purification was performed by column chromatography (25 g silica, 0-25% EtOAc / heptane) to give the title product (2.40 g, 38% yield) as the yellow oil.

[0188] LCMS m / z: No mass-charged ions observed, Rt = 0.87, 58 1H NMR (400MHz, CDCl3) δ [ppm]: 10.34 (s, 1H), 8.18 (dd, J = 5.6, 2.6 Hz, 1H), 7.97 (dd, J = 6.1, 2.6 Hz, 1H). (N1).

[0189] The intermediates in Table 1 were synthesized according to General Scheme 1, taking intermediate A4 (steps B-D) as an example, using the corresponding starting materials. Diastereomers were isolated in the final purification, or as required by chiral separation methods. The intermediates were obtained as the title compound or its salt.

[0190] Table 1 Specification 42 / 484 pages 91 CN 121335883 A Specification 43 / 484 pages 92 CN 121335883 A.

[0191] Synthesis of intermediate A11 in general route 1b (R)-N-[(E)-(5-bromo-2-fluoro-3-methylphenyl)methylene]-2-methylpropane-2-sulfinamide (step A) Specification 44 / 484 pages 93 CN 121335883 A Prepared using 5-bromo-2-fluoro-3-methylbenzaldehyde as the starting material in a manner similar to intermediate A1.

[0192] LCMS m / z: 320.1 / 322.1 [M+H]+, (ESI+), Rt = 1.12 (S1) 1H NMR (400 MHz, CDC13) δ [ppm]: 8.85 (s, 1H), 7.94 (dd, J = 5.6, 2.5 Hz, 1H), 7.49 (dd, J = 6.5, 1.9 Hz, 1H), 2.33 (d, J = 2.2 Hz, 3H), 1.30 (s, 9H).

[0193] Synthesis of intermediate A12 (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propionate ethyl ester (step B) was prepared using intermediate A11 as the starting material in a manner similar to intermediate A2, under condition B.

[0194] LCMS m / z: 408.0 / 410.0 [M+H]+, (ESI+), Rt = 1.02 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.55 –7.47 (m, 1H), 7.43 (d, J = 6.1 Hz, 1H) , 5.74 (d, J = 7.0 Hz, 1H) , 4.92 (q, J = 7.2 Hz, 1H) , 4.02 (q, J = 7.1 Hz, 2H) , 2.98(dd, J = 15.5, 7.2 Hz, 1H), 2.82 (dd, J = 15.5, 7.4 Hz, 1H), 2.21 (s, 3H), 1.18 – 1.07 (m, 3H), 1.06 (s, 9H).

[0195] Synthesis of intermediate A13 (3S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propionate ethyl hydrochloride (step C) was prepared using intermediate A12 as the starting material in a manner similar to intermediate A4, under condition B.

[0196] LCMS m / z: 304.1 / 306.1 [M+H]+, (ESI+), Rt = 0.57 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.69 (s, 3H), 7.82 – 7.71 (m, 1H), 7.63 – 7.54 (m, 1H) , 4.87 – 4.74 (m, 1H) , 4.10 – 3.94 (m, 2H) , 3.16 (dd , J = 15.9, 6.4 Hz, 1H) , 3.05 (dd , J = 16.3, 8.8 Hz, 1H) ,2.25 (d , J = 1.5 Hz, 3H), 1.16 – 1.05 (m, 3H). Specification 45 / 484 pages 94 CN 121335883 A

[0197] The intermediates in Table 2 are synthesized according to general diagram 1B, taking intermediate A13 (steps A-C) as an example, using the corresponding starting materials. Diastereomers are isolated in the final purification, or as required by chiral separation methods. The intermediates are obtained as the title compound or its salt.

[0198] Table 2 Specification 46 / 484 pages 95 CN 121335883 A.

[0199] Synthesis of intermediate B1 in general route 2: Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionate (step A) DIPEA (2.3 mL, 13.0 mmol) was added to a solution of ethyl intermediate A4 (1.85 g, 4.50 mmol) and (2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido acid (1.30 g, 5.63 mmol) in DCM (40 mL) under stirring, followed by HATU (2.31 g, 6.08 mmol). The reaction mixture was stirred at room temperature for 72 hours. The reactants were used...(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentanoic acid (1.30 g, 5.63 mmol) and HATU (2.31 g, 6.08 mmol) were used for further treatment, and stirring was continued for 1 hour before dilution with water (30 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4), and concentrated under vacuum to give crude oil. Purification was performed by column chromatography (50 g silica, 5-60% EtOAc / heptane) to give the title product as a colorless solid (1.85 g, 70% yield).

[0200] LCMS m / z: 547.8 [M+H]+, (ESI+), Rt = 0.71 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.57 – 8.33 (m, 1H), 7.22 – 7.14 (m, 2H), 7.15 – 7.08 (m, 2H) , 7.02 – 6.93 (m, 1H) , 6.83 (d , J = 8.2 Hz, 1H) , 5.53 (q, J = 7.6 Hz, 1H) , 4.02 (qd , J = 7.1, 4.3 Hz, 2H) , 3.91 (td , J = 8.7, 6.1 Hz, 1H) ,2.83 (d , J = 7.6 Hz, 2H) , 1.95 (d , J = 7.7 Hz, 6H) , 1.69 – 1.56 (m, 3H) , 1.31 (s, 9H) , 1.12 (t, J = 6.8 Hz, 3H) , 0.88 – 0.83 (m, 6H).

[0201] Synthesis of Intermediate B2: (1R,2S,5S)-3-{imidazo[1,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid was added to a stirred solution of (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionate (1.85 g, 3.38 mmol) in DCM (15 mL) with HCl (4 M in dioxane, 3.0 mL, 12.0 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was concentrated under vacuum, and the residue was dried in a vacuum oven at 40°C for 2 hours to give the title product (1.73 g, 97% yield) as a white solid.LCMS m / z: 447.6 [M+H]+, (ESI+), Rt=0.80 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.32 – 9.10 (m, 1H), 8.21 (s, 3H), 7.29 –7.09 (m, 4H) , 7.04 – 6.97 (m, 1H) , 5.56 (q, J = 7.6 Hz, 1H) , 4.03 (qd , J = 7.1 , 2.0 Hz , 2H) , 3.75 (d , J = 8.4 Hz , 1H) , 2.93 (d , J = 7 0.6 Hz, 2H), 1.96 (d, J = 2.4 Hz, 6H), 1.47 – 1.38 (m, 2H), 1.12 (t, J = 7.1 Hz, 3H), 0.93 – 0.87 (m, 1H), 0.75 (dd, J = 13.0, 5.7 Hz, 6H). (N1).

[0203] The intermediates in Table 3 were synthesized according to General Scheme 2, taking intermediate B2 (steps A-B) as an example, using the corresponding starting materials. Diastereomers were isolated in the final purification, or as required by chiral separation methods. The intermediates were obtained as the title compound or its salt.

[0204] Table 3 Specification 48 / 484 pages 97 CN 121335883 A Specification 49 / 484 pages 98 CN 121335883 A Specification 50 / 484 pages 99 CN 121335883 A Specification 51 / 484 pages 100 CN 121335883 A.

[0205] Synthesis of Intermediate B17 (2R)-2-{[(1S)-1-{[(1S)-1-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl]carbamoyl}-3-methoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}piperidine-1-carboxylic acid tert-butyl ester (Instructions 52 / 484 pages 101 CN 121335883 A) A solution of intermediate B4 (200 mg, 0.43 mmol) in pyridine (10 mL) was added to (2R)-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (100 mg, 0.43 mmol), followed by the addition of EDC.HCl (129 mg, 0.64 mmol). The reverse...The mixture was stirred at room temperature for 12 hours. The solvent was removed under vacuum to obtain the residue. The residue was redissolved in EtOAc (25 mL), washed successively with NaHCO3 (saturated aqueous solution, 25 mL), water (25 mL), dried over MgSO4, and concentrated under vacuum to give the title product as a pale yellow solid (200 mg, yield 73%).

[0206] LCMS m / z: 544.2 [M−Boc+H]+, (ESI+), Rt = 3.14 (S6).

[0207] Synthesis of Intermediate B18: Methyl propionate hydrochloride of (3S)-3-{4,5-difluoro-2',6'-dimethyl-1,1'-biphenyl-3-yl}-3-[(2S)-4-methyl-2-{[(2R)-piperidin-2-yl]formamido}pentamido]propionate was added to a solution of (2R)-2-{[(1S)-1-{[(1S)-1-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}-3-methylbutyl]carbamoyl}piperidin-1-carbamate (intermediate B17, 200 mg, 0.311 mmol) in 1,4-dioxane (10 mL) with HCl (4 mmol / L). M in dioxane, 0.78 mL, 3.11 mmol). The reaction mixture was stirred at room temperature for 4 hours. HCl (4 M in dioxane, 0.78 mL, 3.11 mmol) was then added, and the reaction mixture was stirred at room temperature for another 2 hours. The solvent was removed under vacuum to give the title product as a yellow solid (180 mg, 100% yield).

[0208] LCMS m / z: 544.2 [M+H]+, (ESI+), Rt = 2.63 (S6) Synthesis of intermediate B19 (3S)-3-[(2S)-2-[[(2R)-1-acetylpiperidin-2-yl]formamido]-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}propionate to methyl(3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-{[(2R)-piperidin-2-yl]formamido}pentamido] (intermediate B18, 180 mg, 0.310 mmol) and DIPEA (0.24 A solution of acetyl chloride (0.024 mL, 0.341 mmol) in DCM (5 mL) was added at room temperature, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under vacuum to obtain a crude residue, which was analyzed by column chromatography. (Instructions for use 53 / 484, page 102 CN)121335883 A (12 g silica, 0–50% EtOAc / heptane, followed by 0–5% MeOH / DCM, followed by 0–2% MeOH / DCM) was purified to give the title compound as a white solid (122 mg, 61% yield).

[0209] LCMS m / z: 586.2 [M+H]+, (ESI+), Rt = 2.85 (S6).

[0210] Synthesis of intermediate C1 of general route 3a 1-fluoro-4-iodo-2,3,5-trimethylbenzene (step A) CuI (10.6 g, 55.66 mmol) and tert-butyl nitrite (10.0 mL, 84.08 mmol) were added to a stirred solution of 4-fluoro-2,3,6-trimethylaniline (7.27 g, 42.71 mmol) in MeCN (120 mL). The solution was stirred at 60°C for 18 hours, and then stirred at room temperature for 48 hours. The reaction mixture was concentrated under vacuum, and the residue was suspended in EtOAc (100 mL) and then filtered. The filtrate was concentrated under vacuum, and the residue was purified by column chromatography (350 g silica, 0-100% EtOAc / heptane) to give the title product as oil (4.07 g, 33% yield).

[0211] LCMS m / z: non-ionized, (ESI+), Rt = 1.23 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.09 (d, J = 10.5 Hz, 1H), 2.45 (s, 3H), 2.39 (s, 3H), 2.25 – 2.19 (m, 3H).

[0212] Synthesis of Intermediate C2 (Intermediate 555a) 2-(4-fluoro-2,3,6-trimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (Step B) Palladium acetate (16.0 mg, 0.07 mmol), triethylamine (0.3 mL, 2.15 mmol), and pinacolborane (0.31 mL, 2.14 mmol) were added to a degassed suspension of 1-fluoro-4-iodo-2,3,5-trimethylbenzene (200.0 mg, 0.72 mmol), triethylamine (0.3 mL, 2.15 mmol), and pinacolborane (0.31 mL, 2.14 mmol) in anhydrous 1,4-dioxacyclohexane (3.5 mL). The reaction mixture was heated at 80 °C for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was suspended in EtOAc (15 mL). The mixture was filtered, and the filtrate was concentrated under vacuum. The solution was then analyzed by column chromatography (10 g silica, 0–100%).Purified with EtOAc / heptane, the title product (181 mg, 86% yield) was obtained as a yellow solid.

[0213] LCMS m / z: non-ionized, (ESI+), Rt = 1.25 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 6.66 (d, J = 10.7 Hz, 1H), 2.34 (s, 3H), 2.31 (s, 3H), 2.13 – 2.08 (m, 3H), 1.39 (s, 12H).

[0214] Schematic diagram of general route 3b, page 54 / 484, CN 121335883 A. Synthesis of intermediate C3: 4,4,5,5-Tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxacyclopentaborane. Pd(dppf)Cl2 (59 mg, 0.0813 mmol) was added to a degassed suspension of 2-iodo-1,3,4-trimethylbenzene (0.20 g, 0.813 mmol), B2(pin)2 (310 mg, 1.22 mmol), and potassium acetate (239 mg, 2.44 mmol) in 1,4-dioxacyclohexane-anhydrous (7 mL). The reaction mixture was heated at 100 °C for 3 hours. After cooling, the reactants were purged with nitrogen for 2 minutes, and then Cs₂CO₃ (397 mg, 1.22 mmol), tris(4-methoxyphenyl)phosphine (3.2 mg, 8.94 μmol), and Pd(OAc)₂ (18 mg, 0.0813 mmol) were added. The reaction mixture was heated at 100 °C for 3 hours. After cooling, the reactants were diluted with EtOAc (40 mL) and filtered. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (25 g silica, 0–20% EtOAc / heptane) to give 4,4,5,5-tetramethyl-2-(2,3,6-trimethylphenyl)-1,3,2-dioxane (86 mg, 0.346 mmol, 43% yield) as a colorless oil.

[0215] LCMS m / z: No mass observed, (ESI+), Rt = 1.18 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.01 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 2.24 (s, 3H), 2.19 (s, 3H), 2.14 (s, 3H), 1.33 (s, 12H). (N1).

[0216] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate C3 as outlined in general route 3b.

[0217] Table 4.

[0218] Schematic diagram of general route 4, page 55 / 484, CN 121335883 A. Synthesis step A of intermediate D1: (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propionate (step A) Ethyl (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]propionate (5.5 g, 10.6 mmol) and 2-(4-fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (3.07 g, 10.6 mmol) A stirred solution of K3PO4 (9.25 g, 42.97 mmol) in 1,4-dioxane (90 mL) and water (9 mL) was added. The mixture was degassed with N2 for 5 min, and then Pd(dppf)Cl2·DCM (0.83 g, 1.01 mmol) was added. The reaction mixture was stirred at 100 °C for 3.5 h. The mixture was concentrated under vacuum, and the residue was dissolved in EtOAc (100 g) and washed with water (50 mL) and brine (30 mL). The aqueous phase was then extracted with EtOAc (2 x 50 mL), and the combined organic phases were dried over MgSO4 and concentrated under vacuum. Purification by column chromatography (100 g silica, 0–100% gradient EtOAc / heptane) gave the title product (5.29 g, 88% yield) as a grayish-white solid.

[0219] LCMS m / z: 583.4 [M+Na]+, (ESI+), Rt=1.23 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.39 (d, J=8.4 Hz, 1H), 6.99 – 6.91 (m, 4H), 6.82 (d , J = 8.2 Hz, 1H) , 5.52 (q, J = 7.6 Hz, 1H) ,4.08 – 3.97 (m, 2H) , 3.96 – 3.86 (m, 1H) , 2.76 (d , J = 7.4 Hz, 2H) , 2.28 – 2.20 (m, 3H) , 2.04 – 1.91 (m, 6H) , 1.49 – 1.40 (m, 1H) , 1.33 – 1.24 (m, 11H) ,1.11(t, J = 7.1 Hz, 3H), 0.79 – 0.73 (m, 6H).

[0220] Synthesis of intermediate D2 (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}ethyl propionate hydrochloride (step B) Specification 56 / 484 pages 105 CN 121335883 A Add 4 M HCl / dioxane (11.7 mL, 46.8 mmol) to a stirred solution of (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}ethyl propionate (5.27 g, 9.39 mmol) in anhydrous DCM (42 mL). The reaction mixture was stirred at room temperature for 18 hours. The mixture was concentrated under vacuum to give the title product (5.75 g, 100% yield) as a white solid. LCMS m / z: 461.3 [M+H]+, (ESI+), Rt=0.86 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.17 (d, J=8.0 Hz, 1H), 8.19 (s, 3H), 7.02 - 6.93 (m, 4H) , 5.55 (q, J = 7.6 Hz, 1H) , 4.08 – 3.96 (m, 2H) , 3.76 – 3.70 (m, 1H) , 2.92 – 2.80 (m, 2H) , 2.28 – 2.23 (m, 3H) , 1.95 – 1.93(m, 6H), 1.49 – 1.38 (m, 3H), 1.11 (t, J = 7.1 Hz, 3H), 0.79 – 0.71 (m, 6H).

[0222] The intermediates in Table 5 were synthesized according to General Scheme 4, taking intermediate D2 (steps A-B) as an example, using the corresponding starting materials. Diastereomers were isolated in the final purification or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salt.

[0223] Table 5 Specification 57 / 484 pages 106 CN 121335883 A Specification 58 / 484 pages 107 CN 121335883 A Specification 59 / 484 pages 108 CN 121335883 A Specification 60 / 484 pages 109 CN 121335883 AInstructions for use, page 61 / 484, 110 CN 121335883 A.

[0224] Synthesis of intermediate E1 in general route 5: Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2-fluoro-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate (step A) was prepared using intermediate B13 as the starting material in a manner similar to intermediate C2. Instruction manual, page 62 / 484, 111 CN 121335883 A

[0225] LCMS m / z: 565.5 [M+Na]+, (ESI+), Rt = 1.21 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.45 (d, J = 8.0 Hz, 1H), 7.62 – 7.51 (m, 1H), 7.47 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 1H), 5.49 – 5.34 (m, 1H), 4.14 – 3.68 (m, 3H), 2.83 – 2.70 (m, 2H) , 2.22(s, 3H), 1.56 – 1.43 (m, 1H), 1.40 – 1.31 (m, 11H), 1.28 (s, 12H), 1.12 (t, J = 7.1 Hz, 3H), 0.89 – 0.77 (m, 6H).

[0226] Synthesis of intermediate E2 (3S)-3-[(2S)-2-{[(tert-butoxycarbonyl)amino]-4-methylpentamido]-3-[5-(2,5-dimethyl-2H-indazole-4-yl)-2-fluoro-3-methylphenyl]propionate (step B) was prepared from intermediate E1 and 4-bromo-2,5-dimethylindazole in a manner similar to that of intermediate D1. LCMS m / z: 583.5 [M+Na]+, (ESI+), Rt=1.08 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.41 (d, J=8.2 Hz, 1H), 7.84 (s, 1H), 7.48 (d, J = 8.8 Hz, 1H) , 7.27 – 7.21 (m, 2H) , 7.16 (d, J = 8.8 Hz, 1H) , 6.79 (d , J = 8.5 Hz, 1H) , 5.59 – 5.51(m, 1H) ,4.09 (s, 3H) , 4.06 – 4.00 (m, 2H) , 3.95 – 3.90 (m , 1H) , 2.79 (d , J = 7.5 Hz, 2H) , 2.30 (s , 3H) , 2.21 (s , 3H) , 1.50 – 1.41 (m, 1H) , 1.29 (s, 9H) , 1.25 – 1.18(m, 2H) , 1.16 (t, J = 7.1 Hz, 3H) , 0.72 (d, J = 6.6 Hz, 6H) . Synthesis of Intermediate E3: Methyl (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2-fluoro-3-methylphenyl]propionate (Step C) 4M HCl / dioxane (2.5 mL) was added to a solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2-fluoro-3-methylphenyl]propionate (1.5 g, 2.06 mmol) in methanol (2.5 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was partitioned between EtOAc (50 mL) and a saturated NaHCO3 solution (15 mL). The organic layer was passed through a phase separator and concentrated under vacuum to obtain the title product (804 mg, 67% yield) as a light brown glassy solid.

[0228] LCMS m / z: 469.4 [M+Na]+, (ESI+), Rt = 0.76 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.48 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.48 (dd, J = 9.0, 1.0 Hz, 1H), 7.27 (dd, J = 6.8, 2.3 Hz, 1H), 7.23 (dd, J = 7.0, 2.3 Hz, 1H), 7.17 (d, J = 8.8 Hz, 1H) ,5.59 – 5.50 (m, 1H) , 4.09 (s, 3H) , 3.58 (s, 3H) , 3.14 (dd , J = 8.7, 5.6 Hz, 1H) , 2.89 – 2.79 (m, 2H) , 2.31(s, 3H), 2.22 (s, 3H), 1.62 – 1.52 (m, 1H), 1.37 – 1.28 (m, 1H), 1.21 – 1.10 (m, 1H), 0.86 – 0.71 (m, 6H).

[0229] Table 6 Specification 64 / 484 pages 113 CN 121335883 A.

[0230] Synthesis of intermediate F1 in general route 6: (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinoline-8-yl)formamido]pentamido]ethyl propionate was added to a solution of (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}ethyl propionate hydrochloride (intermediate B2, 80 mg, 0.154 mmol) and quinoline-8-carboxylic acid (32 mg, 0.185 mmol) in DCM (1.54 mL) with DIPEA (0.059 mg / mL). The reaction mixture was stirred for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product as a colorless solid (59 mg, yield 64%). LCMS m / z: 602.5 [M+H]+, (ESI+), Rt=4.71 (S4) H NMR (500 MHz, CDC13) δ [ppm]: 11.62 (d, J=7.2 Hz, 1H), 8.94 (dd, J=4.3, 1.8 Hz, 1H) , 8.67 (dd , J = 7.4, 1.6 Hz, 1H) , 8.28 (dd , J = 8.3,2.3 Hz, 1H) , 7.97 (dd , J = 8.1, 1.6 Hz, 1H) , 7.77 (d , J = 8.5 Hz, 1H) , 7.63 (dd , J = 8.1 , 7.3 Hz, 1H), 7.50 (dd, J = 8.3, 4.3 Hz, 1H), 7.20 – 7.13 (m, 1H), 7.07 (d, J = 7.7 Hz, 2H), 6.91 – 6.83 (m,2H), 5.70 (dt, J = 8.5, 6.2 Hz, 1H), 4.77 – 4.71 (m, 1H), 3.96 – 3.82 (m, 2H), 2.91 (dd, J = 15.7, 6.1 Hz, 1H), 2.84(dd , J = 15.8, 6.3 Hz, 1H) , 1.98 (s, 3H) , 1.95 (s, 3H) , 1.94 – 1.88 (m, 1H) , 1.86 – 1.75 (m, 2H) , 1.03 (t, J = 7.1 Hz, 3H) , 0.95 (d , J = 6.5 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H). (N1).

[0232] The intermediates in Table 7 below are prepared using the corresponding starting materials in a manner similar to intermediate F1 as outlined in general route 6.

[0233] Table 7 Specification 66 / 484 pages 115 CN 121335883 A Specification 67 / 484 pages 116 CN 121335883 A Specification 68 / 484 pages 117 CN 121335883 A Specification 69 / 484 pages 118 CN 121335883 A Specification 70 / 484 pages 119 CN 121335883 A Specification 71 / 484 pages 120 CN 121335883 A Specification 72 / 484 pages 121 CN 121335883 A Specification 73 / 484 pages 122 CN 121335883 A Specification 74 / 484 pages 123 CN 121335883 A Specification 75 / 484 pages 124 CN 121335883 A Instruction Manual 76 / 484 pages 125 CN 121335883 A Instruction Manual 77 / 484 pages 126 CN 121335883 A Instruction Manual 78 / 484 pages 127 CN 121335883 A Instruction Manual 79 / 484 pages 128 CN 121335883 A Instruction Manual 80 / 484 pages 129 CN 121335883 A Instruction Manual 81 / 484 pages 130 CN 121335883 A Instruction Manual 82 / 484 pages 131 CN 121335883 A Instruction Manual 83 / 484 pages 132 CN 121335883 A .

[0234] Synthesis of Intermediate F39: Ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate]-4-methylpentamido]propionate was added to a solution of methyl 1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-carboxylate (100 mg, 0.497 mmol) in THF (4 mL) with LiOH·H2O (104 mg, 2.48 mmol) dissolved in water (1 mL). The reaction mixture was stirred for 48 hours. The reaction mixture was concentrated under vacuum to give the intermediate. The intermediate acid was redissolved in DMF (4 mL), and intermediate B2 (150 mg, 0.311 mmol), DIPEA (190 µL, 1.09 mmol), and HATU (142 mg, 0.373 mmol) were added. The resulting mixture was stirred for 72 hours. The reaction was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give a crude residue. Purification by column chromatography (12 g Redisep Gold silica, 0–100% EtOAc / heptane) yielded a colorless gel (20 mg, 9% yield). LCMS m / z: 596.4 [M+H]+, (ESI+), Rt=2.85 (S6).

[0236] Synthesis of intermediate G1 in general route 7: (3S)-3-{2',6'-dichloro-4,5-difluoro-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate to (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate (intermediate F6, 70 mg, 0.107 mmol), 2,6-dichlorophenylboronic acid (35 mg, 0.183 mmol) and K3PO4 (70 mg, 0.330 mmol). A degassed suspension of Pd(dppf)Cl2 (18 mg, 0.0214 mmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added. The reaction mixture was heated at 90 °C for 18 hours. The reaction mixture was concentrated under vacuum to obtain a crude residue. The residue was analyzed by column chromatography (10...The product was purified from silica (0-100% EtOAc / heptane) to give the title product as orange oil (47 mg, yield 45%). LCMS m / z: 622.4 / 624.3 [M+H]+, (ESI+), Rt=1.07 (S1) H NMR (500 MHz, CDC13) δ [ppm]: 10.11 (d, J=7.6 Hz, 1H), 8.43 (dd, J=7.2,2.2 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.40 – 7.36 (m, 2H), 7.02 – 6.98 (m, 2H), 6.39 (t, J = 6.9 Hz, 1H), 5.69 (dt, J = 8.4, 6.2 Hz , 1H), 4.60 – 4.54 (m, 1H), 4.02 – 3.97 (m, 2H), 3.64 (s, 3H), 2.91 – 2.81 (m, 4H), 1.81 (td, J = 10.1, 5.0 Hz, 1H), 1.72 – 1.70 (m, 1H), 1.14 – 1.11 (m, 3H), 0.92 – 0.87 (m, 6H).

[0238] The intermediates in Table 8 below are prepared using the corresponding starting materials in a manner similar to intermediate G1 as outlined in general route 7.

[0239] Table 8 Specification 85 / 484 pages 134 CN 121335883 A Specification 86 / 484 pages 135 CN 121335883 A.

[0240] Synthesis of intermediate H1 in general route 8: (3S)-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate to (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate (intermediate F6, 100 mg, 0.153 mmol), B2(pin)2 (58 mg, 0.228 mmol), and KOAc (45 mg, 0.459 mmol). Add Pd(dppf)Cl2 (6.0 mmol) to the degassed solution in DMF (1 mL).The reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth pad, washed with excess EtOAc (3 × 5 mL). The filtrate was concentrated under vacuum to give the title product (142 mg, 77% yield) as a dark brown gel, as per the specification, page 87 / 484, 136 CN 121335883 A.

[0241] LCMS m / z: 604.6 [M+H]+, (ESI+), Rt=1.08 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.14 – 10.03 (m, 1H), 9.02 – 8.89 (m, 1H), 8.35 – 8.23 ​​(m, 1H) , 8.10 – 8.04 (m, 1H) , 7.69 – 7.39 (m, 2H) , 6.54 – 6.41 (m, 1H) , 5.59 – 5.38 (m, 1H) , 4.64 – 4.43 (m,1H) , 4.07 – 3.96 (m, 2H) , 3.58 – 3.56 (m , 3H) , 2.88 – 2.76 (m , 2H) , 1.54 – 1.37 (m , 3H) , 1.17 – 1.16 (m, 12H) , 1.13 – 1.09 (m, 3H) , 0.89 – 0.78 (m, 6H). (N1).

[0242] Synthesis of intermediate H2: (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]valerate is prepared by hydrolysis of methyl (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]valerate as described in general route 6, the route outlined in step B.

[0243] LCMS m / z: 267.2 [M+H]+, (ESI+), Rt=0.60, S1 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.73(s, 1H), 10.13 (d, J=7.9 Hz, 1H), 8.31 (dd, J = 7.3, 2.2 Hz, 1H), 8.08 (dd, J= 6.5, 2.2 Hz, 1H), 6.51 (dd, J = 7.3, 6.5 Hz, 1H), 4.55 – 4.37 (m, 1H), 3.57 (s, 3H) , 1.71 – 1.55(m, 3H), 0.98 – 0.80 (m, 6H). (N1).

[0244] Synthesis of intermediate H3 (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate was prepared in DMF starting from intermediate H2 and intermediate A18 in a manner similar to that of intermediate B1.

[0245] LCMS m / z: 521.2 / 523.2 [M+H]+, (ESI+), Rt = 0.79,S1.

[0246] Synthesis of intermediate H3B (3S)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl]pentamido]-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-3-yl]propionate specification 88 / 484 pages 137 CN 121335883 A It was prepared using intermediate H3 as the starting material in a manner similar to that of intermediate H1.

[0247] LCMS m / z: 547.3 [M+H]+, (ESI+), Rt=0.82, S1 1H NMR (400 MHz, DMSO) δ 10.10 – 9.98 (m, 1H), 8.82 – 8.70 (m, 1H), 8.55 – 8.48 (m, 1H) , 8.28 – 8.15 (m, 2H) , 8.08 – 8.01(m, 1H) , 7.68 – 7.51 (m, 1H) , 7.26 – 7.07 (m , 3H) , 6.53 – 6.43 (m , 1H) , 5.36 – 5.24 (m , 1H), 4.55 – 4.44 (m, 1H), 4.07 – 3.92 (m, 2H), 2.92 – 2.81 (m, 2H), 2.78 – 2.62 (m, 4H), 1.90 (d, J = 30.4 Hz, 6H), 1.61 – 1.40 (m, 2H), 1.18 – 1.02 (m, 3H), 0.93 – 0.76 (m, 6H).

[0248] Synthesis of intermediate H4 of general route 8B (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2,3-difluoro-5-Ethyl (4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate was prepared from intermediate B15 under the same conditions as intermediate H1.

[0249] LCMS m / z: 569.5 [M+H]+, (ESI+), Rt = 1.18 (S1) Specification 89 / 484 pages 138 CN 121335883 A 1H NMR (400 MHz, DMSO) δ [ppm]: 8.57 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 6.3 Hz, 1H), 7.47 – 7.38 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 5.43 (q, J = 7.6 Hz, 1H), 4.07 – 3.90 (m, 3H), 2.88 – 2.72 (m, 2H) ,1.52 – 1.41 (m, 1H) , 1.36 (s, 9H) , 1.33 – 1.26 (m, 14H) , 1.12 (t, J = 7.1 Hz, 3H) , 0.90 – 0.77 (m, 6H).

[0250] Synthesis of intermediate H5: Ethyl (3S)-3-[(2S)-2-{[(tert-butoxycarbonyl)amino]-4-methylpentamido}-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2,3-difluorophenyl]propionate was added to a MW tube flask with Pd(dppf)2Cl2 (33.041 mg, 0.04 mmol), K2CO3 (223.673 mg, 1.62 mmol), ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl]propionate (460.0 mg, 0.81 mmol) and 4- Bromo-2,5-dimethylindazole (204.352 mg, 0.91 mmol) was degassed in a mixture of 1,4-dioxane (4 mL) and water (0.5 mL) for 5 minutes, and then capped. The reaction mixture was heated at 150 °C under MW radiation for 15 minutes. The reaction mixture was filtered through a thiol column and washed with excess EtOAc (3 x 10 mL). The solvent of the filtrate was concentrated under vacuum. Purification was performed by column chromatography (25 g silica, 0-100% EtOAc / heptane) to give the title product as an oil (389 mg, 70% yield).

[0251] LCMS m / z: 587.5 [M+H]+, (ESI+), Rt =1.07 (S1) 1H NMR (500 MHz, DMSO‑d6) δ [ppm]: 8.51(d , J = 8.1 Hz, 1H) , 7.90 (s, 1H) , 7.51 (d, J = 8.8 Hz, 1H) , 7.43 – 7.37 (m, 1H) , 7.24 (d, J = 5.7 Hz, 1H), 7.17 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 5.55 (q, J = 7.6 Hz, 1H), 4.09 (s, 3H), 4.08 – 4.01 (m, 2H) , 3.95 – 3.87 (m, 1H), 2.86 (d, J = 7.5 Hz, 2H), 2.22 (s, 3H), 1.46 – 1.39 (m, 1H), 1.30 – 1.22 (m, 11H), 1.13 (t, J = 7.1 Hz, 3H), 0.73 – 0.68 (m, 6H).

[0252] Synthesis of intermediate H6: Ethyl (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2,3-difluorophenyl]propionate dihydrochloride was prepared using intermediate H5 as the starting material, similar to intermediate A4.

[0253] LCMS m / z: 487.3 [M+H-HCl]+, (ESI+), Rt = 0.75 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.37 (d, J = 7.7 Hz, 1H), 8.24 (s, 2H), 7.95 (s, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.48 – 7.40 (m, 1H), 7.29 (d, J = 5.7 Hz, 1H), 7.19 (d, J = 8.8 Hz, 1H), 5.57 (q, J= 7.5 Hz, 1H) , 4.13 – 4.01 (m, 6H) , 3.77 – 3.69 (m, 2H) , 3.01 – 2.91 (m, 2H) , 2.23 (s, 3H) , 1.49 – 1.36 (m, 3H) , 1.13 (t, J = 7.1 Hz, 3H), 0.73 – 0.63 (m,6H).

[0254] Synthesis of Intermediate H7: {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid was added to a MW tube containing PdCl2(dppf)2 (40.0 mg, 0.05 mmol), (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]propionate ethyl ester (intermediate B12, 0.45 g, 0.601 mmol), bis(pinacol)diboron (0.23 g, 0.906 mmol), and KOAc (0.18 g, 1.78 mmol), and 1,4-dioxane (1.8 g). Add 1 drop of DMF to the reaction mixture. Degas the reaction mixture for 5 minutes, then heat at 150 °C under MW radiation for 15 minutes. Filter the reaction mixture through a thiol column and wash with EtOAc (2 x 10 mL). Remove the solvent under vacuum to give a dark brown residue. Purify by column chromatography (10 g silica, 75–100% EtOAc / heptane) to give the title product as a brown solid (200 mg, 42% yield).

[0255] LCMS m / z: 452.3 [M+H]+, (ESI+), Rt=0.65 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.65 – 8.61 (m, 1H), 8.61 – 8.57 (m, 1H), 8.52 – 8.41 (m, 1H) , 8.01 – 7.91 (m, 1H) , 6.87 – 6.77 (m, 1H) , 5.75 (s, 2H) , 5.25 – 5.15 (m, 1H) , 4.08 – 3.95 (m, 2H) ,3.95 – 3.91 (m, 1H) , 2.91 – 2.81 (m, 2H), 1.54 – 1.44 (m, 1H), 1.32 – 1.29 (m, 9H), 1.26 – 1.21 (m, 2H), 1.13 – 1.08 (m, 3H), 0.89 – 0.77 (m, 6H). Synthesis of intermediate H8: Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate. Condition AIn a pressure vessel, a mixture of {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxypropyl]pyridin-3-yl}boronic acid (intermediate H7, 42.5 mg, 0.05 mmol), 4-bromo-3,5-dimethylpyridine hydrochloride (22 mg, 0.0989 mmol), Pd(dppf)2Cl2 (8.0 mg, 9.77 μmol), and K2CO3 (27 mg, 0.195 mmol) in 1,4-dioxane (0.5 mL) and water (50 μL) was degassed. The reaction mixture was sealed and heated at 100 °C for 1 hour. The reaction mixture was diluted with EtOAc (2 mL) and water (2 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (2 x 1 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under vacuum to obtain a brown oil residue. Purification by reversed-phase column chromatography (10 g C-18 silica, 10% to 100% MeCN / H2O, containing 0.1% formic acid) gave the title product (13 mg, 50% yield) as a brown viscous oil.

[0256] Condition B: In a pressure vessel, {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid (intermediate H7, 250.0 mg, 0.51 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (143.777 mg, 0.62 mmol), K3PO4 (464.014 mg, 2.19 mmol), and Pd(dppf)2Cl2.DCM (98.818 mg, 0.12 mmol) were added. 1,4-dioxacyclohexane (4 mL) and water (0.4 mL) were added. The reaction vessel was capped and heated at 100 °C for 3 hours. The reaction mixture was concentrated under vacuum to give a brown residue. Purification by column chromatography (10 g silica, 0-100% EtOAc / heptane) yielded the title product (39 mg, 15% yield) as a colorless oil and the starting material (183 mg, 73% recovery).

[0257] LCMS m / z: 513.3 [M+H]+, (ESI+), Rt = 0.72 (S1) 1H NMR (400 MHz, d3-MeCN) δ [ppm]: 8.58 (d, J = 2.2 Hz, 1H), 8.34 (s, 2H),8.28 (d, J = 2.0 Hz, 1H) , 7.51 (t, J = 2.2 Hz, 1H) , 7.39 (d, J = 8.2 Hz, 1H) , 5.60 – 5.46 (m, 1H) , 5.35 (q, J = 7.3 Hz,1H) , 4.04 (q, J = 7.1 Hz, 2H) , 3.98 – 3.90 (m, 1H) , 2.96 – 2.82 (m, 2H) , 1.98 (s, 6H) , 1.65 – 1.54 (m, 1H) , 1.48 – 1.39 (m, 2H) , 1.32 (s, 9H) , 1.14 (t, J = 7.1 Hz, 3H), 0.89 – 0.84 (m, 6H).

[0258] Synthesis of intermediate H9: Ethyl (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate trihydrochloride was added to a solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate (1.04 g, 1.83 mmol) in 1,4-dioxane (6 mL) with 4M HCl / dioxane (1.9 mL, 7.6 mmol). Within 5 minutes, a gel-like substance formed in the flask. 1,4-dioxane (6 mL) was then added, the suspended solid was sonicated for 10 minutes, and the mixture was stirred at room temperature for 18 hours. The reactants were concentrated under vacuum and azeotropically reacted with DCM (2 x 50 mL) to give the title product (1.00 g, 1.55 mmol, 85% yield) as a grayish-white powder.

[0259] LCMS m / z: 413.4 [M+H-3HCl]+, (ESI+), Rt = 0.64 (S2).

[0260] The intermediates in Table 9 were synthesized according to general formula 8B, using the corresponding starting materials, with intermediate H6 as an example. Diastereomers were isolated in the final purification or, if necessary, by chiral separation methods. The intermediates were obtained as the title compound or its salts. Specification 92 / 484 pages 141 CN 121335883 A

[0261] Table 9.

[0262] Schematic diagram of general route 9, page 93 / 484, CN 121335883 A

[0263] Synthesis of intermediate I1(2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (Step A) HATU (8.40 g, 22.1 mmol) was added to a stirred solution of (2S)-2-amino-4-methylpentanoate methyl hydrochloride (1.75 g, 9.63 mmol), (2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1.57 g, 7.29 mmol), and DIPEA (6.3 mL, 36.1 mmol) in DMF (23 mL). The solution was stirred at room temperature for 3 hours, and then EtOAc (30 mL) and water (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted again with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), concentrated under vacuum, and purified by column chromatography (50 g silica, 0–100% TBME / heptane) to give the title product (2.30 g, 87% yield). LCMS m / z: 365.1 [M+H]+, (ESI+), Rt=0.88, S1 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.26 – 7.95 (m, 1H), 4.39 – 4.29 (m, 1H), 4.13 – 4.06 (m, 1H) , 3.64 – 3.58 (m, 3H) , 3.50 – 3.35 (m, 1H) , 3.30 – 3.18 (m, 1H) , 2.18 – 1.99 (m, 1H) , 1.82 – 1.69 (m, 3H) , 1.67 – 1.57 (m, 2H) , 1.55 – 1.43(m, 1H) , 1.43 – 1.25 (m, 9H) , 0.92 – 0.77 (m, 6H). (N1).

[0265] Synthesis of Intermediate I2 (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylpentanoic acid (Step B) To a stirred solution of (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1- (Specification 94 / 484 pages 143 CN 121335883 A) tert-butyl formate (2.30 g, 6.38 mmol) in THF (57 mL) and MeOH (1.9 mL), 2M LiOH aqueous solution (20 mL, 40.8 mmol) was added. The reaction mixture was stirred at 45°C for 30 minutes. The solution was cooled and water (10) was added.The mixture was concentrated under vacuum to remove organic matter. The aqueous phase was acidified to approximately pH 3 with 1M HCl aqueous solution, and the resulting precipitate was extracted with DCM (3 × 15 mL). The combined organic layers were concentrated under vacuum to give the title product (2.10 g, 95% yield) as a white solid. LCMS m / z: 351.3 [M+H]+, (ESI+), Rt=0.75, S1 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.59 – 12.40 (m, 1H), 8.09 – 7.81 (m, 1H) ,4.34 – 4.22 (m, 1H) , 4.15 – 4.07 (m, 1H) , 3.48 – 3.35 (m, 1H) , 3.29 – 3.21 (m , 1H) , 2.17 – 2.01 (m , 1H) , 1.87 – 1.68 (m , 3H) , 1.68 – 1.54 (m, 2H), 1.54 – 1.43 (m, 1H), 1.43 – 1.26 (m, 9H), 0.93 – 0.77 (m, 6H). (N1).

[0267] Synthesis of Intermediate I3: (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-oxypropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (step C) was prepared by adding (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylvaleric acid (150 mg, 0.434 mmol) and (3S)-3-amino-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate ethyl ester (218 mg, 0.478 mmol) to the solution. A solution of DIPEA (152 µL, 0.870 mmol) and HATU (182 mg, 0.479 mmol) in DCM (3 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL), washed with water (5 mL), and passed through a phase separator. The solvent was concentrated under vacuum to obtain crude oil. Purification was performed by rapid column chromatography (10 g silica, 0.100% EtOAc / heptane) to give the title product as a pale yellow oil (314 mg, 98% yield).

[0268] LCMS m / z: 716.4 [M+H]+, (ESI+), Rt = 1.25, S1 1HNMR (500 MHz, CDCl3) δ [ppm]: 7.62 – 7.49 (m, 1H), 7.31 (d, J = 6.4 Hz, 2H), 7.21 – 7.13 (m, 1H), 7.13 – 7.06 (m, 2H), 6.89 – 6.29 (m, 1H), 5.71 – 5.60 (m, 1H), 4.38 (q, J = 7.1 Hz, 1H), 4.24 – 4.17 (m, 1H), 4.09 – 3.99 (m, 2H), 3.38 (d, J = 54.1 Hz, 2H) , 2.98 – 2.82 (m, 2H), 2.01 – 1.95 (m, 6H), 1.86 – 1.77 (m, 1H), 1.43 (s, 6H), 1.20 – 1.16 (m, 3H), 0.91 – 0.84 (m, 15H). (N1).

[0269] Synthesis of intermediate I4 (6a) (3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl-2-{[(2R)-pyrrolidine-2-yl]formamido}pentamido]ethyl propionate hydrochloride (step D) Specification 95 / 484 pages 144 CN 121335883 A To (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-oxypropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyrrolidine-1-carboxylate tert-butyl (314 mg, 0.425 HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) was added to a solution of the product in DCM (4.5 mL). The reaction mixture was stirred at room temperature for 45 minutes. HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) was added again, and the reaction mixture was stirred for another 15 minutes. The reaction mixture was concentrated under vacuum, ground with heptane (2 × 5 mL), the solvent was decanted, and the residue was dried under vacuum to give the title product (193 mg, 62% yield) as a grayish-white powder.

[0270] LCMS m / z: 594.6 [M+H]+, (ESI+), Rt = 1.05, S1 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.81 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.49 (d, J = 7.6 Hz, 1H), 8.50 mmol, ...J = 7.5 Hz, 1H), 7.48 – 7.41 (m, 1H), 7.35 – 7.30 (m, 1H), 7.22 – 7.15 (m,1H), 7.14 – 7.07 (m, 2H), 5.74 – 5.63 (m, 1H) , 4.67 – 4.48 (m, 1H) , 4.16 – 4.02 (m, 2H) , 3.49 – 3.28 (m, 2H) , 3.14 – 2.98 (m, 2H) , 2.53 – 2.42 (m, 1H) , 2.06 –1.75 (m , 11H) , 1 .58 – 1.47 (m, 2H), 1.25 – 1.16 (m, 3H), 0.95 – 0.78 (m, 7H). (N1).

[0271] Synthesis of Intermediate I5: Ethyl (3S)-3-[(2S)-2-{[(2R)-1-acetylpyrrolidine-2-yl]formamido}-4-methylpentamido]-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate (Step 5) was added to (3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl-2-{[(2R)-pyrrolidine-2-yl]formamido}pentamido]propionate hydrochloride (100 mg, 0.136 mmol) and DIPEA (38 µL, 0.218 mmol) in DCM (1.2 The solution was prepared in mL, and a stock solution of acetyl chloride (0.1 mL stock solution: 120 µL acetyl chloride / 1 mL DCM) was added. The reaction mixture was stirred and heated to room temperature for 2.5 h. The reaction mixture was cooled to 0 °C, reprocessed with DIPEA (13 µL, 0.0746 mmol) and acetyl chloride stock solution (0.05 mL), and then allowed to be heated to room temperature for 1 h. The reaction mixture was diluted with DCM (2 mL), quenched with saturated sodium bicarbonate (water solution, 3 mL), and the resulting aqueous phase was extracted with DCM (3 mL). The combined organic layers were passed through a phase separator, concentrated under vacuum, and the residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product (39 mg, 43% yield) as a grayish-white semi-solid. LCMS m / z: 636.6 [M+H]+, (ESI+), Rt=1.17, (S1) H NMR (400 MHz, CDC13) δ [ppm]: 7.85(d, J = 8.6 Hz, 1H), 7.31 – Specification 96 / 484 pages 145 CN 121335883 A 7.26 (m, 2H), 7.19 – 7.04 (m, 3H), 6.80 (d, J = 8.1 Hz, 1H), 5.79 – 5.69 (m, 1H), 4.40 – 4.31 (m, 1H), 4.28 (dd, J = 7.6, 3.8 Hz, 1H), 4.13 – 4.00 (m, 2H), 3.39 – 3.21 (m, 2H), 3.03 – 2.79 (m, 2H), 2.20 – 2.11 (m, 1H), 2.04 – 1.98 (m, 4H), 1.96 (s, 3H), 1.94 – 1.81 (m, 3H), 1.79 (s, 3H), 1.72 – 1.62 (m, 1H), 1.54 – 1.45 (m, 1H), 1.20 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H). (N1).

[0273] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate I5 as outlined in general route 6.

[0274]

[0275] Synthesis of intermediate J1 of general route 10A: methyl 1-(1-methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (step A) Specification 97 / 484 pages 146 CN 121335883 A At 0°C, a solution of methyl 2-oxo-2H-pyran-3-carboxylate (800 mg, 5.19 mmol) in DMF (10 mL) was added dropwise to 1-methylazacyclobutane-3-amine (447 mg, 5.19 mmol) in DMF (10 mL). The reaction mixture was stirred at 0°C for 1 hour, and then heated to room temperature. Subsequently, T3P (50% dissolved in EtOAc, 4.6 mL, 7.79 mmol) was added dropwise. The reaction mixture was stirred for 72 hours, and then concentrated under vacuum. Purified by column chromatography (55 g, KPNH silica, 0–100% EtOAc / heptane, 0–20% MeOH / EtOAc), the title product (415 mg, 25% yield) was obtained as a red solid.

[0276] LCMS m / z: 223.1 [M+H]+, (ESI+), Rt = 0.38 (S1).

[0277] Synthesis of Intermediate J2 (Intermediate 7a) 1-(1-methylazacyclobutan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) LiOH (2M, aqueous solution, 1.3 mL, 2.58 mmol) was added to a solution of methyl 1-(1-methylazacyclobutan-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (415 mg, 1.29 mmol) in methanol (6.9 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a red solid. Purification by column chromatography (11 g KPNH silica, 0–100% methanol / EtOAc) gave the title product (100 mg, 34% yield) as a red solid. LCMS m / z: 209.2 [M+H]+, (ESI+), Rt=0.18 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.17 (dd, J=7.0, 2.2 Hz, 1H), 7.96 (dd, J= 6.8, 2.2 Hz, 1H), 6.49 – 6.43 (m, 1H), 5.00 – 4.91 (m, 1H), 3.75 – 3.66 (m, 2H), 3.15 – 3.09 (m, 2H), 2.27 (s, 3H). (N1).

[0279] Synthesis of Intermediate J3 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate methyl ester (Step A) At room temperature, oxetane-3-amine hydrochloride (0.72 g, 6.56 mmol) and DIPEA (3.4 mL, 19.5 mmol) were added to a solution of 2-oxo-2H-pyran-3-carboxylate (1.00 g, 6.49 mmol) in DMF (33.5 mL). The reaction mixture was stirred for 1 hour, and then EDC.HCl (1.87 g, 9.75 mmol) and DMAP (0.20 g, 1.64 mmol) were added. The reaction mixture was stirred for another 3 hours. The reaction mixture was concentrated under vacuum, suspended in water (150 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were free of product. The aqueous layer was extracted with a 4:1 DCM / IPA solution (2 x 60 mL). The combined organic layers were concentrated under vacuum to give the title product as brown oil (352 mg, 24% yield).

[0280] LCMS m / z: 210.1 [M+H]+, (ESI+), Rt = 1.08 (S4) 1H NMR(400 MHz, DMSO‑d6) δ [ppm]: 8.08‑8.02 (m, 2H), 6.41 (t, J = 6.9Hz, 1H), 5.45 (p, J = 7.2 Hz, 1H), 4.86 (t, J = 7.5 Hz, 2H), 4.72 (t, J = 7.2 Hz, 2H), 3.73 (s, 3H).

[0281] Synthesis specification for intermediate J3, 98 / 484 pages, 147 CN 121335883 A 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (step B) A 2 M aqueous solution of lithium hydroxide (1.2 mL, 2.4 mmol) was added to a stirred solution of methyl 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (352.2 mg, 1.57 mmol) in methanol (4.5 mL) and THF (65 mL). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was suspended in water (about 20 mL). The suspension was acidified to pH about 1 with a 2 M aqueous solution of HCl and extracted with a 4:1 DCM:IPA solution (3 x 10 mL). The combined organic layers were concentrated under vacuum to obtain the title product (300 mg, 71% yield) as a pale orange solid. LCMS m / z: 196.1 [M+H]+, (ESI+), Rt=1.04 (S3) H NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26 (s, 1H), 8.40 (dd, J=7.3, 2.0 Hz, 1H), 8.30 (dd, J = 6.7, 2.0 Hz, 1H) , 6.79 (t, J = 7.0 Hz, 1H) , 5.68 – 5.57 (m, 1H) , 4.91 (t, J = 7.4 Hz, 2H) , 4.84 (t, J= 7.4 Hz, 2H).

[0283] Synthesis of intermediate K1 in general route 10B: A solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (200 mg, 1.31 mmol) and CsCO3 (1280 mg, 3.93 mmol) in MeCN (5 mL) was added, along with (2-bromoethyl)dimethylamine hydrobromide (375 mg, 1.58 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction was cooled to room temperature, filtered through a diatomaceous earth mat, and treated with excess EtOAc (100...Wash with DCM (2 × 5 mL) and DCM (2 × 5 mL). Collect the filtrate and concentrate under vacuum to obtain crude oil. Purify by open preparative high performance liquid chromatography (P4) to obtain the methyl title product as brown oil (79 mg, 25% yield).

[0284] LCMS m / z: 225.1 [M+H]+, (ESI+), Rt=0.40 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.04 – 7.96 (m, 1H), 7.96 – 7.90 (m, 1H), 6.33 – 6.25 (m, 1H) , 4.01 (t, J = 6.2 Hz, 2H) , 3.77 – 3.70 (m, 3H) , 2.55 – 2.51 (m, 2H) , 2.23 – 2.10 (m, 6H). (N1).

[0285] Synthesis of Intermediate K2: Lithium (1+)-1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) LiOH (2M, aqueous solution, 900 µL, 1.80 mmol) was added to a solution of methyl 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (79 mg, 0.333 mmol) in MeOH (190 µL) and THF (1.9 mL), and stirred at room temperature for 5 hours. The reactants were concentrated under vacuum and dried overnight in a vacuum oven to give the title product (108 mg, 100% yield) as a colorless solid.

[0286] LCMS m / z: 211.2 [M+H]+, (ESI+), Rt = 0.19 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.15 (dd, J = 7.0, 2.2 Hz, 1H), 7.76 (dd, J = 6.6, 2.3 Hz, 1H), 6.36 (t, J = 6.8 Hz, 1H), 4.04 (t, J = 6.3 Hz, 2H), 2.52 (s, 2H), 2.17 (s, 6H). (N1). The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate K2 as outlined in general route 10B.

[0287] .

[0288] Synthesis of intermediate K5: Methyl 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate to methyl 2-hydroxypyridine-3-carboxylate (3.003-Dimethylaminopropylhydrochloride (3.36 g, 21.26 mmol) was added to a stirred suspension of acetone (60 mL) containing K2CO3 (6.90 g, 49.9 mmol, 19.6 mmol, 19.6 mmol, 19.6 mmol, 6.90 g, 49.9 mmol, 6.90 g, 49.9 mmol, 6.90 g, 49.9 mmol, 6.90 g, 6.90 g, 6.90 mmol ... The oil was then dissolved in ethyl acetate (15 mL), diluted with heptane (15 mL), and the resulting solid was filtered. The filtrate was concentrated under vacuum to give the title product as a yellow oil (2.01 g, yield 36%, purity 83%).

[0289] LCMS m / z: 499.3 [2M+Na]+, (ESI+), Rt = 0.40 (S2).

[0290] Synthesis of intermediate K6 Lithium (1+) 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate was prepared using intermediate K5 in a manner similar to intermediate K2.

[0291] LCMS m / z: 225.1 [M+H]+, (ESI+), Rt = 0.40 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.21 – 8.14 (m, 1H), 7.85 – 7.78 (m, 1H), 6.37 (t, J = 6.8 Hz, 1H) , 4.01 – 3.93 (m, 2H) , 2.22 – 2.14 (m, 2H) , 2.11 (s, 6H) , 1.84 – 1.72 (m, 2H).

[0292] Synthesis of intermediate K7 of schematic 10C of general route methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate Methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.528 g, 2.81 mmol) in DCM (10 mL) was added dropwise with 1 M thionyl chloride / DCM (7.04 mL, 7.04 mmol). The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and methanol (0.57 mL, 14.07 mmol) was added.mmol). After 30 minutes, the reaction mixture was concentrated under vacuum to give the title product as a solid (560 mg, yield 88%).

[0293] LCMS m / z: 202.1 [M+H]+, (ESI+), Rt = 0.56 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.09 (s, 1H), 3.88 (s, 3H), 2.50 (s, 3H).

[0294] Synthesis of Intermediate K8: Methyl 5-chloro-6-methyl-2-(prop-2-en-1-oxy)pyridine-3-carboxylate 3-bromoprop-1-ene (0.59 mL, 6.82 mmol) was added to a stirred suspension of methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (550 mg, 2.73 mmol) and K2CO3 (943 mg, 6.82 mmol) in acetone (12 mL) and acetonitrile (10 mL). The reaction mixture was stirred at 60 °C for 48 hours. The reaction mixture was filtered and washed with acetone (25 mL). The organic reaction mixture was concentrated under vacuum to give the title product as an oil (715 mg, purity 40%, yield 43%).

[0295] LCMS m / z: 242.1 [M+H]+, (ESI+), Rt = 1.08 (S1). Synthesis of intermediate K9: Methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate. A solution of methyl 5-chloro-6-methyl-2-(prop-2-en-1-yloxy)pyridine-3-carboxylate (0.715 g, 1.18 mmol) and palladium(II) dichloride (10.493 mg, 0.06 mmol) in anhydrous xylene (2 mL) was stirred at 130 °C for 16 h. The reaction mixture was filtered and washed with ethyl acetate (10 mL). The solvent was removed under vacuum to give an oil. Purified by column chromatography (10 g silica, 10-80% ethyl acetate / heptane), the title product as the oil was obtained (336 mg, purity 93%, yield 109%).

[0296] LCMS m / z: 242.1 [M+H]+, (ESI+), Rt = 0.69 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.10 (s, 1H), 5.93 – 5.78 (m, 1H), 5.25 – 5.15 (m, 1H), 5.08 – 5.00 (m, 1H), 4.78 – 4.64 (m,2H), 3.83 (s, 3H), 2.48 (s, 3H).

[0297] Synthesis of Intermediate K10 Methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate Methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (330.0 mg, 1.37 mmol) was added to a solution of methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (50.312 mg, 0.14 mmol) and sodium periodate (876.207 mg, 4.1 mmol) in 1,4-dioxane (7 mL) and water (3.5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate (see page 102 / 484 of CN 121335883 A), and concentrated under vacuum to give the title product as a black liquid (165 mg, purity 55%, yield 27%).

[0298] LCMS m / z: 244.1 [M+H]+, (ESI+), Rt = 0.51 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 9.71 (s, 1H), 8.21 (s, 1H), 5.00 (s, 2H), 3.89 (s, 3H), 3.69 (s, 3H).

[0299] Synthesis of Intermediate K11 Methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate A solution of crude methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate (160.0 mg, 0.66 mmol) in 1,2-dichloroethane (5 mL) was added to a solution of 2 M dimethylamine / THF (0.82 mL, 1.64 mmol), followed by the addition of acetic acid (0.02 mL, 0.33 mmol). After stirring the solution at room temperature for 1 hour, STAB (167.02 mg, 0.79 mmol) was added, and the reaction mixture was stirred for another 18 hours. The mixture was diluted with 1,2-dichloroethane (10 mL), washed successively with 0.5 M sodium hydroxide solution (5 mL), water (5 mL), and dried over Na2SO4. The solvent was removed under vacuum to obtain the oil. The oil was then analyzed by reversed-phase chromatography (12 g C-18, 10-100%).Purification with CH3CN / H2O solution (containing 0.1% formic acid) yielded the title product as the oil (65 mg, yield 36%).

[0300] LCMS m / z: 273.2 [M+H]+, (ESI+), Rt = 0.39 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.15 (s, 1H), 4.21 (dd, J = 8.1, 6.3 Hz, 2H), 3.90 (s, 3H), 2.65 – 2.56 (m, 5H), 2.31 (s, 6H).

[0301] Synthesis of intermediate K12: 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate salt was added to a solution of methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (60 mg, 0.220 mmol) in THF (3 mL) at 45 °C. A 2M aqueous solution of lithium hydroxide monohydrate (0.16 mL, 0.330 mmol) was added. The reaction was stirred for 1 hour and then acidified to pH 2 with 1N HCl. The solvent was removed under vacuum to give the title product (68 mg, 98% yield).

[0302] LCMS m / z: 259.1 [M+H-HCl]+, (ESI+), Rt = 0.31 (S2).

[0303] Synthesis of intermediate K13 of general route 10D 2-[[3-(dimethylamino)propyl]carbamoyl]ethyl acetate Specification 103 / 484 pages 152 CN 121335883 A At 0 °C, ethyl 3-chloro-3-oxopropionate (1.14 mL, 8.91 mmol) was added dropwise to a solution of N,N-dimethylpropane-1,3-diamine (0.7 g, 6.85 mmol) and triethylamine (1.91 mL, 13.7 mmol) in DCM (6.0391 mL). The reaction mixture was heated to room temperature and stirred for another 5 minutes. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give the title product (2.36 g, purity 54%, yield 86%) as an orange semi-solid.

[0304] LCMS m / z: 217.2 [M+H]+, (ESI+), Rt = 0.34 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 4.11 – 4.05 (m, 2H), 3.30 (q, J = 6.1 Hz, 2H), 3.25 (s , 2H) , 2.71 (t, J = 7.0 Hz, 2H) ,2.46 (s, 6H), 1.83–1.75 (m, 2H), 1.18 (d, J = 7.1 Hz, 3H). Synthesis of intermediate K14: Ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was added to a solution of ethyl 2-{[3-(dimethylamino)propyl]carbamoyl} (2.36 g, 5.89 mmol) in THF (10 mL) with (E)-4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (1.01 mL, 7.07 mmol) and DBU (0.93 mL, 6.19 mmol). The reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was diluted with EtOAc (75 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (4 x 75 mL). The combined organic layers were washed with brine (50 mL), then passed through a phase separator and concentrated under vacuum to give a blood-red residue. Purification was performed by column chromatography (10 g Kp-NH silica, 0–100% EtOAc / heptane) to give the title product (0.25 g, 13% yield) as a light brown oil. LCMS m / z: 321.3 [M+H]+, (ESI+), Rt=0.46 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 8.05 (d, J=7.4 Hz, 1H), 6.68 (d, J=7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H) , 4.18 – 4.06 (m, 2H) , 2.40 (t, J = 6.8 Hz, 2H) , 2.23 (s, 6H) , 1.89 (p, J = 6.8 Hz, 2H) , 1.38 (t, J = 7.1Hz, 3H).

[0306] Synthesis of Intermediate K15 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate salt At 45°C, a stirred solution of ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (225 mg, 0.702 mmol) in THF (18.75 mL) was added to a 2 M aqueous solution of lithium hydroxide hydrate (0.53 mL, 1.05 mmol). The reaction mixture was stirred for 1 hour. The mixture was acidified to pH 4 with 1 N aqueous HCl solution. The reaction mixture was concentrated under vacuum to give the title product (230 mg / mL) as a pale brown solid.mg, 100% yield). Specification 104 / 484 pages 153 CN 121335883 A

[0307] LCMS m / z: 293.2 [M+H]+, (ESI+), Rt = 0.32 (S1).

[0308] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate K6 as outlined in general route 10D.

[0309] .

[0310] Synthesis of intermediate K17 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]ethyl acetate was prepared in a manner similar to intermediate K4 using N-(4-amino-2-methylbut-2-yl)carbamoyl tert-butyl hydrochloride and ethyl 3-chloro-3-oxopropionate. LCMS m / z: 339.3 [M+Na]+, (ESI+), Rt=0.76 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 7.10 (br.s, 1H), 4.52 (br.s, 1H), 4.18 (q, J= 7.2 Hz, 2H), 3.35 – 3.28 (m, 2H), 3.27 (s, 2H), 1.96 – 1.87 (m, 2H), 1.42 (s, 9H), 1.30 – 1.25 (m, 9H).

[0312] Synthesis of intermediate F1 in general route 6: (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(quinoline-8-yl)formamido]pentamido]ethyl propionate was added to a solution of (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}ethyl propionate hydrochloride (intermediate B2, 80 mg, 0.154 mmol) and quinoline-8-carboxylic acid (32 mg, 0.185 mmol) in DCM (1.54 mL) with DIPEA (0.059 mg). mL, 0.339 mmol) and HATU (64 mg, 0.169 mmol). The reaction mixture was stirred for 18 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product as a colorless solid (59 mg, yield 64%).

[0313] LCMS m / z: 602.5 [M+H]+, (ESI+), Rt = 4.71(S4) 1H NMR (500 MHz, CDCl3) δ [ppm]: 11.62 (d, J = 7.2 Hz, 1H), 8.94 (dd, J = 4.3, 1.8 Hz, 1H), 8.67 (dd, J = 7.4, 1.6 Hz, 1H), 8.28 (dd, J = 8.3,2.3 Hz, 1H) , 7.97 (dd , J = 8.1, 1.6 Hz, 1H) , 7.77 (d , J = 8.5 Hz, 1H) , 7.63 (dd , J = 8.1 , 7.3 Hz, 1H) , 7.50 (dd , J = 8.3, 4.3 Hz, 1H), 7.20 – 7.13 (m, 1H), 7.07 (d, J = 7.7 Hz, 2H), 6.91 – 6.83 (m, 2H), 5.70 (dt, J = 8.5, 6.2 Hz, 1H), 4.77 – 4.71 (m , 1H) , 3.96 – 3.82 (m , 2H) , 2.91 (dd , J = 15.7 , 6.1 Hz, 1H) , 2.84(dd , J = 15.8, 6.3 Hz, 1H) , 1.98 (s, 3H) , 1.95 (s, 3H) , 1.94 – 1.88 (m, 1H), 1.86 – 1.75 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.5 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H). (N1).

[0314] The intermediates in Table 7 below are prepared using the corresponding starting materials in a manner similar to intermediate F1 as outlined in general route 6.

[0315] Table 7 Specification 106 / 484 pages 155 CN 121335883 A Specification 107 / 484 pages 156 CN 121335883 A Specification 108 / 484 pages 157 CN 121335883 A Specification 109 / 484 pages 158 CN 121335883 A Specification 110 / 484 pages 159 CN 121335883 A Specification 111 / 484 pages 160 CN 121335883 A Specification 112 / 484 pages 161 CN 121335883 AInstruction manual 113 / 484 pages 162 CN 121335883 A; Instruction manual 114 / 484 pages 163 CN 121335883 A; Instruction manual 115 / 484 pages 164 CN 121335883 A; Instruction manual 116 / 484 pages 165 CN 121335883 A; Instruction manual 117 / 484 pages 166 CN 121335883 A; Instruction manual 118 / 484 pages 167 CN 121335883 A; Instruction manual 119 / 484 pages 168 CN 121335883 A; Instruction manual 120 / 484 pages 169 CN 121335883 A; Instruction manual 121 / 484 pages 170 CN 121335883 A; Instruction manual 122 / 484 pages 171 CN 121335883 A Instruction manual 123 / 484 pages 172 CN 121335883 A.

[0316] Synthesis of intermediate F39 (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)carbamate]-4-methylpentamido]ethyl propionate A solution of methyl 1,4-dimethyl-2-oxo-1,2-dihydropyridin-3-carboxylate (100 mg, 0.497 mmol) in THF (4 mL) was added to LiOH·H2O (104 mg, 2.48 mmol) dissolved in water (1 mL). The reaction mixture was stirred for 48 hours. The reaction mixture was concentrated under vacuum to give the intermediate. The intermediate acid was redissolved in DMF (4 mL), and intermediate B2 (150 mg, 0.311 mmol), DIPEA (190 µL, 1.09 mmol), and HATU (142 mg, 0.373 mmol) were added. The resulting mixture was stirred for 72 hours. The reaction was then quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum to give a crude residue. Purification by column chromatography (12 g Redisep Gold silica, 0–100% EtOAc / heptane) yielded a colorless gel (20 mg, 9% yield). LCMS m / z: 596.4 [M+H]+, (ESI+), Rt=2.85 (S6).

[0318] Synthesis of intermediate G1 in general route 7: (3S)-3-{2',6'-dichloro-4,5-difluoro-[1,1'-biphenyl]-3-yl}-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate to (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate (intermediate F6, 70 mg, 0.107 mmol), 2,6-dichlorophenylboronic acid (35 mg, 0.183 mmol) and K3PO4 (70 mg, 0.330 mmol) in 1,4-dioxane (1 The degassed suspension of Pd(dppf)Cl2 (18 mg, 0.0214 mmol) in water (0.1 mL) and water (0.1 mL) was added. The reaction mixture was heated at 90 °C for 18 hours. The reaction mixture was concentrated under vacuum to obtain a crude residue. Purification by column chromatography (10 g silica, 0–100% EtOAc / heptane) gave the title product as orange oil (47 mg, 45% yield). LCMS m / z: 622.4 / 624.3 [M+H]+, (ESI+), Rt=1.07 (S1) H NMR (500 MHz, CDC13) δ [ppm]: 10.11 (d, J=7.6 Hz, 1H), 8.43 (dd, J=7.2,2.2 Hz, 1H), 7.58 – 7.53 (m, 2H), 7.40 – 7.36 (m, 2H), 7.02 – 6.98 (m, 2H), 6.39 (t, J = 6.9 Hz, 1H), 5.69 (dt, J = 8.4, 6.2 Hz , 1H), 4.60 – 4.54 (m, 1H), 4.02 – 3.97 (m, 2H), 3.64 (s, 3H), 2.91 – 2.81 (m, 4H), 1.81 (td, J = 10.1, 5.0 Hz, 1H), 1.72 – 1.70 (m, 1H), 1.14 – 1.11 (m, 3H), 0.92 – 0.87 (m, 6H).

[0320] The intermediates in Table 8 below are prepared using the corresponding starting materials in a manner similar to intermediate G1 as outlined in general route 7.

[0321] Table 8 Specification 125 / 484Page 174 CN 121335883 A Instruction manual 126 / 484 Page 175 CN 121335883 A.

[0322] Synthesis of intermediate H1 in general route 8: (3S)-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate to (3S)-3-(5-bromo-2,3-difluorophenyl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate (intermediate F6, 100 mg, 0.153 mmol), B2(pin)2 (58 mg, 0.228 mmol), and KOAc (45 mg, 0.459 mmol). Pd(dppf)Cl2 (6.0 mg, 8.20 μmol) was added to a degassed solution of the product in DMF (1 mL). The reaction mixture was heated at 80 °C for 3 hours. The reaction mixture was cooled to room temperature and filtered through a diatomaceous earth mat, washed with excess EtOAc (3 × 5 mL). The filtrate was concentrated under vacuum to give the title product (142 mg, 77% yield) as a dark brown gel, as per the specification on page 176 of CN 121335883 A. LCMS m / z: 604.6 [M+H]+, (ESI+), Rt=1.08 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 10.14–10.03 (m, 1H), 9.02–8.89 (m, 1H), 8.35 – 8.23 ​​(m, 1H) , 8.10 – 8.04 (m, 1H) , 7.69 – 7.39 (m, 2H) , 6.54 – 6.41 (m, 1H) , 5.59 – 5.38 (m, 1H) , 4.64 – 4.43 (m,1H) , 4.07 – 3.96 (m, 2H), 3.58 – 3.56 (m, 3H), 2.88 – 2.76 (m, 2H), 1.54 – 1.37 (m, 3H), 1.17 – 1.16 (m, 12H), 1.13 – 1.09 (m, 3H), 0.89 – 0.78 (m, 6H). (N1).

[0324] Synthesis of intermediate H2(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]valerate is prepared by hydrolysis of methyl (2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]valerate, as outlined in general route 6, step B. LCMS m / z: 267.2 [M+H]+, (ESI+), Rt=0.60, S1 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.73(s, 1H), 10.13 (d, J=7.9 Hz, 1H), 8.31 (dd, J = 7.3, 2.2 Hz, 1H) , 8.08 (dd, J = 6.5, 2.2 Hz, 1H) , 6.51 (dd , J = 7.3, 6.5 Hz, 1H) , 4.55 – 4.37 (m, 1H) , 3.57(s, 3H) , 1.71 – 1.55 (m, 3H), 0.98 – 0.80 (m, 6H). (N1).

[0326] Synthesis of intermediate H3 (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)formamido]pentamido]ethyl propionate was prepared in DMF starting from intermediate H2 and intermediate A18 in a manner similar to that of intermediate B1.

[0327] LCMS m / z: 521.2 / 523.2 [M+H]+, (ESI+), Rt = 0.79,S1.

[0328] Synthesis of intermediate H3B (3S)-3-[(2S)-4-methyl-2-[(1-methyl-2-oxo-1,2-dihydropyridin-3-yl)carbamoyl]pentamido]-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridin-3-yl]ethyl propionate specification 128 / 484 pages 177 CN 121335883 A It was prepared using intermediate H3 as the starting material in a manner similar to that of intermediate H1. LCMS m / z: 547.3 [M+H]+, (ESI+), Rt=0.82, S1 1H NMR (400 MHz, DMSO) δ 10.10 – 9.98 (m, 1H), 8.82 – 8.70 (m, 1H), 8.55 – 8.48 (m, 1H) , 8.28 – 8.15 (m,2H), 8.08 – 8.01(m, 1H), 7.68 – 7.51 (m, 1H), 7.26 – 7.07 (m, 3H), 6.53 – 6.43 (m, 1H), 5.36 – 5.24 (m, 1H), 4.55 – 4.44 (m, 1H) , 4.07 – 3.92 (m, 2H) , 2.92 – 2.81 (m, 2H) ,2.78 – 2.62 (m, 4H) , 1.90 (d , J = 30.4 Hz, 6H) , 1.61 – 1.40 (m, 2H) , 1.18 – 1.02 (m, 3H), 0.93 – 0.76 (m, 6H).

[0330] Synthesis of intermediate H4 of general route 8B: (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-[2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl]propionate was prepared from intermediate B15 under the same conditions as intermediate H1.

[0331] LCMS m / z: 569.5 [M+H]+, (ESI+), Rt = 1.18 (S1) Specification 129 / 484 pages 178 CN 121335883 A 1H NMR (400 MHz, DMSO) δ [ppm]: 8.57 (d, J = 7.8 Hz, 1H), 7.52 (d, J = 6.3 Hz, 1H), 7.47 – 7.38 (m, 1H), 6.75 (d, J = 8.3 Hz, 1H), 5.43 (q, J = 7.6 Hz, 1H), 4.07 – 3.90 (m, 3H), 2.88 – 2.72 (m, 2H), 1.52 – 1.41 (m, 1H), 1.36 (s, 9H), 1.33 – 1.26 (m, 14H), 1.12 (t, J = 7.1 Hz, 3H), 0.90 – 0.77 (m, 6H).

[0332] Synthesis of intermediate H5: Ethyl (3S)-3-[(2S)-2-{[(tert-butoxycarbonyl)amino]-4-methylpentamido}-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2,3-difluorophenyl]propionate was added to a MW tube flask, along with Pd(dppf)2Cl2 (33.041 mg, 0.04 mmol) and K2CO3 (223.673 mg).Ethyl propionate (460.0 mg, 0.81 mmol) and 4-bromo-2,5-dimethylindazole (204.352 mg, 0.91 mmol) in 1,4-dioxane (4 mL) and water (0.5 mL) were degassed for 5 minutes and then capped. The reaction mixture was heated at 150 °C under MW radiation for 15 minutes. The reaction mixture was filtered through a thiol column and washed with excess EtOAc (3 x 10 mL). The solvent of the filtrate was concentrated under vacuum. Purification by column chromatography (25 g silica, 0-100% EtOAc / heptane) yielded the title product as the oil (389 mg, 70% yield). LCMS m / z: 587.5 [M+H]+, (ESI+), Rt=1.07 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.51 (d, J=8.1 Hz, 1H), 7.90 (s, 1H), 7.51 (d, J = 8.8 Hz, 1H) , 7.43 – 7.37 (m, 1H) , 7.24 (d, J = 5.7 Hz, 1H) , 7.17 (d , J = 8.9 Hz, 1H) , 6.80 (d , J = 8.3 Hz,1H) , 5.55 (q, J = 7.6 Hz, 1H) , 4.09 (s, 3H) , 4.08 – 4.01 (m, 2H) , 3.95 – 3.87 (m, 1H) , 2.86 (d, J = 7.5 Hz, 2H) , 2.22 (s, 3H) , 1.46 – 1.39 (m, 1H) , 1.30 –1.22 (m, 11H), 1.13 (t, J = 7.1 Hz, 3H), 0.73 – 0.68 (m, 6H).

[0334] Synthesis of Intermediate H6: Ethyl (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-[5-(2,5-dimethyl-2H-indazol-4-yl)-2,3-difluorophenyl]propionate dihydrochloride was prepared using intermediate H5 as the starting material, similar to intermediate A4.

[0335] LCMS m / z: 487.3 [M+H-HCl]+, (ESI+), Rt = 0.75 (S1)¹H NMR (400 MHz, DMSO-d⁶) δ [ppm]: 9.37 (d, J = 7.7 Hz, ¹H), 8.24 (s, 2H), 7.95 (s, ¹H), 7.53 (d, J = 8.8 Hz, ¹H), 7.48 – 7.40 (m, ¹H), 7.29 (d, J = 5.7 Hz, ¹H), 7.19 (d, J = 8.8 Hz, ¹H), 5.57 (q, J = 7.5 Hz, ¹H), 4.13 – 4.01 (m, 6H), 3.77 – 3.69 (m, 2H) , 3.01 – 2.91 (m, 2H) , 2.23 (s, 3H) , 1.49 – 1.36 (m, 3H) , 1.13 (t, J = 7.1 Hz, 3H) , 0.73 – 0.63 (m,6H).

[0336] Synthesis of Intermediate H7: {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid was added to a MW tube containing PdCl2(dppf)2 (40.0 mg, 0.05 mmol), (3S)-3-(5-bromopyridin-3-yl)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]propionate ethyl ester (intermediate B12, 0.45 g, 0.601 mmol), bis(pinacol)diboron (0.23 g, 0.906 mmol), and KOAc (0.18 g, 1.78 mmol), and 1,4-dioxane (1.8 g). Add 1 drop of DMF. Degas the reaction mixture for 5 minutes, then heat at 150 °C under MW radiation for 15 minutes. Filter the reaction mixture through a thiol column and wash with EtOAc (2 x 10 mL). Remove the solvent under vacuum to give a dark brown residue. Purify by column chromatography (10 g silica, 75–100% EtOAc / heptane) to give the title product (200 mg, 42% yield) as a brown solid.

[0337] LCMS m / z: 452.3 [M+H]+, (ESI+), Rt = 0.65 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.65 –8.61 (m, 1H), 8.61 – 8.57 (m, 1H), 8.52 – 8.41 (m,1H) , 8.01 – 7.91 (m, 1H) , 6.87 – 6.77 (m, 1H) , 5.75 (s, 2H) , 5.25 – 5.15 (m, 1H) , 4.08 – 3.95 (m, 2H) ,3.95 – 3.91 (m, 1H) , 2.91 – 2.81 (m, 2H) , 1.54 – 1.44 (m, 1H) , 1.32 – 1.29 (m, 9H) , 1.26 – 1.21 (m, 2H) , 1.13 – 1.08 (m, 3H) , 0.89 – 0.77 (m, 6H). Synthesis of Intermediate H8: Ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate. Condition A: In a pressure tube flask, ethyl {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxypropyl]pyridin-3-yl}boronic acid (intermediate H7, 42.5 mg, 0.05 mmol), 4-bromo-3,5-dimethylpyridine hydrochloride (22 mg, 0.0989 mmol), Pd(dppf)2Cl2 (8.0 mg, 9.77 μmol), and K2CO3 (27 mg, 131 / 484 pages, 180 CN) were added. 121335883 A (0.195 mmol) was degassed in a mixture of 1,4-dioxane (0.5 mL) and water (50 μL). The reaction mixture was sealed and heated at 100 °C for 1 hour. The reaction mixture was diluted with EtOAc (2 mL) and water (2 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (2 x 1 mL). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, and concentrated under vacuum to obtain a brown oil residue. Purification by reversed-phase column chromatography (10 g C-18 silica, 10% to 100% MeCN / H2O, containing 0.1% formic acid) gave the title product (13 mg, 50% yield) as a brown viscous oil.

[0338] Condition B: In a pressure tube, add {5-[(1S)-1-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-ethoxy-3-oxopropyl]pyridin-3-yl}boronic acid (intermediate H7, 250.0 mg, 0.51 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (143.777 mg).The following substances were added: 1,4-dioxane (4 mL, 0.62 mmol), K3PO4 (464.014 mg, 2.19 mmol), and Pd(dppf)2Cl2.DCM (98.818 mg, 0.12 mmol). 1,4-Dioxane (4 mL) and water (0.4 mL) were added. The reaction mixture was capped and heated at 100 °C for 3 hours. The reaction mixture was concentrated under vacuum to give a brown residue. Purification by column chromatography (10 g silica, 0–100% EtOAc / heptane) yielded the title product (39 mg, 15% yield) as a colorless oil and the starting material (183 mg, 73% recovery). LCMS m / z: 513.3 [M+H]+, (ESI+), Rt=0.72 (S1) H NMR (400 MHz, d3-MeCN) δ [ppm]: 8.58 (d, J=2.2 Hz, 1H), 8.34 (s, 2H), 8.28 (d, J = 2.0 Hz, 1H) , 7.51 (t, J = 2.2 Hz, 1H) , 7.39 (d, J = 8.2 Hz, 1H) , 5.60 – 5.46 (m, 1H) , 5.35 (q, J = 7.3 Hz,1H) , 4.04 (q, J = 7.1 Hz, 2H) , 3.98 – 3.90 (m, 1H) , 2.96 – 2.82 (m, 2H) , 1.98 (s, 6H) , 1.65 – 1.54 (m, 1H) , 1.48 – 1.39 (m, 2H) , 1.32 (s, 9H) , 1.14 (t, J =7.1 Hz, 3H), 0.89 – 0.84 (m, 6H).

[0340] Synthesis of Intermediate H9: Ethyl (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate trihydrochloride was added to a solution of ethyl (3S)-3-[(2S)-2-{[(tert-butoxy)carbonyl]amino}-4-methylpentamido]-3-{3',5'-dimethyl-[3,4'-bipyridine]-5-yl}propionate (1.04 g, 1.83 mmol) in 1,4-dioxane (6 mL) with 4M HCl / dioxane (1.9 mL, 7.6 mmol). A gel formed in the flask within 5 minutes. 1,4-dioxane (6 mL) was then added, the suspended solid was sonicated for 10 minutes, and the mixture was stirred at room temperature for 18 hours. The reactants were concentrated under vacuum and reacted with DCM (2 x50 mL) azeotropically to obtain the title product (1.00 g, 1.55 mmol, 85% yield) as a grayish-white powder.

[0341] LCMS m / z: 413.4 [M+H-3HCl]+, (ESI+), Rt = 0.64 (S2).

[0342] The intermediates in Table 9 were synthesized according to general formula 8B, taking intermediate H6 as an example, using the corresponding starting materials. Diastereomers were isolated in the final purification, or as required by chiral separation methods. The intermediates were obtained as the title compound or its salt. Specification 132 / 484 pages 181 CN 121335883 A

[0343] Table 9.

[0344] Schematic diagram of general route 9, 133 / 484 pages, 182 CN 121335883 A

[0345] Synthesis of intermediate I1 (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (step A) HATU (8.40 g, 22.1 mmol) was added to a stirred solution of (2S)-2-amino-4-methylpentanoate methyl hydrochloride (1.75 g, 9.63 mmol), (2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-carboxylic acid (1.57 g, 7.29 mmol) and DIPEA (6.3 mL, 36.1 mmol) in DMF (23 mL). The solution was stirred at room temperature for 3 hours, and then EtOAc (30 mL) and water (20 mL) were added. The organic layer was separated, and the aqueous layer was extracted again with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (30 mL), concentrated under vacuum, and purified by column chromatography (50 g silica, 0–100% TBME / heptane) to give the title product (2.30 g, 87% yield). LCMS m / z: 365.1 [M+H]+, (ESI+), Rt=0.88, S1 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.26 – 7.95 (m, 1H), 4.39 – 4.29 (m, 1H), 4.13 – 4.06 (m, 1H) , 3.64 – 3.58 (m, 3H) , 3.50 – 3.35 (m, 1H) , 3.30 – 3.18 (m, 1H) , 2.18 – 1.99 (m, 1H) , 1.82 – 1.69 (m, 3H) , 1.67 – 1.57 (m, 2H) , 1.55 – 1.43(m, 1H) , 1.43 – 1.25 (m,9H), 0.92 – 0.77 (m, 6H). (N1).

[0347] Synthesis of intermediate I2 (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylpentanoic acid (step B) To a stirred solution of (2R)-2-{[(2S)-1-methoxy-4-methyl-1-oxopentane-2-yl]carbamoyl}pyrrolidine-1- (Instructions 134 / 484 pages 183 CN 121335883 A) tert-butyl formate (2.30 g, 6.38 mmol) in THF (57 mL) and MeOH (1.9 mL), 2M aqueous solution of LiOH (20 mL, 40.8 mmol) was added. The reaction mixture was stirred at 45°C for 30 minutes. The solution was cooled, water (10 mL) was added, and the mixture was concentrated under vacuum to remove organic matter. The aqueous phase was acidified to approximately pH 3 with a 1 M HCl aqueous solution, and the resulting precipitate was extracted with DCM (3 × 15 mL). The combined organic layers were concentrated under vacuum to give the title product (2.10 g, 95% yield) as a white solid. LCMS m / z: 351.3 [M+H]+, (ESI+), Rt=0.75, S1 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 12.59 – 12.40 (m, 1H), 8.09 – 7.81 (m, 1H) ,4.34 – 4.22 (m, 1H) , 4.15 – 4.07 (m, 1H) , 3.48 – 3.35 (m, 1H) , 3.29 – 3.21 (m , 1H) , 2.17 – 2.01 (m , 1H) , 1.87 – 1.68 (m , 3H) , 1.68 – 1.54 (m, 2H), 1.54 – 1.43 (m, 1H), 1.43 – 1.26 (m, 9H), 0.93 – 0.77 (m, 6H). (N1).

[0349] Synthesis of intermediate I3: (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]yl-3-yl]-3-oxypropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyrrolidine-1-carboxylic acid tert-butyl ester (step C) to (2S)-2-{[(2R)-1-[(tert-butoxy)carbonyl]pyrrolidine-2-yl]formamido}-4-methylvaleric acid (150 mg, 0.434 mg)A solution of ethyl propionate (218 mg, 0.478 mmol) and (3S)-3-amino-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate in DCM (3 mL) was added to DIPEA (152 µL, 0.870 mmol) and HATU (182 mg, 0.479 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM (5 mL), washed with water (5 mL), and passed through a phase separator. The solvent was concentrated under vacuum to give crude oil. Purification by rapid column chromatography (10 g silica, 0.100% EtOAc / heptane) gave the title product (314 mg, 98% yield) as a pale yellow oil.

[0350] LCMS m / z: 716.4 [M+H]+, (ESI+), Rt=1.25, S1 1H NMR (500 MHz, CDC13) δ [ppm]: 7.62-7.49 (m, 1H), 7.31 (d, J=6.4 Hz, 2H), 7.21 – 7.13 (m, 1H) , 7.13 – 7.06 (m, 2H) , 6.89 – 6.29 (m, 1H) , 5.71 – 5.60 (m , 1H) , 4.38 (q , J = 7.1 Hz, 1H) , 4.24 – 4.17 (m , 1H) , 4.09 – 3.99 (m, 2H) , 3.38 (d, J = 54.1 Hz, 2H) , 2.98 – 2.82 (m, 2H) , 2.01 – 1.95 (m, 6H) ,1.86 – 1.77 (m, 1H) , 1.43 (s, 6H) , 1.20 – 1.16 (m, 3H), 0.91 – 0.84 (m, 15H). (N1).

[0351] Synthesis of intermediate I4 (6a) (3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl-2-{[(2R)-pyrrolidine-2-yl]formamido}pentamido]ethyl propionate hydrochloride (step D) Specification 135 / 484 pages 184 CN 121335883 A To (2R)-2-{[(1S)-1-{[(1S)-3-ethoxy-1-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-oxypropyl]carbamoyl}-3-methylbutyl]carbamoyl}pyrrolidine-1-carboxylic acid tert-A solution of butyl ester (314 mg, 0.425 mmol) in DCM (4.5 mL) was added to HCl (4 M in dioxane, 1.5 mL, 6.00 mmol). The reaction mixture was stirred at room temperature for 45 minutes. HCl (4 M in dioxane, 1.5 mL, 6.00 mmol) was then added, and the mixture was stirred for another 15 minutes. The reaction mixture was concentrated under vacuum, ground with heptane (2 × 5 mL), the solvent was decanted, and the residue was dried under vacuum to give the title product (193 mg, 62% yield) as a grayish-white powder. LCMS m / z: 594.6 [M+H]+, (ESI+), Rt=1.05, S1 1H NMR (400 MHz, CDC13) δ [ppm]: 8.81 (d, J=7.6 Hz, 1H), 8.49 (d, J=7.5 Hz, 1H), 7.48 – 7.41 (m, 1H), 7.35 – 7.30 (m, 1H), 7.22 – 7.15 (m,1H), 7.14 – 7.07 (m, 2H), 5.74 – 5.63 (m, 1H), 4.67 – 4.48 (m, 1H) , 4.16 – 4.02 (m, 2H), 3.49 – 3.28 (m, 2H), 3.14 – 2.98 (m, 2H), 2.53 – 2.42 (m, 1H), 2.06 – 1.75 (m, 11H), 1.58 – 1.47 (m, 2H) , 1.25 – 1.16 (m, 3H), 0.95 – 0.78 (m, 7H). (N1).

[0353] Synthesis of Intermediate I5: Ethyl (3S)-3-[(2S)-2-{[(2R)-1-acetylpyrrolidine-2-yl]formamido}-4-methylpentamido]-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]propionate (Step 5) was added to (3S)-3-[4-fluoro-2',6'-dimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-[(2S)-4-methyl-2-{[(2R)-pyrrolidine-2-yl]formamido}pentamido]propionate hydrochloride (100 mg, 0.136 mmol) and DIPEA (38 µL, 0.218 mmol) in DCM (1.2 Add acetyl chloride stock solution (0.1 mL stock solution: 120 µL acetyl chloride / 1 mL) to the solution in the mL container.The reaction mixture was stirred and heated to room temperature for 2.5 hours. The mixture was cooled to 0 °C, reprocessed with DIPEA (13 µL, 0.0746 mmol) and acetyl chloride stock solution (0.05 mL), and then allowed to be further heated to room temperature for 1 hour. The mixture was diluted with DCM (2 mL), quenched with saturated sodium bicarbonate (water solution, 3 mL), and the resulting aqueous phase was extracted with DCM (3 mL). The combined organic layers were passed through a phase separator, concentrated under vacuum, and the residue was purified by column chromatography (10 g silica, 0–100% EtOAc / heptane) to give the title product (39 mg, 43% yield) as a grayish-white semi-solid.

[0354] LCMS m / z: 636.6 [M+H]+, (ESI+), Rt = 1.17, (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 7.85 (d, J = 8.6 Hz, 1H), 7.31 – 7.26 (m, 2H), 7.19 – 7.04 (m, 3H), 6.80 (d, J = 8.1 Hz, 1H), 5.79 – 5.69 (m, 1H), 4.40 – 4.31 (m, 1H), 4.28 (dd, J = 7.6 , 3.8 Hz, 1H), 4.13 – 4.00 (m, 2H), 3.39 – 3.21 (m, 2H), 3.03 – 2.79 (m, 2H), 2.20 – 2.11 (m, 1H), 2.04 – 1.98 (m,4H) , 1.96 (s, 3H) , 1.94 – 1.81 (m, 3H) , 1.79 (s, 3H) , 1.72 – 1.62 (m, 1H) , 1.54 – 1.45 (m, 1H) , 1.20 (t, J = 7.1 Hz, 3H) , 0.92 (d, J = 6.6 Hz, 3H), 0.88 (d, J = 6.5 Hz, 3H). (N1).

[0355] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate I5 as outlined in general route 6.

[0356] .

[0357] Synthesis of intermediate J1 of general route 10A: methyl 1-(1-methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (step A) Specification 137 / 484 pages186 CN 121335883 A At 0 °C, a solution of methyl 2-oxo-2H-pyran-3-carboxylate (800 mg, 5.19 mmol) in DMF (10 mL) was added dropwise to 1-methylazacyclobutane-3-amine (447 mg, 5.19 mmol) in DMF (10 mL). The reaction mixture was stirred at 0 °C for 1 hour, then heated to room temperature. T3P (50% dissolved in EtOAc, 4.6 mL, 7.79 mmol) was then added dropwise. The reaction mixture was stirred for 72 hours, then concentrated under vacuum. Purification by column chromatography (55 g, KPNH silica, 0–100% EtOAc / heptane, 0–20% MeOH / EtOAc) yielded the title product as a red solid (415 mg, 25% yield).

[0358] LCMS m / z: 223.1 [M+H]+, (ESI+), Rt = 0.38 (S1).

[0359] Synthesis of Intermediate J2 (Intermediate 7a) 1-(1-methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Step B) LiOH (2M, aqueous solution, 1.3 mL, 2.58 mmol) was added to a solution of methyl 1-(1-methylazacyclobutane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (415 mg, 1.29 mmol) in methanol (6.9 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to give a red solid. Purified by column chromatography (11 g KPNH silica, 0–100% methanol / EtOAc), the title product (100 mg, 34% yield) was obtained as a red solid. LCMS m / z: 209.2 [M+H]+, (ESI+), Rt=0.18 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.17 (dd, J=7.0, 2.2 Hz, 1H), 7.96 (dd, J= 6.8, 2.2 Hz, 1H), 6.49 – 6.43 (m, 1H), 5.00 – 4.91 (m, 1H), 3.75 – 3.66 (m, 2H), 3.15 – 3.09 (m, 2H), 2.27 (s, 3H). (N1).

[0361] Synthesis of Intermediate J3: Methyl 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (Step A) At room temperature, methyl 2-oxo-2H-pyran-3-carboxylate (1.00 g, 6.49 g) was added to methyl 2-oxo-2H-pyran-3-carboxylate.0.72 g (6.56 mmol) of oxetane-3-amine hydrochloride and 3.4 mL (19.5 mmol) of DMF (33.5 mL) were added to the reaction mixture. The reaction mixture was stirred for 1 hour, and then EDC.HCl (1.87 g, 9.75 mmol) and DMAP (0.20 g, 1.64 mmol) were added. The reaction mixture was stirred for another 3 hours. The reaction mixture was concentrated under vacuum, suspended in water (150 mL), and extracted with EtOAc (3 x 50 mL). The combined organic layers were free of product. The aqueous layer was extracted with a 4:1 DCM / IPA solution (2 x 60 mL). The combined organic layers were concentrated under vacuum to give the title product (352 mg, 24% yield) as brown oil.

[0362] LCMS m / z: 210.1 [M+H]+, (ESI+), Rt=1.08 (S4) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.08-8.02 (m, 2H), 6.41 (t, J=6.9Hz, 1H), 5.45 (p, J = 7.2 Hz, 1H), 4.86 (t, J = 7.5 Hz, 2H), 4.72 (t, J = 7.2 Hz, 2H), 3.73 (s, 3H).

[0363] Synthesis instructions for intermediate J3, pages 138 / 484, CN 121335883 A 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (step B) A 2 M aqueous solution of lithium hydroxide (1.2 mL, 2.4 mmol) was added to a stirred solution of methyl 1-(oxetane-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (352.2 mg, 1.57 mmol) in methanol (4.5 mL) and THF (65 mL). The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was concentrated under vacuum, and the resulting residue was suspended in water (about 20 mL). The suspension was acidified to pH about 1 with a 2 M aqueous solution of HCl and extracted with a 4:1 DCM:IPA solution (3 x 10 mL). The combined organic layers were concentrated under vacuum to give the title product (300 mg, 71% yield) as a pale orange solid.

[0364] LCMS m / z: 196.1 [M+H]+, (ESI+), Rt = 1.04 (S3) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 14.26 (s, 1H), 8.40 (dd, J =7.3, 2.0 Hz, 1H) , 8.30 (dd, J = 6.7, 2.0 Hz, 1H) , 6.79 (t, J = 7.0 Hz, 1H) , 5.68 – 5.57 (m, 1H) , 4.91 (t, J = 7.4 Hz, 2H) , 4.84 (t, J = 7.4 Hz, 2H).

[0365] Synthesis of intermediate K1 in general route 10B: A solution of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (200 mg, 1.31 mmol) and CsCO3 (1280 mg, 3.93 mmol) in MeCN (5 mL) was added to (2-bromoethyl)dimethylamine hydrobromide (375 mg, 1.58 mmol). The reaction mixture was stirred at room temperature for 24 hours. The reaction was cooled to room temperature, filtered through a diatomaceous earth mat, and washed with excess EtOAc (100 mL) and DCM (2 × 5 mL). The filtrate was collected and concentrated under vacuum to give crude oil. Purification by open preparative high performance liquid chromatography (P4) yielded the methyl title product (79 mg, 25% yield) as a brown oil.

[0366] LCMS m / z: 225.1 [M+H]+, (ESI+), Rt=0.40 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.04 – 7.96 (m, 1H), 7.96 – 7.90 (m, 1H), 6.33 – 6.25 (m, 1H) , 4.01 (t, J = 6.2 Hz, 2H) , 3.77 – 3.70 (m, 3H) , 2.55 – 2.51 (m, 2H) , 2.23 – 2.10 (m, 6H). (N1).

[0367] Synthesis of Intermediate K2: Lithium (1+)-1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) LiOH (2M, aqueous solution, 900 µL, 1.80 mmol) was added to a solution of methyl 1-[2-(dimethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (79 mg, 0.333 mmol) in MeOH (190 µL) and THF (1.9 mL), and stirred at room temperature for 5 hours. The reactants were concentrated under vacuum and dried overnight in a vacuum oven to give the title product (108 mg, 100% yield) as a colorless solid.

[0368] LCMS m / z: 211.2[M+H]+, (ESI+), Rt = 0.19 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.15 (dd, J = 7.0, 2.2 Hz, 1H), 7.76 (dd, J = 6.6, 2.3 Hz, 1H), 6.36 (t, J = 6.8 Hz, 1H), 4.04 (t, J = 6.3 Hz, 2H), 2.52 (s, 2H), 2.17 (s, 6H). (N1). The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate K2 as outlined in general route 10B.

[0369]

[0370] Synthesis of Intermediate K5 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate methyl 2-hydroxypyridine-3-carboxylate (3.00 g, 19.6 mmol) and K2CO3 (6.90 g, 49.9 mmol) in a stirred suspension in acetone (60 mL) was added 3-dimethylaminopropylhydrochloride (3.36 g, 21.26 mmol). The reaction mixture was heated at 60°C for 5 hours, and then heated at room temperature for 72 hours. Sodium iodide (2.0 g, 13.34 mmol) was added to the reaction mixture, and stirring was continued at 60°C for 2 hours. Another portion of 3-dimethylaminopropylhydrochloride (2 g, 12.7 mmol) was added, and stirring was continued at 60°C for 10 hours. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to obtain a yellow oil. The oil was dissolved in DCM (30 mL), washed with water (30 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a yellow oil. The oil was then dissolved in ethyl acetate (15 mL), diluted with heptane (15 mL), and the resulting solid was filtered. The filtrate was concentrated under vacuum to obtain the title product as the yellow oil (2.01 g, yield 36%, purity 83%).

[0371] LCMS m / z: 499.3 [2M+Na]+, (ESI+), Rt = 0.40 (S2).

[0372] Synthesis of intermediate K6 Lithium (1+) 1-[3-(dimethylamino)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylate was prepared using intermediate K5 in a manner similar to intermediate K2. LCMS m / z: 225.1 [M+H]+, (ESI+), Rt=0.40 (S2) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.21 –8.14 (m, 1H), 7.85 – 7.78 (m,1H), 6.37 (t, J = 6.8 Hz, 1H), 4.01 – 3.93 (m, 2H), 2.22 – 2.14 (m, 2H), 2.11 (s, 6H), 1.84 – 1.72 (m, 2H).

[0374] Synthesis of intermediate K7 of general route 10C: Methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate 1 M thionyl chloride / DCM (7.04 mL, 7.04 mmol) was added dropwise to a solution of 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (0.528 g, 2.81 mmol) in DCM (10 mL). The reaction mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and methanol (0.57 mL, 14.07 mmol) was added. After 30 minutes, the reaction mixture was concentrated under vacuum to give the title product as a solid (560 mg, 88% yield).

[0375] LCMS m / z: 202.1 [M+H]+, (ESI+), Rt = 0.56 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.09 (s, 1H), 3.88 (s, 3H), 2.50 (s, 3H). (See specification 141 / 484 pages 190 CN 121335883 A 3H).

[0376] Synthesis of Intermediate K8: Methyl 5-chloro-6-methyl-2-(prop-2-en-1-oxy)pyridine-3-carboxylate 3-bromoprop-1-ene (0.59 mL, 6.82 mmol) was added to a stirred suspension of methyl 5-chloro-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (550 mg, 2.73 mmol) and K2CO3 (943 mg, 6.82 mmol) in acetone (12 mL) and acetonitrile (10 mL). The reaction mixture was stirred at 60 °C for 48 hours. The reaction mixture was filtered and washed with acetone (25 mL). The organic reaction mixture was concentrated under vacuum to give the title product as an oil (715 mg, purity 40%, yield 43%).

[0377] LCMS m / z: 242.1 [M+H]+, (ESI+), Rt = 1.08 (S1). Synthesis of intermediate K9: Methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (0.715 g, 1.18 mmol)A solution of palladium(II) dichloride (10.493 mg, 0.06 mmol) in anhydrous xylene (2 mL) was stirred at 130 °C for 16 h. The reaction mixture was filtered and washed with ethyl acetate (10 mL). The solvent was removed under vacuum to give the oil. Purification was performed by column chromatography (10 g silica, 10–80% ethyl acetate / heptane) to give the title product as the oil (336 mg, 93% purity, 109% yield).

[0378] LCMS m / z: 242.1 [M+H]+, (ESI+), Rt=0.69 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 8.10 (s, 1H), 5.93 – 5.78 (m, 1H), 5.25 – 5.15 (m, 1H) , 5.08 – 5.00 (m, 1H) , 4.78 – 4.64 (m, 2H) , 3.83 (s, 3H) , 2.48 (s, 3H).

[0379] Synthesis of Intermediate K10 Methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate Methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (330.0 mg, 1.37 mmol) was added to a solution of methyl 5-chloro-6-methyl-2-oxo-1-(prop-2-en-1-yl)-1,2-dihydropyridine-3-carboxylate (50.312 mg, 0.14 mmol) and sodium periodate (876.207 mg, 4.1 mmol) in 1,4-dioxane (7 mL) and water (3.5 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate (see page 142 / 484 of CN 121335883 A), and concentrated under vacuum to give the title product (165 mg, 55% purity, 27% yield) as a black liquid.

[0380] LCMS m / z: 244.1 [M+H]+, (ESI+), Rt = 0.51 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 9.71 (s, 1H), 8.21 (s, 1H), 5.00 (s, 2H), 3.89 (s, 3H), 3.69 (s, 3H).

[0381] Synthesis of intermediate K11Methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was added to a solution of crude methyl 5-chloro-6-methyl-2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate (160.0 mg, 0.66 mmol) in 1,2-dichloroethane (5 mL). 2 M dimethylamine / THF (0.82 mL, 1.64 mmol) was then added, followed by acetic acid (0.02 mL, 0.33 mmol). After stirring the solution at room temperature for 1 hour, STAB (167.02 mg, 0.79 mmol) was added, and the reaction mixture was stirred for another 18 hours. The mixture was diluted with 1,2-dichloroethane (10 mL), washed successively with 0.5 M sodium hydroxide solution (5 mL), water (5 mL), and dried over Na₂SO₄. The solvent was removed under vacuum to obtain the oil. Purification by reversed-phase chromatography (12 g C-18, 10-100% CH3CN / H2O solution, containing 0.1% formic acid) yielded the title product as the oil (65 mg, yield 36%).

[0382] LCMS m / z: 273.2 [M+H]+, (ESI+), Rt = 0.39 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.15 (s, 1H), 4.21 (dd, J = 8.1, 6.3 Hz, 2H), 3.90 (s, 3H), 2.65 – 2.56 (m, 5H), 2.31 (s, 6H).

[0383] Synthesis of intermediate K12: 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate salt was added to a solution of methyl 5-chloro-1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate (60 mg, 0.220 mmol) in THF (3 mL) at 45 °C. A 2M aqueous solution of lithium hydroxide monohydrate (0.16 mL, 0.330 mmol) was added. The reaction was stirred for 1 hour and then acidified to pH 2 with 1N HCl. The solvent was removed under vacuum to give the title product (68 mg, 98% yield).

[0384] LCMS m / z: 259.1 [M+H-HCl]+, (ESI+), Rt = 0.31 (S2).

[0385] Synthesis of intermediate K13 in general route 10D: 2-[[3-(dimethylamino)propyl]carbamoyl]ethyl acetate, specification 143 / 484 pages, 192 CN 121335883 A. At 0°C, N,N-dimethylpropane-1,3-diamine (0.7...Ethyl 3-chloro-3-oxopropionate (1.14 mL, 8.91 mmol) was added dropwise to a solution of triethylamine (1.91 mL, 13.7 mmol) in DCM (6.0391 mL). The reaction mixture was heated to room temperature and stirred for another 5 minutes. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to give the title product as an orange semi-solid (2.36 g, purity 54%, yield 86%). LCMS m / z: 217.2 [M+H]+, (ESI+), Rt=0.34 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 4.11 – 4.05 (m, 2H), 3.30 (q, J=6.1 Hz, 2H), 3.25 (s , 2H) , 2.71 (t, J = 7.0 Hz, 2H) , 2.46 (s , 6H) , 1.83 – 1.75 (m, 2H) , 1.18 (d, J = 7.1 Hz, 3H). Synthesis of Intermediate K14: Ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was added to a solution of ethyl 2-{[3-(dimethylamino)propyl]carbamoyl}acetate (2.36 g, 5.89 mmol) in THF (10 mL) with (E)-4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (1.01 mL, 7.07 mmol) and DBU (0.93 mL, 6.19 mmol). The reaction mixture was stirred at room temperature for 66 hours. The reaction mixture was diluted with EtOAc (75 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted again with EtOAc (4 x 75 mL). The combined organic layers were washed with brine (50 mL) and then passed through a phase separator and concentrated under vacuum to give a blood-red residue. Purified by column chromatography (10 g Kp-NH silica, 0-100% EtOAc / heptane) to give the title product (0.25 g, yield 13%) as a light brown oil.

[0387] LCMS m / z: 321.3 [M+H]+, (ESI+), Rt = 0.46 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.05 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.18 – 4.06 (m, 2H), 2.40 (t, J =6.8 Hz, 2H), 2.23 (s, 6H), 1.89 (p, J = 6.8 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

[0388] Synthesis of intermediate K15 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate salt 2 M lithium hydroxide hydrate aqueous solution (0.53 mL, 1.05 mmol) was added to a stirred solution of ethyl 1-[3-(dimethylamino)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (225 mg, 0.702 mmol) in THF (18.75 mL) at 45 °C. The reaction mixture was stirred for 1 hour. The mixture was acidified to pH 4 with 1N HCl aqueous solution. The reaction mixture was concentrated under vacuum to give the title product (230 mg, 100% yield) as a light brown solid. Specification 144 / 484 pages 193 CN 121335883 A

[0389] LCMS m / z: 293.2 [M+H]+, (ESI+), Rt = 0.32 (S1).

[0390] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate K6 as outlined in general route 10D.

[0391] .

[0392] Synthesis of intermediate K17: 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]ethyl acetate was prepared in a manner similar to intermediate K4 using N-(4-amino-2-methylbut-2-yl)carbamoyl tert-butyl hydrochloride and ethyl 3-chloro-3-oxopropionate. LCMS m / z: 339.3 [M+Na]+, (ESI+), Rt=0.76 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 7.10 (br.s, 1H), 4.52 (br.s, 1H), 4.18 (q, J= 7.2 Hz, 2H), 3.35 – 3.28 (m, 2H), 3.27 (s, 2H), 1.96 – 1.87 (m, 2H), 1.42 (s, 9H), 1.30 – 1.25 (m, 9H).

[0394] Synthesis of intermediate K18: Ethyl 1-(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was converted to ethyl 2-[(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)carbamoyl]ethyl acetate (721.0 mg, 2.28 mg).A solution of (E)-4-ethoxy-1,1,1-trifluoro-but-3-en-2-one (400 μL, 2.81 mmol) and DBU (370 μL, 2.47 mmol) in THF (7 mL) was added. The reaction mixture was heated at 50 °C for 2 hours. The reaction mixture was concentrated under vacuum and then resuspended in EtOAc (40 mL), and washed successively with brine (30 mL), saturated NH4Cl aqueous solution (30 mL), and brine (30 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to obtain the residue. The residue was suspended in toluene (15 mL) and 4-methylbenzenesulfonic acid monohydrate (26 mg, 0.137 mmol) was added. The reaction mixture was stirred at 110 °C for 1 hour. The reaction mixture was cooled to room temperature and then diluted with EtOAc (10 mL), and washed successively with brine (25 mL), saturated NaHCO3 aqueous solution (25 mL), and brine (25 mL). The organic layer was dried over MgSO4 and concentrated under vacuum to obtain a deep red oil. Purification by column chromatography (10 g silica, 0-55% EtOAc / heptane) yielded the title product (389 mg, 0.842 mmol, yield 37%), as described in the product manual (pages 145 / 484, CN 121335883 A). LCMS m / z: 421.4 [M+H]+, (ESI+), Rt=1.05 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.02 (d, J=7.4 Hz, 1H), 6.92 (d, J=7.5 Hz, 1H) , 6.56 (br. s, 1H) , 4.25 (q, J = 7.1 Hz, 2H) , 3.99 – 3.92 (m, 2H) , 1.95 – 1.88 (m , 2H) , 1.39 (s , 9H) , 1.27 (t , J= 7.1 Hz, 3H), 1 .24 (s, 6H).

[0396] Synthesis of intermediate K19 ethyl 1-(3-amino-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate hydrochloride was added to a solution of ethyl 1-(3-{[(tert-butoxy)carbonyl]amino}-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (91%, 389 mg, 0.842 mmol) in DCM (4 ml) with 4 M HCl / dioxane (2.0 mmol).The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then concentrated under vacuum to give the title product as a grayish-white solid (306 mg, 0.815 mmol, 97% yield). LCMS m / z: 321.3 [M+H]+, (ESI+), Rt=0.55 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.13 (br.s, 3H), 8.06 (d, J=7.4 Hz, 1H), 6.98 (d , J = 7.5 Hz, 1H) , 4.26 (q , J = 7.1 Hz, 2H) , 4.06 – 3.99 (m, 2H) , 1.93 – 1.86 (m, 2H) , 1.33 (s, 6H) , 1.27 (t, J = 7.1 Hz, 3H).

[0398] Synthesis of Intermediate K20 The intermediate 1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate ethyl ester was added to a solution of 1-(3-amino-3-methylbutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate hydrochloride (306 mg, 0.858 mmol) and triethylamine (0.3 mL, 2.15 mmol) in DCE (5 mL), followed by the addition of paraformaldehyde (150 mg, 4.83 mmol), and then acetic acid (0.30 mL, 5.24 mmol). The reaction mixture was stirred for 20 minutes, and then STAB (1.00 g, 4.72 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, and then heated at 40 °C for 4 hours. The reaction mixture was diluted with DCM (10 mL) and filtered through a phase separator. The filtrate was washed with saturated NaHCO3 aqueous solution (15 mL). The organic layer was separated, and the aqueous layer was further extracted with DCM (2 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated under vacuum to give the title product as a pale yellow oil (258 mg, purity 85%, yield 73%).

[0399] LCMS m / z: 349.1 [M+H]+, (ESI+), Rt = 0.84 (S2) 1H NMR (500 MHz, CDCl3) δ [ppm]: 8.03 (d, 1H), 6.69 (d, J = 7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.22 – 4.14 (m, 2H),2.29 (s, 6H), 1.87 – 1.79 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.11 (s, 6H).

[0400] Synthesis of intermediate K21 Lithium (1+) 1-[3-(dimethylamino)-3-methylbutyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was prepared using intermediate K20 in a manner similar to intermediate K6. The lithium salt was isolated (the reaction mixture was not acidified).

[0401] LCMS m / z: 321.3 [M+H]+, (ESI+), Rt = 0.46 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.03 (d, J = 7.3 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 4.08 – 3.95 (m, 2H), 2.16 (s, 6H), 1.76 – 1.65 (m, 2H), 0.99 (s, 6H).

[0402] Synthesis of intermediate K22: 2-[[2-(dimethylamino)ethyl]carbamoyl]ethyl acetate was prepared in a manner similar to that of intermediate K14 using N,N-dimethylethane-1,2-diamine.

[0403] LCMS m / z: 203.2 [M+H]+, (ESI+), Rt = 0.36 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.38 – 8.31 (m, 1H), 3.32 (q, J = 7.3 Hz, 2H), 3.25 (s, 2H), 3.36 – 3.18 (m, 2H), 2.78 (t, J = 6.5 Hz, 2H), 1.18 (t, J = 7.2 Hz, 3H).

[0404] Synthesis of Intermediate K23 Ethyl 1-(2-dimethylaminoethyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was added to a suspension of ethyl 2-{[2-(dimethylamino)ethyl]carbamoyl}acetate (intermediate K22, 500 mg, 1.83 mmol) in THF (7 mL), followed by the addition of DBU (0.3 mL, 2.01 mmol), and then (3E)-4-methoxybut-3-en-2-one (0.22 mL, 2.16 mmol). The reaction mixture was stirred at room temperature for 18 hours. Magnesium chloride (200.0 mg, 2.06 mmol) was added.The reaction mixture was stirred at room temperature for 22 hours, followed by stirring at 60°C for 4 hours. The reaction mixture was concentrated under vacuum to obtain a residue. The residue was suspended in water (40 mL) and extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (30 mL) and passed through a phase separator. The solvent was removed under vacuum to obtain a brown oil. Purification by column chromatography (10 g Kp-NH, 0–100% EtOAc / heptane) gave the title product as a colorless oil (131 mg, 74% purity, 21% yield). Instruction manual, pages 147 / 484, 196, CN 121335883 A

[0405] LCMS m / z: 253.2 [M+H]+, (ESI+), Rt = 0.49 (S2) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.90 (d, J = 7.5 Hz, 1H), 6.22 (d, J = 7.5 Hz, 1H), 4.18 (q, J = 7.1 Hz, 2H), 4.05 (t, J = 7.1 Hz, 2H), 2.48 (s, 3H), 2.44 (t, 2H), 2.20 (s, 6H), 1.24 (t, J = 7.1Hz, 3H).

[0406] Synthesis of intermediate K24 Lithium (1+) 1-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate was prepared using intermediate K23 as the starting material in a manner similar to that of intermediate K6. LCMS m / z: 225.2 [M+H]+, (ESI+), Rt=0.21 (S2) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.05 (d, J=7.3 Hz, 1H), 6.28 (d, J=7.3 Hz, 1H) , 4.09 (t, J = 7.1 Hz, 2H), 2.49 – 2.43 (m, 5H), 2.20 (s, 6H).

[0408] Synthesis of intermediate K25 in general route 10E: methyl 1-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate was prepared in a manner similar to intermediate J3 using tert-butyl N-(2-amino-2-methylpropyl)carboxylate and methyl 2-oxo-2H-pyran-3-carboxylate.

[0409] LCMS m / z: 325.3 [M+H]+, (ESI+), Rt = 0.60 (S2)1H NMR (400 MHz, CDCl3) δ [ppm]: 8.11 (dd, J = 7.1, 2.1 Hz, 1H), 7.72 – 7.67 (m, 1H), 6.22 (t, J = 7.1 Hz, 1H), 4.95 (br. m., 1H), 3.90 (s, 3H), 3.84 (d, J = 7.0 Hz, 2H), 1.64 (s, 6H), 1.40 (s, 9H).

[0410] Synthesis of Intermediate K26 1-(1-amino-2-methylpropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate hydrochloride Specification 148 / 484 pages 197 CN 121335883 A A solution of methyl 1-(1-{[(tert-butoxycarbonyl)amino]-2-methylpropan-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (92%, 90 mg, 0.255 mmol) in DCM (2 mL) was added to 4M HCl / dioxane (0.65 mL, 2.60 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The solvent was removed under vacuum to give the title product (73 mg, 91% purity, 100% yield) as a beige powder. LCMS m / z: 225.1 [M+H]+, (ESI+), Rt=0.38 (S2) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.00 (dd, J=7.0, 2.0 Hz, 1H), 7.93-7.81 (m , 4H), 6.35 (t, J = 7.1 Hz, 1H), 3.74 (s, 3H), 3.60 (s, 2H), 1.64 (s, 6H).

[0412] Synthesis of Intermediate K27: Methyl 1-[1-(dimethylamino)-2-methylpropyl-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate was added to a solution of methyl 1-(1-amino-2-methylpropyl-2-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate hydrochloride (73 mg, 0.255 mmol) and triethylamine (40 μL, 0.29 mmol) in DCE (1.5 mL) at room temperature. Paraformaldehyde (45 mg, 1.45 mmol) was then added, followed by acetic acid (85 μL, 1.48 mmol). The mixture was stirred for 60 minutes, and then STAB (310 mg, 1.46 mmol) was added.The reaction mixture was stirred at room temperature for another 18 hours. The reaction mixture was diluted with saturated NaHCO3 aqueous solution (5 mL) and then extracted with DCM (2 x 2 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give an oil. Purification by column chromatography (12 g KP-NH silica, 0–100% ethyl acetate / hexane, followed by 0–20% MeOH / ethyl acetate) gave the title product (50 mg, 90% purity, 70% yield) as the orange oil.

[0413] LCMS m / z: 253.2 [M+H]+, (ESI+), Rt=0.50 (S2) H NMR (400 MHz, CDC13) δ [ppm]: 8.09 (dd, 1H), 7.75 (dd, J=7.1, 2.2 Hz, 1H), 6.16 (t, J = 7.1 Hz, 1H) , 3.89 (s, 3H) , 3.00 (s, 2H) , 2.14 (s, 6H) , 1.67 – 1.65 (m, 6H).

[0414] Synthesis of intermediate K28: Lithium (1+)-1-[1-(dimethylamino)-2-methylpropyl-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate was added to a solution of methyl 1-[1-(dimethylamino)-2-methylpropyl-2-yl]-2-oxo-1,2-dihydropyridine-3-carboxylate (90%, 50 mg, 0.178 mmol) in THF (1 mL) with 2 M aqueous lithium hydroxide solution (100 μL, 0.200 mmol). The solution was stirred at room temperature for 2 hours. The solvent was removed under vacuum to give the title product as a white solid (50 mg, purity 87%, yield 100%).

[0415] LCMS m / z: 239.1 [M+H]+, (ESI+), Rt = 0.31 (S2).

[0416] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate K as outlined in general route 10E. Specification 149 / 484 pages 198 CN 121335883 A

[0417] Synthesis of intermediate L1 of schematic diagram of general route 10F methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate; trifluoroacetic acid (step A) methyl 1-[(1,3-dioxolane-2-yl)methyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (intermediate K3b, 100 mg, 0.410 mmol) was dissolved in water (125 µL) and TFA (500 µL, 6.53 mmol), and the reaction was stirred at 70°C.1 hour. The reaction was cooled to room temperature and placed in a sealed vial overnight. The reaction was concentrated under vacuum, and the resulting oil was milled with DCM (3 × 5 mL) and dried under vacuum to give a light brown oil. The oil was redissolved in water (125 µL) and TFA (500 µL, 6.53 mmol), and the reaction was stirred at 80°C for 1 hour. The reaction was concentrated under vacuum, and the remaining oil was milled with DCM (3 × 5 mL) and dried under vacuum to give the title product (125 mg, 71% yield) as the oil.

[0418] LCMS m / z: 193.9 [M+H]+, (ESI+), Rt = 0.29 (S4).

[0419] Synthesis of Intermediate L2 methyl 1-[2-(azacyclobutane-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (Step B) Specification 150 / 484 pages 199 CN 121335883 A Acetic acid (17 µL, 0.290 mmol) and azacyclobutane (29 µL, 0.436 mmol) were added to a solution of methyl 2-oxo-1-(2-oxoethyl)-1,2-dihydropyridine-3-carboxylate in DCM (1.4 mL). After 20 minutes, STAB (93 mg, 0.439 mmol) was added, and the reaction was stirred at room temperature for 90 hours. The reaction mixture was diluted with MeOH and purified using an SCX column (1 g), eluted with NH3 / MeOH (3.5 M), to give the title product (32 mg, 46% yield) as a deep orange / brown gel. LCMS m / z: 237.1 [M+H]+, (ESI+), Rt=0.42 (S2) H NMR (400 MHz, CDC13) δ [ppm]: 8.16 (dd, J=7.2, 2.3 Hz, 1H), 7.56 (dd, J=6.6, 2.3 Hz, 1H), 6.23 (dd, J = 7.2, 6.6 Hz, 1H), 3.93 (t, J = 6.1 Hz, 2H), 3.90 (s, 3H), 3.20 (t, J =7.1 Hz, 4H), 2.78 (t, J = 6 .1 Hz, 2H), 2.10 – 2.04 (m, 2H). (N1).

[0421] Synthesis of intermediate L3 lithium (1+) 1-[2-(azacyclobutane-1-yl)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (step C) to 1-[2-(azacyclobutane-1-yl)ethyl]-2-oxo-1A solution of methyl 2-dihydropyridine-3-carboxylate (32 mg, 0.135 mmol) in THF (750 µL) and methanol (75 µL) was added to 230 µL (0.460 mmol) of 2M LiOH aqueous solution. The reaction was stirred at room temperature for 3.5 h. The reaction mixture was concentrated and dried under vacuum to give the title product (37 mg, 100% yield) as a yellow solid. LCMS m / z: 223.1 [M+H]+, (ESI+), Rt=0.18 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 8.37 (d, J=7.1 Hz, 1H), 7.38 (d, J=6.5 Hz, 1H), 6.25 – 6.19 (m, 1H) , 3.95 – 3.87 (m, 2H) , 3.13 (t, J = 7.0 Hz, 4H) , 2.74 – 2.68 (m, 2H) , 2.07 – 1.95(m, 2H). (N1).

[0423] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate L3 as outlined in general route 10F. Specification 151 / 484 pages 200 CN 121335883 A

[0424] Synthesis of schematic intermediate M1 of general route 10g methyl 1-(3-hydroxypropyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 3-bromoprop-1-ol (3.5 mL, 38.7 mmol) was added to a suspension of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (3.00 g, 19.6 mmol) and K2CO3 (4.10 g, 29.7 mmol) in acetone (50 mL). The reaction was heated at 60°C for 4 hours. An additional 1 mL of 3-bromoprop-1-ol was added, and the reaction was heated to 60°C for 3 hours. The mixture was filtered to remove excess K2CO3, and the filtrate was concentrated under vacuum to obtain a crude material as a pale yellow oil. Purification by column chromatography (50 g silica, 0–30% MeOH / EtOAc) yielded the title product (3.00 g, purity 87%, yield 63%) as a very pale yellow oil.

[0425] LCMS m / z: 212.1 [M+H]+, (ESI+), Rt = 0.40 (S1) 1H NMR (500 MHz, DMSO–d6) δ [ppm]: 8.01 (dd, J = 7.2, 2.2 Hz, 1H), 7.96 (dd, J = 6.6, 2.2 Hz, 1H), 6.34–6.27 (m, 1H), 4.60 (t, J = 5.1 Hz, 1H), 4.04 – 3.95 (m, 2H), 3.74 (s, 3H), 3.45 – 3.37 (m,2H), 1.84 – 1.74 (m, 2H). Instructions for Use, Pages 152 / 484, 201 CN 121335883 A

[0426] Synthesis of Intermediate M2: Methyl 1-(3-{2-azaspiro[3.4]octan-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3-carboxylate was added to a pressure tube flask and stirred at room temperature for 5 minutes in DCM (2 mL). The mixture was cooled to 0°C and treated with methanesulfonyl methanesulfonate (225.0 mg, 1.29 mmol). The reaction was heated to room temperature and stirred for another 30 minutes. The reaction mixture was further treated with methanesulfonyl methanesulfonate (50.0 mg, 0.29 mmol) at 0°C, followed by stirring at room temperature for another 90 minutes. The solvent was removed under vacuum to obtain the oil. The oil was redissolved in DMF (2 mL), and 2-azaspiro[3,4]octane (150.0 mg, 1.35 mmol) and potassium carbonate (300 mg, 2.17 mmol) were added. The reaction mixture was vigorously stirred at 50°C for 16 hours. The reaction was quenched with ice water (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated under vacuum. Purification by reversed-phase column chromatography (12 g C-18 silica, 10% to 100% MeCN / H2O, with 0.1% ammonium hydroxide modifier) ​​yielded the title product (75 mg, 95% purity, 17% yield) as a colorless colloidal substance. LCMS m / z: 305.3 [M+H]+, (ESI+), Rt=0.63 (S2) H NMR (400 MHz, CDC13) δ [ppm]: 8.15 (dd, J=7.2, 2.3 Hz, 1H), 7.63 (dd, J=6.6, 2.3 Hz, 1H), 6.23 – 6.19 (m, 1H), 4.03 (t, J = 6.9 Hz, 2H), 3.90 (s, 3H), 3.01 (s, 4H), 2.40 (t, J = 6.7 Hz, 2H), 1.80(p, J = 6.8 Hz, 2H), 1.72 – 1.68 (m, 4H), 1.56 – 1.51 (m, 4H).

[0428] Synthesis of intermediate M3 1-(3-{2-azaspiro[3.4]octane-2-yl}propyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid was prepared using intermediate M2 in a manner similar to that of intermediate K15. LCMS m / z: 345.2 [M+H]+, (ESI+), Rt=0.44 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.23 ​​(d, J=7.5 Hz, 1H), 7.15 (d, J=7.5 Hz, 1H), 4.09 (q, J = 6.6 Hz, 2H), 3.91 (s, 1H), 3.09 – 2.84 (m, 5H), 2.11 – 1.86 (m, 4H), 1.59 (dd, J = 30.4, 9.9 Hz, 3H), 1.41 (t, J = 8.5 Hz, 1H).

[0430] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate M3 as outlined in General Route 10g. Specification 153 / 484 pages 202 CN 121335883 A

[0431] Synthesis of intermediate M7 in General Route 10g** methyl 1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate was prepared in a manner similar to intermediate M1 using methyl 2-hydroxypyridine-3-carboxylate and 2-bromoethanol.

[0432] LCMS m / z: 220.1 [M+H]+, (ESI+), Rt = 0.27 (S2) Specification 154 / 484 pages 203 CN 121335883 A 1H NMR (500 MHz, DMSO) δ [ppm]: 8.01 (dd, J = 7.2, 2.2 Hz, 1H), 7.88 (dd, J = 6.6, 2.2 Hz, 1H), 6.29 (t, J = 6.9 Hz, 1H), 4.90 (t, J = 5.3 Hz, 1H), 3.98 (t, J = 5.4 Hz, 2H), 3.73 (s, 3H), 3.62 (q, J = 5.3 Hz, 2H).

[0433] Synthesis of intermediate M8Methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate was added to a stirred solution of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (250.0 mg, 1.26 mmol) in DCM (7 mL) at 0 °C, followed by the dropwise addition of methanesulfonyl chloride (0.15 mL, 1.94 mmol). The reaction mixture was stirred at 0 °C for 45 min, then poured into water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum to give the title product (401 mg, 80% purity, 93% yield) as an orange gel. H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.93 (dd, J = 6.2, 1.6 Hz, 1H), 8.84 (dd, J = 7.8, 1.6 Hz, 1H), 7.69 – 7.61 (m, 1H), 5.20 – 5.11 (m, 2H), 4.99 – 4.90 (m, 2H), 3.92 (s, 3H), 2.29 (s, 3H).

[0435] Amine substitution conditions A for the methanesulfonate of intermediate M8: A suspension of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (80%, 374 mg, 1.09 mmol), 3-(trifluoromethoxy)azacyclobutane hydrochloride (119 mg, 0.670 mmol), K2CO3 (140 mg, 1.01 mmol), and sodium iodide (15 mg, 0.100 mmol) in THF or DMF (3 mL) was stirred at 50°C for 3 hours. The reaction solution was diluted with EtOAc (10 mL), filtered, and the filtrate was concentrated under vacuum to obtain oil. Purified by column chromatography (5 g SCX, 0-100% 7 M NH3 / MeOH), methyl 2-oxo-1-{2-[3-(trifluoromethoxy)azacyclobutan-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate (intermediate M9, 126 mg, purity 54%, yield 32%) was obtained as a brown gel.

[0436] Condition B: N-ethylethylamine (0.1 mL, 0.97 mmol) was added to a solution of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (312 mg, 1.00 mmol) in DMF (5 mL). The reaction mixture was heated to 60 °C.The mixture was heated to ℃ and held for 2 hours, then concentrated under vacuum to obtain a red oil. Purification by column chromatography (5 g SCX, 0-100% 7M NH3 / MeOH) yielded methyl 1-[2-(diethylamino)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (120 mg, yield 43%) as the red oil.

[0437] Condition C: 4-(trifluoromethyl)piperidine hydrochloride (1:1) (125.0 mg, 0.66 mmol) was added to a suspension of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (95%, 200 mg, 0.690 mmol) and triethylamine (0.35 mL, 2.51 mmol) in DMF (3.8 mL). The reaction was heated at 60°C for 3 hours. The reaction was cooled and concentrated under vacuum to obtain the oil. Purified by column chromatography (5g SCX, 0-100% 7M NH3 / MeOH), methyl 2-oxo-1-{2-[4-(trifluoromethyl)piperidin-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate (130 mg, purity 94%, yield 53%) was obtained as the orange oil.

[0438] Condition D Documentation 155 / 484 pages 204 CN 121335883 A K2CO3 (500 mg, 3.62 mmol) and 6-azaspiro[3.5]nonane hydrochloride (250 mg, 1.55 mmol) were added to a solution of methyl 1-[2-(methanesulfonyloxy)ethyl]-2-oxo-1,2-dihydropyridine-3-carboxylate (70%, 600 mg, 1.53 mmol) in DMF (2 mL). The mixture was heated at 70°C for 5 hours. The reaction mixture was cooled to room temperature, poured into crushed ice (5 mL), and extracted with ethyl acetate (2 x 5 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a gel. The gel was purified by reversed-phase column chromatography (12 g C-18 silica, 10-100% MeCN / H2O, with 0.1% ammonium hydroxide modifier) ​​to give methyl 1-[2-(6-azaspiro[3.5]nonane-6-yl)ethyl]-2-oxopyridine-3-carboxylate (270 mg, 90% purity, 52% yield) as a pale orange oil.

[0439] Synthesis of Intermediate M9: 2-oxo-1-{2-[3-(trifluoromethoxy)azacyclobutane-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate methyl ester Used under conditions A (practical example): prepared with 3-(trifluoromethoxy)azacyclobutane hydrochloride.

[0440] LCMS m / z: 321.1 [M+H]+, (ESI+), Rt = 0.55 (S2) 1H NMR (400 MHz,DMSO‑d6) δ [ppm]: 8.02 –7 .97 (m , 1H) , 7 .93 – 7 .89 (m , 1H) , 6.35 – 6.25 (m, 1H) , 4.95 – 4.85 (m, 1H) , 3.88 (t, J = 6.0 Hz, 2H) , 3.73 (s, 3H) , 3.67 – 3.59 (m, 2H) , 3.15 – 3.07 (m,2H) , 2.73 (t, J = 6.0 Hz, 2H).

[0441] Synthesis of intermediate M10: Lithium (1+) 2-oxo-1-{2-[3-(trifluoromethoxy)azacyclobutane-1-yl]ethyl}-1,2-dihydropyridine-3-carboxylate was prepared using intermediate M9 in a manner similar to that of intermediate L3. LCMS m / z: 307.1 [M+H]+, (ESI+), Rt=0.26 (S2) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.16 (dd, J=7.1, 2.2 Hz, 1H), 7.76 (dd, J= 6.5, 2.3 Hz, 1H), 6.40 – 6.31 (m, 1H), 4.94 – 4.86 (m, 1H), 3.93 (t, J = 5.9 Hz, 2H), 3.67 – 3.59 (m, 2H), 3.15 – 3.07(m, 2H) , 2.75 (t, J = 6.0 Hz, 2H).

[0443] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate M10 as outlined in general route 10g**. Instruction manual 156 / 484 pages 205 CN 121335883 A Instruction manual 157 / 484 pages 206 CN 121335883 A Instruction manual 158 / 484 pages 207 CN 121335883 A Instruction manual 159 / 484 pages 208 CN 121335883 A Instruction manual 160 / 484 pages 209 CN 121335883 A Instruction manual 161 / 484 pages 210 CN 121335883 A Instruction manual 162 / 484 pages 211 CN 121335883 A Instruction manual 163 / 484 pages 212 CN 121335883 A (The last part is a repetition of the first and can be omitted.)Specification 165 / 484 pages 214 CN 121335883 A Specification 166 / 484 pages 215 CN 121335883 A Specification 167 / 484 pages 216 CN 121335883 A Specification 168 / 484 pages 217 CN 121335883 A Specification 169 / 484 pages 218 CN 121335883 A Specification 170 / 484 pages 219 CN 121335883 A Specification 171 / 484 pages 220 CN 121335883 A

[0444] .

[0445] General route 10h schematic diagram, page 172 / 484, 221 CN 121335883 A Synthesis of intermediate N1 ethyl 1-(2,2-dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate Ethyl 3-chloro-3-oxopropionate (3.04 mL, 23.78 mmol) was slowly added to a stirred solution of 2,2-dimethoxyethylamine (2.59 mL, 23.78 mmol) and triethylamine (3.48 mL, 24.97 mmol) in DCM (125 mL). The reaction mixture was stirred at room temperature for 45 minutes, and then about half of the solvent was removed under vacuum. The resulting precipitate was filtered. The solvent in the filtrate was removed under vacuum to give an oil. The oil was redissolved in DCM (15 mL), and DBU (3.73 mL, 24.97 mmol) and (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (4.07 mL, 28.53 mmol) were added. The reaction mixture was stirred for 14 hours, and then the solvent was removed under vacuum to obtain the oil. The oil was partitioned between water (100 mL) and DCM (100 mL). The organic layers were separated, and the aqueous layer was further extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine (100 mL), passed through a phase separator, and concentrated under vacuum to give a reddish-brown oil. Purification was performed by column chromatography (50 g silica, 0–30% EtOAc / heptane) to give the title product (1.94 g, 95% purity, 24% yield) as the orange-yellow oil. LCMS m / z: 324.2 [M+H]+, (ESI+), Rt=0.85 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.06 (d, J=7.5 Hz, 1H), 6.94 (d, J=7.5 Hz, 1H) , 4.79 (t, J = 5.5 Hz, 1H) , 4.26 (q, J =7.1 Hz, 2H), 4.04 (d, J = 5.6 Hz, 2H), 3.30 (s, 6H), 1.28 (t, J = 7.1 Hz, 3H).

[0447] Synthesis of intermediate N2 ethyl 2-oxo-1-(2-oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate A solution of ethyl 1-(2,2-dimethoxyethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.94 g, 5.7 mmol) and 4 M HCl (dioxane) (35.0 mL, 140.0 mmol) was stirred at room temperature for 20 minutes. (Instructions for use 173 / 484 pages 222 CN 121335883 A) The solvent was removed under vacuum to obtain the oil, which was then retreated with 4 M HCl / dioxane (35.0 mL, 140.0 mmol) and stirred for 1 hour. The reaction mixture was slowly poured into a stirred saturated aqueous solution of NaHCO3 (200 mL). The solution was extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (50 mL), passed through a phase separator, and concentrated under vacuum to give the title product as an orange solid (1.70 g, purity 82%, yield 88%). LCMS m / z: 278.1 [M+H]+, (ESI+), Rt=0.73 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 9.63 (s, 1H), 8.12 (d, J=7.4 Hz, 1H), 7.01 (d, J = 7.5 Hz, 1H), 4.97 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).

[0449] Synthesis of Intermediate N3 1-(2-{2-azaspiro[3.4]octane-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate ethyl 2-oxo-1-(2-oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.55 g, 4.47 mmol) was added to a stirred solution of ethyl 2-oxo-1-(2-oxoethyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (30 mL) in DCM. 2-azaspiro[3.4]octane (750.0 mg, 6.75 mmol) and DIPEA (2.35 mL, 13.46 mmol) were then added, followed by STAB (2.88 g, 13.59 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give an oily residue. The residue was analyzed by column chromatography (12 g KP-NH silica, 0-Purified with 100% EtOAc / heptane, the title product (703 mg, 90% purity, 38% yield) was obtained as a yellow oil. LCMS m / z: 373.3 [M+H]+, (ESI+), Rt=0.57 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 8.04 (d, J=7.4 Hz, 1H), 6.67 (d, J=7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 4.08 – 4.01 (m, 2H), 3.22 (s, 4H), 2.76 – 2.69 (m, 2H), 1.75 – 1.71 (m, 4H), 1.55 – 1.51 (m, 4H), 1.38 (t, J = 7.1 Hz, 3H).

[0451] Synthesis of intermediate N4 1-(2-{2-azaspiro[3.4]octane-2-yl}ethyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid was prepared using intermediate N3 as the starting material in a manner similar to that of intermediate O7. LCMS m / z: 345.2 [M+H]+, (ESI+), Rt=0.48 (S1) H NMR (500 MHz, CDC13) δ [ppm]: 8.53 (d, J=7.4 Hz, 1H), 7.02 (d, J=7.5 Hz, 1H), 4.38 – 4.31 (m, 2H) , 3.69 (s, 4H) , 3.18 – 3.11 (m, 2H) , 1.88 – 1.80 (m, 4H) , 1.65 – 1.56 (m, 4H). Specification 174 / 484 pages 223 CN 121335883 A

[0453] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate N4 as outlined in general route 10h. Specification 175 / 484 pages 224 CN 121335883 A Specification 176 / 484 pages 225 CN 121335883 A Specification 177 / 484 pages 226 CN 121335883 A Specification 178 / 484 pages 227 CN 121335883 A Specification 179 / 484 pages 228 CN 121335883 A

[0454] .

[0455] Schematic diagram of general route 10j.180 / 484 Page 229 CN 121335883 A Synthesis of Intermediate O1 (3-aminopropoxy)(tert-butyl)dimethylsilane was prepared by adding triethylamine (13.36 mL, 95.86 mmol) and TBDMSCl (13.244 g, 87.87 mmol) to a solution of 3-aminoprop-1-ol (6.00 g, 79.9 mmol) in DCM (90 mL) at 0 °C. After 5 minutes, the reaction was heated to room temperature and stirred for another 18 hours. The reaction mixture was washed with water (100 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum to give the title product (15.30 g, 101% yield) as an oil. LCMS m / z: 190.2 [M+H]+, (ESI+), Rt=0.57 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 3.67 (t, J=6.0 Hz, 2H), 2.80 (t, J=6.8 Hz, 2H), 2.37 (s, 2H) , 1.71 – 1.61 (m, 2H) , 0.86 (d , J = 0.9 Hz, 9H) , 0.02 (d , J = 0.7 Hz, 6H).

[0457] Synthesis of Intermediate O2 Ethyl 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl)ethyl acetate (Instructions for Use, pages 181 / 484, 230, CN 121335883 A) Ethyl 3-chloro-3-oxopropionate (5.1 mL, 39.9 mmol) was added to a solution of (3-aminopropoxy)(tert-butyl)dimethylsilane (7.944 g, 39.85 mmol) and triethylamine (11 mL, 79.7 mmol) in DCM (60 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with DCM (2 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to give a brown oil. The title product (6.80 g, purity 78%, yield 44%), which is a light brown oil, was obtained by column chromatography (100 g silica, 0-100% EtOAc / heptane).

[0458] LCMS m / z: 304.3 [M+H]+, (ESI+), Rt = 1.01 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 4.25 – 4.13 (m, 2H), 3.74 – 3.65 (m, 2H), 3.44 – 3.36 (m, 2H), 3.26 (d, J)= 1.4 Hz, 2H), 1.78 – 1.71 (m, 2H), 1.32 – 1.25 (m, 3H), 0.89 (d, J = 0.8 Hz, 9H), 0.08 – 0.02 (m, 6H).

[0459] Synthesis of Intermediate O3 Ethyl 1-{3-[(tert-butyldimethylsilyl)oxy]propyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was added to a solution of ethyl 2-({3-[(tert-butyldimethylsilyl)oxy]propyl}carbamoyl)acetate (6.55 g, 16.8 mmol) in THF (60 mL) with (3E)-4-ethoxy-1,1,1-trifluorobut-3-en-2-one (4.4 mL, 31.1 mmol) and DBU (4.1 mL, 27.3 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give an oil. Purification by column chromatography (50 g silica, 0-30% EtOAc / heptane) gave the title product (1.83 g, 97% purity, 26% yield) as the oil. LCMS m / z: 408.2 [M+H]+, (ESI+), Rt=1.25 (S1) H NMR (500 MHz, CDC13) δ [ppm]: 8.12 – 7.99 (m, 1H), 6.68 (d, J=7.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.22 – 4.17 (m, 2H), 3.74 (t, J = 5.7 Hz, 2H), 2.00 – 1.89 (m, 2H), 1.38 (t, J= 7.1 Hz, 3H), 0.89 (s , 9H) , 0 .05 (s, 6H).

[0461] Synthesis of intermediate O4 1-(3-hydroxypropyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate ethyl ester was added dropwise to a THF (5 mL) solution containing 1-{3-[(tert-butyldimethylsilyl)oxy]propyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.82 g, 4.33 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was quenched with water (10 mL), and ethyl acetate (3 x 30 g) was added.Extraction was performed using a 10 mL extract. The combined organic layers were dried over sodium sulfate and concentrated under vacuum to obtain the oil. The oil was purified by column chromatography (25 g silica, 0-100% EtOAc / heptane) to give the title product (1.11 g, 96% purity, 84% yield) as the oil. LCMS m / z: 294.2 [M+H]+, (ESI+), Rt=0.64 (S1) H NMR (500 MHz, CDC13) δ [ppm]: 8.06 (d, J=7.4 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H) , 4.29 (t, J = 7.0 Hz, 2H) , 3.67 (t, J = 5.7 Hz, 2H) , 1.97 (d, J = 6.2 Hz,2H) , 1.38 (t, J = 7.1 Hz, 3H).

[0463] Synthesis of Intermediate O5 The intermediate 1-[3-(methanesulfonyloxy)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was added to a stirred solution of 1-(3-hydroxypropyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (1.1 g, 3.6 mmol) in DCM (20 mL) at 0 °C. DMAP (43.994 mg, 0.36 mmol) and triethylamine (1.25 mL, 9.0 mmol) were then added, followed by methanesulfonyl chloride (0.42 mL, 5.4 mmol). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was poured into water (30 mL), and the organic layer was separated. The aqueous phase was further extracted with DCM (2 x 20 mL), the combined organic layers were filtered through hydrophobic glass frit and concentrated under vacuum to give the title product as an orange gel (1.52 g, purity 89%, yield 101%). LCMS m / z: 372.1 [M+H]+, (ESI+), Rt=0.75 (S1) H NMR (500 MHz, CDC13) δ [ppm]: 8.06 (d, J=7.4 Hz, 1H), 6.75 (d, J=7.4 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H) , 4.29 (t, J = 7.0 Hz, 2H) , 3.67 (t, J = 5.7 Hz, 2H) , 1.97 (d, J = 6.2 Hz, 2H) , 1.38 (t, J =7.1 Hz, 3H).

[0465] Synthesis of Intermediate O6 1-(3-{2-azaspiro[3.4]octane-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate ethyl 1-[3-(methanesulfonyloxy)propyl]-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate ethyl ester (250 mg, 0.599 mmol), 2-azaspiro[3.4]octane (100 mg, 0.899 mmol), K2CO3 (0.25 g, 1.80 mmol), and sodium iodide (9.0 mg, 0.0599 mmol) in DMF (5 mL) were heated at 50°C for 2 hours. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum to obtain the oil. The oil was purified by column chromatography (10 g silica, 0-10% MeOH / DCM) to give the title product (108 mg, 98% purity, 46% yield) as a light brown liquid.

[0466] LCMS m / z: 387.2 [M+H]+, (ESI+), Rt = 0.58 (S1) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.04 (d, J = 7.4 Hz, 1H), 6.67 (d, J = 7.5 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H), 4.17 – 4.04 (m, 2H), 3.08 (s, 4H), 2.53 (t, J = 6.9 Hz, 2H), 1.83 – 1.76 (m, 2H), 1.72 (h, J = 3.0 Hz, 4H), 1.58 – 1.50 (m, 4H), 1.38 (t, J = 0.7 Hz, 3H).

[0467] Synthesis of intermediate O7 1-(3-{2-azaspiro[3.4]octane-2-yl}propyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid was added to a stirred solution of ethyl 1-[3-(2-azaspiro[3.4]octane-2-yl)propyl]-2-oxo-6-(trifluoromethyl)pyridine-3-carboxylic acid (98%, 106 mg, 0.269 mmol) in THF (2.94 mL) at 45°C, along with 2 M lithium hydroxide hydrate (0.81 mL, 1.61 mmol).mmol). The reaction mixture was stirred for 4 hours. The mixture was acidified to pH 4 with 1N hydrochloric acid aqueous solution. The reaction mixture was concentrated under vacuum to give the title product (172 mg, 99% yield) as a light brown solid.

[0468] LCMS m / z: 359.2 [M+H]+, (ESI+), Rt = 0.50 (S1).

[0469] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate O7 as outlined in general route 10j. Specification 184 / 484 pages 233 CN 121335883 A Specification 185 / 484 pages 234 CN 121335883 A Specification 186 / 484 pages 235 CN 121335883 A Specification 187 / 484 pages 236 CN 121335883 A

[0470] .

[0471] General route 10k schematic diagram 188 / 484 pages 237 CN 121335883 A Synthesis of intermediate O21 2-({4-[(tert-butyldimethylsilyl)oxy]butyl}carbamoyl)ethyl acetate is prepared in a manner similar to intermediate O2 using 4-[tert-butyl(dimethyl)silyl]oxybut-1-amine and ethyl 3-chloro-3-oxopropionate. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.01 (t, J = 5.6 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.60 – 3.50 (m, 2H), 3.15 (s, 2H), 3.03 (q, J = 6.3 Hz, 2H) , 1.42 (qt, J = 4.2, 2.0 Hz, 4H) , 1.15 (t, J = 7.1Hz, 3H) , 0.83 (s, 9H) , ‑0.00 (s, 6H).

[0473] Synthesis of Intermediate O22 1-{4-[(tert-butyldimethylsilyl)oxy]butyl}-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester specification 189 / 484 pages 238 CN 121335883 A It was prepared using intermediate O21 in a manner similar to intermediate O3.

[0474] LCMS m / z: 444.2 [M+H]+, (ESI+), Rt = 1.27 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.97 (d, J = 7.3 Hz, 1H), 6.88 (d, J =7.4 Hz, 1H), 3.93 – 3.87 (m, 2H), 3.56 (q, J = 5.7 Hz, 2H), 1.62 (p, J = 7.9 Hz, 2H), 1.57 – 1.37 (m, 2H), 1.28 – 1.13 (m, 3H), 0.81 (d, J = 2.9 Hz, 9H), -0.02 (s, 6H).

[0475] Synthesis of intermediate O23 ethyl 1-(4-hydroxybutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was prepared using intermediate O22 in a manner similar to intermediate O4.

[0476] LCMS m / z: 330.2 [M+Na]+, (ESI+), Rt = 0.69 (S1).

[0477] Synthesis of intermediate O24: Ethyl 2-oxo-1-(4-oxobutyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate was added to a solution of ethyl 1-(4-hydroxybutyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (100 mg, 0.33 mmol) in DCM (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, and then at room temperature for 2 h. The reaction was quenched by adding 50% saturated sodium thiosulfate aqueous solution / saturated NaHCO3 aqueous solution (15 mL) and stirring vigorously for 10 min. The organic layer was separated, washed further with saturated NaHCO3 solution (10 mL), and dried over magnesium sulfate. The solvent was removed under vacuum to obtain a brown oil. Purification was performed by column chromatography (10 g silica, 0–60% EtOAc / heptane) to give the title product as an orange gel (144 mg, 72% purity, 104% yield). 1H NMR (400 MHz, CDC13) δ [ppm]: 9.79 (t, 1H), 8.06 (dt, J=Hz, 1H), 6.71 (t, J=Hz, 1H), 4.39 (q, J=Hz, 2H), 4.12 (m, 2H), 2.60 (qt, J = Hz, 2H), 2.00-2.10 (m, 2H), 1.38 (t, J = Hz, 3H).

[0479] Synthesis of intermediate O25: 1-(4-{3-azabicyclo[3.1.1]heptane-3-yl}butyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid ethyl ester, specification 190 / 484, page 239CN 121335883 A A solution of ethyl 2-oxo-1-(4-oxobutyl)-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylate (140 mg, 0.330 mmol) in DCM (2 mL) was reacted with triethylamine (0.14 mL, 1.07 mmol) and 3-azabicyclo[3.1.1]heptane hydrochloride (58 mg, 0.438 mmol), followed by STAB (225 mg, 1.06 mmol). The reaction was stirred at room temperature for 72 hours. The reaction was quenched by a mixture of water (10 mL) and saturated aqueous NaHCO3 solution (10 mL). The reaction mixture was then extracted with dichloromethane (DCM) (3 x 5 mL). The combined organic layers were concentrated under vacuum to obtain the residue. The title product (111 mg, 95% purity, 83% yield) was purified by SCX chromatography (5 g, eluted with 7M NH3 / MeOH) to obtain the yellow oil. LCMS m / z: 387.3 [M+H]+, (ESI+), Rt=0.60 (S1) H NMR (400 MHz, MeOD-d4) δ [ppm]: 8.10 (dd, J=7.7, 0.9 Hz, 1H), 6.86 (d, J= 7.5 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.12 – 3.96 (m, 2H), 2.86 – 2.69 (m, 4H), 2.55 – 2.38 (m, 2H), 2.25 (ddd, J =7.5, 4 .4, 1.6 Hz, 2H), 1.95 (qd, J = 5.9, 2.6 Hz, 2H), 1.73 – 1.59 (m, 2H), 1.59 – 1.47 (m, 2H), 1.49 – 1.35 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

[0481] Synthesis of intermediate O26 1-(4-{3-azabicyclo[3.1.1]heptane-3-yl}butyl)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carboxylic acid was prepared using intermediate O25 in a manner similar to intermediate O74. 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.32 (d, J = 7.5 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 4.15 – 4.02 (m,2H), 2.97 – 2.85 (m, 3H), 2.38 (t, J = 6.0 Hz, 3H), 2.13 – 2.02 (m, 3H), 1.78 – 1.67 (m, 5H), 1.67 – 1.53 (m, 2H).

[0483] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate O26 as outlined in general route 10k. Specification 191 / 484 pages 240 CN 121335883 A

[0484] .

[0485] Synthesis of intermediate O28 of general route 10j: methyl 1-(4-hydroxybutyl)-2-oxo-1,2-dihydropyridine-3-carboxylate 4-bromobut-1-ol (9.60 g, 62.7 mmol) was added to a stirred suspension of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (8.00 g, 52.2 mmol) and cesium carbonate (17.80 g, 54.6 mmol) in acetonitrile (120 mL). The reaction mixture was stirred at 60°C for 4 hours. Another portion of 4-bromobut-1-ol (7.00 g, 45.7 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under vacuum to give a yellow oil. Purification was performed by column chromatography (50 g silica, 0-100% ethyl acetate / heptane, followed by 0-20% methanol / ethyl acetate) to obtain the title product as yellow oil (2.35 g, yield 17%, purity 84%). LCMS m / z: 248.1 [M+Na]+, (ESI+), Rt=0.39 (S2) H NMR (500 MHz, CDC13) δ [ppm]: 8.15 (dd, J=7.2, 2.3 Hz, 1H), 7.54 (dd, J=6.6, 2.3 Hz, 1H) , 6.27 – 6.22 (m, 1H) , 4.07 – 4.00 (m, 2H) , 3.90 (s, 3H) , 3.71 (t, J = 6.2 Hz, 2H) , 1.91– 1.85 (m, 2H) , 1.70 – 1.66 (m, 1H) , 1.64 – 1.58 (m, 2H).

[0487] Synthesis instructions for intermediate O29, pages 192 / 484, 241 CN 121335883 A methyl 1-(4-{2-azaspiro[3,4]octane-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3-carboxylateSynthesis of Intermediate O30: 1-(4-{2-azaspiro[3.4]octane) was prepared using intermediate O28 and 2-azaspiro[3.4]octane in a manner similar to intermediate M2.

[0488] LCMS m / z: 319.4 [M+H]+, (ESI+), Rt = 0.49 (S1).

[0489] Synthesis of Intermediate O30: 1-(4-{2-azaspiro[3.4]octane-2-yl}butyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid was prepared using intermediate O29 in a manner similar to intermediate O7.

[0490] LCMS m / z: 305.4 [M+H]+, (ESI+), Rt = 0.49 (S1).

[0491] Synthesis of intermediate P1 of general route 11A: methyl 6-[(azacyclobutane-1-yl)methyl]pyridine-2-carboxylate (step A) At room temperature, STAB (349 mg, 1.60 mmol) was added to a stirred solution of azacyclobutane (0.071 mL, 0.998 mmol) and methyl 6-formylpyridine-2-carboxylate (219 mg, 1.30 mmol) in a DCE (10 mL). The reaction mixture was stirred at 50 °C for 3 hours. The reaction mixture was quenched with water (10 mL) and then EtOAc (15 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with EtOAc (2 x 10 mL). The aqueous phase was alkalized to pH 9 with a saturated NaHCO3 aqueous solution and extracted with EtOAc (2 x 10 mL). The combined organic layers were passed through a phase separator and concentrated under vacuum. Purified by column chromatography (10 g silica, 0-10% MeOH / DCM), the title product (90 mg, 43% yield) was obtained as a colorless oil.

[0492] LCMS m / z: 206.9 [M+H]+, (ESI+), Rt = 1.60 (S7).

[0493] The synthesis of intermediate P2, step C 6-[(azacyclobutane-1-yl)methyl]pyridine-2-carboxylate (step B), was prepared using intermediate P1 in a manner similar to that of intermediate L3.

[0494] LCMS m / z: 192.7 [M+H]+, (ESI+), Rt = 0.25 (S6). Instructions 193 / 484 pages 242 CN 121335883 A

[0495] Synthesis of intermediate P3 of general route 11B step A 6-[(3-fluorozacricyclobutan-1-yl)methyl]pyridine-2-carboxylate (step A) Add Cs2CO3 (1.00 mg) to a stirred suspension of 6-(chloromethyl)pyridine-2-carboxylate (300 mg, 1.50 mmol) and 3-fluorozacricyclobutanone hydrochloride (180 mg, 1.61 mmol) in acetonitrile (6 mL)The resulting mixture was stirred in a sealed tube under nitrogen for 6 hours at room temperature. Then, 3-fluorozacriane hydrochloride (90 mg, 0.81 mmol) was added, and stirring was continued for 18 hours at room temperature. The reaction mixture was filtered through diatomaceous earth and washed with EtOAc (50 mL). The filtrate was concentrated under vacuum to give a yellow oil. Purification was performed by column chromatography (10 g silica, 0–100% EtOAc / heptane, followed by 0–10% MeOH / EtOAc) to give the title product as the yellow oil (277 mg, 76% yield).

[0496] LCMS m / z: 239.2 [M+H]+, (ESI+), Rt=0.51 (S2) 1H NMR (500 MHz, CDC13) δ [ppm]: 8.02 – 7.97 (m, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.58 – 7.53 (m, 1H) , 5.28 – 5.07 (m, 1H) , 4.46 (q , J = 7.1 Hz, 2H) , 3.97 (s, 2H) , 3.83 – 3.73 (m, 2H) , 3.44 – 3.38 (m, 1H) , 3.38 – 3.32 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H).

[0497] Synthesis of intermediate P4, step B: Lithium 6-[(3-fluorozacricyclobutan-1-yl)methyl]pyridine-2-carboxylate was added to a stirred solution of ethyl 6-[(3-fluorozacricyclobutan-1-yl)methyl]pyridine-2-carboxylate (273 mg, 1.12 mmol) in THF (5 mL) and methanol (0.3 mL) in 2M LiOH aqueous solution (620 µL, 1.24 mmol). The reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated under vacuum to give the title product (219 mg, 86% yield) as a brown solid.

[0498] LCMS m / z: 211.1 [M+H]+, (ESI+), Rt=0.24 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.88 – 7.82 (m, 2H), 7.41 – 7.35 (m, 1H), 5.26 – 5.04 (m, 1H) , 3.67 (s, 2H) , 3.60 – 3.50 (m, 2H) , 3.18 – 3.12 (m, 1H) , 3.12 – 3.05 (m, 1H).

[0499] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate O26, as outlined in general route 10k. Specification 194 / 484 pages 243 CN 121335883 A

[0500] .

[0501] Synthesis of intermediate P5 in general route 11C: Ethyl 6-vinylpyridine-2-carboxylate (Step A) Tributyl(vinyl)tin (1.5 mL, 5.13 mmol) and triphenylphosphine palladium (0.50 g, 0.433 mmol) were added to a degassed solution of ethyl 6-bromopyridine-2-carboxylate (1.00 g, 4.35 mmol) in anhydrous 1,4-dioxane (30 mL). The mixture was heated at 100 °C for 3 hours. The mixture was cooled, diluted with EtOAc (50 mL), and washed with 1 M KF aqueous solution (50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over Na2SO4 and concentrated under vacuum. The product was purified by column chromatography (55 g Sfar Amino-D silica, 0–50% EtOAc / heptane) to give the title product (715 mg, 84% yield) as a yellow free-flowing oil. LCMS m / z: 178.3 [M+H]+, (ESI+), Rt=0.77 (S1) H NMR (500 MHz, CDC13) δ [ppm]: 7.98 (dd, J=7.7, 1.0 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H), 7.59 (dd, J = 7.9, 1.0 Hz, 1H), 6.94 (dd, J = 17.6, 10.9 Hz, 1H), 6.23 (dd, J = 17.7, 0.9 Hz,1H), 5.58 (dd, J = 10.9 , 0.9 Hz, 1H) , 4.48 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

[0503] Synthesis of intermediate P6 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate ethyl ester (step B) Specification 195 / 484 pages 244 CN 121335883 A 2 M dimethylamine (in THF) (1.0 mL, 2.00 mmol) was added to a stirred solution of 6-vinylpyridine-2-carboxylate (200 mg, 1.02 mmol) in ethanol (4 mL). The solution was heated at 80 °C for 24 hours. The mixture was concentrated under vacuum, and the residue was subjected to reversed-phase column chromatography (12 g Sfar)The crude product was purified by C18 silica (10-100% formonitrile / H2O, containing 0.1% formic acid modifier). The crude product was dissolved in EtOAc (2 mL) and washed with saturated NaHCO3 solution (2 x 3 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum to give the title product (160 mg, 71% yield) as a colorless oil. LCMS m / z: 223.2 [M+H]+, (ESI+), Rt=0.39 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 7.95 – 7.92 (m, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.40 – 7.36 (m, 1H) , 4.46 (q, J = 7.1 Hz, 2H) , 3.10 – 3.05 (m, 2H) , 2.74 – 2.69 (m, 2H) , 2.29 (s, 6H) ,1.42 (t, J = 7.1 Hz, 3H).

[0505] Synthesis of Intermediate P7: Lithium (1+)-6-[(2-dimethylamino)ethyl]pyridine-2-carboxylate (Step C) A solution of ethyl 6-[2-(dimethylamino)ethyl]pyridine-2-carboxylate (1.72 g, 7.2 mmol) in THF (33 mL) was added to a 2 M LiOH aqueous solution (4.02 mL, 8.05 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give the title product (1.5 g, 95% purity, 100% yield) as a pale yellow solid.

[0506] LCMS m / z: 195.2 [M+H]+, (ESI+), Rt = 0.44 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.87 –7.75 (m, 2H), 7.34 (dd, J = 7.1, 1.4 Hz, 1H), 2.83 – 2.73 (m, 2H), 2.46 (d, J = 7.7 Hz, 2H), 2.07 (s, 6H).

[0507] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate P7 as outlined in general route 11c.

[0508] Synthesis of intermediate P8: Ethyl 6-vinyl-5-methylpyridine-2-carboxylate (Step A) Specification 196 / 484 pages 245 CN 121335883 A Ethyl 6-bromo-5-methylpyridine-2-carboxylate (350.0 mg, 1.43 mmol) was added to EtOH (5Potassium vinyl(trifluoro)borate (396.0 mg, 2.87 mmol), triethylamine (0.2 mL, 1.43 mmol), and bis[3-(diphenylphosphino)cyclopentan-2,4-dien-1-yl]ferric dichloromethane dichloropalladium (58.0 mg, 0.07 mmol) were added to the solution. The mixture was degassed with nitrogen for 10 min and then stirred at 80 °C for 1 h. The mixture was filtered, and the filtrate was concentrated under vacuum to obtain the oil. Purification by column chromatography (25 g silica, 0-25% EtOAc / heptane) gave the title product (211 mg, 77% yield) as a pale yellow oil. LCMS m / z: 192.1 [M+H]+, (ESI+), Rt=0.86 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.84 (d, J=7.8 Hz, 1H), 7.77 (d, J=0.8 Hz, 1H) , 7.08 (dd , J = 16.9, 10.6 Hz, 1H) , 6.35 (dd , J = 16.9, 2.4 Hz, 1H) , 5.57 (dd , J = 10.7, 2.5 Hz, 1H) , 4.34 (q ,J = 7.1 Hz, 2H) , 2.41 (s, 3H) , 1.33 (t, J = 7.1 Hz, 3H).

[0510] Synthesis of intermediate P9: Ethyl 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (Step B) A mixture of ethyl 6-vinyl-5-methylpyridine-2-carboxylate (211 mg, 1.10 mmol), 2 M dimethylamine / THF (5.5 mL, 11.0 mmol), and AcOH (0.84 mL) was stirred by microwave radiation at 100°C for 30 minutes. Dimethylamine hydrochloride (450 mg, 5.52 mmol) was added, and the mixture was stirred by microwave radiation at 150°C for 2 hours. The reaction mixture was concentrated under vacuum to obtain the residue. Purification was performed by FCC (25 g silica, 0-100% EtOAc / heptane, followed by 0-10% MeOH in EtOAc solution) to obtain the title product as the oil (150 mg, 45% yield).

[0511] LCMS m / z: 237.2 [M+H]+, (ESI+), Rt = 0.52 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.79 (d, J = 7.8 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H),4.32 (q, J = 7.1 Hz, 2H), 2.94 (m, 2H), 2.56 (m, 2H), 2.37 (s, 3H), 2.21 (s, 6H), 1.32 (t, J = 7.1 Hz, 3H).

[0512] Synthesis of intermediate P10 lithium (1+) 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (step C) Add 2 M LiOH aqueous solution (0.48 mL, 0.952 mmol) to a solution of ethyl 6-[2-(dimethylamino)ethyl]-5-methylpyridine-2-carboxylate (150 mg, 0.635 mmol) in THF (2.5 mL) and MeOH (0.25 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to give the title product as an orange solid (150 mg, 95% yield).

[0513] LCMS m / z: 209.2 [M+H]+, (ESI+), Rt = 0.30 (S1) Specification 197 / 484 pages 246 CN 121335883 A 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.72 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 2.87 – 2.78 (m, 2H), 2.45 – 2.36 (m, 2H), 2.32 (s, 3H), 2.12 (s, 6H).

[0514] Synthesis of intermediate P11: ethyl 6-(2-methoxyethyl)pyridine-2-carboxylate (Step A) 4 M HCl / 1,4-dioxane (1.12 mL, 4.48 mmol) was added to a stirred solution of ethyl 6-vinylpyridine-2-carboxylate (350.0 mg, 2.26 mmol) in anhydrous MeOH (10 mL). The reaction mixture was stirred at 80 °C for 18 hours. The pH of the reaction mixture was adjusted to 7 with a saturated aqueous solution of NaHCO3, and then concentrated under vacuum to obtain the residue. Purification by column chromatography (20 g SCX, 0-100% 7M NH3 / MeOH) yielded the title product (427 mg, 77% yield) as a yellow oil.

[0515] LCMS m / z: 210.2 [M+H]+, (ESI+), Rt = 0.62 (S1). Synthesis of intermediate P12: Lithium (1+)-6-(2-methoxyethyl)pyridine-2-carboxylate (step B) was prepared using intermediate P11 in a manner similar to that of intermediate L3.

[0516] 1H NMR (400 MHz,DMSO‑d6) δ [ppm]: 7.97 –7.76 (m, 2H), 7.33 (dd, J = 7.2, 1.6 Hz, 1H), 3.58 (t, J = 6.8 Hz, 2H), 3.17 (s, 3H), 3.05 – 2.86 (m , 2H).

[0517] Synthesis of intermediate P13 in general route 11d: ethyl 6-(2-hydroxyethyl)pyridine-2-carboxylate (step A) Specification 198 / 484, page 247 CN 121335883 A At 0°C, a stirred solution of ethyl 6-vinylpyridine-2-carboxylate (2.5 g, 14.1 mmol) in THF (10 mL) was added dropwise over 15 minutes with 0.5 M 9-BBN in THF (85 mL, 42.5 mmol). The reaction mixture was stirred at 0°C for 5 minutes, then heated to room temperature and stirred for 22 hours. The reaction mixture was cooled to 0°C, and H2O2 (50% aqueous solution) (1.75 mL, 58.14 mmol) was added dropwise, followed by 2 M NaOH (aqueous solution) (0.35 mL, 0.7 mmol). The mixture was stirred at 0°C for 5 minutes, then heated to room temperature. H₂O₂ (50% aqueous solution) (3.5 mL, 116.3 mmol) and 2 M NaOH (aqueous solution) (0.35 mL, 0.7 mmol) were added dropwise at room temperature. The reactants were quenched with saturated Na₂S₂O₃ (aqueous solution) (30 mL), stirred at room temperature for 15 min, and concentrated under vacuum. The residue was diluted with EtOAc (100 mL), water (30 mL), and brine (30 mL), and the pH was adjusted to 8 with saturated NaHCO₃ solution (5 mL). The phases were then separated, and the aqueous phase was extracted with EtOAc (50 mL x 2). The combined organic phases were dried over MgSO₄ and concentrated under vacuum. The residue was purified by reverse-phase FCC (30 g C-18 silica, 10–100% MeCN:H₂O + 0.1% v / v NH₄OH modifier) ​​to give the title product (1.78 g, 64% yield) as a yellow oil.

[0518] LCMS m / z: 196.1 [M+H]+, (ESI+), Rt=0.44 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.94 – 7.85 (m, 2H), 7.58 – 7.49 (m, 1H), 4.70 (t, J = 5.3 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.81 – 3.72(m, 2H), 2.95 (t, J = 6.6 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).

[0519] Synthesis of intermediate P14 ethyl 6-(2-{2-azaspiro[3.4]octyl-2-yl}ethyl)pyridine-2-carboxylate (step B) A solution of ethyl 6-(2-hydroxyethyl)pyridine-2-carboxylate (250 mg, 1.27 mmol) in anhydrous DCM (3 mL) was treated with diisopropylethylamine (663 μL, 3.8 mmol). The mixture was cooled to 0 °C, treated with trifluoromethanesulfonic anhydride (229 μL, 1.39 mmol), and stirred at 0 °C for 10 min. 2-azaspiro[3,4]octane (171 mg, 1.54 mmol) was added, and the reaction mixture was stirred at 0 °C for 5 min, followed by stirring at room temperature for 30 min. The reaction mixture was concentrated under vacuum to obtain the residue. Purification was performed by reversed-phase rapid chromatography (30 g C18 silica, 10–100% MeCN + 0.1% v / v NH4OH) to give the title product (220 mg, 46% yield) as a light brown oil.

[0520] LCMS m / z: 289.2 [M+H]+, (ESI+), Rt=0.89 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.90 – 7.85 (m, 2H), 7.55 – 7.50 (m, 1H), 4.34 (q, J = 7.1 Hz, 2H) , 3.03 (s, 4H) , 2.81 – 2.70 (m, 4H) , 1.67 – 1.63 (m, 4H) , 1.50 – 1.46 (m, 4H) , 1.33 (t, J = 7.1 Hz, 3H).

[0521] Synthesis of intermediate P15 Lithium (1+) 6-(2-{2-azaspiro[3.4]octane-2-yl}ethyl)pyridine-2-carboxylate (step C) Specification 199 / 484 pages 248 CN 121335883 A It is prepared using intermediate P13 in a manner similar to intermediate L3. LCMS m / z: 261.2 [M+H]+, (ESI+), Rt=0.39 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.83 –7.75 (m, 2H), 7.31 (dd, J=7.1, 1.8 Hz, 1H) , 2.89 (s , 4H) , 2.67 – 2.55 (m , 4H) , 1.63 – 1.58 (m, 4H), 1.50 – 1.44 (m, 4H).

[0523] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate P14 as outlined in general route 11d.

[0524] Schematic diagram of general route 11e, page 200 / 484, CN 121335883 A. Synthesis of intermediate P16: Ethyl 6-(3-oxypropyl)pyridine-2-carboxylate (Step A). ​​A suspension of ethyl 6-bromopyridine-2-carboxylate (5.0 g, 21.7 mmol), prop-2-en-1-ol (3.7 mL, 54.3 mmol), NaHCO3 (5.48 g, 65.2 mmol), and TBAB (7.0 g, 21.7 mmol) in anhydrous DMF (60 mL) was degassed with N2 for 5 minutes. Pd(OAc)2 (0.244 g, 1.09 mmol) was added, and the reaction mixture was stirred at 85°C for 6 hours under N2, cooled, and concentrated under vacuum. The residue was suspended in water (100 mL) and extracted with EtOAc (4 x 30 mL). The combined organic layers were washed with water (40 mL) and brine (2 x 30 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by FCC (50 g silica, 10%–100% EtOAc / heptane) to give the title product (1.72 g, 30% yield) as orange oil. LCMS m / z: 208.2 [M+H]+, (ESI+), Rt=0.55 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.77 (t, J=1.2 Hz, 1H), 7.93 – 7.84 (m, 2H) , 7.55 (dd , J = 7.1, 1.8 Hz, 1H) , 4.33 (q, J = 7.1 Hz, 2H) , 3.09 (t, J = 7.1 Hz, 2H) , 2.93 – 2.86 (m, 2H) , 1.32 (t, J= 7.1 Hz, 3H).

[0526] Synthesis of Intermediate P17: Ethyl 6-(3-{2-azaspiro[3.4]octane-2-yl}propyl)pyridine-2-carboxylate (Step B) At room temperature, STAB (369 mg, 1.74 mmol) was added to a solution of ethyl 6-(3-oxypropyl)pyridine-2-carboxylate (135.0 mg, 0.58 mmol), 2-azaspiro[3.4]octane (77.4 mg, 0.7 mmol), and TEA (0.23 mL, 1.74 mmol) in DCM (4 mL).The reaction mixture was heated at 40 °C for 1 hour. The reaction mixture was poured into water (30 mL), diluted with a saturated aqueous solution of NaHCO3 (20 mL), and then extracted with DCM (4 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum. Purification by column chromatography (5 g SCX, 0–100% 7 M NH3 / MeOH) gave the title product as a pale yellow oil (151 mg, 73% yield).

[0527] LCMS m / z: 303.3 [M+H]+, (ESI+), Rt = 0.61 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: .92 –7.80 (m, 2H), 7.49 (dd, J = 6.8, 2.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.94 (s, 4H), 2.80 – 2.74 (m, 2H), 2.38 – 2.31 (m, 2H), 1.68 – 1.59 (m, 6H) , 1.52 –1.41 (m, 4H), 1.32 (t, J = 7.1 Hz, 3H).

[0528] Synthesis of intermediate P18: Lithium (1+) 6-(3-{2-azaspiro[3.4]octane-2-yl}propyl)pyridine-2-carboxylate (step C) was prepared using intermediate P17 in a manner similar to intermediate L3.

[0529] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate P18 as outlined in general route 11d.

[0530] Schematic diagram of general route 11f, page 202 / 484, CN 121335883 A Synthesis of intermediate P22 3-methoxy-1-(2-methylbut-3-yn-2-yl)azacyclobutane (Step A) At 0 °C, acetyl chloride (0.95 mL, 13.4 mmol) was added dropwise to a stirred solution of 2-methylbut-3-yn-2-ol (1.2 mL, 11.9 mmol) in anhydrous DCM (1.8 mL). The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under vacuum to obtain the residue. The residue was dissolved in anhydrous THF (12 mL), and 3-methoxyazacyclobutane hydrochloride (1:1) (1.0 g, 8.09 mmol), triethylamine (3.5 mL, 25.1 mmol), and CuCl (118 mg, 1.19 mmol) were added. The reaction mixture was stirred at 70°C for 3 hours, and then concentrated under vacuum. The residue was dissolved in water (20...The aqueous phase was dissolved in 20 mL of EtOAc and then alkalized to pH 10–11 with saturated NaHCO3 aqueous solution. The phases were separated, and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined organic phases were concentrated under vacuum to obtain the residue. The residue was purified by SCX-2 column (20 g), eluted with MeOH (3 CVs) and then with 7N NH3 / MeOH (4 CVs) to give the title product (448 mg, 22% yield) as a deep orange oil.

[0531] 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 4.05 – 3.98 (m, 1H), 3.52 – 3.48 (m, 2H), 3.33 – 3.20 (m, 5H), 2.39 (s, 1H), 1.23 (s, 6H).

[0532] Synthesis of Intermediate P23: Ethyl 6-[3-(3-methoxyazyrobutan-1-yl)-3-methylbut-1-yn-1-yl]pyridine-2-carboxylate (Step B) At room temperature, CuI (104 mg, 0.546 mmol), Pd(PPh3)2Cl2 (153 mg, 0.218 mmol), and diisopropylamine (1.6 mL, 11.6 mmol) were added to a degassed solution of ethyl 6-bromopyridine-2-carboxylate (722 mg, 3.14 mmol) and 3-methoxy-1-(2-methylbut-3-yn-2-yl)azyrobutane (445 mg, 2.61 mmol) in anhydrous THF (15 mL). The reaction mixture was stirred at 70 °C for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by FCC (50 g Sfar duo, 0-100% EtOAc / heptane) to give the title product (513 mg, 58% yield) as a pale orange oil. Instruction manual, pages 203 / 484, 252, CN 121335883 A

[0533] LCMS m / z: 303.1 [M+H]+, (ESI+), Rt = 0.49 (S2) 1H NMR (400 MHz, CDCl3) δ [ppm]: 8.06 (dd, J = 7.8, 1.1 Hz, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.69 – 7.64 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.08 – 4.03 (m, 1H), 3.62 – 3.56 (m, 2H), 3.37 – 3.29 (m, 5H) , 1.50 – 1.44 (m, 3H) ,1.34 (s, 6H).

[0534] Synthesis of intermediate P24 ethyl 6-[3-(3-methoxyazinobutan-1-yl)-3-methylbutyl]pyridine-2-carboxylate (step C) Under nitrogen, 10% Pd / C (205 mg, 0.193 mmol) was added to a solution of ethyl 6-[3-(3-methoxyazinobutan-1-yl)-3-methylbutan-1-yn-1-yl]pyridine-2-carboxylate (512 mg, 1.52 mmol) in EtOH (10 mL). The reaction mixture was then stirred under hydrogen for 19 hours. The mixture was filtered through diatomaceous earth and washed with MeOH (30 mL). The filtrate was concentrated under vacuum to give the residue. The title product (236.0 mg, 40% yield) was obtained by purification with FCC (5 g silica, 0-100% EtOAc / heptane, 0-30% MeOH / DCM). LCMS m / z: 307.2 [M+H]+, (ESI+), Rt=2.72 (S4) H NMR (500 MHz, CDC13) δ [ppm]: 7.92 (dd, J=7.7, 1.1 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H) , 7.35 (d, J = 7.7 Hz, 1H) , 4.46 (q, J = 7.1 Hz, 2H) , 4.14 – 4.06 (m, 1H) , 3.73 – 3.51 (m,2H) , 3.33 – 3.16 (m, 5H) , 2.98 - 2.88 (m, 2H) , 1.83 – 1.74 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.09 (br s, 6H).

[0536] Synthesis of intermediate P25 lithium (1+) 6-[[3-(3-methoxyazacyclobutane-1-yl)-3-methylbutyl]pyridine-2-carboxylate (step D) 2 M LiOH aqueous solution (463 μL, 0.926 mmol) was added to a stirred solution of ethyl 6-[3-(3-methoxyazacyclobutane-1-yl)-3-methylbutyl]pyridine-2-carboxylate (236 mg, 0.616 mmol) in anhydrous THF (2 mL) and MeOH (2 mL). The reaction mixture was stirred at room temperature for 17 hours. The mixture was concentrated under vacuum, then suspended in a 1:1 DCM / heptane mixture (20 mL), sonicated, and concentrated to give the title product as a brownish-red solid (197 mg, 100% yield).

[0537] LCMS m / z: 279.1 [M+H]+,(ESI+), Rt = 0.32 (S2).

[0538] General route 11g schematic diagram 204 / 484 pages 253 CN 121335883 A Synthesis of intermediate P26 1'-tert-butyl-6-ethyl-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-1',6-dicarboxylate (step A) Add Na2CO3 (1.38 g, 13.0 mmol) / water (7.5 mL) to a solution of ethyl 6-bromopyridine-2-carboxylate (1.00 g, 4.35 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.61 g, 5.22 mmol) in 1,4-dioxacyclohexane (30 mL). The mixture was degassed with a stream of N2 gas, and then Pd(dppf)₂Cl₂·DCM (180 mg, 0.217 mmol) was added. The mixture was stirred at 110 °C for 3 hours. The reaction mixture was cooled, filtered, and the filtrate was concentrated under vacuum. The residue was partitioned between EtOAc (40 mL) and brine (20 mL). The organic layer was separated, dried over MgSO₄, and concentrated under vacuum. The residue was purified by FCC (25 g silica, 0–30% EtOAc / heptane) to give the title product (1.43 g, 99% yield) as a colorless oil. H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.01-7.86 (m, 2H), 7.78 (dd, J=7.8, 1.2 Hz, 1H), 6.75 (s, 1H), 4.34 (q, J=7.1 Hz , 2H) , 4.10 – 3.96 (m , 2H) , 3.54 (t, J = 5.7 Hz, 2H) , 2.58 (dq , J = 5.3, 2.7 Hz,2H) , 1.42 (s, 9H) , 1.32 (t, J = 7.1 Hz, 3H).

[0540] Synthesis of intermediate P27: Ethyl 6-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}pyridine-2-carboxylate (Step B) Under nitrogen protection, 10% Pd / C (206 mg, 0.19 mmol) was added to a solution of 1'-tert-butyl-6-ethyl-1',2',3',6'-tetrahydro-[2,4'-bipyridine]-1',6-dicarboxylate (1.43 g, 4.30 mmol) in ethanol (15 mL). (See specification 205 / 484 pages 254 CN 121335883 A)The mixture was evacuated and stirred under hydrogen for 18 hours. The palladium residue was filtered off through diatomaceous earth, and the filtrate was concentrated under vacuum to give the title product as a colorless oil (1.25 g, yield 87%). LCMS m / z: 357.3 [M+Na]+, (ESI+), Rt=0.98(S2) H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.95 – 7.83 (m, 2H), 7.54 (dd, J=7.5, 1.5 Hz, 1H) , 4.40 – 4.28 (m, 2H) , 4.05 (dd , J = 9.8, 5.8 Hz,2H) , 3.01 – 2.73 (m, 3H) , 1.86 – 1.76 (m, 2H) , 1.58 (qd , J = 12.6, 4.3 Hz, 2H) , 1.40 (s, 9H), 1.31 (t, J = 7.1 Hz, 3H).

[0542] Synthesis of intermediate P28 6-(piperidin-4-yl)pyridine-2-carboxylate hydrochloride (step C) 4 M HCl / dioxane (3.7 mL, 14.8 mmol) was added to a solution of 6-{1-[(tert-butoxycarbonyl)piperidin-4-yl]pyridine-2-carboxylate (1.24 g, 3.71 mmol) in DCM (4 mL). The solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give the title product (1.00 g, 100% yield) as a white solid.

[0543] LCMS m / z: 235.2 [M+H]+, (ESI+), Rt = 0.46 (S2) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.94 (d, J = 152.6 Hz, 2H), 8.04 – 7.89 (m, 2H), 7.55 (dd , J = 7.6, 1.3 Hz, 1H) , 4.36 (q, J = 7.1 Hz, 2H) , 3.39 (s, 2H) , 3.20 – 2.96 (m, 3H) , 2.13 – 1.88 (m,4H) , 1.33 (t, J = 7.1 Hz, 3H).

[0544] Synthesis of Intermediate P29: Ethyl 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylate (Step D) To a solution of ethyl 6-(piperidin-4-yl)pyridine-2-carboxylate hydrochloride (500 mg, 1.85 mmol) in EtOH (6 mL), 37% formaldehyde aqueous solution (0.61 mmol) was added.The mixture was stirred for 15 minutes, and then NaBH3CN (469.977 mg, 7.48 mmol) was added. The solution was stirred at room temperature for 2 hours. The reaction was quenched with water (5 mL) and DCM (20 mL) was added. The aqueous layer was alkalized to pH 9 with a saturated NaHCO3 aqueous solution. The organic layer was separated, and the aqueous layer was extracted again with DCM (2 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to give the title product (440 mg, 81% yield) as a light brown oil. LCMS m / z: 249.2 [M+H]+, (ESI+), Rt=0.45 (S2) H NMR (400 MHz, CDC13) δ [ppm]: 7.88 (dd, J=7.7, 1.1 Hz, 1H), 7.71 (t, J=7.8 Hz, 1H) , 7 .37 – 7 .28 (m , 1H) , 4.39 (q , J = 7 .1 Hz, 2H) , 3.05 – 2.92 (m , 2H) , 2.85 (m , 1H) , 2.28 (d ,J = 13.6 Hz, 3H) , 2.17 – 2.04 (m , 2H), 2.00 – 1.90 (m, 2H), 1.89 – 1.73 (m, 2H), 1.36 (t, J = 7.1 Hz, 3H).

[0546] Synthesis of intermediate P30 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylic acid (step E) Specification 206 / 484 pages 255 CN 121335883 A 1 M LiOH (2.6 mL, 2.6 mmol) was added to a THF (7.5 mL) solution of ethyl 6-(1-methylpiperidin-4-yl)pyridine-2-carboxylic acid (430 mg, 1.73 mmol). The reaction mixture was stirred at 40 °C for 2 hours. 1 N HCl was added until the pH reached 8 (approximately 0.8 mL). The mixture was concentrated under vacuum to give the title product (380 mg, 90% yield) as a white solid.

[0547] LCMS m / z: 221.2 [M+H]+, (ESI+), Rt = 0.33 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.87 – 7.77 (m, 2H), 7.36 – 7.27 (m, 1H), 4.34 – 4.25 (m, 1H), 2.89 – 2.76 (m, 2H), 2.16 (d,J = 2.3 Hz, 3H), 1.89 – 1.76 (m, 2H), 1.76 – 1.61 (m, 4H).

[0548] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate P30 as outlined in general route 11g.

[0549] Synthesis of intermediate Q1 in general route 12a: (3S)-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-[(6-fluoropyridin-2-yl)formamido]-4-methylpentamido]ethyl propionate. TEA (0.68 mL, 4.87 mmol) was added to 6-fluoropyridin-2-carboxylic acid (302 mg, 2.14 mmol) and T3P (50% in DMF) (1.71 mL, 2.92 mmol) in DCM (7 The solution was stirred at room temperature for 10 minutes in mL, and then (3S)-3-[(2S)-2-amino-4-methylpentamido]-3-{4'-chloro-4-fluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}ethyl propionate hydrochloride (1.0 g, 1.95 mmol). After stirring for 3 hours, water (5 mL) was added, and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over MgSO4, and concentrated under vacuum. The residue was purified by reverse-phase FCC (30 g, C18 silica, 10-100% MeCN / water, with 0.1% NH4OH modifier) ​​to give the title product as a white solid (556 mg, yield 48%). LCMS m / z: 600.3 / 602.3 [M+H]+, (ESI+), Rt=1.12 (S2) H NMR (500 MHz, DMSO-d6) δ [ppm]: 8.74 (d, J=8.4 Hz, 1H), 8.39 (d, J=8.9 Hz, 1H), 8.16 (q, J = 8.0 Hz, 1H), 7.93 – 7.86 (m,1H), 7.45 – 7.37 (m, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H) , 7.00 – 6.87 (m, 2H), 5.61 – 5.45 (m, 1H), 4.57 – 4.42 (m, 1H), 4.17– 3.82 (m, 2H), 2.86 – 2.67 (m, 2H), 2.29 – 2.21 (m, 3H), 1.93 (s, 3H), 1.83 (s, 3H), 1.61 – 1.32 (m, 3H), 1.07 (t, J = 7.1 Hz, 3H), 0.91 – 0.70 (m, 6H).

[0551] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate Q1 as outlined in general route 12a.

[0552] Synthesis step B (part 1) of intermediate Q3: (3S)-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-[(2S)-2-({6-[3-(dimethylamino)-3-methylazonobutan-1-yl]pyridin-2-yl}formamido)-4-methylpentamido]ethyl propionate (100 mg, 0.171 mg) A solution of K2CO3 (71 mg, 0.51 mmol) in DMF (1 mL) was added, followed by N,N,3-trimethylazine-3-amine dihydrochloride (64 mg, 0.343 mmol). The mixture was heated at 80 °C for 18 hours. The reaction mixture was concentrated under vacuum to obtain the residue. Purification was performed by reverse-phase FCC (12 g C18 silica, 10-100% water / MeCN, containing 0.1% NH4OH modifier) ​​to give the title compound as a yellow glassy solid (57 mg, 37% yield).

[0553] LCMS m / z: 678.4 [M+H]+, (ESI+), Rt = 0.94 (S1).

[0554] Synthesis of intermediate Q4 of general route 12b: Lithium (1+)-6-chloropyridine-2-carboxylate (step A) To a stirred solution of ethyl 6-chloropyridine-2-carboxylate (500 mg, 2.69 mmol) in THF (5 mL) and MeOH (5 mL), 2 M LiOH aqueous solution (2 mL, 4 mmol) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, suspended in 1:1 DCM-heptane (20 mL), sonicated, and concentrated under vacuum to give the title product (491 mg, 100% yield) as a white solid.

[0555] LCMSm / z: 158.1 [M+H]+, (ESI+), Rt = 0.47 (S1).

[0556] Synthesis of intermediate Q5: (3S)-3-[(2S)-2-[(6-chloropyridin-2-yl)carbamate]-4-methylpentamido]-3-{4,4'-difluoro-2',5,6'-trimethyl-[1,1'-biphenyl]-3-yl}propionate (step B) Specification 209 / 484 pages 258 CN 121335883 A Ethyl (3S)-3-[[(2S)-2-amino-4-methyl-pentamido]amino]-3-[2-fluoro-5-(4-fluoro-2,6-dimethyl-phenyl)-3-methyl-phenyl]propionate hydrochloride (150 mg, 0.257 mmol), lithium (1+)-6-chloropyridin-2-carbamate (115 mg, 0.63 mmol), HATU (327 A solution of EtOA (179 μL, 1.03 mmol) in DMF (5 mL) was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc (15 mL) and water (25 mL) was added. The phases were separated, and the aqueous phase was extracted with EtOAc (15 mL). The combined organic layers were washed with brine, filtered through a phase separator, and concentrated under vacuum. The residue was purified by FCC (0–40% EtOAc / heptane, SfarDuo 25 g) to give the title product (247 mg, 65% yield) as a white solid. LCMS m / z: 600.4 / 602.4 [M+H]+, (ESI+), Rt=1.26 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 8.78 (d, J=8.4 Hz, 1H), 8.39 (d, J=8.9 Hz, 1H), 8.04 (t, J = 7.7 Hz, 1H), 7.94(dd, J = 7.6, 1.0 Hz, 1H), 7.74 (dd, J = 7.9, 0.9 Hz, 1H), 6.98 – 6.87 (m, 4H), 5.60 – 5.50 (m, 1H), 4.59 – 4.49 (m, 1H), 4.07 – 3.91 (m, 2H), 2.83 – 2.68 (m,2H), 2.27 – 2.22 (m, 3H), 1.96 – 1.92 (m, 3H), 1.87 (s, 3H) , 1.58 – 1.38 (m, 3H) ,1.06 (t, J = 7.1 Hz, 3H), 0.82 – 0.76 (m, 6H).

[0558] Synthesis of intermediate Q10 of schematic 12d general route 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyridine-2-carboxylate (step A) Cs2CO3 (1.416 g, 4.35 mmol) and methyl 6-bromo-5-methylpyridine-2-carboxylate (250 mg, 1.09 mmol) were added to a stirred solution of 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (301 mg, 1.41 mmol) in anhydrous 1,4-dioxane (10.5 mL). The solution was purged with nitrogen for 20 minutes, and then Pd(OAc)₂ (19.5 mg, 0.09 mmol) and BINAP (101.5 mg, 0.16 mmol) were added. The reaction mixture was stirred at 80 °C for 18 hours, cooled to room temperature, filtered through diatomaceous earth, and washed with ethyl acetate (2 x 10 mL). The filtrate was concentrated under vacuum, and the residue was purified by FCC (28 g Kp-NH₂ silica, 0-100% EtOAc / heptane) to give the title product (110 mg, 28% yield) as a white solid.

[0559] LCMS m / z: 290.3 [M+H]+, (ESI+), Rt=0.56 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.65 – 7.62 (m, 1H), 7.59 – 7.55 (m, 1H), 3.82 (s , 3H) , 3.01 – 2.96 (m , 4H) , 2.95 (s , 4H) , 2.28 (d , J = 0.8 Hz, 3H) , 2.23 (s, 3H) , 1.82 – 1.74 (m, 4H).

[0560] Synthesis of intermediate Q11: Lithium (1+) 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyridine-2-carboxylate (Step B) A stirred solution of methyl 5-methyl-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyridine-2-carboxylate (110 mg, 0.304 mmol) in THF (1.5 mL) and MeOH (0.15 mL) was treated with 2 M LiOH aqueous solution (0.23 mL, 0.460 mmol) and stirred at room temperature for 3 hours. The reaction mixture was vigorously concentrated under vacuum, and the residue was suspended in DCM (5The residue was sonicated and concentrated in DCM (5 mL) and heptane (3 mL). The residue was resuspended in DCM (5 mL) and heptane (3 mL), sonicated and concentrated under vacuum to give the title product as a white solid (112 mg, 98% yield).

[0561] LCMS m / z: 276.3 [M+H]+, (ESI+), Rt = 0.38 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.72–7.37 (m, 2H), 2.93–2.86 (m, 8H), 2.27–2.11 (m, 6H), 1.86–1.70 (m, 4H).

[0562] Synthesis of intermediate Q12 methyl 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridine-2-carboxylate (step A) was prepared in a manner similar to that of intermediate Q10, using methyl 6-bromo-5-methylpyridine-2-carboxylate and N,N-dimethylpiperidin-4-amine. LCMS m / z: 278.2 [M+H]+, (ESI+), Rt=0.49 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.65 (dd, J=7.6, 0.9 Hz, 1H), 7.58 (d, J= 7.5 Hz, 1H) , 3.83 (s, 3H) , 3.49 (d, J = 12.8 Hz, 2H) , 3.17 (d, J = 5.1 Hz, 1H) , 2.79 – 2.65 (m , 2H) , 2.30 (s , 3H) , 2.21(s , 6H) , 1.91 – 1.80 (m, 2H), 1.52 (qd, J = 12.1, 3.8 Hz, 2H).

[0564] Synthesis of intermediate Q13 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridine-2-carboxylic acid (step B) Specification 211 / 484 pages 260 CN 121335883 A To a solution of methyl 6-[4-(dimethylamino)piperidin-1-yl]-5-methylpyridine-2-carboxylic acid (80 mg, 0.288 mmol) in THF (3 mL), 2 M LiOH aqueous solution (0.87 mL, 1.73 mmol) was added. The solution was stirred at 40 °C for 2 hours. The reaction mixture was cooled and acidified to pH 5 with 1N HCl. The solvent was removed under vacuum to give the title product (76 mg, 100% yield) as a colorless gel.

[0565] LCMS m / z: 264.2[M+H]+, (ESI+), Rt = 0.33 (S1).

[0566] The following intermediates are prepared using the corresponding starting materials in a manner similar to intermediate Q13 as outlined in general route 12d.

[0567] Synthesis of schematic intermediate Q15 of general route 12e: 6-[6-(methoxycarbonyl)-3-methylpyridin-2-yl]-2,6-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (step A) is prepared in a manner similar to intermediate Q10 using methyl 6-bromo-5-methylpyridin-2-carboxylate and tert-butyl 2,6-diazaspiro[3.5]nonane-2-carboxylate.

[0568] LCMS m / z: 398.3 [M+H]+, (ESI+), Rt = 1.05 (S1) 1H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.68 (dd, J = 7.5, 0.9 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 3.84 (s, 3H), 3.57 (s, 4H), 3.19 – 3.08 (m, 2H), 2.99 – 2.89 (m, 2H), 2.31 (d, J = 0.8 Hz, 3H), 1.76–1.67 (m, 2H), 1.64 (q, J = 5.5 Hz, 2H), 1.37 (s, 9H).

[0569] Synthesis of intermediate Q16 6-{2,6-diazaspiro[3.5]nonane-6-yl}-5-methylpyridine-2-carboxylate hydrochloride (step B) To a solution of 6-[6-(methoxycarbonyl)-3-methylpyridine-2-yl]-2,6-diazaspiro[3.5]nonane-2-carboxylate tert-butyl ester (166 mg, 0.442 mmol) in DCM (1 mL), 4M HCl / 1,4-dioxane (0.442 mL, 1.77 mmol) was added. The solution was stirred at room temperature for 2 hours. The solvent was concentrated under vacuum to obtain the title product (200 mg, 74% yield) as a colorless gum.

[0570] LCMS m / z: 276.2 [M+H]+, (ESI+), Rt = 0.53 (S1) 1H NMR (400 MHz, DMSO-d6) δ [ppm]: 9.20 (1H, br s), 7.75 – 7.58 (m, 2H), 3.84 (s, 3H), 3.77 – 3.54 (m, 6H)2.90 (t, J = 5.3 Hz, 2H), 2.33 (s, 3H), 1.84 – 1.68 (m, 2H), 1.68 – 1.55 (m, 2H).

[0571] Synthesis of intermediate Q17 methyl 5-methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonane-6-yl}pyridine-2-carboxylate (step C) Formaldehyde [37% in water] (0.137 mL, 1.69 mmol) was added to a solution of methyl 6-{2,6-diazaspiro[3.5]nonane-6-yl}-5-methylpyridine-2-carboxylate hydrochloride (130 mg, 0.417 mmol) in MeOH (1.4 mL). The mixture was stirred for 15 minutes, then NaBH3CN (106 mg, 1.69 mmol) was added, and the solution was stirred at room temperature for 18 hours. The reaction was quenched with a saturated aqueous solution of NaHCO3 (10 mL), and dichloromethane (DCM) (20 mL) was added. The organic layer was separated, and the aqueous layer was extracted again with DCM (2 x 10 mL). The combined organic layers were dried over MgSO4 and concentrated under vacuum to obtain the residue. Purification was performed by FCC (10 g silica, 0–10% 7 M NH3 in MeOH / DCM) to give the title product (55 mg, 41% yield) as a colorless oil. LCMS m / z: 290.4 [M+H]+, (ESI+), Rt=0.56 (S1) H NMR (500 MHz, DMSO-d6) δ [ppm]: 7.67 (d, J=7.5 Hz, 1H), 7.49 (dd, J=7.5, 0.9 Hz, 1H) , 3.94 (s, 3H) , 3.28 (s, 2H) , 3.16 (d , J = 7.5 Hz, 2H) , 3.09 – 2.95 (m, 4H) , 2.38 – 2.31 (m, 6H) , 1.81 – 1.73(m, 2H) , 1.73 – 1.62 (m, 2H).

[0573] Synthesis of intermediate Q18 5-methyl-6-{2-methyl-2,6-diazaspiro[3.5]nonane-6-yl}pyridine-2-carboxylic acid (step D) Specification 213 / 484 pages 262 CN 121335883 A Prepared using intermediate Q17 in a manner similar to intermediate Q13.

[0574] LCMS m / z: 276.4 [M+H]+, (ESI+), Rt = 0.43 (S1).

[0575] Synthesis of intermediate Q19 according to the schematic of general route 12fEthyl 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (Step A) To a stirred suspension of ethyl 2-hydroxy-6-(trifluoromethyl)pyridine-3-carboxylate (500 mg, 2.13 mmol) and potassium carbonate (735 mg, 5.32 mmol) in acetone (10 mL), (2-chloroethyl)dimethylamine hydrochloride (1:1) (766 mg, 5.32 mmol) was added. The reaction mixture was stirred at 60 °C for 18 hours, cooled, filtered, and washed with acetone (25 mL). The filtrate was concentrated under vacuum, and the residue was purified by FCC (25 g silica, 0–10% MeOH / EtOAc) to give the title product as a solid (370 mg, 55% yield). LCMS m / z: 307.2 [M+H]+, (ESI+), Rt=0.59 (S1) H NMR (400 MHz, CDC13) δ [ppm]: 8.19 (dd, J=7.7, 1.0 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H) , 4.52 (t, J = 5.8 Hz, 2H) , 4.31 (q, J = 7.2 Hz, 2H) , 2.71 (t, J = 5.9 Hz, 2H) , 2.29 (s, 6H) ,1.32 (t, J = 7.1 Hz, 3H).

[0577] Synthesis of intermediate Q20 (illustration on page 110a) 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (step B) At 45°C, ethyl 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (359 mg, 1.17 mmol) was added to a stirred solution of ethyl 2-[2-(dimethylamino)ethoxy]-6-(trifluoromethyl)pyridine-3-carboxylate (0.88 mL, 1.76 mmol) in THF (5 mL) and MeOH (0.5 mL). The reaction mixture was stirred at 45°C for 1 hour. The reaction mixture was cooled and acidified with an aqueous solution of 1 N HCl. The solution was concentrated under vacuum to give the title product (400 mg, 100% yield) as a white solid. LCMS m / z: 279.1 [M+H]+, (ESI+), Rt=0.48 (S1) H NMR (400 MHz, DMSO-d6) δ [ppm]: 7.60 (s, 1H), 7.27 (d, J=7.2 Hz, 1H), 4.32 (t, J = 6.2 Hz,2H), 2.58 (t, J = 6.2 Hz, 2H), 2.21 (s, 6H).

[0579] The following intermediates were prepared using the corresponding starting materials in a manner similar to intermediate Q20 as outlined in general route 12f.

[0580] Synthesis of schematic intermediate R1 of general route 13 methyl 2-fluoro-3-(4-methylpiperazin-1-yl)benzoate (step A) A stirred mixture of methyl 3-bromo-2-fluorobenzoate (1.0 g, 4.29 mmol), 1-methylpiperazine (625 μL, 5.63 mmol) and Cs2CO3 (4.19 g, 12.86 mmol) in anhydrous 1,4-dioxane (40 mL) was degassed with nitrogen for 5 min. Pd(OAc)₂ (71 mg, 0.316 mmol) and rac-BINAP (400.0 mg, 0.64 mmol) were added, and the mixture was stirred at 80 °C for 18 hours. The reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and washed with EtOAc (30 mL). The filtrate was concentrated under vacuum to obtain the residue. Purification by column chromatography (25 g silica, 0–100% EtOAc / heptane, followed by 0–15% MeOH / EtOAc) yielded an impure product. Further purification by SCX column chromatography (0–100% 7M NH₃ / MeOH) gave the title product as a yellow oil (660 mg, 59% yield).

[0581] LCMS m / z: 253.1 [M+H]+, (ESI+), Rt = 0.66 (S2) 1H NMR (500 MHz, CDCl3) δ [ppm]: 7.51 – 7.46 (m, 1H), 7.15 – 7.06 (m, 2H), 3.91 (s, 3H), 3.17 – 3.07 (m, 4H), 2.65 – 2.55 (m, 4H), 2.35 (s, 3H).

[0582] Synthesis of Intermediate R2: Lithium (1+)-2-fluoro-3-(4-methylpiperazin-1-yl)benzoate (Step B) A solution of methyl 2-fluoro-3-(4-methylpiperazin-1-yl)benzoate (655 mg, 2.52 mmol) in THF (10 mL) and MeOH (1 mL) was added to a 2 M LiOH aqueous solution (1.5 mL, 3.00 mmol). The reaction mixture was stirred at room temperature for 3 hours. Then, another 2 M LiOH aqueous solution (1.5 mL, 3.00 mmol)...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in: R y It is -CH(CH3)2, -CF3, -CH2F, CHF2, -CH(CF3)2, cyclopropyl or cyclobutyl; R x It is hydrogen or methyl; R 1 It is -C(O)-R 7 ; Where R 7 It is a -C substituted with 0 or 1 pyridine, phenyl, or cyclopropyl groups. 1-6 alkyl; Or R 7 It is a phenyl or a 5-10 membered heterocyclic group, each independently of R 9 Replace with 0, 1, 2, 3, or 4 instances; Each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl, -OR 11 , phenyl and 4-10 membered heterocycles; and each R 9 Independently selected from R by 0, 1, 2 or 3 independent selections. 17 Substitution of groups; R 17 Selected from halogens, -C 1-6 Alkyl, -OR 15 -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 ), cyclopropyl and 4 to 10 membered heterocycles, when R 17 When it is a heterocyclic ring, it is further selected independently by 0, 1, 2, or 4 ions from halogens, -C 1-6 Alkyl, =O, -C(O)-R 14 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl, -OR 18 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, -C 1-6 Alkyl-C 3-6 cycloalkyl and C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, wherein the 4 to 10-membered heterocycle is separated by 0 or 1 -C 1-6 Alkyl substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated, C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl are substituted with 0, 1, 2, or 3 F atoms; R 14 Independently selected from -C 1-6 Alkyl and C 3-6 cycloalkyl; R 15 It is H, -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, when R 15 When it is a 4- to 10-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; R 18 It is -C 1-6 Alkyl or -C 1-6 Halogenated groups; Among them, in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different; R 2 The group consisting of Br, phenyl, naphthyl and 5-10 heteroaryl groups, each of which can be independently selected by 0, 1, 2, 3 or 4 independently selected from -CN, -C 1-6 Alkyl, halogen, -C 1-6 Halogenated, -OC 1-6 Alkyl, phenyl, 5- to 6-membered heteroaryl, -OC 3-6 Substitution with cycloalkyl, -O-phenyl, and -O- (5- to 6-membered heterocycloalkyl) groups; Y is -N= or -C(R) 3 = R 3 It is halogen, -C 1-6 Halogenated groups, -C 1-4 Alkyl or -C 3-6 cycloalkyl; R 4 It is halogen or hydrogen; R 5 It is halogen or hydrogen; R 6 It is -C(O)-OR 8 , Where R 8 Is it hydrogen or -C? 1-4 Alkyl, -C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(Me)-R 16 -C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(R) 16 ,R 16a - or -C 1-4 Alkyl-OC(O)-R 16 ; R 16 and R 16a Independently selected from -C 1-6 Alkyl, 3- to 6-cycloalkyl, 4- to 6-membered heterocycles, 4- to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycles are further selected by one or two independently from =O or -C. 1-4 Alkyl groups are substituted.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, having formula Ia Where R 1 To R 6 R x R y And Y as defined in claim 1.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein: R x It is hydrogen.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R x It is a methyl group.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R y It is -CH(CH3)2, -CF3, cyclopropyl or cyclobutyl.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R y It is -CH(CH3)2, cyclopropyl or cyclobutyl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R y It is -CH(CH3)2.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R y It is cyclopropyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R y It is cyclobutyl.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated, C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl, and cyclopropyl, wherein C 1-6 alkyl-cyclopropyl, C 1-6 Alkyl-(cyclopropyl)2, cyclobutyl and cyclopropyl are substituted with 0, 1, 2 or 3 F.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein R 17 Selected from halogens, -C 1-6 Alkyl, -OR 15 -C(O)-N(C) 1-4 Alkyl)2, -N(R 12 R 13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a heterocyclic ring, it is further selected by 0, 1, or 2 independently selected from halogens, -C 1-6 Alkyl, =O, -C(O)-R 14 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 cycloalkyl and -OR 18 The group is substituted.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated and cyclopropyl groups.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated groups, 4- to 10-membered heterocycles, or -C 1-6 Alkyl-N(C) 1-6 Alkyl)2, when R 15 When it is a 4- to 10-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution.

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R 2 It can be independently replaced by 0, 1, 2 or 3 groups.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 8 Is it hydrogen or -C? 1-4 Alkyl or -C 1-4 Alkyl-OC(O)-R 16 .

16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 8 Is it hydrogen or -C? 1-4 Alkyl-C 1-4 Alkyl-R 16 -C 1-4 Alkyl-C(O)N(Me)-R 16 -or-C 1-4 Alkyl-OC(O)-R 16 And R 16 Independently selected from -C 1-6 Alkyl, 3- to 6-cycloalkyl, 4- to 6-membered partially saturated heterocycles, wherein the partially saturated heterocycles are further selected by one or two independently from =O or -C. 1-4 Alkyl groups are substituted.

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R 2 It is a phenyl or a 5-10-membered heteroaryl group, each of which is independently selected from -CN, -C by 1, 2, 3 or 4 groups. 1-6 Alkyl, halogen, -C 1-6 Substitution of haloalkyl groups.

18. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected independently by 1, 2, 3 or 4 from -CN, -C 1-6 Alkyl, halogen and -C 1-6 The alkyl group is substituted and selected from... 。 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein: R 2 It is substituted by 1, 2, 3 or 4 independently selected groups chosen from -CN, methyl, F, Cl and -CF3, and selected from 。 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein: R 2 Selected independently by 1, 2, 3 or 4 from -CN, -C 1-6 Alkyl, halogen, -C 1-6 The alkyl group is substituted and selected from... 。 21. The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R) 3 = ).

22. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 21, wherein Y is -N=.

23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R 3 = and R 3 It is halogen, -CF3, methyl, ethyl, cyclopropyl.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein... R 4 It is either halogen or hydrogen.

25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R 4 It is halogen.

26. The compound of claim 25 or a pharmaceutically acceptable salt thereof, wherein R 4 It is F.

27. The compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein R 5 It is either fluorine or hydrogen.

28. The compound according to claim 27, wherein R 5 It is hydrogen.

29. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -C(O)-OR 8 , where R 8 It is hydrogen, methyl, CF3, ethyl, isopropyl, –CH2-(5-methyl-2-oxo-1,3-m-dioxacyclopenten-4-yl) or –CH2-C(O)N(Me)2.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R 6 It is -C(O)-OR 8 , where R 8 It is hydrogen, methyl, ethyl, or isopropyl.

31. The compound according to any one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein R 8 It is hydrogen.

32. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 7 -C is replaced by 0 or 1 pyridine 1-6 alkyl.

33. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 7 It is selected from 0, 1, 2, 3 or 4 of -C 1-6 Alkyl, halogen or -OC 1-6 Phenyl groups substituted with alkyl groups.

34. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein R 7 It is selected from 0, 1, 2 or 3 of -C 1-6 Alkyl, halogen or -OC 1-6 Phenyl groups substituted with alkyl groups.

35. The compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein... R 7 It is selected independently from R by 0, 1, 2, 3 or 4. 9 5-10 membered heterocyclic groups substituted with the group, and Each R 9 Independently selected from halogens, =O, -C 1-6 Alkyl, -C(O)-R 10 -C 1-6 Halogenated groups, -SO2-C 1-6 Alkyl, -NH-C 1-4 Alkyl, -N(C) 1-4 Alkyl)2, -C 3-6 Cycloalkyl, phenyl, 4- to 7-membered heterocycles, -OR 11 Each R 9 Independently selected from R by 0, 1, or 2 independent selections. 17 Substitution of groups; R 10 Independently selected from -C 1-6 Alkyl, C 3-6 cycloalkyl and -C 1-6 Alkyl-C 3-6 cycloalkyl; R 11 It is -C 1-6 Alkyl, -C 1-6 Alkyl-N(-C) 1-6 Alkyl)2, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocyclic rings; R 17 Selected from halogens, -OR 15 -C(O)N(C 1-4 Alkyl)2, -N(R 12 R 13 ) and 4 to 10-membered heterocyclic rings, when R 17 When it is a 4- to 10-membered heterocycle, it is selected by 0, 1, 2, or 4 independently chosen halogens and -C. 1-6 Alkyl or -C 1-6 Halogenated alkylation; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution; And in each -N(C 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

36. The compound of claim 35 or a pharmaceutically acceptable salt thereof, wherein... R 7 It is a 5-10 membered heterocyclic group substituted with 0, 1, 2, or 3 groups, and R 17 It is a 4- to 10-membered heterocyclic ring, in which R 17 It can be replaced by 0, 1, or 2 groups.

37. The compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein R 9 It is selected independently by 0, 1, 2 or 3 from -C(O)-N(C) 1-4 Alkyl)2, -OR 15 -N(R) 12 R 13 -C groups substituted with 4 to 10-membered heterocyclic alkyl groups 1-6 Alkyl groups, wherein the heterocyclic alkyl groups are further selected independently of halogens or -C. 1-6 Alkyl group substitution; R 12 and R 13 Independently selected from -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups and cyclopropyl groups; R 15 It is -C 1-6 Alkyl, -C 1-6 Halogenated alkyl groups or 4- to 7-membered heterocycles, and when R 15 When it is a 4- to 7-membered heterocyclic ring, it is affected by 0 or 1 -C 1-6 Alkyl substitution, and wherein in each -N(C) 1-6 alkyl)2 or -N(C 1-4 In alkyl)2, the two alkyl groups attached to N can be the same or different.

38. The compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein R 7 Choose from the following groups: Each of the following groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, –isobutyl, –isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –CF3, –OMe, –OCF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, 3-N(Me)2-3-Me-azacyclobutane-1-yl, 3-N(Me)2-pyrrolidine-1-yl, 4-Me-piperidin-1-yl, 1-Me-piperidin-4-yl, 1-isopropyl-piperidin-4-yl, 4-N(Me )2-piperidin-1-yl, 4-cyclopropyl-piperazin-1-yl, 4-isopropyl-piperazin-1-yl, 4-Me-1,4-diazacycloheptane-1-yl, 4-isopropyl-1,4-diazacycloheptane-1-yl, 4-cyclopropyl-1,4-diazacycloheptane-1-yl, 5-methyl-2,4,6,7-tetrahydropyrazole[4,3-c]pyridin-2-yl, 2-methyl-2,7-diazaspiro[3.5]nonane-7-yl, 7-methyl-2,7-diazaspiro[3.5]nonane-2-yl, 1-methyl-1,7-diazaspiro[3.5]nonane-7-yl, 2-methyl-2,6-diazaspiro[3.3]heptane-6-yl, 3-(3-azabicyclo[ 3.1.1] Heptane-3-yl)-azacyclobutane-1-yl, 2-methyl-2,5-diazabicyclo[2.2.1] heptane-5-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-CH2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-C(Me)2-(3-OMe-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl), –CH2-CH2-(3-OCF3-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-azacyclobutane-1-yl), –CH2-CH2-(3-OCHF2-azacyclobutane-1-yl), –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(2,2-diMe-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-CH2-(3-MeO-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-CHF2-3-Me-azacyclobutane-1-yl), –CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl) ), –CH2-CH2-CH2-(3-F-3-Me-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2-(3-CF3-pyrrolidine-1-yl), –CH2CH2-(3,3-diF-pyrrolidine-1-yl), Oxycyclobutane-3yl, –CH2CH2OCH3, –CH2CH2OH, –CH2C(O)N(Me)2, –CH2N(Me)2, –CH2CH2N(Me)2, –CH2CH2N(Me)CH(cyclopropyl)2, –CH2CH2N(Me)CH2(cyclopropyl), –CH2CH2CH2N(Me)2, –C(Me)2CH2N(Me)2, –CH2C(Me) )2N(Me)2、–CH2CH2C(Me)2N(Me)2、–CH2CH2N(Me)CH2CF3、–CH2CH2N(Me)CH(Me)2、–CH2CH2N(Me)C(Me)3、–CH2CH2N(Me)cyclopropyl、4-F-phenyl、–CH2CH2-(2-azaspiro[3.4]octane-2-yl、–CH2CH2CH2-(2-azaspiro[3.4]octane-2-yl)4] Octane-2-yl), –CH2CH2CH2CH2-(2-azaspiro[3.4]octan-2-yl), –CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2CH2-(6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2,2-diF-6-azaspiro[3.4]octan-6-yl), –CH2CH2-(2-azaspiro[3.3]heptane-2- –CH2CH2-(6-MeO-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(2-azaspiro[4.5]decane-2-yl), –CH2CH2-(7-azaspiro[3.5]nonane-7-yl), –CH2CH2-(6-azaspiro[3.5]nonane-6-yl), –CH2CH2-(2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(5-oxa-8-yl) -azaspiro[3.5]nonane-8-yl), –CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2CH2CH2-(7-oxa-2-azaspiro[3.5]nonane-2-yl), –CH2CH2-(6,6-diF-2-azaspiro[3.3]heptane-2-yl), –CH2CH2-(8-azabicyclo[3.2.1]octane-8-yl), –CH2CH2- (8-oxa-3-azabicyclo[3.2.1]octan-3-yl), CH2CH2CH2-(2-azabicyclo[2.2.2]octan-2-yl), –CH2CH2CH2-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl), –CH2CH2-(7,7-diF-1,6-diMe-3-azabicyclo[4.1.0]heptane-3-yl), –CH2CH2-(3-azabicyclo[... 3.1.1] heptane-3-yl), – CH2CH2CH2-(2-azabicyclo[2.2.1] heptane-2-yl), CH2CH2CH2-(3-azabicyclo[ 3.1.1] heptane-3-yl), –CH2CH2CH2CH2-(3-azabicyclic[ 3.1.1] heptane-3-yl), –CH2CH2-(2-azabicyclo[ 2.1.1] Hexane-2-yl), –CH2CH2-(6,6-diMe-3-azabicyclo[3.1.0] Hexane-3-yl), –CH2CH2N(Me)cyclobutyl), –CH2CH2N(Me)(3,3-diF)cyclobutyl-1-yl), –CH2-CH2-(4-CF3-piperidin-1-yl), –CH2-CH2-(4,4-diMe-piperidin-1-yl), –CH2-CH2-(morpholin-4-yl), –CH2-CH2-CH2-(morpholin-4-yl) –CH2-CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-CH2-(2,2,6,6-tetra-Me-morpholin-4-yl), –CH2-CH2-CH2-(2,2-diMe-morpholin-4-yl), –CH2-CH2-(2,6-diMe-morpholin-4-yl), –CH2-CH2-(1,4-oxazaza-4-yl), –CH2CH2-CH2-(1,4-oxazaza-4-yl) and –S(O)2Me.

39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein R 7 Choose from the following groups: Each of these groups is substituted by 0, 1, or 2 independent substituents selected from the following: –F, –Cl, oxo, –Me, isobutyl, isopropyl, cyclobutyl, –CH2F, –CHF2, –CH2CF3, –OMe, –O-CF3, –O-azacyclobutane-3-yl, –N(Me)2, –C(O)Me, –C(O)cyclopropyl, 1-Me-azacyclobutane-3-yl, 3-F-azacyclobutane-1-yl, –C(O)CH2cyclopropyl, –CH2-CH2-azacyclobutane-1-yl, –CH2-CH2-(3-F-azacyclobutane-1-yl), –CH2-CH2-(3-CF3-azacyclobutane-1-yl). –CH2-CH2-(3,3-diF-azacyclobutane-1-yl), –CH2-CH2-(3,3-diMe-azacyclobutane-1-yl), –CH2-azacyclobutane-1-yl, –CH2-(3-F-azacyclobutane-1-yl), –CH2-(1-Me-azacyclobutane-3-yl), –CH2-azacyclobutane-3-yl, –CH2CH2-(3-F-pyrrolidine-1-yl), –CH2CH2OCH3, –CH2C(O)N(Me)2, –CH2CH2N(Me)2, –CH2CH2CH2N(Me)2, –CH2CH2N(Me)CH2CF3, –CH2CH2N(Me)cyclopropyl, 4-F-phenyl and –S(O)2Me.

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 39, wherein each R 2 Independently select from the following groups: -Br, -CF3, 。 41. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, wherein each R 2 Choose independently from the following groups: 。 42. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein each R 2 Independently select from the following groups: -Br, -CF3, 。 43. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein each R 2 Choose independently from the following groups: 。 44. The compound according to any one of claims 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: -C(O)-CH3, 。 45. The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: 。 46. ​​The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... 。 47. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from... 。 48. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

49. Use of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical preparation.

50. The compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, used as a pharmaceutical agent.

51. A method for inhibiting the interaction between α4β7 integrin and MAdCAM-1 protein in a subject, the method comprising administering to a subject in need a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

52. A method for treating inflammatory bowel disease in a person in need, the method comprising administering to the person a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

53. A compound selected from any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, used for the treatment of inflammatory bowel disease.

54. The method according to claim 52 or 53, wherein the inflammatory bowel disease is ulcerative colitis.

55. The method according to claim 52 or 53, wherein the inflammatory bowel disease is Crohn's disease.

56. A method for treating ulcerative colitis in humans, the method comprising administering to a person in need a pharmaceutically effective amount of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

57. The compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, for the treatment of ulcerative colitis.

58. The method of claim 56, wherein the ulcerative colitis is ulcerative colitis.

59. The method of claim 56, wherein the ulcerative colitis is Crohn's disease.

60. A medicine box comprising: a) One or more compositions, each composition comprising a pharmaceutically effective amount of the compound of any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and b) Instructions for use of one or more of the compositions in a person in need.

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