Macrocyclic derivative and use thereof

Abstract

The invention discloses a macrocyclic derivative, and particularly discloses a compound shown as a formula (VI), and a stereoisomer and a pharmaceutically acceptable salt thereof.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202511488433.0 (22) Application Date 2023.09.28 (66) Domestic Priority Data 202211213222.2 2022.09.29 CN 202310132699.6 2023.02.17 CN 202310371165.9 2023.04.07 CN 202310685748.9 2023.06.09 CN 202310911632.2 2023.07.24 CN (62) Divisional Application Data 202380053250.9 2023.09.28 (71) Applicant: Guangzhou Jiayue Pharmaceutical Technology Co., Ltd. Address: Unit 3, Building 2, Yunsheng Science Park, No. 11, Guangpu Middle Road, Huangpu District, Guangzhou, Guangdong Province, 510663, China (72) Inventors: Zhang Yang, Zhou Kai, Jiang Fen, Zhang Li, Liu Xiao, Wang Zheng, Chen Xinhai, Li Jian, Chen Shuhui (74) Patent Agency: Shanghai Bixing Law Firm, 31283 Patent Attorneys: Gao Xiaoli, Wang Weibin (51) Int.Cl. C07D 513 / 22 (2006.01) C07D 498 / 22 (2006.01) C07D 519 / 00 (2006.01) A61P 35 / 00 (2006.01) (54) Invention Title: Macrocyclic Derivatives and Their Applications (57) Abstract: This invention discloses a class of macrocyclic derivatives, specifically the compounds shown in formula (VI), their stereoisomers and pharmaceutically acceptable salts. Claims 27 pages, Description 99 pages, Drawings 5 ​​pages, CN 121270581 A 2026.01.06 CN 1 21 27 05 81 A 1. The compound shown in formula (VI), its stereoisomers or pharmaceutically acceptable salts thereof, wherein L is R6 or; L1 is selected from -N(R9)C(=O)-; L2 is selected from C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2 or 3 Ra; L3 is selected from -CH2- and C3-6 cycloalkyl; L4 is selected from single bond and -C1-4 alkyl-N(R10)C(=O)-; ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]heptyl, and 2,3-diazabicyclo[3.1.0]. [0]hexyl, 5,6-diazaspiro[2.5]octyl, 3,4-diazabicyclo[4.2.0]octyl and 2,3-diazabicyclo[3.1.1]heptyl; ring B is selected from 5-membered heteroaryl and 5-membered heteroaryl, indole and; T1, T2, T3 and T4 are independently selected from CH and N, respectively;R1 is selected from H, F, Cl, Br, I, OH, C1-4 alkyl and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are each independently and optionally substituted by 1, 2 or 3 Rh; R2 is selected from -O- and -NH-; R3 is selected from phenyl and 5-6 heteroaryl, wherein the phenyl and 5-6 heteroaryl are each independently and optionally substituted by 1, 2 or 3 Rb; R4 and R5 are each independently selected from H, C1-4 alkyl, C3-6 cycloalkyl and 3-6 heterocyclic alkyl, wherein the C1-4 alkyl, C3-6 cycloalkyl and 3-6 heterocyclic alkyl are each independently and optionally substituted by 1, 2 or 3 Rc; R6 is selected from C3-6 cycloalkyl and 3-6 heterocyclic alkyl, wherein the C3-6 cycloalkyl and 3-6 heterocyclic alkyl are each independently and optionally substituted by 1, 2 or 3 Rd. Each R7 is independently selected from H, halogen, C1-4 alkyl, and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are independently and optionally substituted with 1, 2, or 3 Re; each R8 is independently selected from H, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and 3-10 heterocyclic alkyl, wherein the C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and 3-10 heterocyclic alkyl are independently and optionally substituted with 1, 2, or 3 Rf; R9 and R10 are selected from H and C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1, 2, or 3 Rg; Each Ra, each Rb, each Rc, each Re, each Rf, each Rg, and each Rh is independently selected from H, D, F, Cl, Br, I, OH, C1-3 alkyl, and C1-3 alkoxy, wherein the C1-3 alkyl and C1-3 alkoxy are independently optionally substituted with 1, 2, or 3 Rs; each Rd is independently selected from C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl, and -C(=O)-C2-4 alkenyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl, and -C(=O)-C2-4 alkenyl are independently optionally substituted with 1, 2, or 3 Rs; Each R is independently selected from D, F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; n, p, and q are independently selected from 0, 1, 2, and 3, respectively; the “3-6-membered heterocyclic alkyl,” “3-10-membered heterocyclic alkyl,” and “5-6-membered heteroaryl” each independently contain one or two heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N. 2. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein each Rd is independently selected from CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxocyclobutyl, aziridine, and, wherein CH3,CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine, and each Rd is independently and optionally substituted with 1, 2, or 3 Rs; or, each Rd is independently selected from CH3 and CH2CH3, wherein the CH3 and CH2CH3 are independently and optionally substituted with 1, 2, or 3 Fs; or, each Rd is independently selected from CH3, , and ; or, each Rd is independently selected from CH3. 3. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein each R1 is independently selected from H, F, OH, and CH3. 4. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the structural units are selected from , , , , , , , , , , , , and . 5. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein ring A is selected from 3,4-diazabicyclo[4.1.0]heptyl and 2,3-diazabicyclo[3.1.1]heptyl; or, ring A is selected from […]. 6. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein R2 is selected from -O-. 7. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein R3 is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, thiopheneyl, oxazolyl, pyrazolyl, and imidazolyl, wherein the phenyl, pyridinyl, pyrimidinyl, thiazolyl, thiopheneyl, oxazolyl, pyrazolyl, and imidazolyl groups are each independently and optionally substituted by 1, 2, or 3 Rb groups; or, R3 is selected from […]. 8. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein R6 is selected from C3-6 cycloalkyl groups, wherein the C3-6 cycloalkyl group is optionally substituted with 1, 2, or 3 Rd groups; or, R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, oxacyclobutyl, oxacyclopentyl, and oxacyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, cyclopentyl, aziridinyl, cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, pyrrolyl, piperidinyl, piperazine, morpholinyl, cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, cyclobutyl, pyrrolyl, piperidinyl, morpholinyl, cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, cyclobutyl, pyrrolyl, piperidinyl, morpholinyl, cyclobutyl, cyclopentyl, aziridinyl, cyclobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl, cyclopropyl, cyclobutyl, cyclobutyl, cyclopentyl, cyclobutyl, cyclobutyl, cyclopropyl, cyclobutyl ... The linyl, oxecyclobutyl, oxecyclopentyl, and oxecyclohexyl groups are each independently and optionally substituted with 1, 2, or 3 Rd groups; or, R6 is selected from cyclopropyl, wherein the cyclopropyl group is optionally substituted with 1, 2, or 3 Rd groups; or, R6 is selected from […]. 9. The compound according to claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein each R7 is independently selected from H, F, Cl, and C1-3 alkyl groups, wherein the C1-3 alkyl groups are optionally substituted with 1, 2, or 3 Re groups; or, R7 is selected from H, F, Cl, CH3And CH2CH3, wherein CH3 and CH2CH3 are each independently and optionally replaced by 1, 2 or 3 Re; or, R7 is selected from H, F, Cl, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3 and CD3; or, R7 is selected from H, CH3 and CH2CH3. 10. The compound of claim 1, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein each R8 is independently selected from H, C1-3 alkyl, and 3-10 heterocyclic alkyl, wherein the C1-3 alkyl and 3-10 heterocyclic alkyl are each optionally substituted by 1, 2, or 3 Rf; or, R8 is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, piperidinyl, piperidinenyl, homopiperidinyl, morpholinyl, and, wherein the CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, piperidinenyl, homopiperidinyl, morpholinyl, and are each optionally substituted by 1, 2, or 3 Rf; or, R8 is selected from H, , , , , , , , and. 11. The compound of claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the structural unit is selected from; or, the structural unit is selected from, and; or, the structural unit is selected from and, , , , , and; or, the structural unit is selected from, , , , , and, and. 12. The compound of claim 1, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; or, L3 is selected from -CH2-, and. 13. The compound of any one of claims 1 to 12, its stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from, and. 14. The compound of claim 13, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from, and, wherein T1 and T3 are independently selected from CH and N, respectively; each R1 is independently selected from H, F, OH, and CH3, respectively; R3 is selected from phenyl and 5-6-membered heteroaryl, wherein the phenyl and 5-6-membered heteroaryl are independently optionally substituted by 1, 2, or 3 Rb, respectively; R6 is selected from C3-6-cycloalkyl, wherein the C3-6-cycloalkyl is optionally substituted by 1, 2, or 3 Rd, respectively; R7 is selected from H and C1-3 alkyl, wherein the C1-3 alkyl is optionally substituted by 1, 2, or 3 Re, respectively; each R8 is independently selected from H, C1-3 alkyl, and 5-10-membered heterocyclic alkyl, wherein the C1-3 alkyl and 5-10-membered heterocyclic alkyl are independently optionally substituted by 1, 2, or 3 Rf, respectively; L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Each Rd is independently selected from C1-3 alkyl groups, wherein the C1-3 alkyl groups are optionally substituted by 1, 2 or 3 Rs;Each Rb is independently selected from H, D, F, Cl, OH, and CH3; each Re is independently selected from H, D, F, and Cl; each Rf is independently selected from H, D, F, Cl, CH3, and OCH3, wherein CH3 and OCH3 are independently optionally substituted by 1, 2, or 3 Rs; each R is independently selected from D and F. Claims 4 / 27 pages 5 CN 121270581 A 15. The compound according to claim 14, its stereoisomers, or pharmaceutically acceptable salts thereof, wherein the compound is selected from: 16. The following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof, are: (Claims 5 / 27, page 6, CN 121270581 A; Claims 6 / 27, page 7, CN 121270581 A; Claims 7 / 27, page 8, CN 121270581 A; Claims 8 / 27, page 9, CN 121270581 A; Claims 9 / 27, page 10, CN 121270581 A) 17. The following compounds or pharmaceutically acceptable salts thereof, (Claims 10 / 27, page 11, CN 121270581 A, ..., Claims 11 / 27, page 12, CN 121270581 A, ..., Claims 12 / 27, page 13, CN 121270581 A, ..., Claims 13 / 27, page 14, CN 121270581 A, ..., Claims 14 / 27, page 15, CN 121270581 A, ..., Claims 15 / 27, page 16, CN 121270581 A, ..., Claims 16 / 27, page 17, CN...) 121270581 A, , , , , , , , Claims 17 / 27, page 18 CN 121270581 A, , , , , , , , Claims 18 / 27, page 19 CN 121270581 A, , , , , , , , Claims 19 / 27, page 20 CN 121270581 A, , , , , , , Claims 20 / 27, page 21 CN121270581 A, , , , , , , , Claims 21 / 27, page 22 CN 121270581 A, , , , , Claims 22 / 27, page 23 CN 121270581 A, , , , , , , Claims 23 / 27, page 24 CN 121270581 A, , , , , , , Claims 24 / 27, page 25 CN 121270581 A, , , , , , Claims 25 / 27, page 26 CN 121270581 A, , , , , , , Claims 26 / 27, page 27 CN 121270581 A. Claims 27 / 27, page 28, CN 121270581 A Macrocyclic Derivatives and Their Applications

[0001] This application is a divisional application of 202380053250.9. The original application's filing date was September 28, 2023, application number: 202380053250.9, and the invention title was: Macrocyclic Derivatives and Their Applications.

[0002] The present invention claims the following priority:

[0003] CN202211213222.2, application date: September 29, 2022;

[0004] CN2023101326996, application date: February 17, 2023;

[0005] CN2023103711659, application date: April 7, 2023;

[0006] CN2023106857489, application date: June 9, 2023;

[0007] CN2023109116322, application date: July 24, 2023. Technical Field

[0008] The present invention relates to a class of macrocyclic derivatives and their applications, specifically to compounds of formula (VI), their stereoisomers, and pharmaceutically acceptable salts thereof. Background Art

[0009] RAS (including KRAS, NRAS, and HRAS) are downstream of growth factor receptors such as EGFR. They are small GTPases that act as molecular switches and are key nodes in the RAS-RAF-MEK-ERK signaling pathway and the PI3K-AKT-mTOR signaling pathway, regulating events such as cell proliferation and survival. Mutations in RAS can lead to functional activation of the protein by disrupting the GTP hydrolysis process. Under normal physiological conditions, RAS usually exists in the inactive form of RAS(OFF) that binds GDP; however, in tumor cells with RAS mutations, RAS mainly exists in the activated form of RAS(ON) that binds GTP. RAS-mutant cancer patients account for 30% of all cancer patients.(US data) KRAS, NRAS, and HRAS mutations account for 85%, 11%, and 4% respectively, with each RAS type containing nearly 20 mutations. For example, KRAS exhibits various mutation types such as KRASG12C, KRASG12D, KRASG12V, KRASG12R, and KRASG13C. Since RAS mutations are a crucial factor in cancer development and progression, mutant RAS have become important therapeutic targets. Although covalent inhibitors targeting KRASG12C, such as Sotorasib and Adagrasib, have achieved great success in KRASG12C-mutant non-small cell lung cancer, effective targeted therapies remain lacking for other KRAS mutation types, including KRASG12D, KRASG12V, and KRASG13, as well as other RAS mutation types such as NRAS. Therefore, developing broad-spectrum RAS inhibitors has significant clinical implications.

[0010] Revolution Medicines, Inc. has disclosed a class of macrocyclic compounds (WO2020132597, WO2021091982, WO2021091967, WO2021091956) that can form ternary complexes with the chaperone proteins CypA and RAS(ON) in vivo. The formation of these ternary complexes blocks the binding of RAS downstream RAF, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway and achieving an anti-tumor effect. These RAS inhibitors have good inhibitory effects on various RAS mutations and RAS-dependent tumors. The design and synthesis of broad-spectrum RAS inhibitors with excellent drug-like properties based on this type of macrocyclic compound has significant clinical application value. Summary of the Invention

[0011] The present invention provides compounds of formula (VI), stereoisomers thereof or pharmaceutically acceptable salts thereof, specification 1 / 99 pages 29 CN 121270581 A

[0012] ,

[0013] L is R6 or;

[0014] L1 is selected from -N(R9)C(=O)-;

[0015] L2 is selected from C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted by 1, 2 or 3 Ra;

[0016] L3 is selected from -CH2- and C3-6 cycloalkyl;

[0017] L4 is selected from single bond and -C1-4 alkyl-N(R10)C(=O)-;

[0018] Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexyl, 5,6-diazaspiro[2

[0015] octyl, 3,4-diazabicyclo[4.2.0]octyl and 2,3-diazabicyclo[3.1.1]heptyl;

[0019] ring B is selected from 5-membered heteroaryl and 5-membered heteroaryl, indole and;

[0020] T1, T2, T3, and T2 are each independently selected from CH and N;

[0021] R1 is selected from H, F, Cl, Br, I, OH, C1-4 alkyl, and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are each independently optionally substituted by 1, 2, or 3 Rh;

[0022] R2 is selected from -O- and -NH-;

[0023] R3 is selected from phenyl and 5-6 heteroaryl, wherein the phenyl and 5-6 heteroaryl are each independently optionally substituted by 1, 2, or 3 Rb;

[0024] R4 and R5 are each independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, and 3-6 heterocyclic alkyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, and 3-6 heterocyclic alkyl are each independently optionally substituted by 1, 2, or 3 Rc;

[0025] R6 is selected from C3-6 cycloalkyl and 3-6 heterocyclic alkyl, wherein the C3-6 cycloalkyl and 3-6 heterocyclic alkyl are each optionally substituted by 1, 2 or 3 Rd;

[0026] Each R7 is each independently selected from H, halogen, C1-4 alkyl and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are each optionally substituted by 1, 2 or 3 Re;

[0027] Each R8 is each independently selected from H, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl and 3-10 heterocyclic alkyl, wherein the C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl and 3-10 heterocyclic alkyl are each optionally substituted by 1, 2 or 3 Rf;

[0028] R9 and R10 are selected from H and C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by 1, 2 or 3 Rg;

[0029] Each Ra, each Rb, each Rc, each Re, each Rf, each Rg, and each Rh is independently selected from H, D, F, Cl, Br, I, OH, C1-3 alkyl, and C1-3 alkoxy, wherein the C1-3 alkyl and C1-3 alkoxy are independently optionally substituted with 1, 2, or 3 Rs;

[0030] Each Rd is independently selected from C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl, and -C(=O)-C2-4 alkenyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl, and -C(=O)-C2-4 alkenyl are independently optionally substituted with 1, 2, or 3 Rs;

[0031] Each R is independently selected from D, F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3;

[0032] n, p and q are independently selected from 0, 1, 2 and 3;

[0033] The “3-6-membered heterocyclic alkyl”, “3-10-membered heterocyclic alkyl” and “5-6-membered heteroaryl” each independently contain 1 or 2 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S- and N.

[0034] The present invention also provides compounds of formula (III), their stereoisomers or pharmaceutically acceptable salts thereof,

[0035] ,

[0036] L is R6 or;

[0037] L1 is selected from -N(R9)C(=O)-;

[0038] L2 is selected from C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2 or 3 Ra;

[0039] L3 is selected from -CH2- and C3-6 cycloalkyl;

[0040] L4 is selected from single bond and -C1-4 alkyl-N(R10)C(=O)-;

[0041] Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexyl, 5,6-diazaspiro[2.5]octyl, 3,4-diazabicyclo[4.2]

[0042] Octanyl and 2,3-diazabicyclo[3.1.1]heptyl;

[0043] Ring B is selected from 5-membered heteroaryl and 5-membered heteroaryl, indole and;

[0044] R1 is selected from H, F, Cl, Br, I, OH, C1-4 alkyl and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are each independently optionally substituted by 1, 2 or 3 Rh;

[0045] R2 is selected from -O- and -NH-;

[0046] R3 is selected from phenyl and 5-6-membered heteroaryl, wherein the phenyl and 5-6-membered heteroaryl are each independently optionally substituted by 1, 2 or 3 Rb;

[0047] R4 and R5 are each independently selected from H, C1-4 alkyl, C3-6 cycloalkyl and 3-6-membered heterocycloalkyl, wherein the C1-4 alkyl, C3-6 cycloalkyl and 3-6-membered heterocycloalkyl are each independently substituted by 1, 2 or 3 Rb; The cycloalkyl and 3-6-membered heterocyclic alkyl groups are each independently and optionally substituted with 1, 2, or 3 Rc groups;

[0047] R6 is selected from C3-6 cycloalkyl and 3-6-membered heterocyclic alkyl groups, wherein the C3-6 cycloalkyl and 3-6-membered heterocyclic alkyl groups are each independently and optionally substituted with 1, 2, or 3 Rd groups;

[0048] Each R7 is each independently selected from H, halogen, C1-4 alkyl, and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy groups are each independently and optionally substituted with 1, 2, or 3 Re groups;

[0049] Each R8 is each independently selected from H, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl groups, wherein the C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and 3-7-membered heterocyclic alkyl groups are each independently and optionally substituted with 1, 2, or 3 Rf groups; Specification 3 / 99 pages 31 CN 121270581

[0050] R9 and R10 are selected from H and C1-4 alkyl groups, wherein the C1-4 alkyl group is optionally substituted with 1, 2, or 3 Rg groups;

[0051] Each Ra, each Rb, each Rc, each Re, each Rf, each Rg, and each Rh is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3;

[0052] Each Rd is independently selected from C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl, and -C(=O)-C2-4 alkenyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl, and -C(=O)-C2-4 alkenyl are independently optionally substituted by 1, 2, or 3 Rs;

[0053] Each R is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3;

[0054] n, p, and q are independently selected from 0, 1, 2, and 3;

[0055] The "3-6 heterocyclic alkyl", "3-7 heterocyclic alkyl", and "5-6 heteroaryl" each independently contain 1 or 2 heteroatoms or heterogroups independently selected from -NH-, -O-, -S-, and N.

[0056] The present invention also provides compounds of formula (I), their stereoisomers or pharmaceutically acceptable salts thereof,

[0057] ,

[0058] L1 is selected from -N(R9)C(=O)-;

[0059] L2 is selected from C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with 1, 2 or 3 Ra;

[0060] L3 is selected from -CH2-;

[0061] L4 is selected from single bonds and -C1-4 alkyl-N(R10)C(=O)-;

[0062] Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexane and 5,6-diazaspiro[2.5]octane;

[0063] R1 is selected from H, F, Cl, Br, I, OH, C1-4 alkyl and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are each independently optionally substituted by 1, 2 or 3 Rh;

[0064] R2 is selected from -O- and -NH-;

[0065] R3 is selected from phenyl and 5-6 heteroaryl, wherein the phenyl and 5-6 heteroaryl are each independently optionally substituted by 1, 2 or 3 Rb;

[0066] R4 and R5 are each independently selected from H, C1-4 alkyl, C3-6 cycloalkyl and 3-6 heterocyclic alkyl, wherein the C1-4 alkyl, C3-6 cycloalkyl and 3-6 heterocyclic alkyl are each independently optionally substituted by 1, 2 or 3 Rc;

[0067] R6 is selected from C3-6 cycloalkyl and 3-6 heterocyclic alkyl, wherein the C3-6 cycloalkyl and 3-6 heterocyclic alkyl are each independently optionally substituted by 1, 2 or 3 Rd;

[0068] R7 is selected from H, C1-4 alkyl, and C1-4 alkoxy, wherein the C1-4 alkyl and C1-4 alkoxy are independently optionally substituted by 1, 2, or 3 Re atoms, respectively;

[0069] R8 is selected from H, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, and 3-7 heterocyclic alkyl, wherein the C1-4 alkyl, C1-4 alkyl, and C3-6 cycloalkyl are selected from H, C1-4 alkyl, C1-4 cycloalkyl, and C3-7 heterocyclic alkyl, wherein the C1-4 alkyl, C1-4 cycloalkyl, and C3-6 cycloalkyl are selected from H, C1-4 alkyl, C1-4 cycloalkyl, C3-6 cycloalkyl, and C3-7 heterocyclic alkyl are selected from H, C1-4 alkyl, C1-4 cycloalkyl, C3-6 cycloalkyl,Oxygen, C3-6 cycloalkyl and 3-7 heterocyclic alkyl are each independently and optionally substituted with 1, 2 or 3 Rf;

[0070] R9 and R10 are selected from H and C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted with 1, 2 or 3 Rg; Specification 4 / 99 pages 32 CN 121270581 A

[0071] Each Ra, Rb, Rc, Re, Rf, Rg and Rh are each independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3;

[0072] Each Rd is each independently selected from C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl and -C(=O)-C2-4 alkenyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, 3-6 heterocyclic alkyl, phenyl, 5-6 heteroaryl and -C(=O)- The C2-4 alkenyl groups are each independently and optionally substituted by 1, 2, or 3 Rs;

[0073] Each R is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3;

[0074] n, p, and q are each independently selected from 0, 1, 2, and 3;

[0075] The “3-6-membered heterocyclic alkyl,” “3-7-membered heterocyclic alkyl,” and “5-6-membered heteroaryl” each independently contain 1 or 2 heteroatoms or heterogroups independently selected from -NH-, -O-, -S-, and N.

[0076] In some embodiments of the present invention, each of the above Rs is independently selected from D and F, and other variables are as defined in the present invention.

[0077] In some embodiments of the present invention, each of the above Rs is independently selected from F, and other variables are as defined in the present invention.

[0078] In some embodiments of the present invention, each of the above Ras is independently selected from H, D, F, Cl, and CH3, and other variables are as defined in the present invention.

[0079] In some embodiments of the present invention, each of the above-mentioned Rb is independently selected from H, D, F, Cl, OH and CH3, and other variables are as defined in the present invention.

[0080] In some embodiments of the present invention, each of the above-mentioned Rc is independently selected from H, D, F and Cl, and other variables are as defined in the present invention.

[0081] In some embodiments of the present invention, each of the above-mentioned Rd is independently selected from CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine and, wherein CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxacyclobutyl, aziridine and are independently optionally substituted by 1, 2 or 3 Rs, and other variables are as defined in the present invention.

[0082] In some embodiments of the present invention, each of the above-mentioned Rd is independently selected from CH3, , and, and other variables are as defined in the present invention.

[0083] In some embodiments of the present invention, each of the above-mentioned Rd is independently selected from C1-3 alkyl groups, wherein the C1-3 alkyl groups are optionally substituted with 1, 2, or 3 Rs, and other variables are as defined in the present invention.

[0084] In some embodiments of the present invention, each of the above-mentioned Rd is independently selected from CH3 and CH2CH3, wherein CH3 and CH2CH3 are independently and optionally replaced by 1, 2 or 3 F, and other variables are as defined in the present invention.

[0085] In some embodiments of the present invention, each of the above-mentioned Rd is independently selected from CH3, wherein CH3 is optionally replaced by 1, 2 or 3 F, and other variables are as defined in the present invention.

[0086] In some embodiments of the present invention, each of the above-mentioned Rd is independently selected from CH3, and other variables are as defined in the present invention.

[0087] In some embodiments of the present invention, each of the above-mentioned Rd is independently selected from CH3, and other variables are as defined in the present invention.

[0088] In some embodiments of the present invention, each of the above-mentioned Re is independently selected from H, D, F and Cl, and other variables are as defined in the present invention.

[0089] In some embodiments of the present invention, each of the above-mentioned Re is independently selected from D and F, and other variables are as defined in the present invention.

[0090] In some embodiments of the present invention, each of the above-mentioned Rf is independently selected from H, D, F, Cl, CH3 and OCH3, and CH3 and OCH3 are independently and optionally replaced by 1, 2 or 3 R, and other variables are as defined in the present invention.

[0091] In some embodiments of the present invention, each of the above-mentioned Rf is independently selected from H, D, F, Cl, CH3, CD3, CF3 and OCH3, and other variables are as defined in the present invention.

[0092] In some embodiments of the present invention, each of the above-mentioned Rg is independently selected from H, D, F and Cl, and other variables are as defined in the present invention.

[0093] In some embodiments of the present invention, each of the above-mentioned Rh is independently selected from H, D, F and Cl, and other variables are as defined in the present invention.

[0094] In some embodiments of the present invention, each of the above-mentioned R1 is independently selected from H, F, OH and CH3, and other variables are as defined in the present invention.

[0095] In some embodiments of the present invention, each of the above-mentioned R1s is independently selected from H, F, and CH3, and other variables are as defined in the present invention.

[0096] In some embodiments of the present invention, the above-mentioned structural units are selected from H, F, CH3 ...In some embodiments of the present invention, the ring A is selected from 3,4-diazabicyclo[4.1.0]heptyl and 2,3-diazabicyclo[3.1.1]heptyl, and other variables are as defined in the present invention.

[0101] In some embodiments of the present invention, the ring A is selected from and, and other variables are as defined in the present invention. Specification 6 / 99 Page 34 CN 121270581 A

[0102] In some embodiments of the present invention, the ring A is, and other variables are as defined in the present invention.

[0103] In some embodiments of the present invention, the structural unit is selected from, , , , and, and other variables are as defined in the present invention.

[0104] In some embodiments of the present invention, R2 is selected from -O-, and other variables are as defined in the present invention.

[0105] In some embodiments of the present invention, R3 is selected from 5-6-membered heteroaryl, wherein the 5-6-membered heteroaryl is optionally substituted by 1, 2 or 3 Rb, and other variables are as defined in the present invention.

[0106] In some embodiments of the present invention, R3 is selected from 5-membered heteroaryl groups, wherein the 5-membered heteroaryl group is optionally substituted by 1, 2, or 3 Rb, and other variables are as defined in the present invention.

[0107] In some embodiments of the present invention, R3 is selected from thiazolyl, thiophene, oxazolyl, pyrazolyl, and imidazolyl, wherein the thiazolyl, thiophene, oxazolyl, pyrazolyl, and imidazolyl groups are each independently and optionally substituted by 1, 2, or 3 Rb, and other variables are as defined in the present invention.

[0108] In some embodiments of the present invention, R3 is selected from thiazolyl and thiophene, and other variables are as defined in the present invention.

[0109] In some embodiments of the present invention, R3 is selected from […], […], and […], and other variables are as defined in the present invention.

[0110] In some embodiments of the present invention, R3 is selected from […], and other variables are as defined in the present invention.

[0111] In some embodiments of the present invention, R3 is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, thiopheneyl, oxazolyl, pyrazolyl, and imidazolyl, wherein the phenyl, pyridinyl, pyrimidinyl, thiazolyl, thiopheneyl, oxazolyl, pyrazolyl, and imidazolyl are each independently and optionally substituted by 1, 2, or 3 Rb, and other variables are as defined in the present invention.

[0112] In some embodiments of the present invention, R3 is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, and imidazolyl, wherein the phenyl, pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, and imidazolyl are each independently and optionally substituted by 1, 2, or 3 Rb, and other variables are as defined in the present invention.

[0113] In some embodiments of the present invention, R3 is selected from [missing information], [missing information], and [missing information], and other variables are as defined in the present invention.

[0114] In some embodiments of the present invention, R3 is selected from [missing information], [missing information], and other variables are as defined in the present invention.

[0115] In some embodiments of the present invention, R3 is selected from [variables], and other variables are as defined in the present invention.

[0116] In some embodiments of the present invention, R4 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, and cyclopentyl, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, and cyclopentyl are each independently selected and replaced by 1, 2, or 3 Rc, and other variables are as defined in the present invention.

[0117] In some embodiments of the present invention, R5 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, and cyclopentyl, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, and cyclopentyl are each independently selected and replaced by 1, 2, or 3 Rc, and other variables are as defined in the present invention.

[0118] In some embodiments of the present invention, R4 is selected from H, R5 is selected from H, CH(CH3)2, and other variables are as defined in the present invention.

[0119] In some embodiments of the present invention, R6 is selected from cyclopentyl, aziridinyl, aziridine, pyrrolyl, piperidinyl, piperazine, morpholinyl, oxecyclobutyl, oxecyclopentyl, and oxecyclohexyl, wherein the cyclopentyl, aziridinyl, aziridine, pyrrolyl, piperidinyl, piperazine, morpholinyl, oxecyclobutyl, oxecyclopentyl, and oxecyclohexyl are each independently and optionally substituted by 1, 2, or 3 Rd, and other variables are as defined in the present invention.

[0120] In some embodiments of the present invention, R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, aziridine, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxecyclobutyl, oxecyclopentyl, and oxecyclohexyl, wherein the cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, pyrrolyl, piperidinyl, piperazinyl, morpholinyl, oxecyclobutyl, oxecyclopentyl, and oxecyclohexyl are each independently and optionally substituted by 1, 2, or 3 Rd, and other variables are as defined in the present invention.

[0121] In some embodiments of the present invention, R6 is selected from , , , and , and other variables are as defined in the present invention.

[0122] In some embodiments of the present invention, R6 is selected from , , and , and other variables are as defined in the present invention.

[0123] In some embodiments of the present invention, R6 is selected from C3-6 cycloalkyl groups, wherein the C3-6 cycloalkyl group is optionally substituted by 1, 2, or 3 Rd groups, and other variables are as defined in the present invention.

[0124] In some embodiments of the present invention, R6 is selected from cyclopropyl groups, wherein the cyclopropyl group is optionally substituted by 1, 2, or 3 Rd groups, and other variables are as defined in the present invention.

[0125] In some embodiments of the present invention, R6 is selected from […] and […], and other variables are as defined in the present invention.

[0126] In some embodiments of the present invention, R6 is selected from […] and […].Other variables are as defined in this invention.

[0127] In some embodiments of this invention, each of the above R7s is independently selected from H, F, Cl and C1-3 alkyl groups, wherein the C1-3 alkyl groups are optionally substituted by 1, 2 or 3 Res, and other variables are as defined in this invention.

[0128] In some embodiments of this invention, the above R7s are selected from H, F, Cl, CH3 and CH2CH3, wherein the CH3 and CH2CH3 are independently optionally substituted by 1, 2 or 3 Res, and other variables are as defined in this invention.

[0129] In some embodiments of this invention, the above R7s are selected from H, F, Cl, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3 and CD3, and other variables are as defined in this invention.

[0130] In some embodiments of this invention, the above R7s are selected from H, F, Cl, CH3 and CH2CH3, and other variables are as defined in this invention.

[0131] In some embodiments of the present invention, the R7 is selected from H, CH3, and CH2CH3, and other variables are as defined in the present invention.

[0132] In some embodiments of the present invention, each of the R8 is independently selected from H, C1-3 alkyl, and 3-10 heterocyclic alkyl, wherein the C1-3 alkyl and 3-10 heterocyclic alkyl are independently optionally substituted by 1, 2, or 3 Rf, and other variables are as defined in the present invention.

[0133] In some embodiments of the present invention, each of the R8 is independently selected from H, C1-3 alkyl, and 5-10 heterocyclic alkyl, wherein the C1-3 alkyl and 5-10 heterocyclic alkyl are independently optionally substituted by 1, 2, or 3 Rf, and other variables are as defined in the present invention.

[0134] In some embodiments of the present invention, each of the above-mentioned R8s is independently selected from H, C1-3 alkyl, and 5-6 membered heterocyclic alkyl, wherein the C1-3 alkyl and 5-6 membered heterocyclic alkyl are independently optionally substituted by 1, 2, or 3 Rfs, and other variables are as defined in the present invention.

[0135] In some embodiments of the present invention, the above-mentioned R8s are selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropyridinyl, homopiperidinyl, morpholinyl, and, wherein the CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropyridinyl, homopiperidinyl, morpholinyl, and are independently optionally substituted by 1, 2, or 3 Rfs, and other variables are as defined in the present invention.

[0136] In some embodiments of the present invention, the above-mentioned R8s are selected from H, , , , , , , and, and other variables are as defined in the present invention.

[0137] In some embodiments of the present invention, the R8 is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, morpholinyl, and the CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, morpholinyl, andEach R8 is independently and optionally replaced by 1, 2, or 3 Rf, and other variables are as defined in this invention.

[0138] In some embodiments of this invention, the R8 is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperridinyl, and morpholinyl, wherein each of the CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperridinyl, and morpholinyl is independently and optionally replaced by 1, 2, or 3 Rf, and other variables are as defined in this invention.

[0139] In some embodiments of this invention, the R8 is selected from H, , , , , , and other variables are as defined in this invention.

[0140] In some embodiments of this invention, the R8 is selected from H, and, and other variables are as defined in this invention. Specification 9 / 99 Page 37 CN 121270581 A

[0141] In some embodiments of this invention, the structural unit is selected from, and, and other variables are as defined in this invention.

[0142] In some embodiments of the present invention, the above-mentioned structural units are selected from [specifications], and other variables are as defined in the present invention.

[0143] In some embodiments of the present invention, the above-mentioned structural units are selected from [specifications], [specifications], and [specifications], and other variables are as defined in the present invention.

[0144] In some embodiments of the present invention, the above-mentioned structural units are selected from [specifications], ...

[0149] In some embodiments of the present invention, the above-mentioned structural unit is selected from [ ] and [ ], and other variables are as defined in the present invention.

[0150] In some embodiments of the present invention, the above-mentioned structural unit is selected from [ ] and [ ], and other variables are as defined in the present invention.

[0151] In some embodiments of the present invention, the above-mentioned ring B is selected from [ ], [ ] and [ ], and other variables are as defined in the present invention.

[0152] In some embodiments of the present invention, the above-mentioned ring B is selected from indole, and other variables are as defined in the present invention.

[0153] In some embodiments of the present invention, the above-mentioned ring B is selected from [ ], and other variables are as defined in the present invention.

[0154] In some embodiments of the present invention, the above-mentioned L1 is selected from -N(CH3)C(=O)-, and other variables are as defined in the present invention.

[0155] In some embodiments of the present invention, the above-mentioned L2 is selected from [ ], and other variables are as defined in the present invention.

[0156] In some embodiments of the present invention, L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and other variables are as defined in the present invention.

[0157] In some embodiments of the present invention, L3 is selected from -CH2-, and, and other variables are as defined in the present invention.

[0158] In some embodiments of the present invention, L3 is selected from -CH2-, and other variables are as defined in the present invention. Specification 11 / 99 Page 39 CN 121270581 A

[0159] In some embodiments of the present invention, L3 is selected from and, and other variables are as defined in the present invention. In some embodiments of the present invention, L4 is selected from single bond and -CH2-N(CH3)C(=O)-, and other variables are as defined in the present invention.

[0160] In some embodiments of the present invention, L is selected from,,,, and, and other variables are as defined in the present invention.

[0161] In some embodiments of the present invention, L is selected from,,,,, and, and other variables are as defined in the present invention.

[0162] In some embodiments of the present invention, L is R6, and other variables are as defined in the present invention.

[0163] In some embodiments of the present invention, L is selected from and, and other variables are as defined in the present invention.

[0164] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from,

[0165] and,

[0166] wherein ring A, T1, T3, R1, R3, R6, R7, R8, L3 and n are as defined in the present invention.

[0167] In some embodiments of the present invention, the above-mentioned compound, its stereoisomers or pharmaceutically acceptable salts thereof, are selected from,

[0168] and,

[0169] wherein,

[0170] the structural unit is selected from, , , , , , , , , , , , and;

[0171] the structural unit is selected from, and;

[0172] R6 is selected from C3-6 cycloalkyl, wherein the C3-6 cycloalkyl is optionally substituted by 1, 2 or 3 Rd;

[0173] each Rd is independently selected from C1-4 alkyl, wherein the C1-4 alkyl is optionally substituted by 1, 2 or 3 R;

[0174] L3, R3, R7, each R8 and each R are as defined in the present invention.

[0175] In some embodiments of the present invention, the compounds of formula (VI-1), formula (VI-2), or formula (VI-3), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein the structural units are selected from , , , and , and other variables are as defined in the present invention.

[0176] In some embodiments of the present invention, the compounds of formula (VI-1), their stereoisomers, or pharmaceutically acceptable salts thereof, are selected from , ...

[0177] and,

[0178] wherein,

[0179] T1 and T3 are independently selected from CH and N, respectively;

[0180] each R1 is independently selected from H, F, OH and CH3, respectively;

[0181] R3 is selected from phenyl and 5-6 heteroaryl, wherein the phenyl and 5-6 heteroaryl are independently optionally substituted by 1, 2 or 3 Rb, respectively;

[0182] R6 is selected from C3-6 cycloalkyl, wherein the C3-6 cycloalkyl are optionally substituted by 1, 2 or 3 Rd, respectively;

[0183] R7 is selected from H and C1-3 alkyl, wherein the C1-3 alkyl are optionally substituted by 1, 2 or 3 Re, respectively;

[0184] each R8 is independently selected from H, C1-3 alkyl and 5-10 heterocyclic alkyl, wherein the C1-3 alkyl and 5-10 heterocyclic alkyl are independently optionally substituted by 1, 2 or 3 Rf, respectively;

[0185] L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl;

[0186] Each Rd is independently selected from C1-3 alkyl groups, wherein the C1-3 alkyl groups are optionally substituted by 1, 2, or 3 Rs;

[0187] Each Rb is independently selected from H, D, F, Cl, OH, and CH3;

[0188] Each Re is independently selected from H, D, F, and Cl;

[0189] Each Rf is independently selected from H, D, F, Cl, CH3, and OCH3, wherein the CH3 and OCH3 are optionally substituted by 1, 2, or 3 Rs;

[0190] Each R is independently selected from D and F.

[0191] In some embodiments of the present invention, the compounds of formula (P-1) or (P-2), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein each of R1, R3, R6, R7, each of R8, T1, T3, and L3 is as defined in formula (VI), formula (III), or formula (I) of the present invention.

[0192] In some embodiments of the present invention, the compounds of formula (P-1) or (P-2), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R3 is a 5-6 member heteroaryl group, and other variables are as defined in the present invention.

[0193] In some embodiments of the present invention, the compounds of formula (P-1) or (P-2), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R3 is a thiophene group and a thiazolyl group, and other variables are as defined in the present invention.

[0194] In some embodiments of the present invention, the compounds of formula (P-1) or (P-2), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein each R8 is independently selected from H, C1-3 alkyl, and 5-6-membered heterocyclic alkyl, wherein the C1-3 alkyl and 5-6-membered heterocyclic alkyl are independently optionally substituted by 1, 2, or 3 Rf, and other variables are as defined in the present invention.

[0195] In some embodiments of the present invention, the compounds of formula (P-1) or (P-2), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein T1 is CH, T3 is CH, and other variables are as defined in the present invention.

[0196] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomer or its pharmaceutically acceptable salt, wherein L3 is selected from -CH2-, and, and other variables are as defined in the present invention. Specification 14 / 99 pages 42 CN 121270581 A

[0197] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomer or its pharmaceutically acceptable salt, wherein, is selected from,

[0198]

[0199] ,

[0200] wherein each R1, R3, R6, R7, each R8, T1, T3 and L3 are as defined in formula (P-1) or (P-2) of the present invention.

[0201] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from,

[0202] , and, Specification 15 / 99 pages 43 CN 121270581 A

[0203] wherein R1, R3, R4, R5, R6, R7, R8, L1, L3, L4 and n are as defined in the present invention.

[0204] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof, is selected from,

[0205] ,

[0206] wherein R1, R3, R6, R7 and R8 are as defined in the present invention.

[0207] In some embodiments of the present invention, the above-mentioned compound of formula (IV), its stereoisomer or pharmaceutically acceptable salt thereof, is selected from,

[0208] ,

[0209] wherein R1, R3, R6, R7 and R8 are as defined in the present invention.

[0210] In some embodiments of the present invention, the compounds of formula (IV-1a), formula (IV-1b), their stereoisomers or pharmaceutically acceptable salts thereof are selected from,

[0211]

[0212] , Specification 16 / 99 pages 44 CN 121270581 A

[0213] wherein R1, R3, R6, R7 and R8 are as defined in the present invention.

[0214] In some embodiments of the present invention, the compounds of formulas (IV), (IV-1a), (IV-1b), (IV-1a-1), (IV-1a-2), (IV-1b-1), (IV-1b-2), their stereoisomers, or pharmaceutically acceptable salts thereof, wherein R1 is selected from H, F, OH, and CH3; R3 is selected from phenyl and thiazolyl, wherein the phenyl and thiazolyl groups are each independently and optionally substituted by 1, 2, or 3 Rb groups; R6 is selected from cyclopropyl, wherein the cyclopropyl group is optionally substituted by 1, 2, or 3 Rd groups; R7 is selected from H, F, Cl, CH3, and CH2CH3; R8 is selected from H, and; each Rb is each independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; each Rd is each independently selected from CH3, , and.

[0215] The present invention also includes some solutions derived from arbitrary combinations of the above variables.

[0216] The present invention also provides the following compounds, their stereoisomers or pharmaceutically acceptable salts thereof,

[0217]

[0218]

[0219]

[0220] Specification 17 / 99 pages 45 CN 121270581 A

[0221]

[0222]

[0223]

[0224]

[0225]

[0226] Specification 18 / 99 pages 46 CN 121270581 A

[0227]

[0228]

[0229]

[0230]

[0231]

[0232] Specification 19 / 99 pages 47 CN 121270581 A

[0233]

[0234]

[0235]

[0236]

[0237] Specification 20 / 99 pages 48 CN 121270581 A

[0238]

[0239]

[0240]

[0241]

[0242] Specification 21 / 99 pages 49 CN 121270581 A

[0243]

[0244]

[0245]

[0246]

[0247] .

[0248] In some embodiments of the present invention, the above-mentioned compounds, their stereoisomers, or pharmaceutically acceptable salts thereof are selected from, Specification 22 / 99 pages 50 CN 121270581 A

[0249]

[0250]

[0251]

[0252]

[0253]

[0254] Specification 23 / 99 pages 51 CN 121270581 A

[0255]

[0256]

[0257]

[0258]

[0259]

[0260] Specification 24 / 99 pages 52 CN 121270581 A

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267] Specification 25 / 99 pages 53 CN 121270581 A

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274] Specification 26 / 99 pages 54 CN 121270581 A

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281] Specification 27 / 99 pages 55 CN 121270581 A

[0282]

[0283]

[0284]

[0285]

[0286]

[0287] Specification 28 / 99 pages 56 CN 121270581 A

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294] Specification 29 / 99 pages 57 CN 121270581 A

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301] Specification 30 / 99 pages 58 CN 121270581 A

[0302]

[0303]

[0304]

[0305]

[0306]

[0307] Specification 31 / 99 pages 59 CN 121270581 A

[0308]

[0309]

[0310]

[0311]

[0312] Specification 32 / 99 pages 60 CN 121270581 A

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319] Specification 33 / 99 pages 61 CN 121270581 A

[0320]

[0321]

[0322]

[0323]

[0324]

[0325] Specification 34 / 99 pages 62 CN 121270581 A

[0326]

[0327]

[0328]

[0329]

[0330] Specification 35 / 99 pages 63 CN 121270581 A

[0331]

[0332]

[0333] Specification 36 / 99 pages 64 CN 121270581 A

[0334]

[0335]

[0336]

[0337]

[0338]

[0339] Specification 37 / 99 pages 65 CN 121270581 A

[0340]

[0341]

[0342]

[0343] Specification 38 / 99 pages 66 CN 121270581 A

[0344] 。

[0345] The present invention also provides the use of the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof in the preparation of RAS inhibitor drugs.

[0346] The RAS inhibitor drugs of the present invention are used to treat RAS-mutant and RAS-dependent tumors, such as solid tumors; further, the solid tumors are pancreatic cancer, lung cancer or colorectal cancer.

[0347] The present invention also provides the following synthetic methods:

[0348] Method 1 - Intermediate:

[0349] 。

[0350] Method 2 - Intermediate:

[0351] 。

[0352] Method 3 - Intermediate:

[0353] 。

[0354] Method 4 - Intermediate:

[0355]

[0356] Method 5 - Intermediate:

[0357] Specification 39 / 99 pages 67 CN121270581 A

[0358]

[0359] 。

[0360] Method 6 - Intermediate:

[0361] 。

[0362] Method 7 - Intermediate

[0363] 。

[0364] Method 8 - Intermediate

[0365] 。

[0366] Method 9 - Intermediate

[0367] 。

[0368] Method 10 - Intermediate

[0369] 。

[0370] Method 11: Specification 40 / 99 pages 68 CN 121270581 A

[0371]

[0372]

[0373]

[0374]

[0375] 。

[0376] Method 12:

[0377] Specification 41 / 99 pages 69 CN 121270581 A

[0378]

[0379]

[0380] 。

[0381] Method 13:

[0382]

[0383]

[0384] Specification 42 / 99 pages 70 CN 121270581 A

[0385] 。

[0386] Method 14:

[0387]

[0388] 。

[0389] Method 15:

[0390]

[0391]

[0392] 。

[0393] Method 16: Specification 43 / 99 pages 71 CN 121270581 A

[0394]

[0395]

[0396]

[0397]

[0398] 。

[0399] Method 17:

[0400]

[0401] Specification 44 / 99 pages 72 CN 121270581 A

[0402]

[0403]

[0404] .

[0405] Method 18:

[0406]

[0407]

[0408]

[0409] Specification 45 / 99 pages 73 CN 121270581 A

[0410] .

[0411] Technical Effects

[0412] The compounds of the present invention have a good binding effect with the chaperone protein CypA. The binding with CypA will block the binding of RAS downstream RAF to RAS, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway to achieve an anti-tumor effect. The compounds of the present invention have significant inhibitory activity on the cell proliferation of RAS mutant cell lines (such as GP2D, PK-59, AsPC-1, PSN-1, RKN, Capan-1, SW620, HCT116, LOVO, A549, H441, H727, LU99 and A427), but do not show obvious inhibitory effect in wild-type independent cell lines (such as A375), showing good selectivity. They also have a good effect on the pERK level of AsPC-1 and GP2D cells.Significant inhibitory activity; in various pharmacokinetic experiments, the compounds of the present invention all exhibited good pharmacokinetic properties (such as high exposure and long half-life), and compared with human and mouse plasma, the compounds of the present invention had a higher distribution in whole blood and erythrocytes; in in vivo pharmacodynamic experiments, the compounds of the present invention exhibited excellent antitumor effects, and the dosage was small and the safety was high, with broad application prospects.

[0413] Definitions and Explanations

[0414] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to the corresponding trade product or its active ingredient.

[0415] The term "pharmaceuticalally acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that, within the scope of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0416] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a relatively non-toxic acid or base. When the compounds of the present invention contain relatively acidic functional groups, a base addition salt can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, an acid addition salt can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0417] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of both.

[0418] The compounds of the present invention can exist in specific geometric or stereoisomer forms. This invention envisions all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0419] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.Configuration. Specification 46 / 99 pages 74 CN 121270581 A

[0420] Unless otherwise stated, the terms "cis-trans isomer" or "geometric isomer" are due to the fact that the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0421] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror image relationship.

[0422] Unless otherwise stated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0423] Unless otherwise stated, the absolute configuration of a stereocenter is represented by wedge-shaped solid bonds ( ) and wedge-shaped dashed bonds ( ), the relative configuration of a stereocenter is represented by straight solid bonds ( ) and straight dashed bonds ( ), and wedge-shaped solid bonds ( ) and / or wedge-shaped dashed bonds ( ) are represented by wavy lines ( ), or straight solid bonds ( ) and / or straight dashed bonds ( ).

[0424] Some compounds of the present invention may exist as transisomers, which are conformational isomers that occur when rotation around a single bond in the molecule is prevented or greatly slowed due to spatial interactions with other parts of the molecule. The compounds disclosed in this invention include all transisomers, which may be pure single transisomers, or rich in one of the transisomers, or nonspecific mixtures of each. Separation of isomers may be allowed if the rotational potential around the single bond is high enough and the interconversion between conformations is slow enough.

[0425] Unless otherwise stated, the terms “rich in one isomer,” “isomer enrichment,” “rich in one enantiomer,” or “enantiomer enrichment” mean that the content of one isomer or enantiomer is less than 100%, and that the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0426] Unless otherwise stated, the terms “isomer excess” or “enantiomer excess” mean the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the excess of the isomer or enantiomer (ee value) is 80%.

[0427] Optically active (R)- and (S)- isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the present invention is desired, it can be obtained by asymmetric synthesis.Alternatively, it can be prepared by derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide a pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric is formed with a suitable optically active acid or base, followed by diastereomeric resolution by conventional methods known in the art, and then recovery of the pure enantiomer. Furthermore, the separation of enantiomers and diastereomeric is generally accomplished by using chromatography with a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates). The compounds of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compound may be labeled with radioactive isotopes such as tritium (3H), iodine-125 (125I), or C-14 (14C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic transformations of the compounds of the present invention, regardless of radioactivity, are included within the scope of the present invention.

[0428] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent. The substituent may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it can be substituted, or it may not be substituted, unless otherwise specified. The type and number of substituents can be arbitrary on the basis of chemical feasibility.

[0429] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and each case of R has independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0430] When the number of a linking group is 0, such as -(CRR)O-, it indicates that the linking group is a single bond.

[0431] When the number of a substituent is 0, it indicates that the substituent is not present; for example, -A-(R)O indicates that the structure is actually -A.

[0432] When a substituent is vacant, it indicates that the substituent is not present; for example, when X is vacant in A-X, it indicates that the structure is actually A.

[0433] When one of the variables is selected as a single bond, it means that the two groups it connects are directly connected. For example, in A-L-Z, when L represents a single bond, it means that the structure is actually A-Z.

[0434] When the connecting group listed does not specify its connection direction, its connection direction is arbitrary. For example, in , the connecting group L is -M-W-. In this case, -M-W- can be connected to ring A and ring B in the same direction as the reading order from left to right, or in the opposite direction to the reading order from left to right. The combination of the connecting group, substituent and / or its variants is only permitted if such a combination produces a stable compound.

[0435] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and there is an H atom at the connectable site, the number of H atoms at the site will decrease accordingly with the number of chemical bonds connected, becoming a group with the corresponding valence. The chemical bonds connecting the site to other groups can be represented by straight solid line bonds ( ), straight dashed line bonds ( ), or wavy lines ( ). For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in the group is connected to other groups; a straight dashed line bond in indicates that the nitrogen atom in the group is connected to other groups through both ends; a wavy line in indicates that the carbon atoms at positions 1 and 2 in the phenyl group are connected to other groups through ; indicates that any connectable site on the piperidinyl group can be connected to other groups through one chemical bond, including at least the four connection methods of , , , , . Even if H atoms are drawn on -N-, groups with this connection method are still included. However, when connecting one chemical bond, the H at the site will be reduced by one to become the corresponding monovalent piperidinyl group.

[0436] Unless otherwise specified, the number of atoms on the ring is usually defined as the element number of the ring. For example, "5-7 membered ring" refers to a "ring" with 5-7 atoms arranged around it.

[0437] Unless otherwise specified, the term "C1-6 alkyl" on its own or in combination with other terms is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms. The C1-6 alkyl includes C1-5, C1-4, C1-3, C1-2, C2-6, C2-4, C6, and C5 alkyl groups, etc.; it can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of C1-6 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), pentyl (including n-pentyl, isopentyl, and neopentyl), hexyl, etc. Unless otherwise specified, the term "C1-4 alkyl"The term "C1-4 alkyl" is used, either alone or in combination with other terms, to refer to a straight-chain or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C1-4 alkyl group includes C1-2, C1-3, and C2-3 alkyl groups, etc.; it can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). Examples of C1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl), etc.

[0438] Unless otherwise specified, the term "C1-4 alkoxy" is used, either alone or in combination with other terms, to refer to those alkyl groups comprising 1 to 4 carbon atoms that are attached to the remainder of the molecule by an oxygen atom. The C1-4 alkoxy group includes C1-3, C1-2, C2-4, C4, and C3 alkoxy groups, etc. It can be monovalent, divalent, or polyvalent. Examples of C1-4 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), etc.

[0439] Unless otherwise specified, "C3-6 cycloalkyl" on its own or in combination with other terms respectively refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms. The C3-6 cycloalkyl group includes monocyclic and polycyclic groups, wherein the polycyclic group includes spirocyclic, fused, and bridged rings. The C3-6 cycloalkyl group includes C3-5, C4-5, and C5-6 cycloalkyl groups, etc.; it may be monovalent, divalent, or polyvalent. Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, etc.

[0440] Unless otherwise specified, the term "3-10 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated or partially unsaturated cyclic group consisting of 3 to 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 3-10 membered heterocyclic alkyl includes monocyclic and polycyclic compounds, wherein the polycyclic compounds include spirocyclic, fused, and bridged rings. Furthermore, with respect to the "3-10 membered heterocyclic alkyl", heteroatoms may occupy the connection positions between the heterocyclic alkyl and the rest of the molecule. The 3-10 membered heterocyclic alkyl groups include 3-6, 4-6, 5-6, 4-7, 5-7, 5-8, 6-8, 6-9, 6-10, 4, 5, 6, 7, 8, 9, and 10 membered heterocyclic alkyl groups. They can be monovalent, divalent, or polyvalent. Examples of 3-10 membered heterocyclic alkyl groups include, but are not limited to, nitrogen-containing heterocyclic butyl, oxocyclic butyl, thiocyclic butyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, and tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-2-yl).3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazine (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl or hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, tetrahydropyridinyl, etc.

[0441] Unless otherwise specified, the term "3-7 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated or partially unsaturated cyclic group consisting of 3 to 7 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, p is 1 or 2). The 3-7 membered heterocyclic alkyl includes monocyclic and polycyclic compounds, wherein the polycyclic compounds include spirocyclic, fused, and bridged rings. Furthermore, with respect to the "3-7 membered heterocyclic alkyl", heteroatoms may occupy the connection position between the heterocyclic alkyl specification page 49 / 99 77 CN 121270581 A and the rest of the molecule. The 3-7 membered heterocyclic alkyl groups include 3-6, 4-6, 5-6, 4-7, 5-7, 4, 5, 6, and 7-membered heterocyclic alkyl groups. They can be monovalent, divalent, or polyvalent. Examples of 3-7 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl or hexahydropyridazinyl, homopiperidinyl, homopiperidinyl, tetrahydropyridinyl, etc.

[0442] Unless otherwise specified, the term "3-6 membered heterocyclic alkyl" on its own or in combination with other terms respectively refers to a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)p, p is 1 or 2). The 3-6 membered heterocyclic alkyl includes monocyclic and polycyclic compounds, wherein the polycyclic compounds include spirocyclic, fused, and bridged rings. Furthermore, with respect to the "3-6 membered heterocyclic alkyl", heteroatoms may occupy the heterocyclic alkyl group.The connection position with the rest of the molecule. The 3-6 membered heterocyclic alkyl group includes 4-6, 5-6, 4, 5, and 6 membered heterocyclic alkyl groups, etc. It can be monovalent, divalent, or polyvalent. Examples of 3-6 membered heterocyclic alkyl groups include, but are not limited to, azirrobutyl, oxacyclobutyl, thiocyclobutyl, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl or piperidinylene, etc.

[0443] Unless otherwise specified, the terms "5-6-membered heteroaryl" and "5-6-membered heteroaryl" are used interchangeably in this invention. The term "5-6-membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The carbon atoms are optionally oxidized (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)p, where p is 1 or 2). The 5-6-membered heteroaryl can be attached to the rest of the molecule via heteroatoms or carbon atoms. The 5-6-membered heteroaryl includes 5-membered and 6-membered heteroaryl groups. It can be monovalent, divalent, or polyvalent. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), and imidazole (including N-pyrrole). Imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridinyl (including 2-pyridinyl, 3-pyridinyl and 4-pyridinyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0444] Unless otherwise specified, the term "5-membered heteroaryl-5-membered heteroaryl" in this invention means that one 5-membered heteroaryl group is fused to another 5-membered heteroaryl group by two adjacent atoms. Examples of "5-membered heteroaryl-5-membered heteroaryl" include, but are not limited to, and

[0445] Unless otherwise specified, Cn-n+m or Cn-Cn+m includes any specific case of n to n+m carbon atoms. For example, C1-12 includes C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, and C12, and also includes any range from n to n+m. For example, C1-12 includes C1-3, C1-6, C1-9, C3-6, C3-9, C3-12, C6-9, C6-12, and C9-12, etc. Similarly, n-element to n+m-element indicates that the number of atoms on the ring is n. The range of n to n+m members, for example, 3-12 membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, and 12-membered rings, and also includes any range from n to n+m, for example, 3-12 membered rings include 3-6 membered rings, 3-9 membered rings, 5-6 membered rings, 5-7 membered rings, 6-7 membered rings, 6-8 membered rings, and 6-10 membered rings, etc.

[0446] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.

[0447] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0448] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and those in the art.Equivalent substitutions known to those skilled in the art, preferred embodiments include but are not limited to the embodiments of the present invention.

[0449] The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD), the cultured single crystal is collected using a Bruker D8 venture diffractometer, the light source is CuKα radiation, the scanning mode is φ / ω scan, after collecting relevant data, the crystal structure is further analyzed by the direct method (Shelxs97), and the absolute configuration can be confirmed.

[0450] The solvent used in the present invention can be obtained commercially. The compounds are named according to the conventional naming principles in the art or using ChemDraw® software, and commercially available compounds are named according to the supplier catalog name. Brief Description of the Drawings

[0451] Figure 1 is a diagram of the binding mode of compound A with CypA protein.

[0452] Figure 2 is a diagram of the binding mode of compound B with CypA protein.

[0453] Figure 3 is a diagram showing the binding pattern of compound C with CypA protein.

[0454] Figure 4 is a diagram showing the binding pattern of compound D with CypA protein.

[0455] Figure 5 is a diagram showing the binding pattern of compound E with CypA protein.

[0456] Figure 6 is a diagram showing the binding pattern of compound F with CypA protein.

[0457] Figure 7 is a diagram showing the binding pattern of compound G with CypA protein.

[0458] Figure 8 is a diagram showing the binding pattern of compound H with CypA protein.

[0459] Figure 9 is a diagram showing the binding pattern of compound I with CypA protein. Specification 51 / 99 pages 79 CN 121270581 A

[0460] Figure 10 is a diagram showing the binding pattern of compound J with CypA protein. Detailed Description

[0461] The present invention will be described in detail below by way of examples, but this does not imply any adverse limitation on the present invention. This invention has been described in detail, and its specific embodiments have also been disclosed. It will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of this invention without departing from the spirit and scope of this invention.

[0462] Calculation Example 1

[0463]

[0464] Specification 52 / 99 pages 80 CN 121270581 A

[0465]

[0466] The cocrystal complex of human CypA protein and natural product Sanglifehrin A (PDB ID code: 1YND) was used as the docking template for the binding pattern prediction. In order to prepare the protein, hydrogen atoms were added using the protein preparation wizard module of Maestro[1] and the cocrystal structure was optimized for hydrogen bonding using the OPLS 4 force field to remove ligands in the cocrystal complex.Water molecules beyond 3 Å of Sanglifehrin A, and energy optimization for the whole. For ligand preparation: 3D structures of the molecules to be docked were generated and energy was minimized using LigPrep [2]. Using the Induced Fit Docking [3] and Protocol: Extended Sampling options in Maestro (Schrödinger version 2021-2), compound A was docked into the prepared 1YND protein structure. The best binding model was selected, as shown in Figure 1. The selected model maintained the main hydrogen bonding between ligand Sanglifehrin A and the protein in the original cocrystal complex. A 30 Å docking grid was generated with the centroid of compound A in this binding model, and the docking model was generated using the Glide [4] Receptor Grid Generation module. Based on this docking model, compounds B~J were docked using the SP docking mode in Glide [3]. The binding modes of compounds B~J are shown in Figures 2~10.

[0467] [1] Maestro, Schrödinger, LLC, New York, NY, 2021.

[0468] [2] LigPrep, Schrödinger, LLC, New York, NY, 2021.

[0469] [3] Induced Fit Docking protocol; Glide, Schrödinger, LLC, New York, NY, 2021; Prime, Schrödinger, LLC, New York, NY, 2021.

[0470] [4] Glide, Schrödinger, LLC, New York, NY, 2021.

[0471] Conclusion: The compounds of the present invention bind well to human Cyp A protein. The compounds of the present invention form hydrogen bonds with Arg55, Gln63, Asn102 and His126. In addition, Arg55 forms a cationic π bond with the indole ring. Since the compounds of the present invention act on the protein surface, the listed hydrogen bonds, as anchor points, not only reproduce the binding mode of the natural product Sanglifehrin A in the cocrystal complex, but also tightly fix the compounds of the present invention to the protein surface. The binding of the compounds of the present invention to CypA will block the binding of RAF downstream of RAS to RAS, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway to achieve an anti-tumor effect.

[0472] Reference Example 1: Compound M1

[0473]

[0474] Compound M1-1 (39 g, 106.78 g) was used to treat the protein surface.13.44 g (320.33 mmol) of lithium hydroxide monohydrate was dissolved in water (100 mL) and tetrahydrofuran (200 mL). The reaction mixture was stirred at 25 °C for 1.5 hours. After the reaction was completed, the pH of the reaction mixture was adjusted to 5-6 with 2M dilute hydrochloric acid. The reaction mixture was then extracted with ethyl acetate (200 mL * 3). The phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed by vacuum distillation to obtain compound M1. LCMS: m / z = 372.8, 374.8 [M+23]+.

[0475] Reference Example 2: Compound M2

[0476]

[0477]

[0478] Step 1

[0479] Compound M2-1 (150 g, 1.14 mol) was dissolved in pyridine (200 mL), and then 4-dimethylaminopyridine (7.4 g, 60.57 mmol) and acrolein (38.58 g, 688.11 mmol) were added. The reaction solution was stirred at 50 °C for 48 hours. The reaction solution was cooled to room temperature and then poured into 2000 mL of water. It was extracted with ethyl acetate (300 mL*3), the combined organic phases were washed with dilute hydrochloric acid (2 M, 300 mL*3), then washed once with water (500 mL), and then washed once with saturated brine (200 mL). The solution was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then distilled under reduced pressure at approximately -0.1 MPa and 90-95 °C to obtain compound M2-2.

[0480] Step 2

[0481] Compound M2-2 (17 g, 134.76 mmol) and di-tert-butyl azodicarbonate (31.03 g, 134.76 mmol) were dissolved in toluene (170 mL), and the reaction solution was stirred at 80 °C for 16 hours. The reaction solution was concentrated, and the crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~15%) to obtain compound M2-3. ¹H NMR (400 MHz, CDCl₃) δ ppm 5.93 (s, 2 H), 5.06–5.37 (m, 1 H), 4.13–4.24 (m, 3 H), 3.57–3.79 (m, 1 H), 1.48 (s, 18 H), 1.27–1.30 (m, 3 H).

[0482] Step 3

[0483] Compound M2-3 was chirally separated by SFC (column: DAICEL CHIRALPAK IC (250 mm * 50 mm, 10 μm);Mobile phase: A phase supercritical carbon dioxide, B phase [0.1% ammonia in isopropanol]; B%: 20%-20%) to obtain compound M2-3A. SFC analysis method (column: Cellulose 2 (150mm*4.6mm, ID, 5um; mobile phase: phase A supercritical carbon dioxide, phase B [0.05% diethylamine in isopropanol]; isogradient elution B%: 5%-5%, column temperature: 35℃, column pressure: 1500 psi), ee=100%, the peak time of compound M2-3A was 2.798 min, and the peak time of its enantiomer was 2.133 min. LCMS: m / z = 379.0 [M+23]+.

[0484] Step 4

[0485] Under nitrogen protection, trimethyl sulfoxide (3.09 g, 14.03 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then potassium tert-butoxide (1.26 g, 11.22 mmol) was added. The mixture was heated at 50℃. Stir for 2 hours. Then add compound M2-3A (1 g, 2.81 mmol), and stir the reaction solution at 70°C for 12 hours. Dilute the reaction solution with water (100 mL), and extract the solution with ethyl acetate (50 mL * 3). Combine the organic phases, wash once with saturated brine (50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, instruction manual page 54 / 99, 82 CN 121270581 A, ethyl acetate ratio: 0~15%) to give compound M2-5. LCMS: m / z = 371.2 [M+1]+; 1H NMR (400 MHz, CDCl3) δ ppm 4.22–4.33 (m, 1 H), 4.07–4.20 (m, 2 H), 2.56–2.73 (m, 1 H), 2.11–2.24 (m, 1 H), 1.84–1.95 (m, 2 H), 1.71–1.82 (m, 1 H), 1.45–1.53 (m, 18 H), 1.23–1.31 (m, 3 H), 0.97–1.07 (m, 1 H).

[0486] Step 5

[0487] Compound M2-5 (630.00 mg, 1.70 mmol) was dissolved in dichloromethane (2 mL), and then trifluoroacetic acid (3.07 g, 26.93 mmol, 2 mL) was added. The reaction solution was stirred at 20 °C for 2 hours. The reaction solution was concentrated to obtainThe crude trifluoroacetate of M2-6 was used directly in the next step.

[0488] Step 6

[0489] The crude trifluoroacetate of compound M2-6 obtained in step 5 was dissolved in dichloromethane (10 mL), and then N-methylmorpholine (959.97 mg, 9.49 mmol), compound M1 (0.4 g, 1.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (364 mg, 1.90 mmol), and 1-hydroxybenzotriazole (39 mg, 284.8 μmol) were added. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was diluted with water (50 mL), and the solution was extracted with dichloromethane (50 mL*3). The combined organic phases were washed once with saturated brine (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~60%) to give compound M2. LCMS: m / z = 503.1, 505.1 [M+1]+.

[0490] Reference Example 3: Compound M3

[0491]

[0492] Step 1

[0493] Tetrabutylammonium bromide (116.14 mg, 360.26 μmol) and difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) were added to a toluene (24 mL) solution of compound M2-3A (4.28 g, 12.01 mmol). The mixture was stirred at 110 °C for 4 hours. Difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added, and the mixture was stirred at 110 °C for 16 hours. Difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added, and the mixture was stirred at 110 °C for 4 hours. Difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added again, and the mixture was stirred at 110 °C for 16 hours. The mixture was concentrated under reduced pressure to remove toluene. The residue was added to 20 mL of water and extracted with ethyl acetate (20 mL * 3). The organic phases were combined, washed with saturated brine (10 mL * 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel column chromatography (0–10% ethyl acetate / petroleum ether) to give compound M3-1. LCMS: m / z = 206 .9 [M‑2Boc+1]+; 1H NMR (400 MHz, CDCl3) δ 4.96‑5.25 (m, 1H) , 4.17‑4.51 (m, 3H) , 3.19 (br s, 1H) , 2.18 (br d, J=10.54 Hz, 1H) , 2.00‑2.11 (m, 1H), 1.40-1.55 (m, 18H), 1.30-1.38 (m, 3H).

[0494] Step 2

[0495] Compound M3-1 (1 g, 2.46 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (7.68 g, 67.31 mmol, 5 mL) was added. The reaction solution was stirred at 25 °C for 3 hours. After the reaction was completed, the organic solvent was removed by vacuum distillation to obtain crude trifluoroacetate of compound M3-2, which was used for the next step. LCMS: m / z = 206.8 [M+1]+. Instructions for Use, Pages 55 / 99, 83, CN 121270581 A

[0496] Step 3

[0497] At 0°C, compound M1 (1.04 g, 2.95 mmol) and compound M3-2 (507 mg, crude trifluoroacetate) were dissolved in dichloromethane (10 mL), and N-methylmorpholine (2.49 g, 24.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.41 g, 7.38 mmol), and 1-hydroxybenzotriazole (66.45 mg, 491.78 μmol) were added sequentially. The reaction solution was stirred at 25°C for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (20-60% ethyl acetate / petroleum ether) to obtain compound M3. LCMS: m / z = 539.1, 541.1 [M+1]+.

[0498] Reference Example 4: Compound M4

[0499]

[0500] Step 1

[0501] At 0°C, under nitrogen protection, a tetrahydrofuran solution of compound M4-1 (25 g, 136.61 mmol) was added to a methyl magnesium bromide tetrahydrofuran solution (3 M, 91.07 mL), and the mixture was stirred at 0°C for two hours. The reaction solution was slowly poured into ice water, and concentrated hydrochloric acid was added to adjust the pH to 6-7. Ethyl acetate was added for extraction (500 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to rapid silica gel column chromatography (ethyl acetate / petroleum ether 0-30%) to give M4-2. LCMS: m / z = 200.0, 202.0 [M+1]+; 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=3.2 Hz, 1H), 8.00 (d, J=8.4 Hz, 1H), 7.29 (dd, J=8.4, 4.8 Hz, 1H), 2.69 (s, 3H).

[0502] Step 2

[0503] Under nitrogen protection at 0 °C, compound (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (700.83 mg, 1.10 mmol) was added to a mixed solvent of formic acid (12.68 g, 263.96 mmol) and triethylamine (133.55 g, 1.32 mol, 183.70 mL). The mixture was then stirred at 40 °C for 15 minutes, cooled to 25 °C, and M4-2 (22 g, 109.98 mmol) was added. The mixture was then stirred at 40 °C for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was diluted with 100 mL, extracted with ethyl acetate (50 mL * 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to rapid silica gel column chromatography (ethyl acetate / petroleum ether 0-40%) to give compound M4-3. LCMS: m / z = 202.0, 204.0 [M+1]+; 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J=4.8 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.13 (dd, J=8.0, 4.8 Hz, 1H), 5.11 (br s, 1H), 4.44 (br s, 1H) 1.44 (d, J=4.8 Hz, 3H).

[0504] Step 3

[0505] Under nitrogen protection at 0°C, sodium hydroxide (5.23 g, 130.66 mmol, 60% purity) was added in portions to a tetrahydrofuran (200 mL) solution of compound M4-3 (22 g, 108.88 mmol). The mixture was stirred at 0°C for 1 hour, and iodomethane (217.77 mmol, 13.56 mL) was added. After the addition was complete, the mixture was slowly heated from 0°C to 25°C and stirred at this temperature for 2 hours. The mixture was quenched at 0°C by adding a saturated ammonium chloride aqueous solution (100 mL), followed by the addition of water (200 mL), and then extracted with ethyl acetate (100 mL * 2). The combined organic phases were collected, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate: petroleum ether 0-20%) to obtain compound M4-4. LCMS: m / z = 216.0, 218.0[M+1]+; 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J=3.2 Hz, 1H), 7.82 (dd, J=8.4, 3.2 Hz, 1H), 7.08 (dd, J=8.0, 4.4 Hz, 1H) , 4.91(dd,J=13.2, 6.4 Hz, 1H), 3.29 (s, 3H), Specification 56 / 99 pages 84 CN 121270581 A 1.44 (d, J=4.8 Hz, 3H).

[0506] Step 4

[0507] To a toluene (50 mL) solution of compound M4-4 (5 g, 23.14 mmol), add bis-pinacol boronic acid ester (7.05 g, 27.77 mmol), Pd(dppf)Cl2 (1.69 g, 2.31 mmol) and potassium acetate (4.54 g, 46.28 mmol). After the addition, purge with nitrogen three times. Stir at 100°C for 3 hours. Cool to room temperature, add water (100 mL), then extract with ethyl acetate (50 mL * 2), collect and combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the crude product by silica gel column chromatography (ethyl acetate: petroleum ether 0-25%) to obtain compound M4. LCMS: m / z = 182.0 [boric acid M+ 1]+; 1H NMR (400 MHz, CDCl3) δ 8.59 (dd, J=4.8, 1.6 Hz, 1H), 7.90 (dd, J=7.6, 2.0 Hz, 1H), 7.16 (dd, J=8.4, 4.8 Hz, 1H), 4.77(dd, J=13.2, 6.4 Hz, 1H), 3.61 (s, 3H), 3.26(s, 3H) 1.37 (s, 12H).

[0508] Reference Example 5: Compound M5

[0509]

[0510] Step 1

[0511] Compound M5-1 (18.3 g, 138.47 mmol), tert-butyldiphenylchlorosilane (40 g, 145.53 mmol) and imidazole (12.3 g, 180.68 mmol) were dissolved in 300 mL of anhydrous water, and the mixture was stirred at 15°C for 20 hours. The crude product was concentrated, diluted with 200 mL of water, extracted with ethyl acetate (3 x 200 mL), dried over anhydrous sodium sulfate on the organic phase, filtered, concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-10%) to give compound M5-2. ¹H NMR (400 MHz, CDCl₃) δ = 7.67 (dd, J = 1.6, 8.0 Hz, 4H), 7.49–7.36 (m, 6H), 3.70 (s, 3H), 3.66 (s, 2H), 1.22 (s, 6H), 1.05 (s, 9H).

[0512] Step 2

[0513] Dissolve compound M5-2 (51 g, 137.63 mmol) and potassium hydroxide (16.51 g, 294.35 mmol) in 200 mL of water and 200 mL of ethanol, and stir the mixture at 90 °C for 3 hours. The reaction solution was concentrated to approximately 250 mL, diluted with 500 mL of ethyl acetate, and the pH was adjusted to 3-4 with concentrated hydrochloric acid. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (2 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound M5-3. ¹H NMR (400 MHz, CDCl₃) δ = 7.58 (dd, J = 1.6, 8.0 Hz, 4H), 7.39–7.27 (m, 6H), 3.58 (s, 2H), 1.15 (s, 6H), 0.97 (s, 9H).

[0514] Step 3

[0515] At 0°C, oxalyl chloride (233.64 mmol, 20.45 mL) was slowly added dropwise to 500 mL of anhydrous dichloromethane containing compound M5-3 (49 g, 137.44 mmol) and DMF (13.74 mmol, 1.06 mL), and the mixture was stirred at 20°C for 15 hours. The reaction solution was concentrated, and 300 mL of anhydrous toluene was added, followed by concentration under reduced pressure to obtain compound M5-4.

[0516] Step 4

[0517] At 0°C, tin tetrachloride (136.00 mmol, 15.92 mL) was slowly added to 200 mL of anhydrous dichloromethane solution of compound M5-4 (51.00 g, 136.00 mmol). The mixture was stirred under a nitrogen atmosphere for half an hour. At 0°C, 200 mL of anhydrous dichloromethane solution of compound M5-5 (26.66 g, 136 mmol) was slowly added dropwise to the above reaction mixture. The reaction system was stirred at 0°C under a nitrogen atmosphere for 1 hour. 500 mL of water was added to quench the reaction mixture, and the mixture was filtered. The filtrate was allowed to stand and separated. The aqueous phase was extracted with dichloromethane (3*500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0–30%) to give compound M5–6. LCMS: m / z = 534.1, 536.1 [M+1]+; 1H NMR (400MHz, CDCl3) δ = 8.70 (d, J=1.6 Hz, 1H), 8.62 (br s, 1H), 7.69 (d, J=3.2 Hz, 1H), 7.57–70.51 (m, 4H), 7.44-7.39 (m, 2H), 7.38-7.27 (m, 6H), 3.96-3.88 (m, 2H), 1.44 (s, 6H), 0.98 (s, 9H).

[0518] Step 5

[0519] Under a nitrogen atmosphere at 0°C, a lithium borohydride tetrahydrofuran solution (1 M, 123.47 mL) was slowly added dropwise to 220 mL of anhydrous tetrahydrofuran containing compound M5-6 (22 g, 41.16 mmol). After the addition was complete, the temperature was raised to 60°C and stirred for 15 hours. Cool to room temperature, slowly add 10 mL of saturated ammonium chloride aqueous solution dropwise, then add 100 mL of ethyl acetate, wash with 50 mL of saturated brine, collect the organic phase, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate. Purify the residue by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~20%) to obtain compound M5-7. LCMS: m / z = 520.1, 522.1 [M+1]+.

[0520] Step 6

[0521] Add compound M5-7 (18.5 g, 35.54 mmol), elemental iodine (9.02 g, 35.54 mmol) and silver trifluoromethanesulfonate (10.04 g, 39.09 mmol) sequentially to 185 mL of anhydrous tetrahydrofuran, and stir the mixture at 20°C for 2 hours. Quenching was performed with 50 mL of saturated sodium sulfite aqueous solution, followed by dilution with 200 mL of ethyl acetate. The mixture was filtered, and the filtrate was allowed to stand before separation. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound M5. ¹H NMR (400 MHz, CDCl₃) δ = 8.07 (s, 1H), 7.78–7.69 (m, 5H), 7.49–7.40 (m, 6H), 7.24–7.20 (m, 1H), 7.19–7.16 (m, 1H), 3.50 (s, 2H), 2.71 (s, 2H), 1.17 (s, 9H), 0.95 (s, 6H).

[0522] Reference Example 6: Compound M6

[0523]

[0524]

[0525] Step 1

[0526] Compound M6-1 (10 g, 78.05 mmol) was dissolved in DCM (100 mL) and MeOH (20 mL), and a trimethylsilyldiazomethane-n-hexane solution (2 M, 78.05 mL) was added dropwise at 0 °C. The mixture was stirred for 10 minutes at 0 °C. The concentration yielded compound M6-2, which was used directly in the next step.

[0527] Step 2

[0528] Compound M6-2 (10 g, 70.35 mmol) was dissolved in n-heptane (200 mL), and tert-butyl hydrazine carboxylate (11.69 g, 70.35 mmol) was added. The mixture was then heated to 70 °C and stirred for 12 hours. Stirring was stopped, and the system was allowed to cool to room temperature. Water (100 mL) and ethyl acetate (100 mL) were added. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound M6-3, which was used directly in the next step. LCMS: m / z = 201 [M+1-56]+.

[0529] Step 3

[0530] At 0°C, under nitrogen protection, a tetrahydrofuran (10 mL) solution of compound M6-3 (7 g, 27.31 mmol) was slowly added dropwise to boron dimethyl sulfide (10 M, 273.12 mL). After stirring at 0°C for half an hour, the temperature was raised to room temperature and stirring was continued for 1 hour. The reaction was quenched by slowly adding methanol (250 mL) at 0°C. The quenched reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-4. LCMS: m / z = 203 [M +1-56]+.

[0531] Step 4

[0532] Compound M6-4 (1.7 g, 6.58 mmol) was dissolved in tetrahydrofuran (30 mL), and di-tert-butyl dicarbonate (2.15 g, 9.87 mmol), triethylamine (2.00 g, 19.74 mmol), and 4-dimethylaminopyridine (80.40 mg, 658.12 μmol) were added sequentially at 25 °C, and the mixture was stirred at 25 °C for 1 hour. Water (50 mL) and ethyl acetate (30 mL) were added to the reaction system, and the extracted organic phase was dried over anhydrous sodium sulfate. The filtrate was concentrated, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-5. LCMS: m / z = 359 [M+1]+.

[0533] Step 5

[0534] Compound M6-5 (585 mg, 1.63 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection, lithium bis(trimethylsilyl)amino (1 M, 4.90 mL) was added dropwise at -70 °C. After stirring at -70 °C for half an hour, trimethylchlorosilane (531.94 mg, 4.90 mmol) was added dropwise. After stirring at -70 °C for one hour, N-bromosuccinimide (1.16 g, 6.53 mmol) was added. The temperature was slowly raised to 25 °C and stirring was continued for 1 hour. Saturated saline solution (30 mL) was added, and ethyl acetate (30 mL) was used to dissolve the compound.Extracted with ethyl acetate (m / z), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound M6-6, which was directly used in the next step. LCMS: m / z = 353,355 [M+1-100-56]+.

[0535] Step 6

[0536] A solution of citric acid (618.66 mg, 2.94 mmol) in water (5 mL) was added to a tetrahydrofuran (20 mL) of compound M6-6 (500 mg, 981.34 μmol), and stirred at 25°C for 1 hour. After the reaction was completed, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-7. LCMS: m / z = 281,283 [M+1-100-56]+.

[0537] Step 7

[0538] Compound M6-7 (150 mg, 342.99 μmol) was dissolved in acetonitrile (20 mL), and cesium carbonate (447.02 mg, 1.37 mmol) was added. The mixture was heated to 60 °C and stirred for 12 hours. After filtration, the filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-8. LCMS: m / z = 201 [M+1-100-56]+. 1H NMR (400MHz, CDCl3) 5.24 ‑ 4.93 (m, 1H) , 4.45 (br d , J=4.6 Hz, 1H) , 3.77 ‑ 3.71 (m , 3H) , 2.89 (qd , J=5.8, 11.6 Hz, 1H) , 2.39 (td, J=4.9, 10.0 Hz, 1H), 2.13 (td, J= 5.0, 10.0 Hz, 1H), 1.62 (s, 2H), 1.52 - 1.48 (m, 18H).

[0539] Step 8

[0540] Compound M6-8 (50 mg, 140.29 μmol) was dissolved in methanol (5 mL) and ethyl acetate (5 mL), and ethyl hydrochloride solution (5 mL, 4 M) was added. The mixture was stirred at 40 °C for 1 hour. The reaction solution was concentrated to obtain the hydrochloride salt of compound M6. LCMS: m / z = 157 [M+1]+. Specification 59 / 99 pages 87 CN 121270581 A

[0541] Reference Example 7: Compound M8

[0542]

[0543]

[0544]

[0545] Step 1

[0546] M8-1 (22.5 g, 111.94 μmol) was dissolved in methanol (5 mL) and ethyl acetate (5 mL), and ethyl hydrochloride solution (5 mL, 4 M) was added. The mixture was stirred at 40 °C for 1 hour.Triethylamine (111.94 mmol, 15.58 mL) and 1-methylpiperazine (16.82 g, 167.91 mmol, 18.63 mL) were added to a tetrahydrofuran solution (250 mL), and the mixture was stirred at 60 °C for 16 hours. The reaction solution was diluted with water (200 mL), and the solution was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was added to petroleum ether (100 mL), filtered, and the filter cake was dried to give compound M8-2. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.40 (d, J=2.4 Hz, 1 H), 7.65 (d, J=2.4 Hz, 1 H), 3.42–3.48 (m, 4 H), 2.36–2.44 (m, 4 H), 2.21 (s, 3 H).

[0547] Step 2

[0548] Compound M8-2 (10 g, 35.57 mmol) was dissolved in tetrahydrofuran (150 mL), and methyl magnesium chloride (3 M tetrahydrofuran solution, 23.7 mL) was added under nitrogen protection at 0 °C. The reaction solution was stirred at 0 °C for 2 hours. Saturated ammonium chloride (100 mL) was poured into the reaction solution to quench the reaction, and the solution was extracted with ethyl acetate (100 mL*3). The combined organic phases were washed once with saturated brine (100 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0~10%) to obtain compound M8-3. LCMS: m / z = 298.1, 300.1 [M+1]+. 1H NMR (400 MHz, DMSO‑d6) δ ppm 8.38 (d, J=2.4 Hz, 1 H), 7.53 (d, J=2.4 Hz, 1 H), 3.39‑3.47 (m, 4 H), 2.54 (s, 3 H), 2.40‑2.45 (m, 4 H), 2.22 (s, 3 H).

[0549] Step 3

[0550] Under nitrogen protection at 0 °C, triethylamine (57.1 g, 563.9 mmol) was added dropwise to formic acid (5.27 g, 109.67 mmol), followed by (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (140 mg, 220 μmol). The mixture was stirred at 40 °C for 15 minutes.Minutes. Then, the temperature was lowered to room temperature, and compound M8-3 (6.54 g, 21.93 mmol) was added in portions. The reaction solution was heated to 50 °C and stirred for 12 hours. The reaction solution was directly concentrated, and the crude product was purified by rapid chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0~10%) to obtain compound M8-4. LCMS: m / z = 300.0, 302.0 [M+1]+.

[0551] Step 4

[0552] Under nitrogen protection, compound M8-4 (1 g, 3.33 mmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0 °C, and then sodium hydrogen (160 mg, 4.00 mmol, purity 60%) was added in portions. The solution was stirred at 0 °C for 1 hour, then iodomethane (520 mg, 3.68 mmol) was added dropwise, and the reaction was continued at 0 °C for 2 hours. The reaction was quenched by adding saturated ammonium chloride (50 mL), and the solution was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to obtain the crude product. Purification was performed using a rapid column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0–10%) to obtain compound M8-5. LCMS: m / z = 313.9, 316.0 [M+1]+.

[0553] Step 5

[0554] Compound M8-5 (0.72 g, 2.29 mmol) and neopentyl glycol diboronate (777 mg, 3.5 mmol) were dissolved in toluene (20 mL), and potassium acetate (563 mg, 5.75 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (168 mg, 230 μmol) were added sequentially. The mixture was purged with nitrogen three times and heated to 70 °C for 12 hours. The reaction solution was filtered, and the filtrate was directly concentrated. The crude M8-6 obtained was used directly in the next step. LCMS: m / z = 348.1[M+1]+.

[0555] Step 6

[0556] Compound M8-6 (11.05 g, 31.82 mmol) and compound M5 (24.69 g, 38.18 mmol) were dissolved in dioxane (100 mL) and water (20 mL). Potassium carbonate (13.19 g, 95.46 mmol) was added, and the mixture was purged with nitrogen three times. 1,1-bis(diphenylphosphine)ferrocene palladium chloride (22.07 mg, 33.86 μmol) was added. The reaction mixture was stirred at 70°C under nitrogen for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography.(0-15% methanol / dichloromethane) yielded compound M8-7. LCMS: m / z = 753.2,755.2 [M+1]+.

[0557] Step 7

[0558] Compound M8-7 (15 g, 19.90 mmol) was dissolved in tetrahydrofuran (150 mL), and sodium hydrogen (4 g, 100.00 mmol, purity 60%) was added in batches at 0°C. The mixture was stirred for 30 min under nitrogen protection, and then iodoethane (30.01 mmol, 2.4 mL) was added dropwise. The reaction mixture was stirred at 0°C for 1 hour, and then iodoethane (25.01 mmol, 2 mL) was added. The reaction mixture was stirred at 20°C for 30 min. The reaction solution was quenched in batches with ice water (100 mL), extracted with dichloromethane (50 mL * 3), the organic phase was washed with saturated brine (50 mL * 3), dried over anhydrous sodium sulfate, and the filtrate was concentrated to obtain crude compound M8-8. LCMS: m / z = 781.3, 783.3 [M+1]+.

[0559] Step 8

[0560] Compound M8-8 (13.7 g, 17.52 mmol) was dissolved in tetrahydrofuran (150 mL), and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 175.21 mL) was added. The reaction solution was stirred under nitrogen and 50 °C for 12 hours. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (50 mL * 3), the aqueous phase was extracted with dichloromethane (50 mL * 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (0-15% methanol / dichloromethane) to obtain a crude product. The crude product was then added to acetonitrile (10 mL), stirred for 10 min, filtered, and the filter cake was further purified by prep-HPLC (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: the proportion of acetonitrile in the mobile phase increased from 13% to 43% within 8 min) to obtain the trifluoroacetate salt of compound M8-9A (HPLC analysis method: column: ChromCore 120 C18 3μm 3.0*30 mm; phase A: 4 L aqueous solution containing 1.5 mL trifluoroacetic acid; phase B: 4 L acetonitrile solution containing 0.75 mL trifluoroacetic acid; elution gradient: phase B increased from 10% to 80% within 6 min, held at 80% for 0.5 min, and then held at 10% for 0.5 min; the retention time of compound M8-9A was 3.205). min, the retention time of its isomer is 3.146 min). LCMS: m / z = 543.5, Specification 61 / 99 pages 89 CN 121270581 A 545.5 [M+1]+.

[0561] Step 9

[0562] Compound M8-9A (0.6 g, 1.10 mmol) and bis(diphenylphosphine)boronic acid ester (420.47 mg, 1.66 mmol) were dissolved in toluene (6 mL) and dioxane (2 mL). Potassium acetate (216.67 mg, 2.21 mmol) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (80.77 mg, 110.39 μmol) were added. The reaction solution was stirred at 90 °C under nitrogen for 5 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound M8. LCMS: m / z = 591.4 [M+1]+.

[0563] Reference Example 8: Compound M9

[0564]

[0565]

[0566] Step 1

[0567] Compound M6-1 (78.5 g, 612.68 mmol), compound M9-2 (119.42 g, 673.95 mmol), 4-dimethylaminopyridine (7.49 g, 61.27 mmol) and triethylamine (185.99 g, 1.84 mol) were added sequentially to 1.5 L of anhydrous dichloromethane. Then, 2-chloro-1-methylpyridine (salt) iodide (266.10 g, 1.04 mol) was added in portions, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the organic phase was washed with water (2*1 L). The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give compound M9-3. ¹H NMR (400MHz, CDCl₃) δ = 7.40–7.31 (m, 3H), 7.25–7.19 (m, 2H), 4.79–4.66 (m, 1H), 4.29–4.20 (m, 2H), 3.43–3.26 (m, 5H), 3.01–2.79 (m, 4H).

[0568] Step 2

[0569] Compound M9-3 (220 g, 765.72 mmol) and acetic acid (91.97 g, 1.53 mol) were added sequentially to 2 L of anhydrous tetrahydrofuran. Sodium borohydride (23.18 g, 612.58 mmol) was slowly added in portions to the above solution at 0 °C. After the addition was complete, the mixture was stirred at 0 °C for 2 hours. After the reaction was complete, 500 mL of saturated ammonium chloride aqueous solution was slowly added dropwise, and the mixture was concentrated under reduced pressure to approximately 1 L of residue. Extraction was performed with ethyl acetate (3 x 500 mL). The organic phase was purified by saturated bicarbonate extraction.The sodium was washed to pH ~8, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound M9-4. LCMS: m / z = 290.1 ​​[M+1]+.

[0570] Step 3

[0571] At 0°C, 4-dimethylaminopyridine (74.32 g, 608.31 mmol), compound M9-4 (220 g, 760.39 mmol) and N,N-diisopropylethylamine (147.41 g, 1.14 mol) were added sequentially to 2 liters of anhydrous dichloromethane. Then, p-toluenesulfonyl chloride (159.46 g, 836.43 mmol) was added in portions to the above solution. After the addition was completed, the mixture was stirred at 25°C for 3 hours. After the reaction was complete, the mixture was washed with water (1.5 L), the aqueous phase was extracted with dichloromethane (2 x 500 mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to obtain compound M9-5. ¹H NMR (400 MHz, CN 121270581 A CDCl3, page 62 / 99, δ = 7.81 (br d, J=8.0 Hz, 2H), 7.41–7.28 (m, 5H), 7.19 (br d, J=7.2 Hz, 2H), 4.84–4.70 (m, 1H), 4.65 (br s, 1H), 4.29–4.18 (m, 2H), 3.26 (br d, J=13.6 Hz, 1H), 3.17-2.96 (m, 2H), 2.85-2.71 (m, 1H), 2.60-2.49 (m, 2H), 2.47 (s, 3H), 2.37-2.20 (m, 1H), 1.90 (br s, 2H).

[0572] Step 4

[0573] Compound M9-5 (90 g, 202.93 mmol) and lithium bromide (35.25 g, 405.85 mmol) were added sequentially to 900 mL of 1-methyl-2-pyrrolidone, and the mixture was stirred at 90 °C for 13 hours. After the reaction was complete, 2 L of saturated saline solution was added for dilution, followed by extraction with ethyl acetate (3 x 1 L). The organic phase was washed again with saturated saline solution (2 x 1 L), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-20%) to obtain compound M9-6. LCMS: m / z = 352.0, 354.0[M+1]+.

[0574] Step 5

[0575] At -78°C, compound M9-6 (9.5 g, 23.80 mmol) was dissolved in 95 mL of anhydrous tetrahydrofuran, and then a mixture of lithium diisopropylamine 2M tetrahydrofuran and n-heptane (15.47 mL, 30.94 mmol) was slowly added dropwise while the mixture was stirred for half an hour under a nitrogen atmosphere. A 20 mL solution of di-tert-butyl azodicarbonate (6.58 g, 28.56 mmol) in anhydrous dichloromethane was added to the above solution at once, and the mixture was stirred for another half hour. 1,3-Dimethyl-tetrahydro-2-pyrimidinone (91.50 g, 713.89 mmol) was slowly added to the above reaction solution, and the mixture was allowed to warm naturally to room temperature and stirred for another 13 hours. After the reaction was complete, 100 mL of water was slowly added for extraction, followed by the addition of lithium hydroxide monohydrate (3.00 g, 71.39 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was diluted with 200 mL of saturated brine. The residue was washed with ethyl acetate (3 x 200 mL), and the organic phase was discarded. The aqueous phase was adjusted to pH 5 with 1 N hydrochloric acid, and then extracted with ethyl acetate (3 x 200 mL). The organic phase was washed with saturated brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified using a rapid chromatography column (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0–30%) to obtain compound M9-7. LCMS: m / z = 365.1 [M+23]+.

[0576] Step 6

[0577] At 25°C, a 2M n-hexane solution of trimethylsilyldiazomethane (11.68 mL, 23.36 mmol) was slowly added dropwise to 32 mL of anhydrous methanol solution of compound M9-7 (1.6 g, 4.67 mmol), and the mixture was stirred at 25°C for 10 minutes. After the reaction was complete, 0.1 mL of acetic acid was added to quench the reaction. The reaction solution was concentrated to obtain compound M9-8. LCMS: m / z = 379.1 [M+23]+. The SFC analysis method detected the retention time of compound M9-8 (column: Cellulose-4 (100 mm * 4.6 mm, 3 μm; mobile phase: phase A supercritical carbon dioxide, phase B [0.05% diethylamine in isopropanol]; B%: from 5% to 40% in 4 minutes, then held at 40% for 0.5 minutes, then held at 5% for 1.5 minutes) as 1.342 min, with a chiral purity of 93.38%; its enantiomer had a retention time of 1.431 min, with a chiral purity of 6.62%.

[0578] Step 7

[0579] Compound M9-8 (1.6 g, 4.49 mmol) was dissolved in 5 mL of trifluoroacetic acid and 15 mL of dichloromethane, and the mixture was heated at 25 °C.The mixture was stirred at ℃ for 12 hours. After the reaction was complete, the mixture was concentrated, and the residue was added to 20 mL of methyl tert-butyl ether and stirred at room temperature for 10 min. The mixture was then filtered, and the filter cake was dried to obtain the trifluoroacetate of compound M9. 1H NMR (400MHz, D2O) δ = 4.30 (d, J=3.8 Hz, 1H) , 3.97 (q, J=4.9 Hz, 1H) , 3.73 (s, 3H) , 2.93 ‑ 2.83 (m, 1H) , 2.54 (ddd, J=4.5, 6.5, 11.5 Hz, 1H), 2.39 (td, J=5.7, 11.7 Hz, 1H), 2.04 (dd, J=9.4, 11.7 Hz, 1H), 1.76 (dd, J=9.5, 12.0 Hz, 1H).

[0580] Reference Example 9: Compound M10 Specification 63 / 99 pages 91 CN 121270581 A

[0581]

[0582] Step 1

[0583] Compound M4-4 (9.2 g, 42.58 mmol), bis(diphenyl benzoyl borate) (16.22 g, 63.87 mmol), 1,5-cyclooctadiene iridium chloride dimer (858 mg, 1.28 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (1.71 g, 6.39 mmol) were dissolved in tetrahydrofuran (200 mL), purged with nitrogen three times, and the reaction solution was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated, and then 150 mL of water and 150 mL of ethyl acetate were added for dilution. Then, alkaline water (400 mL of aqueous solution of 7.5 g sodium hydroxide and 30 g sodium carbonate) was added to adjust the pH to 10. The liquid was separated and the organic phase was discarded. The aqueous phase was adjusted to pH 6 with concentrated hydrochloric acid and then extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound M10-1.

[0584] Step 2

[0585] Compound M10-1 (5 g, 19.24 mmol) was dissolved in acetonitrile (50 mL), and cuprous iodide (733 mg, 3.85 mmol), potassium iodide (6.39 g, 38.48 mmol), potassium carbonate (5.32 g, 38.48 mmol), and 1,10-phenanthroline (694 mg, 3.85 mmol) were added in sequence. The reaction mixture was stirred at 60 °C for 2 hours. After the reaction was complete, the reaction mixture was filtered, and the filtrate was directly concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-10%) to give compound M10-2. LCMS: m / z=341.8, 343.8 [M+1]+.

[0586] Step 3

[0587] Compound M10-2 (0.27 g, 789.54 μmol) and compound M10-3 (170 mg, 790.54 μmol, 2HCl) were dissolved in toluene (5 mL), cooled to 0 °C, and then cesium carbonate (1.29 g, 3.95 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (50 mg, 80.95 μmol) and palladium acetate (36 mg, 158.91 μmol) were added. Nitrogen was purged three times, and the reaction solution was stirred at 90 °C for 12 hours. After the reaction was complete, the reaction solution was directly concentrated, and the crude product was purified by rapid chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0~10%) to obtain compound M10. LCMS: m / z = 356.0, 358.0 [M+1]+.

[0588] Reference Example 10: Compound M11

[0589]

[0590]

[0591] Step 1

[0592] Compound M11-1 (5 g, 20.58 mmol) and potassium carbonate (8.53 g, 61.75 mmol) were dissolved in methylpyrrolidone (25 mL), and then tert-butyl cyanoacetate (4.65 g, 32.93 mmol) was added. The reaction was stirred at 85°C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature and water (25 mL) was added. The pH was adjusted to 2 with 3M hydrochloric acid, and a solid precipitated. The solid was filtered and the filter cake was dried to obtain compound M11-2. 1H NMR (400 MHz, CD3OD) δ ppm 1.53 (s, 9 H), 4.85 (s, 1 H), 6.93 (s, 1 H).

[0593] Step 2

[0594] Compound M11-2 (6.2 g, 20.45 mmol) was dissolved in hydrochloric acid (4 M, 24 mL), and then acetic acid (439.68 mmol, 25.17 mL) was added. The mixture was stirred at 80 °C for 15 minutes. After the reaction was complete, water (100 mL) was added, and the mixture was extracted with ethyl acetate (150 mL*3). The organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound M11-3. 1H NMR (400 MHz, CD3OD) δ ppm 4.90 (s, 2 H), 7.61 (s, 1 H).

[0595] Step 3

[0596] Compound M11-3 (3 g, 14.77 g) was placed in the container.The compound M11-4 was dissolved in tetrahydrofuran (30 mL) and sodium hydrogen (1.48 g, 36.93 mmol, 60% purity) was added at 0 °C. The mixture was stirred at 0 °C for 20 minutes under nitrogen protection, followed by the addition of 1,2-dibromoethane (22.16 mmol, 1.67 mL). The mixture was stirred at 25 °C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (150 mL * 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to give compound M11-4. ¹H NMR (400 MHz, CD3OD) δ ppm 1.78–1.83 (m, 2 H) 1.84–1.89 (m, 2 H) 7.07 (s, 1 H).

[0597] Step 4

[0598] Compound M11-4 (1 g, 4.36 mmol) was dissolved in tetrahydrofuran (10 mL), and then diisobutylaluminum hydride toluene solution (1 M, 10.91 mL) was added at 0 °C. The mixture was stirred at 0 °C for 1 hour under nitrogen protection. After the reaction was completed, water (120 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (50 mL*3). The organic phase was dried with anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product. The crude product was subjected to column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound M11-5. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.97 - 2.01 (m, 2 H) 2.07 - 2.11 (m, 2 H) 7.79 (s, 1 H) 8.90 (s, 1 H).

[0599] Step 5

[0600] Compound M11-5 (0.2 g, 861.71 μmol) and ammonium carbonate (248.39 mg, 2.59 mmol) were dissolved in ethanol (5 mL) and water (5 mL). Potassium cyanide (84.17 mg, 1.29 mmol) was added and the mixture was stirred at 80 °C for 6 hours. After the reaction was completed, water (150 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL * 3). The organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the crude product, yielding compound M11-6. LCMS: m / z = 302.1, 304.1 [M+1]+. ¹H NMR (400 MHz, CD3OD) δ ppm 1.20–1.32 (m, 2H) 1.37–1.50 (m, 2H) 4.06 (s, 1H) 7.39 (s, 1H).

[0601] Step 6

[0602] Compound M11-6 (0.17 g, 562.64 μmol) was dissolved in dioxane (1Barium hydroxide (385.61 mg, 2.25 mmol) was added to a mixture of water (1 mL) and water (1 mL), and the reaction system was microwaved at 130 °C for 30 min. Water (50 mL) was added to the reaction system, and the mixture was washed with ethyl acetate (50 mL * 3), collecting the aqueous phase to obtain an aqueous solution of compound M11. LCMS: m / z = 277.1, 279.1 [M+1]+.

[0603] Reference Example 11: Compound M12 Specification 65 / 99 pages 93 CN 121270581 A

[0604]

[0605] Step 1

[0606] Compound M10-2 (0.1 g, 292.42 μmol), compound M12-1 (108 mg, 350.91 μmol), potassium carbonate (101 mg, 731.06 μmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (21 mg, 29.24 μmol) were dissolved in dioxane (5 mL) and water (1 mL), and the mixture was purged with nitrogen three times. The reaction solution was stirred at 60 °C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated, and the crude product was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~40%) to obtain compound M12-2. LCMS: m / z = 397.1, 399.0 [M+1]+.

[0607] Step 2

[0608] Trimethyl sulfoxide (139 mg, 629.24 μmol) and potassium tert-butoxide (71 mg, 629.24 μmol) were added to dimethyl sulfoxide (3 mL) and stirred at 50 °C for 2 hours. Then the temperature was lowered to 25 °C and a dimethyl sulfoxide solution of compound M12-2 (0.05 g, 125.85 μmol) in 1 mL was added dropwise. The reaction solution was stirred at 80 °C for 12 hours. After the reaction was completed, water (50 mL) was added to dilute the reaction mixture. The solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined and washed once with saturated brine (50 mL). The mixture was dried with anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~50%) to obtain compound M12. LCMS: m / z = 410.9, 412.9 [M+1]+.

[0609] Example 1

[0610]

[0611]

[0612] Specification 66 / 99 pages 94 CN 121270581 A

[0613]

[0614]

[0615]

[0616] Step 1

[0617] Compound M4 (5 g, 19.00 mmol) and compound M5 (7.02 g,To a mixture of 70 mL of dioxane and 15 mL of water (10.86 mmol), K₂CO₃ (3.75 g, 27.14 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (794.48 mg, 1.09 mmol) were added. The mixture was purged with nitrogen three times and stirred at 85 °C for 4 hours. The reaction solution was concentrated. The residue was diluted with 100 mL of water, extracted with ethyl acetate (3 x 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0–100%) to give compound 1–1. LCMS: m / z = 655.1, 657.1 [M+1]+.

[0618] Step 2

[0619] At 0°C, iodoethane (2.14 g, 13.73 mmol) and cesium carbonate (4.47 g, 13.73 mmol) were added sequentially to a DMF (50 mL) solution of compound 1-1 (4.5 g, 6.86 mmol). After the addition was complete, the temperature was raised to 25°C and stirred at 25°C for 16 hours. The reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (2*50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-2. LCMS: m / z = 683.2, 685.2 [M+1]+.

[0620] Step 3

[0621] Compound 1-2 (3.4 g) and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 34.81 mL) were added sequentially to 35 mL of anhydrous tetrahydrofuran, and the mixture was stirred at 50 °C for 16 hours. The reaction solution was diluted with 100 mL of water, extracted with ethyl acetate (2*50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~80%) to obtain compound 1-3A (TLC eluent: ethyl acetate, Rf of compound 1-3A = 0.38, Rf of its isomer = 0.17). LCMS: m / z = 445.1, 447.1 [M+1]+; 1H NMR (400 MHz, CDCl3) δ 8.85 (dd, J=1.76, 4.77 Hz, 1H), 7.92 (d, J=1.76 Hz, 1H), 7.71 (dd, J=1.76, 7.78 Hz, 1H), 7.33–7.41 (m, 2H), 7.24–7.28 (m, 1H), (See specification 67 / 99 pages, CN 121270581 A)4.08‑4.14 (m, 1H) , 3.96‑4.08 (m, 1H) , 3.83‑3.96 (m, 1H) , 3.19‑ 3.33 (m , 2H) , 3.09 (s , 3H) , 2.74 (d , J=14.05 Hz, 1H) , 2.27 (d, J=14.05 Hz, 1H), 1.50 (d, J=6.27 Hz, 3H), 1.16-1.24 (m, 4H), 0.80 (s, 6H).

[0622] Step 4

[0623] Compound 1-3A (0.4 g, 898.09 μmol) and neopentyl glycol diboronate (406 mg, 1.80 mmol) were dissolved in toluene (10 mL). 1,1-bis(diphenylphosphine)ferrocene palladium chloride (131 mg, 179.62 μmol) and potassium acetate (264 mg, 2.69 mmol) were added sequentially. The mixture was purged with nitrogen three times, and the reaction solution was heated to 90 °C and stirred for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain compound 1-4A. LCMS: m / z = 411.2 [Mboronic acid + 1]+.

[0624] Step 5

[0625] Compound 1-4A (300.00 mg, 627.05 μmol), compound M2 (0.36 g, 715.12 μmol), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (47 mg, 71.51 μmol), and potassium phosphate (455 mg, 2.15 mmol) were dissolved in toluene (6 mL), dioxane (2 mL), and water (2 mL), and the mixture was purged with nitrogen three times. The reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~100%) to obtain compound 1-5A. LCMS: m / z = 789.4 [M+1]+.

[0626] Step 6

[0627] Compound 1-5A (100.00 mg, 126.74 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.2 mL), and then lithium hydroxide monohydrate (16 mg, 380.23 μmol) was added. The reaction solution was stirred at 15°C for 12 hours. The pH of the reaction solution was adjusted to ~5 by adding 1M HCl. The solution was extracted with ethyl acetate (50 mL * 3), and the organic phases were washed once with saturated brine (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 1-7A. LCMS: m / z = 761.3 [M + 1]+.

[0628] Step 7

[0629] Compound 1-7A (50.00 mg, 65.71 μmol) was dissolved in dichloromethane (5 mL), and then N,N-diisopropylethylamine (260 mg, 2.01 mmol, 0.35 mL), 1-hydroxybenzotriazole (0.044 g, 325.63 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.35 g, 1.83 mmol) were added. The reaction solution was stirred at 20 °C for 12 hours. The reaction solution was diluted with water (50 mL), and the solution was extracted with dichloromethane (20 mL * 3). The organic phases were washed once with saturated brine (20 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~80%) to obtain compound 1-8A. LCMS: m / z = 743.4 [M+1]+.

[0630] Step 8

[0631] At 0 °C, compound 1-8A (20.00 mg, 26.92 μmol) was dissolved in dichloromethane (1 mL), and then trifluoroacetic acid (1.54 g, 13.46 mmol, 1 mL) was added. The reaction solution was stirred at 15 °C for 12 hours. The reaction solution was concentrated to obtain crude trifluoroacetate of compound 1-9A. LCMS: m / z = 643.3 [M+1]+.

[0632] Step 9

[0633] Compound 1-9A (20.00 mg, crude trifluoroacetate) was dissolved in N,N-dimethylformamide (2 mL), and then N,N-diisopropylethylamine (311.13 μmol, 54 μL), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (7 mg, 62.3 μmol) and O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethylurea hexafluorophosphine (36 mg, 93.4 μmol) were added. The reaction solution was stirred at 20 °C for 1.5 hours. The reaction solution was diluted with water (20 mL), and the solution was extracted with ethyl acetate (20 mL * 3). The organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the crude product obtained by concentrating the filtrate was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0.80%) to give compound 1A. LCMS: m / z = 725.3 [M+1]+; 1H NMR (400 MHz, CD3OD) δ ppm 8.64 (dd, J=4.8, 1.6)Hz, 1 H) , 8.12 (s, 1 H) , 7.79 (dd , J=7.6, 1.6 Hz, 1 H) , 7.54 (d, J=8.4 Hz, 1 H) , 7.44 (dd, J=7.6, 4.8 Hz, 1 H) , 7.34 - 7.39 (m, 2 H) , 6.02 (t, J=6.2 Hz, 1 H) , 4.03 ‑ 4.13 (m, 2 H) , 3.71 ‑ 3.86 (m, 3 H) , 3.43 ‑ 3.56 (m, 2 H) , 3.03 (s, 3 H) , 2.64 ‑ 2.72 (m, 1 H) , 2.37 - 2.44 (m, 1 H) , 2.06 - 2.13 (m, 1 H) , 1.89 - 1.97 (m, 2 H) , 1.70 - 1.80 (m, 1 H) , 1.48 - 1.60 (m, 3 H) , 1.32 - 1.37 (m, 2 H) , 1.18 ‑ 1.23 (m, 6 H) , 0.90 ‑ 0.97 (m, 2 H) , 0.76 ‑ 0.83 (m, 2 H) , 0.57 ‑ 0.66 (m, 6 H) , 0.45 ‑ 0.51 (m, 1 H).

[0634] Example 2

[0635]

[0636]

[0637]

[0638]

[0639] Step 1

[0640] Compound 1-3A (295 mg, 662.34 μmol) and bis(diphenylphosphine)boronic acid ester (252.29 mg, 993.51 μmol) were dissolved in toluene (2 mL), and potassium acetate (130.01 mg, 1.32 mmol) and [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride (48.46 mg, 66.23 μmol) were added. The reaction solution was stirred at 110°C for 12 hours under a nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-1A. LCMS: m / z = 493.3 [M+1]+.

[0641] Step 2

[0642] Compound 2-1A (300 mg, 609.19 μmol) and compound M3 (492.89 mg, 913.79 μmol) were dissolved in a mixed solvent of 1,4-dioxane (3 mL), toluene (3 mL), and water (0.5 mL), and potassium phosphate (387.94 mg, 1.83 μmol) was added.1,1-bis(tert-butylphosphine)ferrocene palladium chloride (39.70 mg, 60.92 μmol) was added, and the reaction solution was stirred at 70°C for 12 hours under a nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (20-80% ethyl acetate / petroleum ether) on page 97 of the specification (69 / 99 pages) to give compound 2-2A. LCMS: m / z = 825.1 [M+1]+.

[0643] Step 3

[0644] Compound 2-2A (280 mg, 339.40 μmol) was dissolved in a mixed solution of tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide monohydrate (71.21 mg, 1.70 mmol) was added. The reaction solution was stirred at 25°C for 2 hours. Then, the pH of the reaction solution was adjusted to neutral with 1M dilute hydrochloric acid, and then extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 2-3A. LCMS: m / z = 797.2 [M+1]+.

[0645] Step 4

[0646] Compound 2-3A (0.3 g, 376.45 μmol) was dissolved in dichloromethane (30 mL), and 1-hydroxybenzotriazole (508.67 mg, 3.76 mmol), N,N-diisopropylethylamine (11.29 mmol, 1.97 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.16 g, 11.29 mmol) were added. The reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether), and then separated by high performance liquid chromatography (column: C18 100×40mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 39%-69%) to obtain compound 2-4A. LCMS: m / z = 779.3 [M+1]+.

[0647] Step 5

[0648] Compound 2-4A (20 mg, 25.68 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (25.68 μmol, 1.91 μL) was added. The reaction solution was stirred at 25°C for 5 hours, and concentrated under reduced pressure to obtain crude trifluoroacetate of compound 2-5A. LCMS: m / z = 679.3 [M+1]+.

[0649] Step 6

[0650] Compound 2-5A (17 mg, trifluoroacetate), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (3.76 mg,37.57 μmol) was dissolved in N,N-dimethylformamide (1 mL), and then N,N-diisopropylethylamine (9.71 mg, 75.13 μmol, 13.09 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (19.05 mg, 50.09 μmol) were added under stirring. The reaction solution was stirred at 25 °C for 12 hours. After extraction with ethyl acetate (5 mL × 3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the residue was concentrated under reduced pressure. The residue was then prepared by high performance liquid chromatography (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 27%–57%) to give trifluoroacetate of compound 2A. LCMS: m / z = 761.2 [M+1]+; 1H NMR (CDCl3, 400 MHz) δ 9.1‑ 9.2 (m, 1H) , 8.3‑8.4 (m, 1H) , 8.0‑8.2 (m, 1H) , 7.7‑7.8 (m, 1H) , 7.6‑7.7 (m, 1H) , 7.3‑7.5 (m, 1H) , 6.6‑6.7 (m, 1H) , 5.7‑5.8 (m, 1H) , 4.4‑4.5 (m, 1H) , 4.17 (br d , J=5.8 Hz, 1H) , 4.11 (br d , J=10.5 Hz, 1H) , 4.0‑4.1 (m, 1H) , 3.88 (br d , J=10.3 Hz, 1H) , 3.64 (br d , J=15.6 Hz, 1H) , 3.1‑3.3 (m, 6H) , 2.1‑2.2 (m, 1H) , 1.9‑2.0 (m, 2H) , 1.6‑1.7 (m, 1H) , 1.52 (br d, 3H, J=5.8 Hz) , 1.2‑1.4 (m, 8H) , 1.1‑1.2 (m, 1H) , 1.07 (br d, 3H, J=5.5 Hz) , 0.92 (br s, 3H) , 0.6‑0.7 (m, 3H), 0.5-0.6 (m, 1H).

[0651] Example 3 Specification 70 / 99 pages 98 CN 121270581 A

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658] Step 1

[0659] Compound M4-4 (30 g, 138.84 mmol), bis(phenanthoxylate) borate (52 g)1,5-cyclooctadiene iridium chloride dimer (2.80 g, 4.17 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (5.59 g, 20.83 mmol) were sequentially added to 600 mL of anhydrous tetrahydrofuran. The mixture was purged with nitrogen three times and stirred at 80 °C for 20 hours. The reaction solution was then concentrated. The residue was diluted with 300 mL of water and 200 mL of ethyl acetate. The pH was adjusted to 10 with alkaline solution (400 mL of a solution of 10 g NaOH and 40 g sodium carbonate). The mixture was separated, the organic phase was discarded, and the aqueous phase was adjusted to pH 6 with concentrated salt (see page 71 / 99 of the manual, CN 121270581 A). The mixture was extracted three times with 500 mL of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 3-1. ¹H NMR (400 MHz, CDCl₃) δ = 8.93 (d, J = 1.6 Hz, 1H), 8.22 (d, J = 1.6 Hz, 1H), 4.96 (q, J = 6.4 Hz, 1H), 3.32 (s, 3H), 1.50 (d, J = 6.4 Hz, 3H). 1.37 (s, 12H).

[0660] Step 2

[0661] Compound 3-1 (40 g, 116.95 mmol) was slowly added dropwise to a 1.5 L acetonitrile suspension of benzyl-1-piperazine carbonate (77.28 g, 350.84 mmol), copper acetate (21.24 g, 116.95 mmol), and triethylamine (116.95 mmol, 16.28 mL). The mixture was stirred at 80 °C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~30%) to give compound 3-2. MS-ESI calculated values ​​[M+1]+434.1, 436.1; measured values ​​434.3, 436.3; 1H NMR (400MHz, CDCl3) δ = 8.23 ​​(d, J=2.4 Hz, 1H), 7.39–7.25 (m, 5H), 7.23 (d, J=2.4 Hz, 1H), 5.09 (s, 2H), 4.78 (q, J=6.4 Hz, 1H), 3.68–3.55 (m, 4H), 3.21 (s, 3H), 3.13 (br s, 4H), 1.39 (d, J=6.4 Hz, 3H).

[0662] Step 3

[0663] Compound 3-2 (7A mixture of neopentyl glycol diboronate (5.46 g, 24.18 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (589.65 mg, 805.85 μmol), and potassium acetate (3.95 g, 40.29 mmol) was added to 140 mL of anhydrous dioxane. The mixture was purged with nitrogen three times and stirred at 80 °C for 20 hours. The reaction mixture was concentrated. The residue was purified by rapid column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0–10%) to give compound 3–3. LCMS: m / z = 400.1 [M+1]+.

[0664] Step 4

[0665] Compound 3-3 (9 g, 22.54 mmol), compound M5 (14.57 g, 22.54 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (824.72 mg, 1.13 mmol), and potassium phosphate (11.96 g, 56.36 mmol) were added sequentially to 250 mL of anhydrous dioxane and 80 mL of water. The mixture was purged with nitrogen three times and stirred at 70 °C for 12 hours. The reaction solution was concentrated. The residue was diluted with 200 mL of water, extracted with ethyl acetate (3 x 200 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to obtain compound 3-4. LCMS: m / z = 873.3, 875.3 [M+1]+.

[0666] Step 5

[0667] Compound 3-4 (6.2 g, 7.09 mmol), iodoethane (14.19 mmol, 1.13 mL), and cesium carbonate (4.62 g, 14.19 mmol) were added sequentially to 100 mL of anhydrous DMF, and the mixture was stirred at 20 °C for 10 hours. The reaction solution was concentrated. The residue was diluted with 100 mL of water, extracted with ethyl acetate (3*150 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-5. LCMS: m / z = 901.4, 903.4 [M+1]+.

[0668] Step 6

[0669] Compound 3-5 (6.2 g, 6.87 mmol) and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 13.75 mL) were added sequentially to 100 mL of anhydrous tetrahydrofuran, and the mixture was stirred at 50 °C for 15 hours. The reaction solution was concentrated. The residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~100%) to obtain compound 3-6A.(TLC eluent: ethyl acetate, Rf = 0.43 for compound 3-6A, Rf = 0.33 for its isomers). LCMS: m / z = 663.2, 665.2 [M+1]+.

[0670] Step 7

[0671] Compound 3-6A (1.70 g, 2.56 mmol), bis(diphenylphosphine)ferrocene palladium chloride (975.74 mg, 3.84 mmol), potassium acetate (754.21 mg, 7.68 mmol) were added sequentially to 50 mL of anhydrous dioxane. The mixture was purged with nitrogen three times and stirred at 90 °C for 20 hours. The reaction solution was concentrated. The residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~100%) to give compound 3-7A. LCMS: m / z = 711.1 [M+1]+.

[0672] Step 8

[0673] Compound 3-7A (0.38 g, 534.68 μmol), compound M2 (322.99 mg, 641.61 μmol), 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (34.85 mg, 53.47 μmol), and potassium phosphate (283.74 mg, 1.34 mmol) were added sequentially to 15 mL of dioxane and 5 mL of water. The mixture was purged with nitrogen three times and stirred at 70 °C for 4 hours. The reaction solution was concentrated. The residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~100%) to give compound 3-8A. LCMS: m / z = 1007.4 [M+1]+.

[0674] Step 9

[0675] Compound 3-8A (650 mg, 645.33 μmol) and lithium hydroxide monohydrate (54.16 mg, 1.29 mmol) were added sequentially to 20 mL of tetrahydrofuran and 20 mL of water, and the mixture was stirred at 15 °C for 20 hours. The reaction solution was concentrated. The residue was diluted with 5 mL of water, and the pH was adjusted to 6-7 by adding 1N dilute hydrochloric acid. The mixture was extracted with ethyl acetate (3*30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-9A. LCMS: m / z = 979.4 [M+1]+.

[0676] Step 10

[0677] Compound 3-9A (650 mg, 663.81 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.82 g, 19.91 μmol)N,N-diisopropylethylamine (26.55 mmol, 4.62 mL) and 1-hydroxybenzotriazole (896.94 mg, 6.64 mmol) were sequentially added to 65 mL of acetonitrile, and the mixture was stirred at 25 °C for 40 hours. The reaction solution was concentrated. The residue was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0–100%) to give compound 3-10A. LCMS: m / z = 961.4 [M+1]+.

[0678] Step 11

[0679] Compound 3-10A (150 mg, 156.06 μmol), paraformaldehyde (23.45 mg, 780.30 μmol), and palladium hydroxide on carbon (100 mg, 10% w / w, 50% water content) were sequentially added to 10 mL of methanol. The mixture was purged with hydrogen three times, and stirred at 20 °C for 2 hours under a hydrogen atmosphere (15 psi). Filtered. The filtrate was concentrated. The residue was purified by rapid column chromatography (silica gel, eluent methanol / dichloromethane, methanol ratio: 0~10%) to give compound 3-11A. LCMS: m / z = 841.4 [M+1]+.

[0680] Step 12

[0681] At 0°C, 1 mL of trifluoroacetic acid was slowly added dropwise to 5 mL of anhydrous dichloromethane containing compound 3-11A (56 mg, 58.26 μmol), and the mixture was stirred at 0°C for 5 hours. The reaction solution was concentrated to obtain the trifluoroacetate salt of compound 3-12A. LCMS: m / z = 741.3 [M+1]+.

[0682] Step 13

[0683] Compound 3-12A (45 mg, trifluoroacetate), compound (1S,2S)-2-methylcyclopropane-1-carboxylic acid (9.12 mg, 91.10 μmol), N,N-diisopropylethylamine (303.66 μmol, 52.89 μL) and HATU (69.28 mg, 182.20 μmol) were added sequentially to 5 mL of anhydrous DMF, and the mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated, and the crude product was separated by preparative high performance liquid chromatography (preparation method: column type: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile %): from 14% to 44% within 8 minutes) to obtain trifluoroacetate of compound 3A. LCMS: m / z = 823.4 [M+1]+; 1H NMR (400MHz, CDCl3) δ = 8.67 (br s, 1H), 8.38 (s, 1H), 7.57 (br d, J=8.4 Hz, 1H) , 7.37 (d , J=8.4 Hz, 1H) , 7.27 (s , 1H) , 7.20 (s , 1H) , 6.78 (br d , J=7.6 Hz, 1H) , 5.91 (br s , 1H) , 4.22 (br d , J=6.0 Hz, 1H) , 4.14 ‑ 4.06 (m, 2H) , 3.99 ‑ 3.91 (m, 2H) , 3.67 (br s, 4H) , 3.53 (br dd , J=5.6, 14.8 Hz, 4H) , 3.27 (s, 3H) , 3.26 ‑ 2.99 (m, 3H) , 2.92 (br s, 3H) , 2.81 (br d , J=14.4 Hz, 1H) , 2.52 (br d , J=14.2 Hz, 1H) , 2.12 ‑ 1.71 (m, 4H) , 1.47 (br d, J=6.0 Hz, 3H), 1.43-1.14 (m, 6H), 1.14-1.06 (m, 6H), 0.79 (s, 3H), 0.66 (s, 3H), 0.63 (br s, 1H).

[0684] Example 4

[0685]

[0686] Compound 3-12A (0.1 g, 134.96 μmol) and (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (31 mg, 269.98 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then N,N-diisopropylethylamine (175 mg, 1.35 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (154 mg, 404.9 μmol) were added. The reaction solution was stirred at 20 °C for 2 hours. The reaction solution was filtered, and the filtrate was directly purified by HPLC (purification method: column type: C18 100×40mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 16% to 46% over 8 minutes) to obtain the trifluoroacetate of compound 4A. LCMS: m / z = 837.4 [M+1]+; 1H NMR (400 MHz, CD3OD) δ ppm 8.53 (s, 1 H), 8.27 (s, 1 H), 7.93 (s, 1 H), 7.70 (d, J=8.8 Hz, 1 H), 7.49–7.57 (m, 2 ppm)H) , 6.16 (t, J=6.0 Hz, 1 H) , 4.95 ‑ 5.04 (m, 3 H) , 4.10 ‑ 4.28 (m, 3 H) , 3.88 ‑ 4.06 (m, 4 H) , 3.45 ‑ 3.70 (m, 3 H) , 3.24 , 1.68 - 1.74 (m, 1 H), 1.58-1.66 (m,1 H), 1.42-14.7 (m, 3 H), 1.26-1.41 (m, 7 H), 1.17-1.23 (m, 3 H), 1.08-1.15 (m, 7 H) , 0.75 - 0.85 (m, 6 H).

[0687] Example 5

[0688] Specification 74 / 99 pages 102 CN 121270581 A

[0689]

[0690]

[0691]

[0692] Step 1

[0693] Compound M8 (200 mg, 338.64 μmol) and compound M3 (274 mg, 507.98 μmol) were dissolved in dioxane (4 mL), toluene (1.3 mL) and water (1.3 mL). Potassium phosphate (215.65 mg, 1.02 mmol) and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (22.07 mg, 33.86 μmol) were added. The reaction solution was stirred at 70°C under a nitrogen atmosphere for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound 5-1A. LCMS: m / z = 923.5 [M+1]+.

[0694] Step 2

[0695] Compound 5-1A (205 mg, 222.07 μmol) was dissolved in a mixed solution of tetrahydrofuran (2 mL) and water (0.5 mL), and lithium hydroxide monohydrate (46.59 mg, 1.11 mmol) was added. The reaction solution was stirred at 25°C for 1 hour. Then the pH of the reaction solution was adjusted to 7-8 with 1M dilute hydrochloric acid, and then extracted with ethyl acetate (10 mL * 5). The organic phase was washed with saturated brine.(10 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain compound 5-2A, which was directly used in the next step. LCMS: m / z = 895.3 [M+1]+.

[0696] Step 3

[0697] Compound 5-2A (45 mg, 50.28 μmol) was dissolved in acetonitrile (4.5 mL), and tetramethylchlorourea hexafluorophosphate (21.16 mg, 75.41 μmol) and N-methylimidazole (12.38 mg, 150.83 μmol) were added. The reaction solution was stirred at 25 °C for 1 hour. Water (20 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (5 mL*3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-3A. LCMS: m / z = 877.4 [M+1]+.

[0698] Step 4

[0699] Compound 5-3A (50 mg, 57.01 μmol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (767.50 mg, 6.73 mmol, 0.5 mL) was added. The reaction solution was stirred at 25°C for 1 hour, and the solution was concentrated under reduced pressure to obtain crude trifluoroacetate of compound 5-4A, which was directly used in the next step.

[0700] Step 5 Instructions 75 / 99 pages 103 CN 121270581 A

[0701] The crude trifluoroacetate of compound 5-4A obtained in step 4 was dissolved in N,N-dimethylformamide (1 mL), and (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (9.70 mg, 84.95 μmol) was added. Then, under stirring, N,N-diisopropylethylamine (21.96 mg, 169.90 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (43.07 mg, 113.27 μmol) were added. The reaction solution was stirred at 25°C for 3 hours, and then prepared by prep-HPLC (column: C18 100×40 mm; mobile phase: [Water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile ratio increased from 16% to 46% over 8 min) purification yielded the trifluoroacetate of compound 5A. LCMS: m / z = 873.9 [M+1]+. 1H NMR (CD3OD, 400 MHz) δ 8.5–8.6 (m, 1H), 8.2–8.3 (m, 1H), 7.7–7.7 (m, 1H), 7.61 (br d, J=2.3 Hz, 1H), 7.4–7.5 (m, 2H), 5.5–5.6 (m, 3H), 5.3–5.4(m, 3H) , 4.0‑4.3 (m, 6H) , 3.8‑3.9 (m, 2H) , 3.4‑3.6 (m, 5H) , 3.0‑3.1 (m, 5H) , 2.2‑2.3 (m, 3H) , 2.1‑2.2 (m, 2H) , 2.0‑2.1 (m, 6H) , 1.6‑1.7 (m, 3H) , 1.4‑1.5 (m, 3H) , 1.0‑1.1 (m, 3H) , 0.8‑1.0 (m, 6H).

[0702] Example 6

[0703]

[0704]

[0705]

[0706]

[0707] Step 1

[0708] Compound M8 (120 mg, 203.18 μmol) and M1-1 (89.05 mg, 243.82 μmol) were dissolved in toluene (9 mL), 1,4-dioxane (3 mL) and water (3 mL) on page 76 / 99 of the specification. Potassium phosphate (129.39 mg, 609.55 μmol) and [1,1'-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (26.48 mg, 40.64 μmol) were added under nitrogen protection and stirred at 70 °C for 12 hours. After the reaction solution cooled, it was directly concentrated and then purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound 6-1A. LCMS: m / z = 749.6 [M+1]+.

[0709] Step 2

[0710] Compound 6-1A (130 mg, 173.57 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL) and water (3 mL), and lithium hydroxide monohydrate (36.42 mg, 867.86 μmol) was added. The mixture was stirred at 25 °C for half an hour. The pH of the system was adjusted to 7.0 with 1M hydrochloric acid, then diluted with saturated saline (50 mL), and extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-2A, which was directly used in the next step. LCMS: m / z = 735.6 [M+1]+.

[0711] Step 3

[0712] Compound M6 (21.82 mg, 95.25 μmol) and compound 6-2A (70 mg, 95.25 μmol) were dissolved in N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (952.45 μmol, 165.90 μL) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (43.46 mg,114.29 μmol), and stirred at 25 °C for half an hour. After the reaction was complete, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-3A, which was directly used in the next step. LCMS: m / z = 874.0 [M+1]+.

[0713] Step 4

[0714] Compound 6-3A (130 mg, 173.57 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL) and water (3 mL), and lithium hydroxide monohydrate (36.42 mg, 867.86 μmol) was added. The mixture was stirred at 25 °C for half an hour. The pH of the system was adjusted to 7.0 with 1M hydrochloric acid, then diluted with saturated saline (50 mL), and extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-4A, which was directly used in the next step. LCMS: m / z = 860.0 [M+1]+.

[0715] Step 5

[0716] Compound 6-4A (61 mg, 71.01 μmol) was dissolved in acetonitrile (20 mL), and N,N,N',N'-tetramethylchloromethanemidazone hexafluorophosphate (597.68 mg, 2.13 mmol) and N-methylimidazole (174.89 mg, 2.13 mmol, 169.80 μL) were added. The mixture was stirred at 25 °C for 1 hour under nitrogen protection. The reaction solution was concentrated and then separated by pre-TLC (DCM / MeOH = 10:1) to obtain compound 6-5A. LCMS: m / z = 842.0 [M+1]+.

[0717] Step 6

[0718] Compound 6-5A (52 mg, 61.83 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (798.20 mg, 7.00 mmol, 520.00 μL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction solution was concentrated to obtain crude trifluoroacetate of compound 6-6A, which was directly used in the next step.

[0719] Step 7

[0720] Compound 6-6A (35 mg, 40.9 μmol) and (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (9.35 mg, 81.8 μmol) were dissolved in DMF (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (31.13 mg, 81.87 μmol) and N,N-diisopropylethylamine (409.37 μmol, 71.30 μL) were added. The solution was heated to 25 °C.Stir at ℃ for 1 hour. Dilute with saturated brine (50 mL), extract twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL), combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the crude product by pre-TLC (developing solvent: dichloromethane / methanol = 10:1), and then separate and purify by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: [phase A is supercritical carbon dioxide, phase B is ethanol (0.1% ammonia)]; gradient (B%): 50%, isobaric elution) to obtain compounds 6A and 6B.

[0721] SFC analysis (column: Chiralcel OD-3 50 * 4.6 mm ID, 3 μm, mobile phase: A: supercritical carbon dioxide B: ethanol (containing 0.05% diethylamine), gradient elution: mobile phase B increased from 5% to 40% in two minutes, then held at 40% for 1.2 minutes, and then held at 5% for 0.8 minutes), the RT of compound 6A was 1.896 min, ee = 96.98%; the RT of compound 6B was 2.201 min, ee = 98.82%. Compound 6A: LCMS: m / z = 837.5 [M+1]+; 1H NMR (400MHz, CD3OD) δ = 8.33 (br d , J=10.5 Hz , 2H) , 7.59 (br d , J=8.3 Hz , 1H) , 7.45 (s , 1H) , 7.39 (br d, J=8.5 Hz, 1H) , 7.25 (br s, 1H) , 5.48 (br s, 1H) , 4.61 ‑ 4.50 (m, 2H) , 4.24 ‑ 4.05 (m, 2H) , 3.64 ‑ 3.50 (m, 2H) , 3.28 (br s, 3H) , 3.21 (br s , 6H) , 2.97 (br d , J=13 .3 Hz , 1H) , 2.63 (br s , 4H) , 2.58 ‑ 2 .44 (m , 2H) , 2.33 (br s, 4H) , 2.10 (br t, J=9.0 Hz, 1H) , 1.46 (br s, 1H) , 1.38 ‑ 1.16 (m, 8H) , 1.05 (br dd , J=6.0, 13.3 Hz, 6H) , 0.93 ‑ 0.85 (m, 3H) , 0.81 (br s, 3H) ,0.38 (br s, 3H). Compound 6B: LCMS: m / z=837.5 [M+1]+; H NMR (400MHz, CD3OD) δ=8.57 (d, J=2.8 Hz, 1H), 8.53 (s, 1H), 8.28 (d, J=3.0 Hz, 1H), 7.76 (d, J=9.8 Hz, 1H) , 7.60 ‑ 7.52 (m, 2H) , 6.05 (dd, J=3.6, 7.9 Hz, 1H) , 4.64 (br d, J=5.0 Hz, 1H) , 4.49 (s, 1H) , 4.32 ‑ 4.08 (m, 5H), 3.97- 3.86 (m, 2H) , 3.79 - 3.61 (m, 3H) , 3.41 - 3.35 (m, 4H) , 3.24 (s, 3H) , 3.01 (s, 3H) , 2.70 (br d , J=5.8 Hz, 1H) , 2.57 - 2.49 (m, 1H) , 2.48 ‑ 2.41 (m, 1H) , 2.38 ‑ 2.28 (m, 1H) , 2.17 (br d, J= 13.8 Hz, 1H) , 1.80 (t, J=9.3 Hz, 1H) , 1.43 (d, J=6.3 Hz, 3H) , 1.37 - 1.25 (m, 6H), 1.09 (dd, J=5.6, 9.7 Hz, 8H), 0.90 (s, 3H), 0.80 (s, 3H).

[0723] Example 7

[0724]

[0725]

[0726] Compound 6-6A (60 mg, 70.18 μmol) and (1S,2S)-2-methylcyclopropyl-1-carboxylic acid (14.05 mg, 81.8 μmol) were dissolved in DMF (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (53.37 mg, 140.35 μmol) and N,N-diisopropylethylamine (72.56 mg, 561.42 μmol) were added. The mixture was stirred at 25 °C for 1 hour. The solution was diluted with saturated saline (50 mL), extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The solution was filtered, and the crude product obtained after concentration was purified by rapid silica gel column chromatography (mobile phase: dichloromethane / methanol = 100:1), followed by SFC separation and purification (column: DAICEL).CHIRALCEL OD (250mm* 30mm, 10μm); Mobile phase: [A phase is supercritical carbon dioxide, B phase is ethanol (0.1% ammonia)]; Gradient (B%): 50%) Compounds 7A and 7B were obtained. SFC analysis (method: column: chiral OD-3 100 * 4.6mm ID, 3μm, mobile phase: A: supercritical carbon dioxide, B: ethanol (containing 0.05% diethylamine), gradient (B%): 40%) showed that the RT for compound 7A was 1.365 min, ee = 100%; the RT for compound 7B was 2.325 min, ee = 88.2%. (Instructions 78 / 99, page 106, CN 121270581 A) Compound 7A: LCMS: m / z = 823.7[M +1]+; 1H NMR (400MHz, CD3OD) δ = 8.34 (s, 1H), 8.31 (d, J=2.8 Hz, 1H), 7.58 (dd, J=1.5, 8.8 Hz, 1H), 7.44 (s, 1H) , 7.38 (d, J=8.5 Hz, 1H) , 7.24 (d, J=3.0 Hz, 1H) , 5.47 (br s , 1H) , 4.60 ‑ 4.44 (m , 3H) , 4.22 ‑ 4.03 (m , 3H) , 3.64-3.50 (m, 2H), 3.31-3.26 (m, 4H), 3.25 (s, 2H), 3.02-2.91 (m, 1H), 2.61 (br t, J=4.9 Hz, 5H), 2.53-2.46 (m, 1H), 2.38- 2.32 (m, 1H) , 2.31 (s, 3H) , 2.09 (t, J=9.9 Hz, 1H) , 1.50 ‑ 1.36 (m, 2H) , 1.32 (d , J=6.3 Hz, 3H) , 1.21 ‑ 1.11 (m, 3H) , 1.08 (t, J=7.0 Hz, 1H), 1.04–0.98 (m, 4H), 0.88 (br t, J=7.0 Hz, 3H), 0.81 (s, 3H), 0.60–0.52 (m, 1H), 0.37 (s, 3H).

[0727] Compound 7B: LCMS: m / z = 823.7 [M+1]+; 1H NMR (400MHz, CD3OD) δ = 8.38 (s, 1H), 1.04–0.98 (m, 4H), 0.88 (br t, J=7.0 Hz, 3H), 0.81 (s, 3H), 0.60–0.52 (m, 1H), 0.37 (s, 3H).1H) , 8.33 (d , J=2.8 Hz, 1H) , 7.60 ‑ 7.54 (m, 1H) , 7.39 ‑ 7.34 (m, 2H) , 7.31 (d , J=3.0 Hz, 1H) , 5.98 ‑ 5.88 (m , 1H) , 4.57-4.50 (m, 1H), 4.37 (s, 1H), 4.07-3.98 (m, 1H), 3.96-3.88 (m, 2H), 3.86-3.74 (m, 2H), 3.55-3.46 (m, 1H) , 3.36 - 3.26 (m, 4H) , 2.97 (br d , J=14.3 Hz, 1H) , 2.90 (s, 3H) , 2.62 (br s, 5H) , 2.46 - 2.38 (m, 1H) , 2.32 (s, 3H) , 2.26 - 2.11 (m, 2H) , 1.70 (t, J=9.5 Hz, 1H) , 1.36 ‑ 1.28 (m, 4H) , 1.20 ‑ 1.11 (m, 1H) , 1.23 ‑ 1.10 (m, 5H) , 0.98 ‑ 0.98 (m , 1H), 0.99 (d, J=6.0 Hz, 2H), 0.91 (td, J=4.3, 8.5 Hz, 1H), 0.69 (s, 3H), 0.63-0.57 (m, 3H), 0.50-0.41 (m, 1H).

[0728] Example 8

[0729]

[0730]

[0731] Using compounds 8-1 and 6-6A as raw materials, the reaction solution obtained was directly purified by high performance liquid chromatography (column: C18 100×40mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 16% to 46% within 8 min) to obtain the trifluoroacetate of compound 8A. LCMS: m / z = 859.5 [M+1]+. 1H NMR (400 MHz, DMSO‑d6) δ = 8.88 (br d , J = 9.0 Hz, 1H), 8.51‑8.47 (m, 1H), 8.41 (s, 1H), 7.84‑7.80 (m, 1H), 7.76‑ 7.71 (m, 1H) , 7.59 - 7.55 (m, 1H) , 7.44 - 7.39 (m, 1H), 6.01 (br d , J = 11.3 Hz, 1H) , 5.46 ‑ 5.37 (m, 1H) , 5.34 ‑ 5.30 (m , 1H) , 4.68 ‑ 4.61 (m , 1H) , 4.53‑ 4.47 (m , 1H) , 4.37 ‑ 4.23 (m, 1H) , 4.20 ‑ 4.09 (m, 2H) , 4.06 ‑ 3.99 (m, 2H) , 3.20 (s, 3H) , 3.05 (br s, 2H) , 2.95 ‑ 2.89 (m, 1H) , 2.86 (s, 3H) , 2.65–2.58 (m, 1H), 2.33 (br d, J = 1.5 Hz, 1H), 2.20–2.13 (m, 1H), 2.11–2.05 (m, 1H), 2.04–1.94 (m, 3H), 1.70–1.63 (m, 1H), 1.62–1.54 (m, 1H), 1.48–1.43 (m, 1H), 1.34 (br d, J = 6.3 Hz, 4H), 1.05 (br t, J = 6.9 Hz, 3H) (Instruction manual, pages 79 / 99, 107, CN 121270581 A) , 0.94 - 0.83 (m, 10H), 0.39 - 0.28 (m, 3H).

[0732] Example 9

[0733] ​​

[0734]

[0735]

[0736]

[0737]

[0738] Step 1

[0739] Compound M5-7 (6.83 g, 13.12 mmol) was dissolved in tetrahydrofuran (50 mL), and then tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 65.60 mL) was added. The reaction solution was stirred at 50 °C for 16 hours. After the reaction was completed, the reaction solution was directly concentrated. The crude product was diluted with water (100 mL), and the solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined and washed once with saturated brine (50 mL). The solution was dried with anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid chromatography column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~55%) to obtain compound 9-1A. LCMS: m / z = 281.9 [M+1]+.

[0740] Step 2

[0741] Compound 9-1A (3.31 g, 11.73 mmol) was...Dissolved in dichloromethane (30 mL), then triethylamine (3.56 g, 35.19 mmol) and 4-dimethylaminopyridine (72 mg, 596.51 μmol) were added. The mixture was cooled to 0 °C, and acetic anhydride (1.16 g, 11.38 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 10 minutes. After the reaction was complete, the mixture was diluted with water (50 mL), and the solution was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~30%) to obtain compound 9-2A. LCMS: m / z = 323.9 [M+1]+.

[0742] Step 3

[0743] Compound 9-2A (3.4 g, 10.49 mmol), bis(diphenylphosphine)boronic acid ester (6.66 g, 26.22 mmol), potassium acetate (2.57 g, 26.22 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (0.768 g, 1.05 mmol) were dissolved in 40 mL of toluene. The mixture was purged with nitrogen three times, and the reaction solution was stirred at 90 °C for 3 hours. After the reaction was completed, the reaction solution was directly concentrated. The crude product was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~30%) to obtain compound 9-3A. LCMS: m / z = 372.1 [M+1]+.

[0744] Step 4

[0745] Compound 9-3A (3.8 g, 10.23 mmol), M1-1 (5.61 g, 15.35 mmol), potassium phosphate (5.43 g, 25.59 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (750 mg, 1.12 mmol) were dissolved in toluene (30 mL), dioxane (10 mL), and water (10 mL). The mixture was purged with nitrogen three times, and the reaction solution was stirred at 70 °C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated. The crude product was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~50%) to obtain compound 9-4A. LCMS: m / z = 530.2 [M+1]+.

[0746] Step 5

[0747] Compound 9-4A (5.4 g, 10.20 mmol) was dissolved in tetrahydrofuran (50 mL), cooled to 0 °C, and then sodium bicarbonate (1.03 g, 12.28 mmol) and silver trifluoromethanesulfonate (3.15 g,12.25 mmol), then iodine (2.33 g, 9.18 mmol) in tetrahydrofuran (5 mL) solution was added dropwise. The reaction solution was stirred at 0 °C for 15 minutes. After the reaction was completed, the reaction solution was quenched at 0 °C by adding saturated sodium sulfite solution (100 mL). The resulting solution was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~40%) to obtain compound 9-5A. LCMS: m / z = 656.1 [M+1]+.

[0748] Step 6

[0749] Compound 9-5A (3.2 g, 4.88 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL), and lithium hydroxide monohydrate (615 mg, 15.64 mmol) was added at 0 °C. The reaction solution was stirred at 25 °C for 12 hours. After the reaction was complete, the pH of the reaction solution was adjusted to approximately 6 with saturated citric acid solution. The resulting solution was extracted with ethyl acetate (100 mL * 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product obtained was purified by high-performance liquid chromatography (HPLC) (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: acetonitrile from 30% to 60% within 8 minutes). The target separation solution was concentrated under reduced pressure, and the pH was adjusted to 7-8 with dilute ammonia. Extraction was performed with ethyl acetate (30 mL * 3). The combined organic phases were concentrated to obtain compound 9-6A. LCMS: m / z = 600.1 [M+1]+.

[0750] Step 7

[0751] Compound 9-6A (0.32 g, 1.18 mmol) was dissolved in N,N-dimethylformamide (7 mL), and then N,N-diisopropylethylamine (1.44 g, 11.18 mmol), compound M9 (0.67 g, 1.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (510 mg, 1.44 mmol) were added to the solution. The reaction mixture was stirred at 25 °C for 2 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), and the solution was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to obtain the desired product.The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~60%) to obtain compound 9-7A. LCMS: m / z = 738.2 [M+1]+.

[0752] Step 8

[0753] 9-7A (0.63 g, 854.07 μmol) was dissolved in tetrahydrofuran (6 mL) and methanol (6 mL), and then a solution of lithium hydroxide monohydrate (0.18 g, 4.29 mmol) in water (6 mL) was added dropwise at 0 °C. The reaction solution was stirred at 0 °C for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to about 6 with saturated citric acid solution. The solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined and washed once with saturated brine (50 mL). The solution was dried with anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~100%) to obtain compound 9-8A. LCMS: m / z = 724.1 [M+1]+.

[0754] Step 9

[0755] Compound 9-8A (0.2 g, 276.39 μmol) was dissolved in acetonitrile (20 mL) and N,N-dimethylformamide (2 mL), and then N-methylimidazolium (1.13 g, 13.82 mmol) and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (388 mg, 1.48 mmol) were added. The reaction solution was stirred at 80℃ for 2 hours. After the reaction was complete, the reaction solution was directly concentrated to remove acetonitrile, then diluted with water (30 mL), and the solution was extracted with ethyl acetate (30 mL * 3). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~40%) to obtain compound 9-9A. LCMS: m / z = 706.1 [M+1]+.

[0756] Step 10

[0757] Compound 9-9A (0.1 g, 141.72 μmol), potassium acetate (48.68 mg, 496.03 μmol), 2-dicyclohexylphosphine-2,6-dimethoxybiphenyl (30 mg, 71.86 μmol), and tris(dibenzylacetone)dipalladium (26 mg, 28.54 μmol) were dissolved in toluene (5 mL). Under nitrogen protection, pinacol borane (145.10 mg, 1.13 mmol) was added dropwise at 0 °C. The reaction solution was stirred at 60 °C for 3 hours under nitrogen protection. After the reaction was completed, saturated ammonium chloride (10 mL) was added dropwise to quench the reaction solution.The solution was extracted with ethyl acetate (50 mL * 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0–40%) to obtain compound 9–10A. LCMS: m / z = 706.4 [M+1]+.

[0758] Step 11

[0759] Compound 9-10A (0.1 g, 141.71 μmol), M10 (76 mg, 212.76 μmol), potassium carbonate (58.76 mg, 425.13 μmol), and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (21 mg, 28.54 μmol) were dissolved in toluene (3 mL), dioxane (1 mL), and water (1 mL). The mixture was purged with nitrogen three times, and the reaction solution was stirred at 65 °C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated, and the crude 9-11A was directly used in the next step. LCMS: m / z = 855.6 [M+ 1]+.

[0760] Step 12

[0761] Compound 9-11A (0.1 g, 116.95 μmol) and cesium carbonate (115 mg, 351.85 μmol) were dissolved in N,N-dimethylformamide (3 mL), and iodoethane (28 mg, 176.43 μmol) was added dropwise at 0 °C. The reaction solution was stirred at 25 °C for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (column: C18, manual page 82 / 99, 110 CN 121270581 A 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 22% to 52% within 8 minutes) to obtain the trifluoroacetate of compound 9-12A. LCMS: m / z = 883.4 [M+1]+.

[0762] Step 13

[0763] Compound 9-12A (30 mg, 33.97 μmol) was dissolved in hydrochloric acid / dioxane (2 M, 2 mL), and the reaction solution was stirred at 25 °C for 1 hour. After the reaction was completed, the reaction solution was directly concentrated, and the crude 9-13A was directly used for the next step. LCMS: m / z = 783.3 [M+1]+.

[0764] Step 14

[0765] Compound 9-13A (0.03 g, 38.31 μmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (8 mg, 79.91 μmol) were dissolved in N,N-dimethylformamide (2 mL), and then N,N-diisopropylethylamine (50 mg) was added.The reaction mixture consisted of 386.87 μmol of O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphine salt (30 mg, 78.90 μmol). The reaction solution was stirred at 25 °C for 12 hours. After the reaction was complete, the reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (HPLC) (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile from 17% to 47% within 8 minutes) to obtain the trifluoroacetate of compound 9A. LCMS: m / z = 865.3 [M+1]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.88 (s, 1 H) , 8.57 (s, 1 H) , 8.20 (s, 1 H) , 7.74 (s, 1 H) , 7.54 (s, 2 H) , 6.8 ‑ 6.41 (m, 2 H) , 4.54 ‑ 4.45 (m, 1 H) , 4.29 - 4.11 (m, 9 H) , 4.03 - 3.89 (s, 3 H) , 3.77 - 3.57 (m, 6 H) , 3.06 - 2.97 (m, 1 H) , 2.44 - 2.35 (m, 1 H) , 2.27- 2.15 (m, 5 H), 2.09 - 1.95 (m, 10 H), 1.66 - 1.57 (m, 5 H), 1.13 - 1.06 (m, 3 H), 0.92 - 0.96 (m, 6 H).

[0766] Example 10

[0767]

[0768]

[0769] Specification 83 / 99 pages 111 CN 121270581 A

[0770]

[0771]

[0772] Step 1

[0773] Compound 3-4 (1 g, 1.14 mmol) and cesium carbonate (2.61 g, 8.01 mmol) were dissolved in 1-methyl-2-pyrrolidone (10 mL), cooled to 0 °C, and then trifluoroethyl trifluoromethanesulfonate (2.66 g, 11.44 mmol) was added dropwise. The reaction solution was stirred at 25 °C for 48 hours. After the reaction was complete, the solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed once with saturated brine (50 mL). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid column chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0–50%) to give compound 10⁻¹A. LCMS: m / z = 955.3[M+1]+.

[0774] Step 2

[0775] At 0 °C, tetrabutylammonium fluoride (1 M tetrahydrofuran solution, 5 mL) was added to compound 10-1A (0.5 g, 523.01 μmol). The reaction solution was stirred at 40 °C for 12 hours. After the reaction was completed, water (50 mL) was added to dilute the reaction solution, and the solution was extracted with ethyl acetate (50 mL*3). The organic phases were combined and washed once with saturated brine (50 mL), dried with anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by rapid chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0~80%) to obtain compound 10-2A (LC-MS analysis method: 5-95AB_1.5 min, the retention time of compound 10-2A was 1.009 min, and the retention time of its isomer was 0.981 min). LCMS: m / z = 717.1 [M+1]+.

[0776] Steps 3-11

[0777] Following the synthesis methods of Examples 6-9, the reaction solution of compound 10A was obtained. The reaction solution was filtered, and the filtrate was purified by high performance liquid chromatography (column: C18 100×40mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 20% to 50% within 8 minutes) to obtain the trifluoroacetate of Example 10A. LCMS: m / z = 891.5 [M+1]+. 1H NMR (400 MHz, CD3OD) δ ppm 8.57 ‑ 8.43 (m, 2 H) , 7.80 ‑ 7.71 (m, 1 H) , 7.64 (s, 1 H) , 7.59 ‑ 7.48 (m, 2 H) , 5.54 ‑ 5.49 (m, 1 H) , 5.38-5.34 (m, 2 H), 4.12-4.00 (m, 1 H), 3.70-3.68 (m, 1 H), 3.62 (s, 1 H), 3.37-3.35 (m, 3 H), 3.05- 2.99 (m, 4H) , 2.25 - 2.18 (m, 4 H), 2.11 - 2.01 (m, 4 H), 1.71 - 1.56 (m, 5 H), 1.49 - 1.42 (m, 5 H), 1.41 - 1.36 (m, 10 H), 1.22 - 1.13 (m, 5 H), 1.12 - 1.04 (m, 3 H).

[0778] Example 11 Specification 84 / 99 pages 112 CN 121270581 A

[0779]

[0780] Following the synthesis methods of Examples 6-9, a reaction solution for compound 11A was obtained. Water was added to the reaction solution until no more solid precipitated, the solution was filtered, the solid was collected, and then purified by high-performance liquid chromatography (HPLC) (column: C18 100×40mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile from 15% to 45% within 8 minutes) to obtain the trifluoroacetate of compound 11A. LCMS: m / z = 825.4 [M+1]+. 1H NMR (400 MHz, CDCl3) δ = 8.92-8.78 (m, 1H), 8.28-8.21 (m, 1H), 7.62-7.56 (m, 1H), 7.44-7.37 (m, 2H), 7.36 - 7.31 (m, 1H), 7.11 - 7.04 (m, 1H), 5.43 - 5.31 (m, 1H), 4.97 - 4.86 (m, 1H), 4.80 - 4.71 (m, 1H), 4.41 - 4.32 (m, 1H) , 4.23 ‑ 4.13 (m, 2H) , 3.73 ‑ 3.66 (m, 5H) , 3.59 ‑ 3.55 (m , 2H) , 3.41 (br s , 4H) , 3.21 (br dd , J = 11.8, 12.8 Hz, 3H) , 2.96-2.87 (m, 1H), 2.81-2.72 (m, 1H), 2.65-2.56 (m, 1H), 2.47-2.34 (m, 2H), 2.13-2.02 (m, 1H), 1.78- 1.67(m, 1H), 1.48 (br d, J = 5.5 Hz, 3H), 1.44-1.36 (m, 1H), 1.31-1.19 (m, 3H), 1.13 (br d, J = 5.8 Hz, 3H), 1.02-0.93 (m, 6H), 0.73-0.64 (m, 1H), 0.49-0.34 (m, 3H).

[0781] Example 12

[0782]

[0783] The reaction solution of compound 12A was obtained by referring to the synthesis method of Examples 6-9. Water was added to the reaction solution until no more solids precipitated. The mixture was filtered, and the solids were collected. The solids were then subjected to high-performance liquid chromatography (HPLC) (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: ...).The acetonitrile content increased from 17% to 47% within 8 minutes, and the trifluoroacetate of the target compound 12A was obtained through purification. LCMS: m / z = 862.2 [M+23]+. 1H NMR (400 MHz, CDCl3) δ = 8.64 ‑ 8.48 (m , 1H) , 8.32 ‑ 8.19 (m , 1H) , 7.52 (br d , J = 8.8 Hz, 1H) , 7.29 (br d , J = 8.5 Hz, 1H) , 7.25 ‑ 7.22 (m, 1H) , 7.17 ‑ 7.13 (m, 1H) , 6.81 ‑ 6.73 (m, 1H) , 5.45 ‑ 5.35 (m, 1H) , 4.78 (br s, 1H) , 4.70 ‑ 4.63 (m, 1H) , 4.24 (br d, J = 6.0 Hz, 1H), 4.15–4.08 (m, 2H), 3.62 (br d, J = 10.8 Hz, 3H), 3.51 (br d, J = 11.3 Hz, 3H), 3.46 (br d, J = 5.8 Hz, 1H), 3.31 (s, 3H), 3.16–3.05 (m, 3H), 2.84–2.77 (m, 1H), 2.71–2.63 (m, 1H), 2.55–2.47 (m, 1H), 2 .36-2.29 (m, 2H), 2.22-2.11 (m, 2H), 2.04-1.91 (m, 3H), 1.67-1.53 ​​(m, 3H), 1.51-1.41 (m, 2H), 1.37 (br d , J = 5.8 Hz, 4H) , 1.07 (br d , J = 6.0 Hz, 3H) , 1.03 (br d , J = 6.0 Hz, 3H) , 0.85 ‑ 0.79 (m, 3H) , 0.33 (br s, 3H).

[0784] Example 13

[0785]

[0786]

[0787]

[0788]

[0789]

[0790] Step 1

[0791] Compound M11 (1.36 g, 4.90 mmol) was dissolved in tetrahydrofuran (40 mL) and water (10 mL), and sodium bicarbonate (1.44 g) was added.Compound 13-1A (Rt=3.625; 17.14 mmol) and Boc2O (1.17 g, 5.34 mmol) were stirred at 25 °C for 12 hours. After the reaction was completed, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried and concentrated, and then purified by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: [phase A: supercritical carbon dioxide, phase B: isopropanol containing 0.1% ammonia]; phase B was eluted at a 30% isogradient) to obtain compound 13-1A (Rt=3.625; SFC analytical method: column: DAICEL CHIRALPAK IG (100*4.6 mm ID, 3 μm); mobile phase: [phase A: supercritical carbon dioxide, phase B: isopropanol containing 0.05% ammonia]; phase B was increased from 5% to 40% in 4.5 minutes, and then held at 5% for 1.5 minutes). Instructions for use, pages 86 / 99, 114, CN 121270581 A (flow rate 2.5 mL / min, column temperature: 40℃) and 13-1B (Rt=4.200; SFC analytical method: column: DAICEL CHIRALPAK IG (100*4.6mm ID, 3um); mobile phase: [phase A: supercritical carbon dioxide fluid, phase B: isopropanol containing 0.05% ammonia]; phase B is increased from 5% to 40% in 4.5 min, then held at 5% for 1.5 min, flow rate 2.5 mL / min, column temperature: 40 ℃). LCMS: m / z = 321.1, 323.1 [M+1-56]+.

[0792] Step 2

[0793] Compound 3-6A (1.2 g, 1.81 mmol) and bis(pinnatrol)boronic acid ester (688.76 mg, 2.71 mmol) were added to toluene (10 mL), followed by potassium acetate (354.91 mg, 3.62 mmol). The mixture was purged with nitrogen, and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (132.31 mg, 180.82 μmol) was added. The reaction mixture was stirred at 70°C under nitrogen for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound 13-2A. LCMS: m / z = 711.4 [M+1]+.

[0794] Step 3

[0795] Compound 13-1A (0.05 g, 132.54 μmol) was dissolved in dichloromethane (2 mL), and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.49 mg, 159.04 μmol) and 1-hydroxybenzotriazole (21.49 mg) were added.The reaction mixture was prepared with N-methylmorpholine (26.81 mg, 265.07 μmol) and stirred at 0°C for 0.5 hours. Then, trifluoroacetate of compound M9 (35.81 mg, 132.54 μmol) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. After the reaction was complete, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL * 3). The organic phase was dried and concentrated to give compound 13-3A. LCMS: m / z = 515.0, 517.0 [M+1]+.

[0796] Step 4

[0797] Compound 13-3A (52.00 mg, 100.89 μmol) and compound 13-2A ​​(89.63 mg, 126.11 μmol) were dissolved in dioxane (1 mL), water (1 mL), and toluene (3 mL). Then potassium phosphate (64.25 mg, 302.67 μmol) and 1,1-bis(tert-butylphosphine)ferrocene palladium chloride (13.15 mg, 20.18 μmol) were added. The mixture was stirred at 70 °C for 12 hours under nitrogen protection. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL * 3). After drying and concentrating the organic phase, the crude product was separated by thin-layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 13-4A. LCMS: m / z = 510.0 [M / 2+1]+.

[0798] Step 5

[0799] Following the synthesis methods of Examples 6-9, a reaction solution for compound 13A was obtained. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL * 3). After drying and concentrating the organic phase, the crude product was separated by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain compound 13A. LCMS: m / z = 850.0 [M+1]+. 1H NMR (400 MHz, CD3OD) δ ppm 0.59 (s, 3 H) 0.67 (s, 3 H) 0.99 (s, 3 H) 1.06 (br t, J=7.15 Hz, 6 H) 1.50 (br s, 2 H) 1.59 (br d , J=9.29 Hz, 1 H) 1 .94 (s , 2 H) 2.10 (t, J=7 .53 Hz, 1 H) 2.19 ‑ 2.28 (m, 1 H) 2.40 (br d , J=5.02 Hz, 2 H) 2.59 ‑ 2.64 (m, 1 H) 2.73 - 2.77 (m, 3 H) 2.80 (s, 1 H) 2.95 (d, J=7.28 Hz, 1 H) 3.03 (s, 3H) 3.09-3.17 (m, 8H) 3.43 (br d, J=9.03 Hz, 3H) 3.58-3.67 (m, 7H) 3.87 (s, 1H) 7.36 (s, 1H) 7.38-7.42 (m, 2H) 7.59 (d, J=8.78 Hz, 1H) 8.34-8.38 (m, 2H).

[0800] Example 14 Specification 87 / 99 pages 115 CN 121270581 A

[0801]

[0802] Using compound 13-1B as raw material, compound 14A was prepared according to the synthesis method of Example 13. LCMS: m / z=850.0 [M+1]+. 1H NMR (400 MHz, CD3OD) δ ppm 0.56 (br s, 3 H) 0.66 (br s, 1 H) 0.90 (s, 3 H) 1.04 (br s, 3 H) 1.13 (br d , J=5.77 Hz, 4 H) 1.24 ‑ 1.29 (m, 1 H) 1.31 (br s, 2 H) 1.33 ‑ 1.38 (m, 2 H) 1.44 (br d, J=6.02 Hz, 3 H) 1 .61 (br s , 1 H) 1 .73 ‑ 1 .79 (m , 1 H) 2.23 (s , 1 H) 2.38 (s , 3 H) 2.47 (br d , J=10.04 Hz, 1 H) 2.60 (br s, 1 H) 2.67 (br s, 4 H) 2.74 (br s, 1 H) 2.97 (s, 1 H) 3.27 (s, 3 H) 3.37 (br s, 4 H) 3.60 (br d , J=10.79 Hz, 1 H) 3 .74 (br d , J=12 .55 Hz , 1 H) 4 .24 (br d , J=6 .53 Hz , 1 H) 4 .58 (br s , 5 H) 4.68 (br s, 1 H) 7.37 (s, 1 H) 7.46 ‑ 7.50 (m, 2 H) 7.66 (br d , J=8.53 Hz, 1 H) 8.43 (s, 2 H).

[0804] Example 15

[0805]

[0806]

[0807] Step 1

[0808] Compound M10-2 (728.03 mg, 2.13Compound 15-1A (570 mg, 2.55 mmol) was dissolved in 1,4-dioxane (10 mL) and water (2 mL), followed by the addition of potassium carbonate (735.57 mg, 5.32 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (155.77 mg, 212.89 μmol). The reaction mixture was stirred at 50°C under nitrogen for 2 hours. The reaction mixture was then filtered to remove insoluble impurities, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography (0-5% methanol / dichloromethane) to obtain compound 15-2A. LCMS: m / z = 312.9 [M+1]+.

[0809] Step 2

[0810] Compound 15-2A (580 mg, 1.86 mmol) and neopentyl glycol diboronate (505.16 mg, 2.24 mmol) were dissolved in toluene (10 mL), and then potassium acetate (457.26 mg, 4.66 mmol) and 1,1-bis(diphenylphosphine)ferrocene palladium chloride (136.37 mg, 186.37 μmol) were added. The reaction solution was stirred at 80°C under nitrogen for 2 hours. The reaction solution was then filtered to remove insoluble impurities, and the filtrate was concentrated to dryness to obtain compound 15-3A. LCMS: m / z = 345.1 [M+1]+. Instructions for Use, pages 88 / 99, 116, CN 121270581 A

[0811] Step 3

[0812] Compound 15-3A (640 mg, 1.86 mmol, 1 eq) and compound M5 (1.20 g, 1.86 mmol, 1 eq) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). Potassium carbonate (770.83 mg, 5.58 mmol) was added, and the mixture was purged with nitrogen three times. 1,1-bis(diphenylphosphine)ferrocene palladium chloride (136.03 mg, 185.91 μmol) was added. The reaction mixture was stirred under nitrogen and at 70°C for 3 hours. After the reaction was completed, the reaction solution was filtered to remove insoluble impurities, and the organic solvent was removed by vacuum distillation to obtain a crude product. The crude product was purified by column chromatography (0-10% methanol / dichloromethane) to obtain compound 15-4A. LCMS: m / z = 750.2 [M+1]+.

[0813] Step 4

[0814] Compound 15A was prepared by referring to the synthesis method of Examples 6-9. LCMS: m / z = 834.5 [M+H]+.

[0815] Example 16

[0816]

[0817]

[0818] Specification 89 / 99 pages 117 CN 121270581 A

[0819]

[0820] Following the synthesis methods of Examples 6-9, compounds 16A (LCMS: m / z = 820.5 [M+H]+), 17A (LCMS: m / z = 836.0 [M+H]+), 18A (LCMS: m / z = 848.5 [M+H]+), and 19A (LCMS: m / z = 834.5 [M+H]+) were prepared.

[0821] Biological test data

[0822] Experiment 1: In vitro AsPC-1 cell proliferation experiment

[0823] Experimental materials:

[0824] RPMI 1640 medium, penicillin / streptomycin antibiotics were purchased from Gibco, fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (a chemiluminescent cell viability assay reagent) reagent was purchased from Promega. AsPC-1 cell line was purchased from ATCC, and Envision multi-label analyzer (PerkinElmer) was used.

[0825] Experimental Methods:

[0826] AsPC-1 cells were seeded in 96-well U-shaped plates with ultra-low adsorption, with 80 μL of cell suspension per well containing 1000 AsPC-1 cells. The cell plates were incubated overnight in a CO2 incubator.

[0827] The test compound was diluted 5-fold to 8 concentrations using a multi-channel pipette, i.e., from 2 mM to 25.6 nM, and a double-duplicate experiment was set up. 78 μL of culture medium was added to the intermediate plate, and then 2 μL of serially diluted compound per well was transferred to the intermediate plate according to the corresponding positions. After mixing, 20 μL of the compound per well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10 μM to 0.128 nM. The cell plates were incubated in a CO2 incubator for 10 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0828] Add 100 μL of chemiluminescent cell viability detection reagent to the cell plate and incubate at room temperature for 30 minutes to stabilize the luminescence signal. Read the data using a multi-label analyzer.

[0829] Data analysis:

[0830] Convert the raw data into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%. The IC50 value can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism). Table 1 provides the inhibitory activity of the compounds of the present invention on AsPC-1 cell proliferation.

[0831] Table 1: Results of in vitro screening test of the compounds of the present invention

[0832]

[0833] Conclusion: The compounds of the present invention have significant inhibitory activity on AsPC-1 cell proliferation.

[0834] Experimental Example 2: In vitro cell proliferation experiment

[0835] Experimental materials: Instruction manual, pages 90 / 99, 118 CN 121270581 A

[0836] RPMI 1640 medium, DMEM medium, Ham's F12 medium, F12K medium, IMDM medium and penicillin / streptomycin antibiotics were purchased from Gibco, fetal bovine serum was purchased from Hyclone, and Envision multilabel analyzer (PerkinElmer) was used.

[0837] 3D CellTiter-Glo (chemiluminescent cell viability assay) reagent was purchased from Promega; GP2D cell line (DMEM + 10% FBS + 1% penicillin / streptomycin) was purchased from ECACC; PK-59 cell line (DMEM + 10% FBS + 1% penicillin / streptomycin), LOVO cells (RPMI1640 + 10% FBS + 1% penicillin / streptomycin), NCI-H727 cells (RPMI1640 + 10% FBS + 1% penicillin / streptomycin), A427 cell line (RPMI1640 + 10% FBS + 1% penicillin / streptomycin), Capan-1 Cells (IMDM + 20% FBS + 1% penicillin / streptomycin) were purchased from Nanjing Kebai Biotechnology Co., Ltd.; A375 cell line (DMEM + 10% FBS + 1% penicillin / streptomycin), AsPC-1 cells (RPMI1640 + 10% FBS + 1% penicillin / streptomycin), PSN-1 cell line (RPMI1640 + 10% FBS + 1% penicillin / streptomycin), and SW620 cells (RPMI1640 + 10% FBS + 1% penicillin / streptomycin) were purchased from Nanjing Kebai Biotechnology Co., Ltd. 1% penicillin / streptomycin), HCT116 cells (RPMI1640+10%FBS+1% penicillin / streptomycin), A549 cells (F12K+10%FBS+1% penicillin / streptomycin), and NCI-H441 cells (RPMI1640+10%FBS+1% penicillin / streptomycin) were purchased from ATCC; RKN cell lines (Ham's F12+10%FBS+1% penicillin / streptomycin) and LU99 cell lines (RPMI1640+10%FBS+1% penicillin / streptomycin) were purchased from JCRB.

[0838] Experimental methods:

[0839] Cells were seeded in 96-well U-shaped plates with ultra-low adsorption, with 80 μL of cell suspension per well, containing 1000 cells. The cell plates were incubated overnight in a carbon dioxide incubator.

[0840] The test compound was diluted 5-fold to 8 concentrations using a multi-channel pipette, i.e., from 2 mM to 25.6 nM, and a double-duplicate assay was performed. 78 μL of culture medium was added to the intermediate plate, and then 2 μL of the serially diluted compound was transferred to each well according to the corresponding position.After mixing, 20 μL of the compound was transferred to each well of the cell plate. The concentration range of the compound transferred to the cell plate was 10 μM to 0.128 nM. The cell plate was incubated in a CO2 incubator for 5 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0841] 50 μL of cell viability chemiluminescence detection reagent was added to each well of the cell plate and incubated at room temperature for 30 minutes to stabilize the luminescence signal. The readings were taken using a multi-label analyzer.

[0842] Data analysis:

[0843] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%. The IC50 value can be obtained by curve fitting using four parameters (obtained in the "log(inhibitor) vs. response - Variable slope" mode in GraphPad Prism). Table 2 provides the experimental results of the inhibitory activity of the compound of the present invention on cell proliferation.

[0844] Table 2: Results of in vitro cell proliferation inhibition experiment of the compounds of the present invention 91 / 99 pages 119 CN 121270581 A

[0845]

[0846] Conclusion: The compounds of the present invention have significant inhibitory activity on the cell proliferation of RAS mutant cell lines (such as GP2D, PK-59, AsPC-1, PSN-1, RKN, Capan-1, SW620, HCT116, LOVO, A549, H441, H727, LU99 and A427), but do not show obvious inhibitory effect in wild-type independent cell lines (such as A375), and have good selectivity.

[0847] Experimental Example 3: Detection of p-ERK Levels in AsPC-1 Cells

[0848] Experimental Materials:

[0849] AsPC-1 cells were purchased from ATCC; RPMI-1640 medium was purchased from GIbco; fetal bovine serum was purchased from Hyclone; Advanced Phospho-ERK1 / 2 (THR202 / TYR204) KIT was purchased from Bioauxilium-Advanced Phospho; The components of the ERK1 / 2 (THR202 / TYR204) KIT were: Advanced PhosphoERK1 / 2 Eu Cryptate antibody, Advanced PhosphoERK1 / 2 d2 antibody, Blocking reagent (stock solution 100X), Lysis buffer #1 (stock solution 4X), Detection buffer (ready-to-use), and storage temperature.All are ≤-16℃.

[0850] Experimental method:

[0851] (1) Cells were seeded in white 384-well cell culture plates, 8 μL of cell suspension per well, each well containing 7500 cells. The cell plate was placed in a carbon dioxide incubator and incubated overnight at 37°C;

[0852] (2) The test compound was diluted with 100% DMSO to 3 mM as the first concentration, and then diluted with pipette to ten concentrations of 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 μM. Take 2 μL of the compound and add it to 198 μL of cell starvation medium. After mixing, take 15 μL of the compound solution and add it to 35 μL of cell starvation medium and mix. Then add 4 μL of the compound solution from the last step to the corresponding cell plate wells. Place the cell plate back into the CO2 incubator and continue incubation for 3 hours. At this time, the compound concentrations are 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 nM.

[0853] (3) After the incubation is finished, add 3 μL of 5X cell lysis buffer to each well and incubate at room temperature with shaking for 30 minutes.

[0854] (4) Use detection buffer to dilute Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2 d2 antibody 20 times and mix them at a 1:1 ratio. Add 5 μL of the compound solution to each well. μL was added to the cell culture plate and incubated at room temperature for 2 h;

[0855] (5) After incubation, the HTRF excitation was read using a multi-label analyzer: 320nm, emission: 615nm, 665nm.

[0856] Data analysis:

[0857] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%, and the IC50 value was obtained by curve fitting using four parameters (obtained in GraphPad Prism log(inhibitor) vs. response - Variable slope mode). Table 4 provides the inhibitory effect of the compound of the present invention on p-ERK. Max well: positive control well reading is 1X lysis buffer; Min well: negative control well reading is 0.5% DMSO cell well cell lysis buffer. The experimental results are shown in Table 3.

[0858] Table 3: Results of in vitro pERK inhibition screening test of the compounds of the present invention

[0859]

[0860] Conclusion: The compounds of the present invention have significant inhibitory activity on pERK levels in AsPC-1 cells.

[0861] Experimental Example 4: Detection of p-ERK levels in GP2D cells

[0862] Experimental materials:

[0863] GP2D cell line (DMEM+10%FBS+1% penicillin / streptomycin) was purchased from ECACC; RPMI-1640 medium was purchased from GIbco; fetal bovine serum was purchased from Hyclone; Advanced Phospho-ERK1 / 2 (THR202 / TYR204) KIT was purchased from Bioauxilium-Advanced Phospho; the components of ERK1 / 2 (THR202 / TYR204) KIT were: Advanced PhosphoERK1 / 2 Eu Cryptate antibody, Advanced PhosphoERK1 / 2 d2 antibody, Blocking reagent (stock solution 100X), Lysis buffer #1 (stock solution 4X), Detection buffer (ready-to-use), and the storage temperature was ≤-16℃.

[0864] Experimental methods:

[0865] (1) Cells were seeded in white 384-well cell culture plates, with 8 μL of cell suspension per well, each well containing 7500 cells. The cell plate was placed in a carbon dioxide incubator and incubated overnight at 37°C;

[0866] (2) The test compound was diluted with 100% DMSO to 3 mM as the first concentration, and then diluted with pipette to ten concentrations of 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 μM. Take 2 μL of the compound and add it to 198 μL of cell starvation medium. After mixing, take 15 μL of the compound solution and add it to 35 μL of cell starvation medium. Mix well. Then add 4 μL of the compound solution from the last step to the corresponding cell plate wells. Place the cell plate back into the CO2 incubator and continue incubating for 3 hours. At this time, the compound concentrations are 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, 0.1 nM.

[0867] (3) After the incubation is finished, add 3 μL of 5X cell lysis buffer to each well and incubate at room temperature with shaking for 30 minutes. Instructions 93 / 99 pages 121 CN 121270581 A

[0868] (4) Use detection buffer to dilute Phospho-ERK1 / 2 Eu Cryptate antibody and Phospho-ERK1 / 2 d2 antibody 20 times and mix them at a 1:1 ratio. Add 5 μL of the compound solution to each well. μL was added to the cell culture plate and incubated at room temperature for 2 h;

[0869] (5) After incubation, the HTRF excitation was read using a multi-label analyzer: 320 nm.Emission: 615nm, 665nm.

[0870] Data Analysis:

[0871] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)*100%. The IC50 value can be obtained by curve fitting using four parameters (obtained in GraphPad Prism log(inhibitor) vs. response - Variable slope mode). Table 4 provides the inhibitory effect of the compound of the present invention on p-ERK. Max well: positive control well reading is 1X lysis buffer; Min well: negative control well reading is 0.5% DMSO cell well cell lysis buffer. The experimental results are shown in Table 4.

[0872] Table 4: Results of in vitro pERK inhibition screening test of the compound of the present invention

[0873]

[0874] Conclusion: The compound of the present invention has significant inhibitory activity on pERK level in GP2D cells.

[0875] Experimental Example 5: In vivo pharmacodynamic study

[0876] Experimental objective:

[0877] To study the in vivo pharmacodynamics of the compound of the present invention in a subcutaneous xenograft tumor model of human bronchial benign tumor NCI-H727 cells in BALB / c nude mice.

[0878] Experimental methods and steps:

[0879] Experimental animals: female BALB / c nude mice, 6-8 weeks old, weighing 18-22 grams; Supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0880] (1) Cell culture: Human bronchial benign tumor cells were cultured in vitro in a monolayer. The culture conditions were Gibco RMPI1640 medium with 10% fetal bovine serum, 37 ºC, and 5% CO2 incubator. The cells were passaged twice a week by routine digestion with trypsin-EDTA. When the cell saturation was 80%-90% and the number reached the required level, the cells were harvested, counted, and seeded.

[0881] (2) Tumor cell inoculation and grouping: 0.2 mL (2×10⁶ cells) of NCI-H727 cells (with matrix gel, volume ratio 1:1) were subcutaneously inoculated into the right back of each mouse. When the average tumor volume reached about 134 mm³, grouping and administration began, with 6 animals in each group.

[0882] The solvent was 5% DMSO / 10% solutol / 85% water. Control group: The solvent was administered twice daily by gavage at a dose of 10 µL / g; Treatment group: The test compound was dissolved in the solvent and administered once daily by gavage at the dose shown in Table 4.

[0883] (3) The tumor diameter was measured twice a week using calipers, and the tumor volume (V) was calculated using the formula: V = 0.5a × b², where a and b are the long and short diameters of the tumor, respectively. The tumor-inhibiting efficacy of the test compound was evaluated by the tumor growth inhibition rate (TGI). The calculation formula is: TGI(%) = [1–(Average tumor volume at the end of treatment - average tumor volume at the start of treatment (page 94 / 99, CN 121270581 A)) / (Average tumor volume at the end of treatment in the solvent control group - average tumor volume at the start of treatment in the solvent control group)] × 100%.

[0884] Experimental results:

[0885] The body weight of mice in each treatment group remained good after administration. The TGI was calculated based on the average tumor volume on day 21 after administration. The specific experimental results are shown in Table 5.

[0886] Table 5: Evaluation of the antitumor efficacy of the compound of the present invention in the human pulmonary bronchial benign tumor NCI-H727 model

[0887]

[0888] Conclusion: The compound of the present invention showed excellent antitumor effect in the NCI-H727 tumor model.

[0889] Experimental Example 6: In vivo pharmacodynamic study

[0890] Experimental objective:

[0891] To study the in vivo pharmacodynamics of the compound of the present invention in a subcutaneous xenograft tumor model of human pancreatic cancer PK59 cells in BALB / c nude mice.

[0892] Experimental methods and steps:

[0893] Experimental animals: female BALB / c nude mice, 6-8 weeks old, weighing 18-22 grams; supplier: Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0894] (1) Cell culture: Human pancreatic cancer PK59 cells were cultured in vitro in a monolayer. The culture conditions were Gibco RMPI1640 medium with 10% fetal bovine serum, 37 ºC, and 5% CO2 incubator. The cells were passaged twice a week by routine digestion with trypsin-EDTA. When the cell saturation was 80%-90% and the required number was reached, the cells were collected, counted, and inoculated.

[0895] (2) Tumor cell inoculation and grouping: 0.2 mL (2×106 cells) of PK59 cells (with matrix gel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each mouse. When the average tumor volume reached about 104.4 mm3, grouping and administration began, with 6 animals in each group.

[0896] The solvent was 5% DMSO / 10% solutol / 85% water. Control group: The solvent was administered by gavage once a day at a dose of 10 µL / g; Treatment group: The test compound was dissolved in the solvent and administered by gavage once a day at a dose shown in Table 5.

[0897] (3) The tumor diameter was measured twice a week using calipers, and the tumor volume (V) was calculated using the formula: V = 0.5a × b2, where a and b are the long and short diameters of the tumor, respectively. The tumor-inhibiting efficacy of the test compound was evaluated by the tumor growth inhibition rate (TGI). The calculation formula is: TGI(%) = [1 – (mean tumor volume at the end of treatment – ​​mean tumor volume at the start of treatment) / (mean tumor volume at the end of treatment in the solvent control group – mean tumor volume at the start of treatment in the solvent control group)] × 100%. (Instructions for use, pages 95 / 99, 123)CN 121270581 A

[0898] Experimental results:

[0899] The body weight of mice in each treatment group was well maintained after administration. The TGI was calculated based on the average tumor volume on the 22nd day after administration. The specific experimental results are shown in Table 6.

[0900] Table 6 Experimental results of the antitumor efficacy of the compound of the present invention in the human pancreatic cancer PK59 model

[0901]

[0902] Conclusion: The compound of the present invention showed excellent antitumor effect in the PK59 tumor model.

[0903] Experimental example 7: In vitro determination of the concentration ratio in whole blood and plasma

[0904] Experimental steps:

[0905] (1) Collect fresh mouse and human whole blood using blood collection tubes containing EDTAK2 anticoagulant (the number of animal individuals n≥3 and the number of human individuals n≥2). The whole blood samples should be mixed evenly and stored at 2~8℃ or on wet ice before use. The whole blood should be used within 36 hours after collection. Blank whole blood was centrifuged at 2000 × g for 15 minutes at room temperature to obtain blank plasma. The plasma condition was checked, and plasma samples showing hemolysis were not used.

[0906] (2) Whole blood samples were centrifuged in microvolume centrifuge tubes to determine hematocrit (the percentage of red blood cells in whole blood by volume).

[0907] (3) Diclofenac (all species), chlorthalidone (mouse), or chloroquine (human) were used as control compounds.

[0908] (4) An ACN solution containing 2% DMSO of the test compound was added to the blank whole blood sample to a final concentration of 1 µM, and three parallel treatments were performed. The final content of the organic phase in the system should not exceed 0.5% (the content of DMSO should not exceed 0.1%). A certain volume of drug-containing whole blood sample was transferred to a sample receiving plate (three parallels), and an equal volume of blank plasma was added and mixed evenly to obtain T0 sample.

[0909] (5) Incubate the whole blood sample containing the test compound at 37°C with shaking for 60 minutes.

[0910] (6) After incubation, transfer a certain volume of the drug-containing whole blood sample to the sample receiving plate (three parallel plates) as T60-whole blood sample.

[0911] (7) Centrifuge the remaining whole blood sample at 37°C at 2000 ×g for 15 minutes to obtain plasma sample. Transfer a certain volume of plasma to the sample receiving plate (three parallel plates) as T60-plasma sample.

[0912] (8) During sample processing, all samples are balanced with the matrix (i.e., the same volume of blank whole blood or blank plasma is added) and mixed evenly.

[0913] (9) Add 1 volume of pure water to the balanced sample, and then add a certain volume of the stop solution containing the internal standard compound (page 96 / 99, CN 121270581 A) to terminate the reaction.

[0914] (10) The analytes and control compounds in the sample were measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS).The concentration in the sample was determined by the ratio of the peak area of ​​the analyte to the peak area of ​​the internal standard.

[0915] Experimental results:

[0916] The experimental results are shown in Table 7. Wherein, KB / P represents the concentration ratio of the compound in whole blood and plasma, KE / P represents the concentration ratio of the compound in erythrocytes and plasma, and recovery rate (%) represents the recovery rate of the compound in whole blood.

[0917] Table 7 Distribution results of the compound of the present invention in whole blood and plasma

[0918]

[0919] Conclusion: Compared with human and mouse plasma, the compound of the present invention has a higher distribution in whole blood and erythrocytes.

[0920] Experimental Example 8: Pharmacokinetic test in mice

[0921] Experimental objective:

[0922] To evaluate the pharmacokinetic behavior of the compound of the present invention in male CD-1 (ICR) mice.

[0923] Experimental method:

[0924] The test compound was dissolved in solvent (5% DMSO / 10% solutol / 85% water). Four male CD-1 mice were divided into two groups of two. Group 1 mice received a single intravenous bolus injection of the compound at a dose of 1 mg / kg. Group 2 mice received a single gavage injection of the compound at a dose of 10 mg / kg. Whole blood samples were collected at 0.083 (intravenous bolus group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. The concentration of the test compound in the whole blood samples was determined using LC-MS / MS.

[0925] Results:

[0926] All animals tolerated the experiment well, and no abnormalities were observed. After intravenous bolus injection of compound 7A, the whole blood clearance (Cl) was 6.29 mL / min / kg, the steady-state apparent volume of distribution (Vd) was 2.18 L / kg, the elimination half-life (T1 / 2) was 4.29 h, and the area under the whole blood concentration-time curve (AUC0-last) from 0 to the last quantifiable time point was 3160 h·nmol / mL. After gavage administration of compound 7A, the time to peak concentration (Tmax) occurred 3.0 h after administration, the peak concentration (Cmax) was 2000 nmol / mL, the AUC0-last was 17119 h·nmol / mL, and the bioavailability (F) was 54.3%.

[0927] Conclusion: The compound of the present invention has high exposure, long half-life, and good pharmacokinetic properties.

[0928] Experimental Example 9: Pharmacokinetic Study in Rats

[0929] Experimental Objective:

[0930] To evaluate the pharmacokinetic behavior of the compound of the present invention in male SD rats.

[0931] Experimental Method:

[0932] The test compound was dissolved in a solvent (5% DMSO / 10% solutol / 85% water). Four male SD mice were used. (Instruction manual pages 97 / 99, 125 CN 121270581 A)Rats were divided into two groups of two. Group 1 rats received a single intravenous bolus (iv) injection of the compound at a dose of 1 mg / kg. Group 2 rats received a single oral gavage (po) administration of the compound at a dose of 10 mg / kg. Whole blood samples were collected at 0.083 (IV bolus group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentration of the test compound in the whole blood samples was determined using LC-MS / MS.

[0933] Experimental Results:

[0934] All animals tolerated the experiment well, and no abnormalities were observed. Specific experimental results are shown in Table 8.

[0935] Table 8: Pharmacokinetic Test Results of the Compound of the Present Invention in Rats

[0936]

[0937] Conclusion: The compound of the present invention has high exposure levels, a long half-life, and good pharmacokinetic properties.

[0938] Experimental Example 10: Pharmacokinetic Study in Beagle Dogs

[0939] Experimental Objective:

[0940] To evaluate the pharmacokinetic behavior of the compound of the present invention in male beagle dogs.

[0941] Experimental Methods:

[0942] The test compound was dissolved in a solvent (5% DMSO / 10% solutol / 85% water). Four male beagle dogs were divided into two groups of two. The animals in group 1 were administered the compound by a single intravenous bolus (iv) at a dose of 1 mg / kg. The animals in group 2 were administered the compound by a single oral gavage (po.) at a dose of 5 mg / kg. Whole blood samples were collected at 0.083 (IV bolus group only), 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration. The concentration of the test compound in the whole blood samples was determined by LC-MS / MS.

[0943] Experimental Results:

[0944] During the experiment, all animals showed good tolerance to the compound, and no abnormal behavior was observed. Specific experimental results are shown in Table 9.

[0945] Table 9 Pharmacokinetic Test Results of the Compound of the Present Invention in Beagle Dogs (Instructions for Use, Pages 98 / 99, 126, CN 121270581 A)

[0946]

[0947] Conclusion: The compound of the present invention has high exposure levels, a long half-life, and good pharmacokinetic properties. Instruction manual, page 99 / 99, 127 CN 121270581 A, Figure 1, Figure 2; Instruction manual, Figure 1 / 5, page 128 CN 121270581 A, Figure 3, Figure 4; Instruction manual, Figure 2 / 5, page 129 CN 121270581 A, Figure 5, Figure 6; Instruction manual, Figure 3 / 5, page 130 CN 121270581 A, Figure 7, Figure 8; Instruction manual, Figure 4 / 5, page 131 CN 121270581 A, Figure 9, Figure 10; Instruction manual, Figure 5 / 5, page 132 CN 121270581 AABSTRACT The application disclosed a macrocyclic derivative. Specifically a(VI),formulabyrepresentedcompoundaaredisclosed stereoisomer thereof, and a pharmaceutically acceptable salt thereof.

Claims

1. A compound represented by Formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, ， L is R6or ; L1is selected from -N(R9)C(=0)-; L2is selected from C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with 1, 2, or 3 R a substituents; L3is selected from -CH2- and C 3-6 cycloalkyl; L4is selected from a single bond and -C 1-4 alkyl-N(R 10 )C(=O)-; Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3- diazabicyclo[3.1.0]hexanyl, 5,6-diazaspiro[2.5]octanyl, 3,4-diazabicyclo[4.2.0]octanyl, and 2,3-diazabicyclo[3.1.1]heptanyl; Ring B is selected from 5-membered heteroaryl and 5-membered heteroaryl, indolyl and ; T1, T2, T3, and T4are each independently selected from CH and N; R1is selected from H, F, CI, Br, I, OH, C 1-4 alkyl and C 1-4 alkoxy, said C 1-4 alkyl and C 1-4 alkoxy are each independently optionally substituted with 1, 2, or 3 R h substituents; R2is selected from -0- and -NH-; R3is selected from phenyl and 5-6 membered heteroaryl, each independently optionally substituted with 1, 2, or 3 R b substituents; R4and R5are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, said C 1-4 alkyl, C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R c substituents; R6is selected from C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, said C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R d substituents; each R7is independently selected from H, halo, C 1-4 alkyl and C 1-4 alkoxy, said C 1-4 alkyl and C 1-4 alkoxy is independently optionally substituted with 1, 2, or 3 R e substituents; each R8is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and 3-10 membered heterocycloalkyl, said C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl, and 3-10 membered heterocycloalkyl, each independently optionally substituted with 1, 2, or 3 R f substituents; R9, R 10 selected from H and C 1-4 alkyl, said C 1-4 alkyl is optionally substituted with 1, 2, or 3 R g substituents; each R a , each R b , each R c , each R e , each R f , each R g , and each R h is independently selected from H, D, F, Cl, Br, I, OH, CN, N3, NO2, a straight 1-3 alkyl group and a straight 1-3 alkoxy group, each of which is independently optionally substituted with 1, 2, or 3 R; and each R is independently selected from H, D, F, Cl, Br, I, OH, CN, N3, NO2, a straight 1-3 alkyl group and a straight 1-3 alkoxy group, each of which is independently optionally substituted with 1, 2, or 3 R. each R d are each independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and -C(=O)-C 2-4 alkenyl, said C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, and -C(=O)-C 2-4 alkenyl are each independently optionally substituted with 1, 2, or 3 R; each R is independently selected from D, F, CI, Br, I, OH, CH3, CF3, OCH3, and OCF3; n, p, and q are each independently selected from 0, 1, 2, and 3; said "3-6 membered heterocycloalkyl", "3-10 membered heterocycloalkyl", and "5-6 membered heteroaryl" each independently contains 1 or 2 heteroatoms or groups of heteroatoms independently selected from -NH-, -0-, -S-, and N.

2. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, each R d is independently selected from the group consisting of CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and is independently selected from the group consisting of CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and is independently optionally substituted with 1, 2, or 3 R; or, each R d is independently selected from the group consisting of CH3and CH2CH3, which are each independently optionally substituted with 1, 2, or 3 F; or, each R d is independently selected from the group consisting of CH3, , and ; or, each R d is independently selected from the group consisting of CH3.

3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, each R1is independently selected from H, F, OH, and CH3.

4. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, Structural unit selected from , , , , , , , , , , and .

5. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, Ring A is selected from 3,4-diazabicyclo[4.1.0]heptyl and 2,3-diazabicyclo[3.1.1]heptyl; or, Ring A is selected from and .

6. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R2is selected from -0-.

7. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R3is selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, pyrazolyl, and imidazolyl, each of which is independently optionally substituted with 1, 2, or 3 R b substituents; alternatively, R3is selected from , and ; alternatively, R3is selected from .

8. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, R6is selected from C 3-6 cycloalkyl, said C 3-6 cycloalkyl is optionally substituted with 1, 2, or 3 R d substituents; or, R6is selected from cyclopropyl, cyclobutyl, cyclopentyl, azirdinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxetanyl, and oxepanyl, each independently optionally substituted with 1, 2, or 3 R d substituents; or, R6is selected from cyclopropyl, said cyclopropyl optionally substituted with 1, 2, or 3 R d substituents; or, R6is selected from and ; or, R6is .

9. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, Each R7 is independently selected from H, F, Cl, and C. 1-3 Alkyl, the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. e Alternatively, R7 is selected from H, F, Cl, CH3, and CH2CH3, wherein CH3 and CH2CH3 are independently and optionally replaced by 1, 2, or 3 R7 groups. e Substitution; or, R7 is selected from H, F, Cl, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3 and CD3; or, R7 is selected from H, CH3 and CH2CH3.

10. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, each R8is independently selected from the group consisting of H, C 1-3 alkyl and 3-10 membered heterocycloalkyl, said C 1-3 alkyl and 3-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R f ; or, R8is selected from the group consisting of H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, piperidinylalkenyl, homopiperidinyl, morpholinyl, and CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, piperidinylalkenyl, homopiperidinyl, morpholinyl, and are each independently optionally substituted with 1, 2, or 3 R f ; or, R8is selected from the group consisting of H, , , , , , and .

11. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, structural unit selected from ; or, a structural unit selected from , and ; or, a structural unit selected from and , , , , and ; or, a structural unit selected from , , , , and , and .

12. The compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, L3is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; or, L3is selected from -CH2-, and .

13. The compound according to any one of claims 1-12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from and .

14. The compound according to claim 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from and , wherein, T1and T3are each independently selected from CH and N; each R1is independently selected from H, F, OH, and CH3. R3is selected from phenyl and 5-6 membered heteroaryl, each independently optionally substituted with 1, 2, or 3 R b substituents; R6is selected from C 3-6 cycloalkyl, said C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R d substituents; R7is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R e substituents; each R8is independently selected from H, C 1-3 alkyl and 5-10 membered heterocycloalkyl, said C 1-3 alkyl and 5-10 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R f substituents; L3is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; each R is independently selected from the group consisting of C d each R is independently selected from the group consisting of C 1-3 alkyl, said C 1-3 alkyl is optionally substituted with 1, 2, or 3 R; Each R b Each of the following is independently selected from H, D, F, Cl, OH, and CH3; Each R e They were each independently selected from H, D, F, and Cl; Each R f The components are independently selected from H, D, F, Cl, CH3 and OCH3, respectively, wherein CH3 and OCH3 are independently and optionally replaced by 1, 2 or 3 Rs; each R is independently selected from D and F.

15. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of claim 14, wherein, the compound is selected from: 。 16. A compound represented by Formula (XVII), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 17. A compound represented by Formula (XVIII) or a pharmaceutically acceptable salt thereof, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。

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