Macrocyclic derivatives and uses thereof

Abstract

Macrocyclic Derivatives Specifically disclosed are compounds represented by formula (VI), their stereoisomers, and pharmaceutically acceptable salts thereof: [Formula 1] JPEG2025532258000233.jpg6784

Description

[Technical Field]

[0001] This disclosure claims priority to: CN202211213222.2, filing date: September 29, 2022; CN2023101326996, filing date: February 17, 2023; CN2023103711659, filing date: April 7, 2023; CN2023106857489, filing date: June 9, 2023; CN2023109116322, filing date: July 24, 2023.

[0002] The present disclosure relates to a class of macrocyclic derivatives and their applications, and in particular to the compound shown in formula (VI), its stereoisomers, and pharmaceutically acceptable salts thereof. [Background technology]

[0003] RAS (including KRAS, NRAS, and HRAS) is a small GTPase molecular switch downstream of growth factor receptors, such as EGFR. It is a key hub in the RAS-RAF-MEK-ERK signaling pathway and the PI3K-AKT-mTOR signaling pathway, which regulate events such as cell proliferation and survival. Mutations in RAS disrupt the GTP hydrolysis process, leading to functional activation of the protein. Under normal physiological conditions, RAS typically exists in the inactive RAS (OFF) form that binds to GDP; whereas in RAS-mutated tumor cells, RAS exists primarily in the activated RAS (ON) form that binds to GTP. RAS-mutated cancer patients account for 30% of all cancer patients (US data), with KRAS, NRAS, and HRAS mutations accounting for 85%, 11%, and 4%, respectively. There are approximately 20 types of mutations in each RAS, such as KRAS. G12C , KRAS G12D , KRAS G12V , KRAS G12R , KRAS G13CRAS mutations are important factors in the development of cancer, making mutated RAS an important target for cancer treatment. G12C Targeted covalent inhibitors of KRAS, namely sotorasib and adagrasib, G12C Although great success has been achieved in non-small cell lung cancer with RAS mutations, other types of RAS mutations, e.g. G12D , KRAS G12V , KRAS G13 There are still no effective targeted therapeutic agents for cancers with RAS mutations such as NRAS, etc. Therefore, the development of broad-spectrum RAS inhibitors has great clinical significance.

[0004] Revolution Medicines, Inc. (WO2020132597, WO2021091982, WO2021091967, WO2021091956) has disclosed a class of macrocyclic compounds capable of forming ternary complexes with the chaperone CypA and RAS(ON) in the body. The formation of the ternary complex blocks the binding of RAF downstream of RAS, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway and achieving antitumor effects. Such RAS inhibitors have significant inhibitory effects against various RAS mutations and RAS-dependent tumors. Broad-spectrum RAS inhibitors with excellent druggability designed and synthesized based on such macrocyclic compounds have significant clinical application value. Summary of the Invention

[0005] The present disclosure provides a compound represented by formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006] [ka] L is R6 or

[0007] [ka] and; L1 is selected from -N(R9)C(=O)-; L2 is 1, 2, or 3 R a C optionally substituted with 1-6 alkyl; L3 is -CH2- and C 3-6 cycloalkyl; L4 is a single bond and -C1-4 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]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 a 5-membered heteroaryl and a 5-membered heteroaryl, indolyl, and

[0008] [ka] Selected from; T1, T2, T3, and T2 are each independently selected from CH and N; R1 is H, F, Cl, Br, I, OH, C 1-4 Alkyl, and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4 Alkoxy is each independently 1, 2, or 3 R h optionally replaced by; R2 is selected from -O- and -NH-; R3 is selected from phenyl and 5- to 6-membered heteroaryl, each of which is independently selected from 1, 2, or 3 R b optionally replaced by; R4 and R5 are each independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; 1-4 Alkyl, C 3-6cycloalkyl, and 3- to 6-membered heterocycloalkyl each independently have 1, 2, or 3 R c optionally replaced by; R6 is C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 R d optionally replaced by; Each R7 is independently H, halogen, C 1-4 Alkyl, and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4 Alkoxy is each independently 1, 2, or 3 R e optionally replaced by; Each R8 is independently H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, and 3- to 10-membered heterocycloalkyl; 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, and 3- to 10-membered heterocycloalkyl each independently have 1, 2, or 3 R f optionally replaced by; R9 and R 10 However, H and C 1-4 alkyl, C 1-4 alkyl is 1, 2, or 3 R g optionally replaced by; Each R a , each R b , each R c , each R e , each R f , each R g , and each R h are independently H, D, F, Cl, Br, I, OH, C 1-3 Alkyl, and C 1-3 alkoxy, C 1-3 Alkyl and C 1-3 each alkoxy is optionally substituted independently with 1, 2, or 3 R; Each R d But independently, C 1-4 Alkyl, C3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C 2-4 alkenyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C 2-4 alkenyl is optionally substituted with each independently 1, 2, or 3 R; each R is independently selected from D, F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; n, p, and q are each independently selected from 0, 1, 2, and 3; The "3- to 6-membered heterocycloalkyl", "3- to 10-membered heterocycloalkyl", and "5- to 6-membered heteroaryl" each independently contain one or two heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N.

[0009] The present disclosure further provides a compound represented by formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0010] [ka] L is R6 or

[0011] [ka] and; L1 is selected from -N(R9)C(=O)-; L2 is 1, 2, or 3 R a C optionally substituted with 1-6 alkyl; L3 is -CH2- and C 3-6 cycloalkyl; L4 is a single bond and -C1-4 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]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 a 5-membered heteroaryl and a 5-membered heteroaryl, indolyl, and

[0012] [ka] Selected from; R1 is H, F, Cl, Br, I, OH, C 1-4 Alkyl, and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4 Alkoxy is each independently 1, 2, or 3 R h optionally replaced by; R2 is selected from -O- and -NH-; R3 is selected from phenyl and 5- to 6-membered heteroaryl, each of which is independently selected from 1, 2, or 3 R b optionally replaced by; R4 and R5 are each independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; 1-4 Alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl each independently have 1, 2, or 3 R c optionally replaced by; R6 is C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 R d optionally replaced by; Each R7 is independently H, halogen, C 1-4 Alkyl, and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4Alkoxy is each independently 1, 2, or 3 R e optionally replaced by; Each R8 is independently H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, and 3- to 7-membered heterocycloalkyl; C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, and 3- to 7-membered heterocycloalkyl each independently have 1, 2, or 3 R f optionally replaced by; R9 and R 10 However, H and C 1-4 alkyl, C 1-4 alkyl is 1, 2, or 3 R g optionally replaced by; Each R a , each R b , each R c , each R e , each R f , each R g , and each R h are each independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; Each R d But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C 2-4 alkenyl, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C 2-4 alkenyl is optionally substituted with each independently 1, 2, or 3 R; each R is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; n, p, and q are each independently selected from 0, 1, 2, and 3; The "3- to 6-membered heterocycloalkyl", "3- to 7-membered heterocycloalkyl", and "5- to 6-membered heteroaryl" each independently contain one or two heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N.

[0013] The present disclosure further provides a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0014] [ka] L1 is selected from -N(R9)C(=O)-; L2 is 1, 2, or 3 R a C optionally substituted with 1-6 alkyl; L3 is selected from -CH2-; L4 is a single bond and -C1-4 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]hexane, and 5,6-diazaspiro[2.5]octane; R1 is H, F, Cl, Br, I, OH, C 1-4 Alkyl, and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4 Alkoxy is each independently 1, 2, or 3 R h optionally replaced by; R2 is selected from -O- and -NH-; R3 is selected from phenyl and 5- to 6-membered heteroaryl, each of which is independently selected from 1, 2, or 3 R b optionally replaced by; R4 and R5 are each independently H, C 1-4 Alkyl, C 3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl; 1-4 Alkyl, C3-6 cycloalkyl, and 3- to 6-membered heterocycloalkyl each independently have 1, 2, or 3 R c optionally replaced by; R6 is C 3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 R d optionally replaced by; R7 is H, C 1-4 Alkyl and C 1-4 alkoxy, C 1-4 Alkyl and C 1-4 Alkoxy is each independently 1, 2, or 3 R e optionally replaced by; R8 is H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, and 3- to 7-membered heterocycloalkyl; C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 cycloalkyl, and 3- to 7-membered heterocycloalkyl each independently have 1, 2, or 3 R f optionally replaced by; R9 and R 10 However, H and C 1-4 alkyl, C 1-4 alkyl is 1, 2, or 3 R g optionally replaced by; Each R a , R b , R c , R e , R f , R g , and R h are each independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; Each R d But independently, C 1-4 Alkyl, C 3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C 2-4 alkenyl, C 1-4 Alkyl, C3-6 Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C 2-4 alkenyl is optionally substituted with each independently 1, 2, or 3 R; each R is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; n, p, and q are each independently selected from 0, 1, 2, and 3; The "3- to 6-membered heterocycloalkyl", "3- to 7-membered heterocycloalkyl", and "5- to 6-membered heteroaryl" each independently contain one or two heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N.

[0015] In some embodiments of the present disclosure, each R above is independently selected from D and F, and the other variables are as defined herein.

[0016] In some embodiments of the present disclosure, each R above is independently selected from F, and the other variables are as defined herein.

[0017] In some embodiments of the present disclosure, each of the above R a is independently selected from H, D, F, Cl, and CH3, and other variables are as defined herein.

[0018] In some embodiments of the present disclosure, each of the above R b are independently selected from H, D, F, Cl, OH, and CH3, and other variables are as defined herein.

[0019] In some embodiments of the present disclosure, each of the above R c is independently selected from H, D, F, and Cl, and other variables are as defined herein.

[0020] In some embodiments of the present disclosure, each of the above R dare independently CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, and

[0021] [ka] wherein each independently is optionally substituted with 1, 2, or 3 R, and the other variables are as defined herein.

[0022] In some embodiments of the present disclosure, each of the above R d are independently CH 3、

[0023] [ka] and other variables are as defined herein.

[0024] In some embodiments of the present disclosure, each of the above R d is independently C optionally substituted with 1, 2, or 3 R 1-3 alkyl, and other variables are as defined herein.

[0025] In some embodiments of the present disclosure, each of the above R d is independently selected from CH and CHCH, each of which is independently optionally substituted with 1, 2, or 3 F, and other variables are as defined herein.

[0026] In some embodiments of the present disclosure, each of the above R d is independently selected from CH optionally substituted with 1, 2, or 3 F, and other variables are as defined herein.

[0027] In some embodiments of the present disclosure, each of the above R d is independently selected from CH3, and other variables are as defined herein.

[0028] In some embodiments of the present disclosure, each of the above R d is independently selected from CH3, and other variables are as defined herein.

[0029] In some embodiments of the present disclosure, each of the above R e is independently selected from H, D, F, and Cl, and other variables are as defined herein.

[0030] In some embodiments of the present disclosure, each of the above R e is independently selected from D and F, and other variables are as defined herein.

[0031] In some embodiments of the present disclosure, each of the above R f is independently selected from H, D, F, Cl, CH, and OCH, wherein CH and OCH are each independently optionally substituted with 1, 2, or 3 R, and other variables are as defined herein.

[0032] In some embodiments of the present disclosure, each of the above R f are independently selected from H, D, F, Cl, CH3, CD3, CF3, and OCH3, and other variables are as defined herein.

[0033] In some embodiments of the present disclosure, each of the above R g is independently selected from H, D, F, and Cl, and other variables are as defined herein.

[0034] In some embodiments of the present disclosure, each of the above R h is independently selected from H, D, F, and Cl, and other variables are as defined herein.

[0035] In some embodiments of the present disclosure, each R1 above is independently selected from H, F, OH, and CH3, and other variables are as defined herein.

[0036] In some embodiments of the present disclosure, each R1 above is independently selected from H, F, and CH3, and other variables are as defined herein.

[0037] In some embodiments of the present disclosure, the above structural unit

[0038] [ka] teeth,

[0039] [ka] and other variables are as defined herein.

[0040] In some embodiments of the present disclosure, the above structural unit

[0041] [ka] teeth,

[0042] [ka] and other variables are as defined herein.

[0043] In some embodiments of the present disclosure, the above structural unit

[0044] [ka] teeth,

[0045] [ka] and other variables are as defined herein.

[0046] In some embodiments of the present disclosure, the above structural unit

[0047] [ka] teeth,

[0048] [ka] and other variables are as defined herein.

[0049] In some embodiments of the present disclosure, ring A above is selected from 3,4-diazabicyclo[4.1.0]heptyl and 2,3-diazabicyclo[3.1.1]heptyl, and other variables are as defined herein.

[0050] In some embodiments of the present disclosure, ring A above is

[0051] [ka] and other variables are as defined herein.

[0052] In some embodiments of the present disclosure, ring A above is

[0053] [ka] and other variables are as defined herein.

[0054] In some embodiments of the present disclosure, the above structural unit

[0055] [ka] teeth,

[0056] [ka] and other variables are as defined herein.

[0057] In some embodiments of the present disclosure, R2 above is selected from -O-, and other variables are as defined herein.

[0058] In some embodiments of the present disclosure, R3 above is 1, 2, or 3 R b and 5-6 membered heteroaryl optionally substituted with , and other variables are as defined herein.

[0059] In some embodiments of the present disclosure, R3 above is 1, 2, or 3 R b and 5-membered heteroaryl optionally substituted with , and other variables are as defined herein.

[0060] In some embodiments of the present disclosure, R3 above is selected from thiazolyl, thienyl, oxazolyl, pyrazolyl, and imidazolyl, each of which independently has 1, 2, or 3 R b and optionally substituted with , other variables are as defined herein.

[0061] In some embodiments of the present disclosure, R3 above is selected from thiazolyl and thienyl, and other variables are as defined herein.

[0062] In some embodiments of the present disclosure, R3 above is

[0063] [ka] and other variables are as defined herein.

[0064] In some embodiments of the present disclosure, R3 above is

[0065] [ka] and other variables are as defined herein.

[0066] In some embodiments of the present disclosure, R3 above is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, pyrazolyl, and imidazolyl, each of which independently has 1, 2, or 3 R b and optionally substituted with , other variables are as defined herein.

[0067] In some embodiments of the present disclosure, R3 above is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl, and imidazolyl, each of which independently has 1, 2, or 3 R b and optionally substituted with , other variables are as defined herein.

[0068] In some embodiments of the present disclosure, R3 above is

[0069] [ka] and other variables are as defined herein.

[0070] In some embodiments of the present disclosure, R3 above is

[0071] [ka] and other variables are as defined herein.

[0072] In some embodiments of the present disclosure, R3 above is

[0073] [ka] and other variables are as defined herein.

[0074] In some embodiments of the present disclosure, R above is selected from H, CH, CHCH, CHCHCH, CH(CH), cyclopropyl, cyclobutyl, and cyclopentyl, wherein CH, CHCH, CHCHCH, CH(CH), cyclopropyl, cyclobutyl, and cyclopentyl are each independently selected from 1, 2, or 3 R c and optionally substituted with , other variables are as defined herein.

[0075] In some embodiments of the present disclosure, the above R 5は、H、CH 3 、CH 2 CH 3 、CH 2 CH 2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, and cyclopentyl, wherein CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl, and cyclopentyl are each independently selected from 1, 2, or 3 R c and optionally substituted with , other variables are as defined herein.

[0076] In some embodiments of the present disclosure, R4 above is selected from H, and R5 is selected from H, CH(CH3)2, and

[0077] [ka] and other variables are as defined herein.

[0078] In some embodiments of the present disclosure, R6 above is selected from cyclopentyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, and oxacyclohexyl, each of which independently has one, two, or three R d and optionally substituted with , other variables are as defined herein.

[0079] In some embodiments of the present disclosure, R6 above is selected from cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl, and oxacyclohexyl, each of which independently has one, two, or three R d and optionally substituted with , other variables are as defined herein.

[0080] In some embodiments of the present disclosure, R6 above is

[0081] [ka] and other variables are as defined herein.

[0082] In some embodiments of the present disclosure, R6 above is

[0083] [ka] and other variables are as defined herein.

[0084] In some embodiments of the present disclosure, R6 above is 1, 2, or 3 R d C optionally substituted with 3-6 cycloalkyl, and other variables are as defined herein.

[0085] In some embodiments of the present disclosure, R6 above is 1, 2, or 3のRd and cyclopropyl, optionally substituted with , and other variables are as defined herein.

[0086] In some embodiments of the present disclosure, R6 above is

[0087] [ka] and other variables are as defined herein.

[0088] In some embodiments of the present disclosure, R6 above is

[0089] [ka] and other variables are as defined herein.

[0090] In some embodiments of the present disclosure, each R7 above is independently selected from H, F, Cl, and C 1-3 alkyl, C 1-3 Alkyl is 1, 2, or 3 R e and optionally substituted with , other variables are as defined herein.

[0091] In some embodiments of the present disclosure, R7 above is selected from H, F, Cl, CH3, and CH2CH3, and CH3 and CH2CH3 are each independently selected from 1, 2, or 3 R e and optionally substituted with , other variables are as defined herein.

[0092] In some embodiments of the present disclosure, R7 above is selected from H, F, Cl, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3, and CD3, and other variables are as defined herein.

[0093] In some embodiments of the present disclosure, R7 above is selected from H, F, Cl, CH3, and CH2CH3, and other variables are as defined herein.

[0094] In some embodiments of the present disclosure, R7 above is selected from H, CH3, and CH2CH3, and other variables are as defined herein.

[0095] In some embodiments of the present disclosure, each R8 above is independently selected from H, C 1-3alkyl, and 3- to 10-membered heterocycloalkyl; 1-3 The alkyl and 3- to 10-membered heterocycloalkyl each independently have 1, 2, or 3 R f and optionally substituted with , other variables are as defined herein.

[0096] In some embodiments of the present disclosure, each R8 above is independently selected from H, C 1-3 alkyl, and 5- to 10-membered heterocycloalkyl; 1-3 The alkyl and 5- to 10-membered heterocycloalkyl each independently have 1, 2, or 3 R f and optionally substituted with , other variables are as defined herein.

[0097] In some embodiments of the present disclosure, each R8 above is independently selected from H, C 1-3 alkyl, and 5- to 6-membered heterocycloalkyl; 1-3 The alkyl and 5- to 6-membered heterocycloalkyl each independently have 1, 2, or 3 R f and optionally substituted with , other variables are as defined herein.

[0098] In some embodiments of the present disclosure, R8 above is selected from the group consisting of H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropyridinyl, piperidinyl, tetrahydropyridinyl, piperidinyl, morpholinyl,

[0099] [ka] selected from CH3, CH2CH3, piperazinyl, homopiperidinyl, piperidinyl, tetrahydropyridinyl, homopiperidinyl, morpholinyl,

[0100] [ka] each independently represents 1, 2, or 3 R fand optionally substituted with , other variables are as defined herein.

[0101] In some embodiments of the present disclosure, R8 above is H,

[0102] [ka] and other variables are as defined herein.

[0103] In some embodiments of the present disclosure, R8 above is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, morpholinyl, and

[0104] [ka] selected from CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, morpholinyl, and

[0105] [ka] each independently represents 1, 2, or 3 R f and optionally substituted with , other variables are as defined herein.

[0106] In some embodiments of the present disclosure, R8 above is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, and morpholinyl, wherein CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, and morpholinyl are each independently selected from 1, 2, or 3 R f and optionally substituted with , other variables are as defined herein.

[0107] In some embodiments of the present disclosure, R8 above is H,

[0108] [ka] and other variables are as defined herein.

[0109] In some embodiments of the present disclosure, R8 above is H, and

[0110] [ka] and other variables are as defined herein.

[0111] In some embodiments of the present disclosure, the above structural unit

[0112] [ka] teeth,

[0113] [ka] and other variables are as defined herein.

[0114] In some embodiments of the present disclosure, the above structural unit

[0115] [ka] teeth,

[0116] [ka] and other variables are as defined herein.

[0117] In some embodiments of the present disclosure, the above structural unit

[0118] [ka] teeth,

[0119] [ka] and other variables are as defined herein.

[0120] In some embodiments of the present disclosure, the above structural unit

[0121] [ka] teeth,

[0122] [ka] and other variables are as defined herein.

[0123] In some embodiments of the present disclosure, the above structural unit

[0124] [ka] teeth,

[0125] [ka] and other variables are as defined herein.

[0126] In some embodiments of the present disclosure, the above structural unit

[0127] [ka] teeth,

[0128] [ka] and other variables are as defined herein.

[0129] In some embodiments of the present disclosure, the above structural unit

[0130] [ka] teeth,

[0131] [ka] and other variables are as defined herein.

[0132] In some embodiments of the present disclosure, the above structural unit

[0133] [ka] teeth,

[0134] [ka] and other variables are as defined herein.

[0135] In some embodiments of the present disclosure, the above structural unit

[0136] [ka] teeth,

[0137] [ka] and other variables are as defined herein.

[0138] In some embodiments of the present disclosure, the above structural unit

[0139] [ka] teeth,

[0140] [ka] and other variables are as defined herein.

[0141] In some embodiments of the present disclosure, the top ring B is

[0142] [ka] and other variables are as defined herein.

[0143] In some embodiments of the present disclosure, ring B above is selected from indolyl, and other variables are as defined herein.

[0144] In some embodiments of the present disclosure, the top ring B is

[0145] [ka] and other variables are as defined herein.

[0146] In some embodiments of the present disclosure, L1 above is selected from -N(CH3)C(=O)-, and other variables are as defined herein.

[0147] In some embodiments of the present disclosure, L2 above is

[0148] [ka] and other variables are as defined herein.

[0149] In some embodiments of the present disclosure, L3 above is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and other variables are as defined herein.

[0150] In some embodiments of the present disclosure, L3 above is -CH2-,

[0151] [ka] and other variables are as defined herein.

[0152] In some embodiments of the present disclosure, L3 above is selected from -CH2-, and other variables are as defined herein.

[0153] In some embodiments of the present disclosure, L3 above is

[0154] [ka] and other variables are as defined herein. In some embodiments of the present disclosure, L4 above is selected from a single bond and -CH 2- N(CH3)C(=O)-, and other variables are as defined herein.

[0155] In some embodiments of the present disclosure, L above is

[0156] [ka] and other variables are as defined herein.

[0157] In some embodiments of the present disclosure, L above is

[0158] [ka] and other variables are as defined herein.

[0159] In some embodiments of the present disclosure, L above is R6, and the other variables are as defined herein.

[0160] In some embodiments of the present disclosure, L above is

[0161] [ka] and other variables are as defined herein.

[0162] In some embodiments of the present disclosure, the above compound, its stereoisomer, or its pharmaceutically acceptable salt is

[0163] [ka] is selected from Ring A, T1, T3, R1, R3, R6, R7, R8, L3, and n are as defined herein.

[0164] In some embodiments of the present disclosure, the above compound, its stereoisomer, or its pharmaceutically acceptable salt is

[0165] [ka] is selected from Structural Unit

[0166] [ka] but,

[0167] [ka] Selected from; Structural Unit

[0168] [ka] but,

[0169] [ka] Selected from; R6 is R 1, 2, or 3 d C optionally substituted with 3-6 cycloalkyl; each Rd C optionally substituted with 1, 2, or 3 R 1-4 alkyl; L3, R3, R7, each R8, and each R are as defined herein.

[0170] In some embodiments of the present disclosure, the above compounds of formula (VI-1), formula (VI-2), or formula (VI-3), their stereoisomers, or pharmaceutically acceptable salts thereof, comprise the structural unit

[0171] [ka] but,

[0172] [ka] and other variables are as defined herein.

[0173] In some embodiments of the present disclosure, the above compound of formula (VI-1), its stereoisomer, or its pharmaceutically acceptable salt is

[0174] [ka] is selected from T1 and T3 are each independently selected from CH and N; each R1 is independently selected from H, F, OH, and CH3; R3 is selected from phenyl and 5- to 6-membered heteroaryl, each of which is independently selected from 1, 2, or 3 R b optionally replaced by; R6 is R 1, 2, or 3 d C optionally substituted with 3-6 cycloalkyl; R7 is H and C1-3 alkyl, C 1-3 alkyl is 1, 2, or 3 R e optionally replaced by; Each R8 is independently H, C 1-3 alkyl, and 5- to 10-membered heterocycloalkyl; 1-3 alkyl and 5- to 10-membered heterocycloalkyl each independently represent 1, 2, or 3 R f optionally each replaced by; L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Each R d C optionally substituted with 1, 2, or 3 R 1-3 alkyl; Each R b is independently selected from H, D, F, Cl, OH, and CH3; Each R e is independently selected from H, D, F, and Cl; Each R f is independently selected from H, D, F, Cl, CH3, and OCH3, wherein CH3 and OCH3 are each independently optionally substituted with 1, 2, or 3 R; Each R is independently selected from D and F.

[0175] In some embodiments of the present disclosure, in the above compounds of formula (P-1) or (P-2), their stereoisomers, or pharmaceutically acceptable salts thereof, each of R1, R3, R6, R7, each of R8, T1, T3, and L3 is as defined by formula (VI), formula (III), or formula (I) herein.

[0176] In some embodiments of the present disclosure, in the above compounds of formula (P-1) or (P-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R3 is a 5-6 membered heteroaryl, and the other variables are as defined herein.

[0177] In some embodiments of the present disclosure, in the above compounds of formula (P-1) or (P-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, R3 is thienyl and thiazolyl, and other variables are as defined herein.

[0178] In some embodiments of the present disclosure, the above compounds of formula (P-1) or (P-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, each R is independently selected from H, C 1-3 alkyl, and 5- to 6-membered heterocycloalkyl; 1-3 alkyl and 5- to 6-membered heterocycloalkyl each independently represent 1, 2, or 3 R f and optionally substituted with , other variables are as defined herein.

[0179] In some embodiments of the present disclosure, in the above compounds of formula (P-1) or (P-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, T1 is CH, T3 is CH, and the other variables are as defined herein.

[0180] In some embodiments of the present disclosure, the compound of formula (P-1) or (P-2) above, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, L3 is -CH2-,

[0181] [ka] and other variables are as defined herein.

[0182] In some embodiments of the present disclosure, the above compound of formula (P-1) or (P-2), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0183] [ka] Each R1, R3, R6, R7, each R8, T1, T3, and L3 is as defined by formula (P-1) or (P-2) herein.

[0184] In some embodiments of the present disclosure, the above compound, its stereoisomer, or its pharmaceutically acceptable salt is

[0185] [ka] is selected from R1, R3, R4, R5, R6, R7, R8, L1, L3, L4, and n are as defined herein.

[0186] In some embodiments of the present disclosure, the above compound, its stereoisomer, or its pharmaceutically acceptable salt is selected from:

[0187] [ka] R1, R3, R6, R7, and R8 are as defined herein.

[0188] In some embodiments of the present disclosure, the above compound of formula (IV), its stereoisomer, or its pharmaceutically acceptable salt is selected from:

[0189] [ka] R1, R3, R6, R7, and R8 are as defined herein.

[0190] In some embodiments of the present disclosure, the above compound of formula (IV-1a) or formula (IV-1b), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is selected from:

[0191] [ka] R1, R3, R6, R7, and R8 are as defined herein.

[0192] In some embodiments of the present disclosure, the above compounds of formula (IV), (IV-1a), (IV-1b), (IV-1a-1), (IV-1a-2), (IV-1b-1), (IV-1b-2), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is selected from H, F, OH, and CH; R is selected from phenyl and thiazolyl, each of which independently has 1, 2, or 3 R b R6 is selected from cyclopropyl, which is optionally substituted with 1, 2, or 3 R d R7 is selected from H, F, Cl, CH3, and CH2CH3; R8 is H,

[0193] [ka] Each R is selected from b is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3, and OCF3; each R d But independently, CH3,

[0194] [ka] is selected from.

[0195] Some embodiments of the present disclosure result from any combination of the above variables.

[0196] The present disclosure further provides the following compounds, their stereoisomers, or pharmaceutically acceptable salts thereof:

[0197] [ka]

[0198] [ka]

[0199] [ka]

[0200] [ka]

[0201] [ka]

[0202] In some embodiments of the present disclosure, the above compound, its stereoisomer, or its pharmaceutically acceptable salt is selected from the following:

[0203] [ka]

[0204] [ka]

[0205] [ka]

[0206] [ka]

[0207] [ka]

[0208] [ka]

[0209] [ka]

[0210] [ka]

[0211] [ka]

[0212] [ka]

[0213] [ka]

[0214] [ka]

[0215] [ka]

[0216] [ka]

[0217] [ka]

[0218] [ka]

[0219] The present disclosure further provides the application of the above compounds, their stereoisomers, or their pharmaceutically acceptable salts in the preparation of RAS inhibitory medicaments.

[0220] The RAS inhibitor drugs of the present disclosure are used to treat RAS-mutated and RAS-dependent tumors, such as solid tumors; further, the solid tumor is pancreatic cancer, lung cancer, or colorectal cancer.

[0221] The present disclosure further provides the following synthetic methods: Method 1 - Intermediate:

[0222] [ka]

[0223] Method 2 - Intermediate:

[0224] [ka]

[0225] Method 3 - Intermediate:

[0226] [ka]

[0227] Method 4 - Intermediate:

[0228] [ka]

[0229] Method 5 - Intermediate:

[0230] [ka]

[0231] Method 6 - Intermediate:

[0232] [ka]

[0233] Method 7 - Intermediate

[0234]

change

[0235]

[0236] Method 8 - Intermediate

[0237]

change

[0238] Method 9 - Intermediate

[0239]

change

[0240] Method 10 - Intermediate

[0241]

change

[0242] Method 11:

[0243]

change

[0244] Method 12:

[0245]

change

[0246] Method 13:

[0247]

change

[0248] Method 14:

[0249] [ka]

[0250] Method 15:

[0251] [ka]

[0252] Method 16:

[0253] [ka]

[0254] Method 17:

[0255] [ka]

[0256] Method 18:

[0257] [ka]

[0258] Technical effects The compounds of the present disclosure bind relatively well to the chaperone CypA, and binding to CypA blocks the binding of RAS downstream RAF to RAS, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway and achieving anti-tumor effects. The compounds of the present disclosure have significant inhibitory activity against the cell proliferation of RAS mutant cell lines (e.g., GP2D, PK-59, AsPC-1, PSN-1RKN, Capan-1, SW620, HCT116, LOVO, A549, H441, H727, LU99, and A427), but do not show significant inhibitory effect against wild-type independent cell lines (e.g., A375), and also have excellent selectivity. They also have significant inhibitory activity against AsPC-1 and GP2D cell pERK levels. In pharmacokinetic experiments in various species, the compounds of the present disclosure have shown good pharmacokinetic properties (e.g., high exposure and long half-life). The compounds of the present disclosure have relatively high distribution in whole blood and red blood cells compared to human and mouse plasma. In in vivo pharmacodynamic experiments, the compounds of the present disclosure have shown excellent antitumor effects requiring low doses, are safe, and have the prospect of widespread application.

[0259] Definitions and Explanations Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. Certain terms or phrases should not be considered uncertain or indefinite without a specific definition, but rather should be understood in their ordinary sense. When a trade name is used herein, it is meant to refer to the corresponding article or its active ingredient.

[0260] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0261] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present disclosure prepared from a compound found in the present disclosure having specific substituents and a relatively non-toxic acid or base. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. When a compound of the present disclosure contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain compounds of the present disclosure contain both basic and acidic functional groups and can be converted into any base or acid addition salt.

[0262] The pharmaceutically acceptable salts of the present disclosure can be synthesized from a parent compound that contains an acid radical or a base by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of the compound with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture thereof.

[0263] The compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. All such compounds are contemplated herein, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereoisomerically enriched mixtures, all of which are encompassed within the scope of the present disclosure. Substituents, such as alkyl, may have additional asymmetric carbon atoms. All of these isomers and mixtures thereof are encompassed within the scope of the present disclosure.

[0264] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

[0265] Unless otherwise specified, the terms "cis-trans isomers" or "geometric isomers" result from the inability of a single or double bond of a ring carbon atom to rotate freely.

[0266] Unless otherwise specified, the term "diastereoisomer" refers to stereoisomers whose molecules each contain two or more centers of chirality and are not mirror images of one another.

[0267] Unless otherwise specified, "+" denotes dextrorotation, "(-)" denotes levorotation, and "±" denotes racemization.

[0268] Unless otherwise specified, the absolute configuration of one stereocenter is indicated by a solid wedge bond.

[0269] [ka] and dashed wedge bonds

[0270] [ka] and the relative configuration of the stereocenters is represented by a linear solid bond

[0271] [ka] and linear dashed bond

[0272] [ka] and the solid wedge joint is represented by

[0273] [ka] and / or dashed wedge bonds

[0274] [ka] is a wavy line

[0275] [ka] or a linear solid line connection

[0276] [ka] and / or straight dashed bond

[0277] [ka] is a wavy line

[0278] [ka] It is expressed using

[0279] Certain compounds of the present disclosure may exist as atropisomers, which are conformational isomers that arise when rotation around a single bond in a molecule is prevented or significantly slowed by steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, which may be pure individual atropisomers, enriched in one of the atropisomers, or non-specific mixtures of each. If the rotational potential around a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, this may allow for isomer separation.

[0280] Unless otherwise specified, the terms "enriched in one isomer," "enriched in one enantiomer," and "enantiomerically enriched" refer to one of the isomers or enantiomers containing less than 100%, where the isomer or enantiomer content is greater than or equal to 60%, greater than or equal to 70%, greater than or equal to 80%, greater than or equal to 90%, greater than or equal to 95%, greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, greater than or equal to 99.5%, greater than or equal to 99.6%, greater than or equal to 99.7%, greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0281] Unless otherwise specified, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomeric or enantiomeric excess (ee value) is 80%.

[0282] Optically active (R) and (S) isomers and D and L isomers may be prepared by chiral synthesis or chiral reagents, or other conventional techniques. Where a single enantiomer of a particular compound disclosed herein is available, the desired pure enantiomer may be prepared by asymmetric synthesis or derivatization using a chiral auxiliary; the resulting diastereomeric mixture is separated, and the auxiliary is cleaved. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, the compound may be reacted with a suitable optically active acid or base to form a diastereomeric salt, which may then be subjected to diastereoisomeric resolution through conventional methods in the art to obtain the pure enantiomers. Furthermore, enantiomers and diastereoisomers are typically separated through chromatography using chiral stationary phases, optionally in combination with chemical derivatization (e.g., carbamates generated from amines). The compounds disclosed herein may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, the compound may contain a radioactive isotope, such as tritium ( 3 H), iodine-125( 125 I), or C-14( 14C), etc. To cite another example, hydrogen may be replaced by deuterium to form a deuterated drug, where the bond formed by deuterium and carbon is stronger than the bond formed by a common hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased stability, enhanced efficacy, extended biological half-life, and the like. All isotopic variations of the compounds described herein, whether radioactive or not, are encompassed within the scope of this disclosure.

[0283] The term "substituted" means that one or more hydrogen atoms on a specified atom are replaced with a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =0), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that the atom may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary, as long as it is chemically achievable.

[0284] When any variable (e.g., R) occurs more than one time in a constituent or structure of a compound, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with up to two R, and its definition at each occurrence is independent. Further, combinations of substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0285] When the number of linking groups is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0286] When the number of substituents is 0, it means that there are no substituents, for example, -A-(R)0 means that the structure is actually -A.

[0287] If a substituent is empty, it means that the substituent is not present. For example, if X is empty in A to X, it means that the structure is actually A.

[0288] If one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected. For example, if L represents a single bond in ALZ, it means that the structure is actually AZ.

[0289] When the direction of the linkage of the listed linking groups is not specified, the linkage direction is arbitrary. For example,

[0290] [ka] The linking group L in the formula (I) is -MW-, and in this case, -MW- connects ring A and ring B in the same direction as the reading order from left to right.

[0291] [ka] or by linking ring A and ring B in the reverse reading order from left to right:

[0292] [ka] Combinations of linking groups, substituents, and / or variants thereof are permissible only if such combinations result in stable compounds.

[0293] Unless otherwise specified, when a group has one or more linking sites, any one or more sites of the group may be linked to other groups through a chemical bond. If the chemical bond is formed in a delocalized manner and an H atom is present at the linking site, when a chemical bond is formed, the number of H atoms at that site decreases according to the number of chemical bonds formed, becoming a group of corresponding valence. The chemical bond linking a site to another group is represented by a straight solid bond.

[0294] [ka] Linear dashed bond

[0295] [ka] or wavy line

[0296] [ka] For example, the straight solid bond in -OCH3 indicates that it is connected to another group through the oxygen atom in the group;

[0297] [ka] The straight dashed bond in indicates that it is connected to another group through both ends of the nitrogen atom in the group;

[0298] [ka] The wavy lines in indicate that it is linked to another group through carbon atoms at positions 1 and 2 in the phenyl group;

[0299] [ka] means that any linking site on the piperidinyl group can be linked in at least four ways, namely:

[0300] [ka] Even when an H atom is depicted on the -N-, it indicates that the group may be linked to another group through a chemical bond containing

[0301] [ka] But still,

[0302] [ka] and only when a chemical bond is formed, the H at this site is reduced by 1 to the corresponding monovalent piperidinyl group.

[0303] Unless otherwise specified, the number of atoms on a ring is typically defined as the number of members in the ring, e.g., a "5- to 7-membered ring" refers to a "ring" arranged around 5 to 7 atoms.

[0304] Unless otherwise specified, the term "C 1-6 "Alkyl" by itself or in combination with other terms refers to a linear or branched saturated hydrocarbon group, each of which contains 1 to 6 carbon atoms. 1-6 Alkyl is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5 alkyl, and the like; which can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-6 Examples of 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, and the like. Unless otherwise specified, the term "C 1-4 The term "alkyl" used by itself or in conjunction with other terms refers to a linear or branched saturated hydrocarbon group, each of which contains 1 to 4 carbon atoms. 1-4 Alkyl is C 1-2 , C 1-3 , C 2-3 C includes alkyl, and the like, and can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methenyl). 1-4Examples of 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), and the like.

[0305] Unless otherwise specified, the term "C 1-4 "Alkoxy" by itself or in combination with other terms refers to alkyl groups containing 1 to 4 carbon atoms each linked to the remainder of the molecule through an oxygen atom. 1-4 Alkoxy is C 1-3 , C 1-2 , C 2-4 , C4, C3 alkoxy, and the like, and can be monovalent, divalent, or polyvalent. 1-4 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy, and t-butoxy), and the like.

[0306] Unless otherwise specified, "C 3-6 "Cycloalkyl" used by itself or in combination with other terms refers to saturated cyclic hydrocarbon groups of 3 to 6 carbon atoms each. 3-6 Cycloalkyl includes monocyclic and polycyclic rings, and polycyclic rings include spiro, parallel, and bridged rings. 3-6 Cycloalkyl is C 3-5 , C 4-5 , C 5-6 C includes cycloalkyl, and the like, and can be monovalent, divalent, or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentanyl, and the like.

[0307] Unless otherwise specified, the term "3 to 10-membered heterocycloalkyl," by itself or in combination with other terms, refers to a saturated or partially unsaturated cyclic group of 3 to 10 ring atoms, respectively, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, which are optionally substituted with oxygen (i.e., forming C=O), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). 3- to 10-membered heterocycloalkyl includes monocyclic and polycyclic rings, and polycyclic rings include spiro, parallel, and bridged rings. Additionally, in this "3- to 10-membered heterocycloalkyl" context, a heteroatom can occupy the position of the heterocycloalkyl that connects it to the remainder of the molecule. 3- to 10-membered heterocycloalkyl includes 3- to 6-membered, 4- to 6-membered, 5- to 6-membered, 4- to 7-membered, 5- to 7-membered, 5- to 8-membered, 6- to 8-membered, 6- to 9-membered, 6- to 10-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, and 10-membered heterocycloalkyl, and the like, and can be monovalent, divalent, or polyvalent. Examples of 3 to 10 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (1-piperidinyl, 2-piperidinyl, piperazinyl (including 1-piperazinyl, 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl, 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, tetrahydropyridinyl,

[0308] [ka] and the like.

[0309] Unless otherwise specified, the term "3 to 7-membered heterocycloalkyl," by itself or in combination with other terms, refers to a saturated or partially unsaturated cyclic group consisting of 3 to 7 ring atoms, respectively, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, which are optionally substituted with oxygen (i.e., forming C=O), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). 3- to 7-membered heterocycloalkyl includes monocyclic and polycyclic rings, and polycyclic rings include spiro, parallel, and bridged rings. Additionally, in this "3- to 7-membered heterocycloalkyl" case, a heteroatom can occupy the position of the heterocycloalkyl that connects it to the remainder of the molecule. 3- to 7-membered heterocycloalkyl includes 3- to 6-membered, 4- to 6-membered, 5- to 6-membered, 4- to 7-membered, 5- to 7-membered, 4-, 5-, 6-, and 7-membered heterocycloalkyl, and the like, and can be monovalent, divalent, or polyvalent. Examples of 3- to 7-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 5-piperidinyl, 6-piperidinyl, 7-piperidinyl, 8-piperidinyl, 9-piperidinyl, 10-piperidinyl, 11-piperidinyl, 12-piperidinyl, 13-piperidinyl, 14-piperidinyl, 15-piperidinyl, 16-piperidinyl, 17-piperidinyl, 18-piperidinyl, 19-piperidinyl, 20-piperidinyl, 21-piperidinyl, 22-piperidinyl, 23-piperidinyl, 24-piperidinyl, 25-piperidinyl, 26-piperidinyl, 27-piperidinyl, 28-piperidinyl, 29-piperidinyl, 30-piperidinyl, 31-piperidinyl, 32-piperidinyl, 33-piperidinyl, 34-piperidinyl, 35-piperidinyl, 36-piperidinyl, 37-piperidinyl, 38-piperidinyl, 39-piperidinyl, 40-piperidinyl, 41-piperidinyl, 42-piperidinyl, 43-piperidinyl, 44-piperidinyl, including hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, and the like), piperazinyl (including 1-piperazinyl, 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl, 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, tetrahydropyridinyl, and the like.

[0310] Unless otherwise specified, the term "3- to 6-membered heterocycloalkyl," by itself or in combination with other terms, refers to a saturated or partially unsaturated cyclic group consisting of 3 to 6 ring atoms, respectively, in which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, which are optionally substituted with oxygen (i.e., forming C=O), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). 3- to 6-membered heterocycloalkyl includes monocyclic and polycyclic rings, and polycyclic rings include spiro, parallel, and bridged rings. Additionally, in this "3- to 6-membered heterocycloalkyl" case, a heteroatom can occupy the position of the heterocycloalkyl that connects it to the remainder of the molecule. 3- to 6-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-, 5-, and 6-membered heterocycloalkyls and the like, and can be monovalent, divalent, or polyvalent. Examples of 3- to 6-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, and the like), tetrahydrofuranyl (including tetrahydrofuran-2-yl, and the like), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, and the like), piperazinyl (including 1-piperazinyl, 2-piperazinyl, and the like), morpholinyl (including 3-morpholinyl, 4-morpholinyl, and the like), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, or hexahydropyridazinyl, piperidinyl, and the like.

[0311] Unless otherwise specified, the terms "5- to 6-membered heteroaryl ring" and "5- to 6-membered heteroaryl" are used interchangeably herein, and the term "5- to 6-membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms having a conjugated π-electron system, in which 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 substituted with oxygen (i.e., forming C=O), the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). A 5- to 6-membered heteroaryl may be linked to the remainder of the molecule through a heteroatom or a carbon atom. A 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryls and can be monovalent, divalent, or polyvalent. Examples of 5- to 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, and the like), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, and the like), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, and the like), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, and the like), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, and the like). thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, and the like), furanyl (including 2-furanyl, 3-furanyl, and the like), thienyl (including 2-thienyl, 3-thienyl, and the like), pyridinyl (including 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, and the like), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, and the like); Unless otherwise specified, the term "5-membered heteroaryl and 5-membered heteroaryl" as used herein refers to one 5-membered heteroaryl fused together with another 5-membered heteroaryl through two adjacent atoms. Examples of "5-membered heteroaryl and 5-membered heteroaryl" include, but are not limited to:

[0312] [ka] Includes.

[0313] Unless otherwise specified, C n-n+m or C n -C n+mは、 This includes any one of the specific cases of n to n+m carbon atoms. For example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 Also, any range between n and n+m may be included. For example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C3-12, C 6-9 , C 6-12 , C 9-12 and the like. Similarly, n to n+m means that the number of atoms in the ring is n to n+m. For example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring. n to n+m also represents any range within n to n+m. For example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, a 6- to 10-membered ring, and the like.

[0314] The term "leaving group" refers to a functional group or atom that can be displaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate esters, such as mesylate, N,N'-dioctadecyloxacarbocyanine p-toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.

[0315] The term "protecting group" includes, but is not limited to, "amino-protecting group," "hydroxy-protecting group," and "mercapto-protecting group." The term "amino-protecting group" refers to a protecting group suitable for blocking lateral reactions on an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, and trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like. The term "hydroxy-protecting group" refers to a protecting group suitable for blocking lateral reactions on a hydroxy. Representative hydroxyl protecting groups include, but are not limited to, alkyl, such as methyl, ethyl, and tert-butyl; acyl, such as alkanoyl (e.g., acetyl); arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (benzhydryl, DPM); silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0316] Example 16 The structure of the compounds of the present disclosure may be confirmed by conventional methods known to those skilled in the art. When the present disclosure relates to the absolute configuration of a compound, the absolute configuration may be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) may be used, and the cultured single crystal is analyzed by a Bruker D8 Venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning mode is φ / ω scanning. After the relevant data is collected, the crystal structure is further analyzed by a direct method (Shelxs97) to confirm the absolute configuration.

[0317] The solvents used in this disclosure are commercially available. Compounds are named according to conventional nomenclature in the art or using ChemDraw® software, with supplier catalog names being used for commercially available compounds. [Brief explanation of the drawings]

[0318] [Figure 1] FIG. 1 shows a diagram of the binding mode of Compound A to CypA protein. [Figure 2] FIG. 2 shows the binding mode diagram of compound B to CypA protein. [Figure 3] FIG. 3 shows the binding mode diagram of compound C to CypA protein. [Figure 4] FIG. 4 shows the binding mode diagram of compound D to CypA protein. [Figure 5] FIG. 5 shows the binding mode diagram of compound E to CypA protein. [Figure 6] FIG. 6 shows the binding mode diagram of compound F to CypA protein. [Figure 7] FIG. 7 shows the binding mode diagram of compound G to CypA protein. [Figure 8] FIG. 8 shows the binding mode diagram of compound H to CypA protein. [Figure 9] FIG. 9 shows the binding mode diagram of Compound I to CypA protein. [Figure 10] FIG. 10 shows the binding mode diagram of compound J to CypA protein. DETAILED DESCRIPTION OF THE INVENTION

[0319] The present disclosure is described in detail below by way of examples. However, this does not in any way adversely limit the scope of the present disclosure. The present disclosure has been described in detail herein, and specific examples have also been disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure.

[0320] Calculation example 1

[0321] [ka] The binding mode was predicted by using the eutectic complex of human CypA protein with the natural product Sanglifehrin A (PDB ID code: 1YND) as a docking template. To prepare the protein, hydrogen atoms were docked using Maestro [1] The protein preparation guide module was used to add hydrogen bonds and optimize the co-crystal structure using the OPLS4 force field. Water molecules other than those of the ligand Sanglifehrin A 3 Å in the co-crystal complex were removed, and the energy was optimized globally. For ligand preparation, the molecules to be docked were generated in 3D structures and energy minimization was performed using LigPrep in Maestro (Schrodinger version 2021-2). [2] Induced Fit Docking [3]Compound A was docked to the final 1YND protein structure using the Protocol:Extended Sampling option. The best binding model was selected (see Figure 1). The selected model maintained the major hydrogen bonds of the ligand Sanglifehrin A to the protein in the original co-crystal complex. A 30 Å docking grid was generated using the centroid of compound A in this binding mode, and the docking model was analyzed using Glide [4] The docking model was generated using the receptor grid generation module. [3] The SP docking mode in was used for docking of compounds B to J, and the binding modes of compounds B to J are shown in Figures 2 to 10. [1] Maestro, Schrodinger, LLC, New York, NY, 2021. [2] LigPrep, Schrodinger, LLC, New York, NY, 2021. [3] Induced Fit Docking protocol; Glide, Schrodinger, LLC, New York, NY, 2021; Prime, Schrodinger, LLC, New York, NY, 2021. [4] Glide, Schrodinger, LLC, New York, NY, 2021.

[0322] Conclusion: The compounds of the present disclosure bind relatively well to human Cyp A protein. The compounds of the present disclosure form hydrogen bonds with Arg55, Gln63, Asn102, and His126. In addition, Arg55 forms a cation π bond with the indole ring. Because the compounds of the present disclosure act on the surface of the protein, the hydrogen bonds listed as anchor points not only replicate the binding mode of the natural product Sanglifehrin A in the eutectic complex, but also firmly anchor the compounds of the present disclosure on the surface of the protein. The binding of the compounds of the present disclosure to CypA blocks the binding of RAS downstream RAF to RAS, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway and achieving an antitumor effect.

[0323] Reference example 1: Compound M1

[0324] [ka] Compound M1-1 (39 g, 106.78 mmol) was dissolved in water (100 mL) and tetrahydrofuran (200 mL), and lithium hydroxide monohydrate (13.44 g, 320.33 mmol) was added. The reaction solution was stirred and reacted at 25 °C for 1.5 hours. After the reaction was completed, the pH of the reaction solution was adjusted to 5-6 with 2M diluted hydrochloric acid, and then the reaction solution was extracted with ethyl acetate (200 mL * 3). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and distilled under reduced pressure to remove the organic solvent, obtaining compound M1. LCMS: m / z = 372.8, 374.8 [M + 23] + .

[0325] Reference example 2: Compound M2

[0326] [ka] Process 1 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 2,000 mL of water and extracted with ethyl acetate (300 mL * 3). The organic phases were combined and washed with dilute hydrochloric acid (2 M, 300 mL * 3), then washed once with water (500 mL), once with saturated brine (200 mL), dried over 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.

[0327] Process 2 Compound M2-2 (17 g, 134.76 mmol) and di-tert-butyl azodicarboxylate (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 using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-15%) to obtain compound M2-3. 1 H NMR (400MHz, CDCl3) δ ppm 5.93(s,2H)5.06~5.37(m,1H)4.13~4.24(m,3H)3.57~3.79(m,1H)1.48(s,18H),1.27~1.30(m,3H).

[0328] Process 3 Chiral separation was performed on compound M2-3 by SFC (column: DAICEL CHIRALPAK IC (250 mm * 50 mm, 10 μm); mobile phase: Phase A supercritical carbon dioxide, Phase B: [0.1% ammonia solution in isopropanol]; B%: 20%-20%) to give compound M2-3A. SFC analytical method (column: cellulose 2 (150 mm * 4.6 mm, ID, 5 μm; mobile phase: Phase A supercritical carbon dioxide, Phase B: [0.05% diethylamine in isopropanol], gradient elution B%: 5%-5%, column temperature: 35 °C, column pressure: 1,500 psi), ee=100%, peak time of compound M2-3A was 2.798 min, peak time of the enantiomer was 2.133 min. LCMS: m / z=379.0 [M+23]+.

[0329] Process 4 Under nitrogen protection, trimethylsulfoxonium iodide (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 stirred at 50 °C for 2 hours. Compound M2-3A (1 g, 2.81 mmol) was then added, and the reaction solution was stirred at 70 °C for 12 hours. The reaction solution was diluted with water (100 mL), and the solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-15%) to obtain compound M2-5. LCMS: m / z = 371.2 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ ppm 4.22~4.33(m,1H),4.07~4.20(m,2H),2.56~2.73(m,1H),2.11~2.24(m,1H),1.84~1.9 5(m,2H), 1.71~1.82(m,1H), 1.45~1.53(m,18H), 1.23~1.31(m,3H), 0.97~1.07(m,1H).

[0330] Process 5 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 obtain crude trifluoroacetic acid salt of M2-6, which was used directly in the next step.

[0331] Process 6 The crude trifluoroacetate salt 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-ethyl-3-(3-dimethylaminopropyl)carbodiimide 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 organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-60%) to obtain compound M2. LCMS: m / z=503.1, 505.1 [M+1] + .

[0332] Reference example 3: Compound M3

[0333] [ka] Process 1 Tetrabutylammonium bromide (116.14 mg, 360.26 μmol) and difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) were added to a solution of compound M2-3A (4.28 g, 12.01 mmol) in toluene (24 mL). The mixture was stirred at 110° C. for 4 hours. More difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added and stirred at 110° C. for 16 hours. More difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added and stirring was continued at 110° C. for 4 hours. More difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added again and stirred at 110° C. for 16 hours. The solution was concentrated under reduced pressure to remove toluene, 20 mL of water was added to the residue, 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 flash silica gel column chromatography (0-10% ethyl acetate / petroleum ether) to give compound M3-1. LCMS: m / z = 206.9 [M-2Boc+1] + ; 1 H NMR(400MHz,CDCl3)δ4.96~5.25(m,1H)4.17~4.51(m,3H)3.19(br s,1H)2.18(br d,J=10.54Hz,1H)2.00~2.11(m,1H)1.40~1.55(m,18H)1.30~1.38(m,3H).

[0334] Process 2 Compound M3-1 (1 g, 2.46 mmol) was dissolved in dichloromethane (10 mL), trifluoroacetic acid (7.68 g, 67.31 mmol, 5 mL) was added, and the reaction solution was stirred and reacted at 25 ° C. for 3 hours. After the reaction, the reaction solution was distilled under reduced pressure to remove the organic solvent, obtaining crude trifluoroacetic acid salt of compound M3-2, which was used in the next step. LCMS: m / z = 206.8 [M + 1] + .

[0335] Process 3 Compound M1 (1.04 g, 2.95 mmol) and compound M3-2 (507 mg, crude trifluoroacetate salt) were dissolved in dichloromethane (10 mL) at 0 °C. N-methylmorphine (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 and reacted 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] + .

[0336] Reference example 4: Compound M4

[0337] [ka] Process 1 Under nitrogen protection, a solution of compound M4-1 (25 g, 136.61 mmol) in tetrahydrofuran was added to a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 91.07 mL) at 0 °C, and the mixture was stirred at 0 °C for 2 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 (500 mL × 2) for extraction. The organic phases were combined, then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether 0-30%) to give M4-2. LCMS: m / z = 200.0, 202.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.58 (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).

[0338] Process 2 Under nitrogen protection, compound [(η-6-cymene)[(S,S)-1,2-diphenyl-N-tosyl-1,2-ethanediaminate]ruthenium] chloride (700.83 mg, 1.10 mmol) was added to a mixture of formic acid (12.68 g, 263.96 mmol) and triethylamine (133.55 g, 1.32 mol, 183.70 mL) at 0 °C. Then, it was stirred at 40 °C for 15 minutes, then cooled to 25 °C, M4-2 (22 g, 109.98 mmol) was added, and then stirred at 40 °C for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was diluted with 100 mL and extracted with ethyl acetate (50 mL * 2). The organic phases were combined, then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was subjected to flash silica gel column chromatography (ethyl acetate / petroleum ether 0-40%) to give compound M4-3. LCMS: m / z = 202.0, 204.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ8.50(d,J=4.8Hz,1H)7.84(d,J=8.0Hz,1H)7.13(dd,J=8.0,4.8Hz,1H)5.11(br s,1H)4.44(br s,1H)1.44(d,J=4.8Hz,3H).

[0339] Process 3 Under nitrogen protection, sodium bicarbonate (5.23 g, 130.66 mmol, 60% purity) was added in batches to a solution of compound M4-3 (22 g, 108.88 mmol) in tetrahydrofuran (200 mL) at 0 °C. The solution was stirred at 0 °C for 1 h, and iodomethane (217.77 mmol, 13.56 mL) was added. After the addition, the mixture was slowly warmed to 0 °C-25 °C and stirred at this temperature for 2 h. The mixture was quenched by adding saturated aqueous ammonium chloride solution (100 mL) at 0 °C, water (200 mL) was added, and then the solution was extracted with ethyl acetate (100 mL * 2). The combined organic phases were collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was isolated and purified using a silica gel column (ethyl acetate:petroleum ether 0-20%) to give compound M4-4. LCMS: m / z=216.0, 218.0 [M+1] + ; 1 H NMR(400MHz,CDCl3)δ8.59(d,J=3.2Hz,1H)7.82(dd,J=8.4,3.2Hz,1H)7.08(dd, J=8.0,4.4Hz,1H)4.91(dd,J=13.2,6.4Hz,1H)3.29(s,3H)1.44(d,J=4.8Hz,3H).

[0340] Process 4 Bis(pinacolato)diboron (7.05 g, 27.77 mmol), Pd(dppf)Cl2 (1.69 g, 2.31 mmol), and potassium acetate (4.54 g, 46.28 mmol) were added to a solution of compound M4-4 (5 g, 23.14 mmol) in toluene (50 mL). After the addition, the nitrogen was replaced three times. The solution was stirred at 100 °C for 3 h. It was cooled to room temperature, water (100 mL) was added, and then extracted with ethyl acetate (50 mL * 2). The combined organic phases were collected, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified using a silica gel column (ethyl acetate:petroleum ether 0-25%) to obtain compound M4. LCMS: m / z = 182.0 [boric acid M+1] + ; 1H NMR(400MHz,CDCl3)δ8.59(dd,J=4.8,1.6Hz,1H)7.90(dd,J=7.6,2.0Hz,1H)7.16(dd ,J=8.4,4.8Hz,1H)4.77(dd,J=13.2,6.4Hz,1H)3.61(s,3H)3.26(s,3H)1.37(s,12H).

[0341] Reference example 5: Compound M5

[0342] [ka] Process 1 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 h. The mixture was concentrated, and the crude product was diluted with 200 mL of water and extracted with ethyl acetate (3 * 200 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-10%) to obtain compound M5-2. 1 H NMR (400MHz, CDCl3) δ=7.67(dd,J=1.6,8.0Hz,4H)7.49~7.36(m,6H)3.70(s,3H)3.66(s,2H)1.22(s,6H)1.05(s,9H).

[0343] Process 2 Compound M5-2 (51 g, 137.63 mmol) and potassium hydroxide (16.51 g, 294.35 mmol) were dissolved in 200 mL of water and 200 mL of ethanol, and the mixture was stirred at 90 °C for 3 hours. The reaction solution was concentrated to approximately 250 mL, and 500 mL of ethyl acetate was added for dilution. The pH was adjusted to 3-4 with concentrated hydrochloric acid, and the solution was separated. The aqueous phase was extracted with ethyl acetate (2 * 500 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to give compound M5-3. 1 H NMR (400MHz, CDCl3) δ=7.58(dd,J=1.6,8.0Hz,4H)7.39~7.27(m,6H)3.58(s,2H)1.15(s,6H)0.97(s,9H).

[0344] Process 3 Oxalyl chloride (233.64 mmol, 20.45 mL) was slowly added dropwise to compound M5-3 (49 g, 137.44 mmol) and DMF (13.74 mmol, 1.06 mL) in 500 mL of anhydrous dichloromethane at 0° C., and the mixture was stirred at 20° C. for 15 hours. The reaction solution was concentrated, and 300 mL of anhydrous toluene was added and concentrated under reduced pressure to give compound M5-4.

[0345] Process 4 Tin tetrachloride (136.00 mmol, 15.92 mL) was slowly added to a solution of compound M5-4 (51.00 g, 136.00 mmol) in 200 mL of anhydrous dichloromethane at 0 °C, and the mixture was stirred for 30 minutes under a nitrogen atmosphere. Compound M5-5 (26.66 g, 136 mmol) in 200 mL of anhydrous dichloromethane was slowly added dropwise to the above reaction mixture at 0 °C, and the reaction was stirred for 1 hour at 0 °C under a nitrogen atmosphere. 500 mL of water was added for quenching, the mixture was filtered, and the filtrate was allowed to separate. The aqueous phase was extracted with dichloromethane (3 * 500 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified using a flash chromatography column (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] + ; 1 H NMR(400MHz, CDCl3)δ=8.70(d,J=1.6Hz,1H)8.62(br s,1H)7.69(d,J=3.2Hz,1H)7.57~7.51(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).

[0346] Process 5 Lithium borohydride-tetrahydrofuran solution (1M, 123.47 mL) was slowly added dropwise to compound M5-6 (22 g, 41.16 mmol) in 220 mL of anhydrous tetrahydrofuran at 0 °C under a nitrogen atmosphere. After the dropwise addition, the temperature was increased to 60 °C, and the mixture was stirred for 15 hours. It was cooled to room temperature, and 10 mL of saturated aqueous ammonium chloride solution was added dropwise in succession, followed by 100 mL of ethyl acetate, which was washed with 50 mL of saturated brine. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-20%) to give compound M5-7. LCMS: m / z = 520.1, 522.1 [M+1] + .

[0347] Process 6 Compound M5-7 (18.5 g, 35.54 mmol), elemental iodine (9.02 g, 35.54 mmol), and silver triflate (10.04 g, 39.09 mmol) were successively added to 185 mL of anhydrous tetrahydrofuran, and the mixture was stirred at 20 ° C. for 2 hours. 50 mL of saturated aqueous sodium sulfite solution was added for quenching, and 200 mL of ethyl acetate was added for dilution. The mixture was filtered, and the filtrate was allowed to separate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound M5. 1 H NMR(400MHz,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).

[0348] Reference example 6: Compound M6

[0349] [ka] Process 1 Compound M6-1 (10 g, 78.05 mmol) was dissolved in DCM (100 mL) and MeOH (20 mL), and a solution of trimethylsilyldiazomethane in n-hexane (2 M, 78.05 mL) was added dropwise at 0° C. Stirring was continued at 0° C. for 10 minutes. The mixture was concentrated to give compound M6-2, which was used directly in the next step.

[0350] Process 2 Compound M6-2 (10 g, 70.35 mmol) was dissolved in n-heptane (200 mL), and tert-butyl carbazate (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 water (100 mL) and ethyl acetate (100 mL) were added when the system was cooled to room temperature. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound M6-3, which was used directly in the next step. LCMS: m / z = 201 [M + 1 - 56] + .

[0351] Process 3 Under nitrogen protection, a solution of compound M6-3 (7 g, 27.31 mmol) in tetrahydrofuran (10 mL) was slowly added dropwise to borane dimethyl sulfide (10 M, 273.12 mL) at 0 °C and stirred at 0 °C for 30 minutes, then warmed to room temperature, and stirring was continued for 1 hour. The reaction was quenched by slowly adding methanol (250 mL) dropwise at 0 °C. The quenched reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to give compound M6-4. LCMS: m / z = 203 [M+1-56] + .

[0352] Process 4 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 successively at 25 °C. The mixture was stirred at 25 °C for 1 hour. Water (50 mL) and ethyl acetate (30 mL) were added to the reaction mixture. The extracted organic phase was dried over anhydrous sodium sulfate, and the filtrate was concentrated. The obtained crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to give compound M6-5. LCMS: m / z = 359 [M+1] + .

[0353] Process 5 Compound M6-5 (585 mg, 1.63 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen protection, lithium bis(trimethylsilyl)amide (1 M, 4.90 mL) was added dropwise at -70 °C and stirred at -70 °C for 30 minutes, and then trimethylsilyl chloride (531.94 mg, 4.90 mmol) was added dropwise. Stirring was continued at -70 °C for 1 hour, followed by dropwise addition of N-bromosuccinimide (1.16 g, 6.53 mmol), followed by slow warming to 25 °C and continued stirring for 1 hour. Saturated brine (30 mL) was added, and the solution was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound M6-6, which was used directly in the next step. LCMS: m / z=353, 355 [M+1-100-56] + .

[0354] Process 6 A solution of citric acid (618.66 mg, 2.94 mmol) in water (5 mL) was added to compound M6-6 (500 mg, 981.34 μmol) in tetrahydrofuran (20 mL) and stirred at 25° C. for 1 hour. After the reaction was completed, saturated brine (30 mL) was added and the solution was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to give compound M6-7. LCMS: m / z=281,283 [M+1-100-56] + .

[0355] Process 7 Compound M6-7 (150 mg, 342.99 μmol) was dissolved in acetonitrile (20 mL), cesium carbonate (447.02 mg, 1.37 mmol) was added, and the mixture was heated to 60° C. and stirred for 12 hours. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to give compound M6-8. LCMS: m / z=201 [M+1-100-56] + . 1 H NMR(400MHz, CDCl3)5.24~4.93(m,1H)4.45(br d,J=4.6Hz,1H)3.77~3.71(m,3H)2.89(qd,J=5.8,11.6Hz,1H)2.39(td,J=4 .9,10.0Hz,1H)2.13(td,J=5.0,10.0Hz,1H)1.62(s,2H)1.52~1.48(m,18H).

[0356] Process 8 Compound M6-8 (50 mg, 140.29 μmol) was dissolved in methanol (5 mL) and ethyl acetate (5 mL), and hydrogen chloride ethyl acetate solution (5 mL, 4 M) was added and stirred at 40° C. for 1 hour. The reaction solution was concentrated to give the hydrochloride salt of compound M6. LCMS: m / z=157 [M+1] + .

[0357] Reference example 7: Compound M8

[0358] [ka] Process 1 Triethylamine (111.94 mmol, 15.58 mL) and 1-methylpiperazine (16.82 g, 167.91 mmol, 18.63 mL) were added to a solution of M8-1 (22.5 g, 111.94 mmol) in tetrahydrofuran (250 mL), and then the mixture was stirred at 60 °C for 16 h. The reaction solution was diluted with water (200 mL), and the solution was extracted with ethyl acetate (100 mL*3). The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The obtained crude product was added with petroleum ether (100 mL), filtered, and the filter cake was dried to obtain compound M8-2. 1 H NMR (400MHz, DMSO-d6) δ ppm8.40(d,J=2.4Hz,1H)7.65(d,J=2.4Hz,1H)3.42~3.48(m,4H)2.36~2.44(m,4H)2.21(s,3H).

[0359] Process 2 Compound M8-2 (10 g, 35.57 mmol) was dissolved in tetrahydrofuran (150 mL). Under nitrogen protection, methylmagnesium chloride (3 M tetrahydrofuran solution, 23.7 mL) was added 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 for quenching, and the solution was extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The obtained crude product was purified using a flash chromatography column (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 (400MHz, DMSO-d6) δ ppm8.38(d,J=2.4Hz,1H)7.53(d,J=2.4Hz,1H)3.39~3.47(m,4H)2.54(s,3H)2.40~2.45(m,4H)2.22(s,3H).

[0360] Process 3 Under nitrogen protection, triethylamine (57.1 g, 563.9 mmol) was added dropwise to formic acid (5.27 g, 109.67 mmol) at 0 °C, followed by the addition of [(η-6-cymene)[(S,S)-1,2-diphenyl-N-tosyl-1,2-ethanediaminate]ruthenium] chloride (140 mg, 220 μmol). The mixture was stirred at 40 °C for 15 minutes. It was then cooled to room temperature, and compound M8-3 (6.54 g, 21.93 mmol) was added in batches. The reaction solution was heated to 50 °C and stirred for 12 hours. The reaction solution was directly concentrated, and the resulting crude product was purified using a flash chromatography column (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to obtain compound M8-4. LCMS: m / z = 300.0, 302.0 [M+1] + .

[0361] Process 4 Under nitrogen protection, compound M8-4 (1 g, 3.33 mmol) was dissolved in N,N-dimethylformamide (DMF) (10 mL) and cooled to 0 °C. Then, sodium bicarbonate (160 mg, 4.00 mmol, purity 60%) was added in batches. The solution was stirred at 0 °C for 1 h, and then iodomethane (520 mg, 3.68 mmol) was added dropwise, and the reaction solution was allowed to react at 0 °C for 2 h. Saturated ammonium chloride (50 mL) was added dropwise to the reaction solution for quenching, and the solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to give the crude product, which was purified using a flash chromatography column (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give compound M8-5. LCMS: m / z=313.9, 316.0 [M+1] + .

[0362] Process 5 Compound M8-5 (0.72 g, 2.29 mmol) and bis(neopentylglycolate)diboron (777 mg, 3.5 mmol) were dissolved in toluene (20 mL), and potassium acetate (563 mg, 5.75 mmol) and 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (168 mg, 230 μmol) were added successively. The nitrogen atmosphere was exchanged three times, and the solution was heated to 70 °C and reacted for 12 hours. The reaction solution was filtered, and the filtrate was directly concentrated. The resulting crude product M8-6 was used directly in the next step. LCMS: m / z = 348.1 [M+1] + .

[0363] Process 6 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 nitrogen was exchanged three times. 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (22.07 mg, 33.86 μmol) was added, and the reaction solution was stirred and reacted under nitrogen at 70 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound M8-7. LCMS: m / z = 753.2, 755.2 [M+1] + .

[0364] Process 7 Compound M8-7 (15 g, 19.90 mmol) was dissolved in tetrahydrofuran (150 mL), sodium hydrogen carbonate (4 g, 100.00 mmol, purity 60%) was added in batches at 0 ° C. and stirred under nitrogen protection for 30 minutes, and then ethyl iodide (30.01 mmol, 2.4 mL) was added dropwise. The reaction solution was stirred at 0 ° C. for 1 hour, and ethyl iodide (25.01 mmol, 2 mL) was added again. The reaction solution was stirred and reacted at 20 ° C. for 30 minutes. The reaction solution was quenched in batches with ice water (100 mL) and extracted with dichloromethane (50 mL * 3). The organic phase was washed with saturated brine (50 mL * 3), dried with anhydrous sodium sulfate, and the filtrate was concentrated to obtain crude compound M8-8. LCMS: m / z=781.3, 783.3 [M+1] + .

[0365] Process 8 Compound M8-8 (13.7 g, 17.52 mmol) was dissolved in tetrahydrofuran (150 mL), and tetrabutylammonium fluoride in tetrahydrofuran solution (1 M, 175.21 mL) was added. The reaction solution was stirred and reacted under nitrogen at 50 °C for 12 hours. The reaction solution was quenched with water (20 mL) and 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 with anhydrous sodium sulfate, and concentrated. The remaining product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain the crude product. Acetonitrile (10 mL) was then added to the crude product, stirred for 10 minutes, filtered, and the filter cake was then prepared and purified by preparative HPLC (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: the proportion of mobile phase acetonitrile increased from 13% to 43% within 8 minutes) to give the trifluoroacetate salt of compound M8-9A (HPLC analytical method: column ChromCore 120 C18 3 μm 3.0*30 mm; Phase A was 4 L of aqueous solution containing 1.5 mL of trifluoroacetic acid, and Phase B was 4 L of acetonitrile solution containing 0.75 mL of trifluoroacetic acid; Elution gradient: Phase B increased from 10% to 80% in 6 min, held at 80% for 0.5 min, then held at 10% for 0.5 min; Retention time of compound M8-9A was 3.205 min, and its isomer was 3.146 min). LCMS: m / z=543.5, 545.5 [M+1] + .

[0366] Process 9 Compound M8-9A (0.6 g, 1.10 mmol) and bis(pinacolato)diboron (420.47 mg, 1.66 mmol) were dissolved in toluene (6 mL) and dioxane (2 mL), and potassium acetate (216.67 mg, 2.21 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80.77 mg, 110.39 μmol) were added. The reaction solution was stirred and reacted under nitrogen at 90°C for 5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to give compound M8. LCMS: m / z = 591.4 [M+1] + .

[0367] Reference Example 8: Compound M9

[0368] [ka] Process 1 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 successively added to 1.5 L of anhydrous dichloromethane, and then 2-chloro-1-methylpyridinium iodide (266.10 g, 1.04 mol) was added in batches, and the mixture was stirred at 25 ° C. for 1 hour. After the reaction was completed, the organic phase was washed with water (2 * 1 L). The organic phase was dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound M9-3. 1 H 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).

[0369] Process 2 Compound M9-3 (220 g, 765.72 mmol) and acetic acid (91.97 g, 1.53 mol) were successively added to 2 L of anhydrous tetrahydrofuran, and sodium borohydride (23.18 g, 612.58 mmol) was slowly added to the above solution in batches at 0 °C. After the addition was completed, the mixture was stirred at 0 °C for 2 hours. After the reaction was completed, 500 mL of saturated aqueous ammonium chloride solution was slowly added dropwise, and the mixture was concentrated under reduced pressure until a residue of about 1 L remained. The solution was extracted with ethyl acetate (3 * 500 mL). The organic phase was washed with saturated sodium bicarbonate to a pH of about 8, and the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated to give compound M9-4. LCMS: m / z = 290.1 ​​[M + 1] + .

[0370] Process 3 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 successively to 2 L of anhydrous dichloromethane at 0 °C, and then tosyl chloride (159.46 g, 836.43 mmol) was added to the above solution in batches. After the addition was completed, the mixture was stirred at 25 °C for 3 h. After the reaction was completed, the mixture was washed with water (1.5 L). The aqueous phase was extracted with dichloromethane (2 * 500 mL). The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to obtain compound M9-5. 1H NMR(400MHz,CDCl3)δ=7.81(br d,J=8.0Hz,2H)7.41~7.28(m,5H)7.19(br d,J=7.2Hz,2H)4.84~4.70(m,1H)4.65(br s,1H)4.29~4.18(m,2H)3.26(br d,J=13.6Hz,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).

[0371] Process 4 Compound M9-5 (90 g, 202.93 mmol) and lithium bromide (35.25 g, 405.85 mmol) were added successively to 900 mL of 1-methyl-2-pyrrolidinone, and the mixture was stirred at 90 °C for 13 hours. After the reaction was completed, 2 L of saturated brine was added for dilution, and the solution was extracted with ethyl acetate (3 * 1 L). The organic phase was washed again with saturated brine (2 * 1 L), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a flash chromatography column (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] + .

[0372] Process 5 Compound M9-6 (9.5 g, 23.80 mmol) was dissolved in 95 mL of anhydrous tetrahydrofuran at -78 ° C., and then lithium diisopropylamide in a 2 M tetrahydrofuran-n-heptane mixed solution (15.47 mL, 30.94 mmol) was slowly added dropwise, and the mixture was stirred under a nitrogen atmosphere for 30 minutes. Di-tert-butyl azodicarboxylate (6.58 g, 28.56 mmol) in 20 mL of anhydrous dichloromethane solution was added to the above solution in one portion, and stirring was continued for 30 minutes. 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (91.50 g, 713.89 mmol) was slowly added to the above reaction solution, and the mixture was allowed to warm to room temperature and stirring was continued for 13 hours. After the reaction was completed, 100 mL of water was slowly added to quench the reaction, and lithium hydroxide monohydrate (3.00 g, 71.39 mmol) was added. 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 and washed with ethyl acetate (3*200 mL). The organic phase was discarded, and the pH of the aqueous phase was adjusted to 5 with 1N hydrochloric acid. The solution was then extracted with ethyl acetate (3*200 mL). The organic phase was washed with saturated brine (2*200 mL), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to give compound M9-7. LCMS: m / z=365.1 [M+23] + .

[0373] Process 6 Trimethylsilyldiazomethane (11.68 mL, 23.36 mmol) in 2M n-hexane was slowly added dropwise to a solution of compound M9-7 (1.6 g, 4.67 mmol) in 32 mL of anhydrous methanol at 25° C., and the mixture was stirred at 25° C. for 10 minutes. After the reaction was completed, 0.1 mL of acetic acid was added to quench the reaction. The reaction solution was concentrated to give compound M9-8. LCMS: m / z=379.1 [M+23] +An SFC analytical method was used for detection (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%: increased from 5% to 40% in 4 minutes, then held at 40% for 0.5 minutes, then held at 5% for 1.5 minutes). The retention time of compound M9-8 was 1.342 minutes, and the chiral purity was 93.38%; the retention time of its enantiomer was 1.431 minutes, and the chiral purity was 6.62%.

[0374] Process 7 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 stirred for 12 hours at 25° C. After the reaction was completed, the mixture was concentrated, 20 mL of methyl tert-butyl ether was added to the residue, and the mixture was stirred at room temperature for 10 minutes, filtered, and the filter cake was dried to obtain the trifluoroacetic acid salt of compound M9. 1 H NMR(400MHz,D2O)δ=4.30(d,J=3.8Hz,1H)3.97(q,J=4.9Hz,1H)3.73(s,3H)2.93~2.83(m,1H)2.54(ddd,J=4 .5,6.5,11.5Hz,1H)2.39(td,J=5.7,11.7Hz,1H)2.04(dd,J=9.4,11.7Hz,1H)1.76(dd,J=9.5,12.0Hz,1H).

[0375] Reference example 9: Compound M10

[0376] [ka] Process 1 Compound M4-4 (9.2 g, 42.58 mmol), bis(pinacolato)diboron (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'-dipyridyl (1.71 g, 6.39 mmol) were dissolved in tetrahydrofuran (200 mL). The nitrogen atmosphere was exchanged 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 diluted with 150 mL of water and 150 mL of ethyl acetate. The pH was adjusted to 10 by adding alkaline water (7.5 g of sodium hydroxide and 30 g of sodium carbonate in 400 mL of aqueous solution) and separated. 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 × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound M10-1.

[0377] Process 2 Compound M10-1 (5 g, 19.24 mmol) was dissolved in acetonitrile (50 mL), and copper(I) 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 sequentially. The reaction solution was stirred at 60 °C for 2 h. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-10%) to obtain compound M10-2. LCMS: m / z = 341.8, 343.8 [M+1] + .

[0378] Process 3 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) and cooled to 0 °C. Cesium carbonate (1.29 g, 3.95 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthalene (50 mg, 80.95 μmol), and palladium(II) acetate (36 mg, 158.91 μmol) were then added. The nitrogen atmosphere was exchanged three times, and the reaction solution was stirred at 90 °C for 12 h. After completion of the reaction, the reaction solution was directly concentrated, and the resulting crude product was purified using a flash chromatography column (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to obtain compound M10. LCMS: m / z=356.0, 358.0 [M+1] + .

[0379] Reference example 10: Compound M11

[0380] [ka] Process 1 Compound M11-1 (5 g, 20.58 mmol) and potassium carbonate (8.53 g, 61.75 mmol) were dissolved in methyl-2-pyrrolidone (25 mL), and then tert-butyl cyanoacetate (4.65 g, 32.93 mmol) was added. The reaction solution was stirred at 85 ° C. for 12 hours. After the reaction was completed, water (25 mL) was added and the mixture was cooled to room temperature. The pH was adjusted to 2 with 3 M hydrochloric acid, and the solid was precipitated, filtered, and the filter cake was dried to obtain compound M11-2. 1 H NMR (400MHz, CD3OD) δ ppm 1.53 (s, 9H) 4.85 (s, 1H) 6.93 (s, 1H).

[0381] Process 2 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, followed by stirring at 80 °C for 15 minutes. After the reaction was completed, water (100 mL) was added, and the solution 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, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound M11-3. 1 H NMR (400MHz, CD3OD) δ ppm4.90(s,2H)7.61(s,1H).

[0382] Process 3 Compound M11-3 (3 g, 14.77 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium bicarbonate (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. 1,2-Dibromoethane (22.16 mmol, 1.67 mL) was then added and the mixture was stirred at 25 °C for 12 hours under nitrogen protection. After the reaction was completed, water (100 mL) was added for quenching, and the solution 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, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound M11-4. 1 H NMR (400MHz, CD3OD) δ ppm 1.78~1.83(m,2H)1.84~1.89(m,2H)7.07(s,1H).

[0383] Process 4 Compound M11-4 (1 g, 4.36 mmol) was dissolved in tetrahydrofuran (10 mL), and then a solution of diisobutylaluminum hydride in toluene (1 M, 10.91 mL) was added at 0 ° C. and stirred at 0 ° C. for 1 hour under nitrogen protection. After the reaction was completed, it was quenched with water (120 mL), and the solution 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, which was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound M11-5. 1 H NMR (400MHz, DMSO-d6) δ ppm 1.97~2.01(m,2H)2.07~2.11(m,2H)7.79(s,1H)8.90(s,1H).

[0384] Process 5 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), and potassium cyanide (84.17 mg, 1.29 mmol) was added and stirred at 80 °C for 6 hours. After the reaction was completed, water (150 mL) was added for quenching, and the solution was extracted with ethyl acetate (150 mL * 3). The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product, compound M11-6. LCMS: m / z = 302.1, 304.1 [M + 1] + . 1 H NMR (400MHz, CD3OD) δ ppm 1.20~1.32(m,2H)1.37~1.50(m,2H)4.06(s,1H)7.39(s,1H).

[0385] Process 6 Compound M11-6 (0.17 g, 562.64 μmol) was dissolved in dioxane (1 mL) and water (1 mL), and barium hydroxide (385.61 mg, 2.25 mmol) was added. The reaction mixture was microwaved at 130° C. for 30 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL*3). The aqueous phase was collected to give an aqueous solution of compound M11. LCMS: m / z=277.1, 279.1 [M+1] + .

[0386] Reference example 11: Compound M12

[0387] [ka] Process 1 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(diphenylphosphino)ferrocene-palladium(II) (21 mg, 29.24 μmol) were dissolved in dioxane (5 mL) and water (1 mL), and the nitrogen atmosphere was exchanged three times. The reaction solution was stirred at 60 °C for 3 h. After completion of the reaction, the reaction solution was directly concentrated, and the crude product was purified using a flash chromatography column (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] + .

[0388] Process 2 Trimethylsulfoxonium iodide (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 mixture was cooled to 25°C, and compound M12-2 (0.05 g, 125.85 μmol) in dimethyl sulfoxide (1 mL) was added dropwise. The reaction solution was stirred at 80°C for 12 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL), and the solution was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified using a flash chromatography column (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] + .

[0389] Example 1

[0390] [ka] Process 1 K2CO3 (3.75 g, 27.14 mmol) and 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (794.48 mg, 1.09 mmol) were added to a mixture of compound M4 (5 g, 19.00 mmol) and compound M5 (7.02 g, 10.86 mmol) in 70 mL of dioxane and 15 mL of water. The nitrogen atmosphere was exchanged three times, and the mixture was stirred at 85 °C for 4 h. The reaction solution was concentrated. The residue was diluted with 100 mL of water and extracted with ethyl acetate (3 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a flash chromatography column (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] + .

[0391] Process 2 Ethyl iodide (2.14 g, 13.73 mmol) and cesium carbonate (4.47 g, 13.73 mmol) were added successively to a solution of compound 1-1 (4.5 g, 6.86 mmol) in DMF (50 mL) at 0 °C. After the addition, the temperature was increased to 25 °C, and the solution was stirred at 25 °C for 16 h. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (2 * 50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 1-2. LCMS: m / z = 683.2, 685.2 [M + 1] + .

[0392] Process 3 Compound 1-2 (3.4 g) and tetrabutylammonium fluoride in tetrahydrofuran solution (1 M, 34.81 mL) were successively added 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 and extracted with ethyl acetate (2 × 50 mL). The organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to give compound 1-3A (TLC developing solvent: ethyl acetate, R of compound 1-3A). f =0.38, and the R of its isomer f =0.17). LCMS: m / z=445.1, 447.1 [M+1] + ; 1H NMR(400MHz,CDCl3)δ8.85(dd,J=1.76,4.77Hz,1H)7.92(d,J=1.76Hz,1H)7.71(dd ,J=1.76,7.78Hz,1H)7.33~7.41(m,2H)7.24~7.28(m,1H)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=14.05Hz,1H ),2.27(d,J=14.05Hz,1H),1.50(d,J=6.27Hz,3H),1.16~1.24(m,4H),0.80(s,6H).

[0393] Process 4 Compound 1-3A (0.4 g, 898.09 μmol) and bis(neopentylglycolate)diboron (406 mg, 1.80 mmol) were dissolved in toluene (10 mL), and 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (131 mg, 179.62 μmol) and potassium acetate (264 mg, 2.69 mmol) were added successively. The nitrogen atmosphere was exchanged 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 give compound 1-4A. LCMS: m / z=411.2 [M boric acid + 1] + .

[0394] Process 5 Compound 1-4A (300.00 mg, 627.05 μmol), compound M2 (0.36 g, 715.12 μmol), 1,1-di(tert-butylphosphino)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 nitrogen was exchanged three times. The reaction solution was stirred at 70 °C for 12 hours. The reaction solution was concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to give compound 1-5A. LCMS: m / z = 789.4 [M+1] + .

[0395] Process 6 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. 1M HCl was added to the reaction solution to adjust the pH to about 5, and the solution was extracted with ethyl acetate (50 mL*3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 1-7A. LCMS: m / z=761.3 [M+1] + .

[0396] Process 7 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-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.35 g, 1.83 mmol) were added. The reaction solution was stirred at 20 °C for 12 h. The reaction solution was diluted with water (50 mL), and the solution was extracted with dichloromethane (20 mL * 3). The organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product, which was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to give compound 1-8A. LCMS: m / z=743.4[M+1] + .

[0397] Process 8 Compound 1-8A (20.00 mg, 26.92 μmol) was dissolved in dichloromethane (1 mL) at 0° C., and 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 give crude trifluoroacetic acid salt of compound 1-9A. LCMS: m / z=643.3 [M+1] + .

[0398] Process 9 Compound 1-9A (20.00 mg, crude trifluoroacetic acid salt) was dissolved in DMF (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-tetramethyluronium hexafluorophosphonate (HATU) (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 combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the crude product, which was purified using a flash chromatography column (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(400MHz,CD3OD)δ ppm8.64(dd.J=4.8,1.6Hz,1H)8.12(s)1H)7.79(dd)J=7.6,1.6Hz,1H)7.54(d)J=8.4Hz,1H)7.44(dd)J=7.6,4 .8Hz,1H)7.34~7.39(m,2H)6.02(t)J=6.2Hz,1H)4.03~4.13(m,2H)3.71~3.86(m,3H)3.43~3.56(m,2H)3.03(s ,3H)2.64~2.72(m,1H)2.37~2.44(m,1H)2.06~2.13(m,1H)1.89~1.97(m,2H)1.70~1.80(m,1H)1.48~1.60(m,3 H)1.32~1.37(m,2H)1.18~1.23(m,6H)0.90~0.97(m,2H)0.76~0.83(m,2H)0.57~0.66(m,6H)0.45~0.51(m,1H).

[0399] Example 2

[0400] [ka] Process 1 Compound 1-3A (295 mg, 662.34 μmol) and bis(pinacolato)diboron (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(diphenylphosphino)ferrocene]dichloropalladium(II) (48.46 mg, 66.23 μmol) were added. The reaction solution was stirred and reacted at 110° C. under a nitrogen atmosphere for 12 hours. 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] + .

[0401] Process 2 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). Potassium phosphate (387.94 mg, 1.83 mmol) and 1,1-di(tert-butylphosphino)ferrocene palladium chloride (39.70 mg, 60.92 μmol) were added. The reaction solution was stirred under a nitrogen atmosphere at 70°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography (20-80% ethyl acetate / petroleum ether) to give compound 2-2A. LCMS: m / z = 825.1 [M+1] + .

[0402] Process 3 Compound 2-2A (280 mg, 339.40 μmol) was dissolved in a mixture 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 and reacted at 25 ° C for 2 hours. The reaction solution was then neutralized with 1 M diluted hydrochloric acid and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine, dried with anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 2-3A. LCMS: m / z = 797.2 [M + 1] + .

[0403] Process 4 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 and reacted at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether), and then prepared and separated by high-performance liquid chromatography (HPLC) (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 39%-69%) to give compound 2-4A. LCMS: m / z = 779.3 [M+1] + .

[0404] Process 5 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 and reacted at 25° C. for 5 hours, and then concentrated under reduced pressure to obtain the crude trifluoroacetic acid salt of compound 2-5A. LCMS: m / z=679.3 [M+1] + .

[0405] Process 6 Compound 2-5A (17 mg, trifluoroacetate salt) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (3.76 mg, 37.57 μmol) were dissolved in DMF (1 mL), and then N,N-diisopropylethylamine (9.71 mg, 75.13 μmol, 13.09 μL) and HATU (19.05 mg, 50.09 μmol) were added with stirring. The reaction solution was stirred and reacted at 25 °C for 12 h, followed by extraction with ethyl acetate (5 mL × 3). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure and purified by HPLC (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile %): 27% to 57%) to obtain the trifluoroacetate salt of compound 2A. LCMS: m / z=761.2[M+1] + ; 1 H NMR(CDCI3,400MHz)δ9.1~9.2(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=5.8Hz,1H),4.11(br d,J=10.5Hz,1H),4.0~4.1(m,1H),3.88(br d)J=10.3Hz,1H),3.64(br d,J=15.6Hz,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=5.8Hz),1.2~1.4(m,8H),1.1~1.2(m,1H),1.07(br d,3H,J=5.5Hz),0.92(br s,3H),0.6~0.7(m,3H),0.5~0.6(m,1H).

[0406] Example 3

[0407] [ka] Process 1 Compound M4-4 (30 g, 138.84 mmol), bis(pinacolato)diboron (52.89 g, 208.26 mmol), 1,5-cyclooctadiene iridium chloride dimer (2.80 g, 4.17 mmol), and 4,4'-di-tert-butyl-2,2'-dipyridyl (5.59 g, 20.83 mmol) were successively added to 600 mL of anhydrous tetrahydrofuran, and the nitrogen was exchanged three times. The mixture was stirred at 80 °C for 20 h. The reaction solution was concentrated. The residue was diluted with 300 mL of water and 200 mL of ethyl acetate, and the pH was adjusted to 10 by adding alkaline water (10 g of NaOH and 40 g of a 400 mL aqueous solution of sodium carbonate). The solution was separated, and the organic phase was discarded. The pH of the aqueous phase was adjusted to 6 using concentrated hydrochloric acid. 500 mL of ethyl acetate was added three times for extraction. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 3-1. 1 H NMR (400MHz, CDCl3) δ=8.93(d,J=1.6Hz,1H)8.22(d,J=1.6Hz,1H)4.96(q,J=6.4Hz,1H)3.32(s,3H)1.50(d,J=6.4Hz,3H)1.37(s,12H).

[0408] Process 2 Compound 3-1 (40 g, 116.95 mmol) was slowly added dropwise to a 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) in 1.5 L of acetonitrile at 80 °C. The mixture was stirred at 80 °C for 1 h. The reaction solution was concentrated under reduced pressure, and the residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to give compound 3-2. MS-ESI calculated value [M+1] + 434.1,436.1 measurements 434.3,436.3; 1H NMR(400MHz, CDCl3)δ=8.23(d,J=2.4Hz,1H)7.39~7.25(m,5H)7.23(d,J=2.4H z,1H)5.09(s,2H)4.78(q,J=6.4Hz,1H)3.68~3.55(m,4H)3.21(s,3H)3.13(br s,4H),1.39(d,J=6.4Hz,3H).

[0409] Process 3 Compound 3-2 (7 g, 16.12 mmol), bis(neopentylglycolate)diboron (5.46 g, 24.18 mmol), 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (589.65 mg, 805.85 μmol), and potassium acetate (3.95 g, 40.29 mmol) were added to 140 mL of anhydrous dioxane. The nitrogen atmosphere was exchanged three times, and the mixture was stirred at 80 °C for 20 h. The reaction solution was concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give compound 3-3. LCMS: m / z = 400.1 [M+1] + .

[0410] Process 4 Compound 3-3 (9 g, 22.54 mmol), compound M5 (14.57 g, 22.54 mmol), 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (824.72 mg, 1.13 mmol), and potassium phosphate (11.96 g, 56.36 mmol) were added successively to 250 mL of anhydrous dioxane and 80 mL of water. The nitrogen atmosphere was exchanged three times, and the mixture was stirred at 70 °C for 12 h. The reaction solution was concentrated. The residue was diluted with 200 mL of water and extracted with ethyl acetate (3 × 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to give compound 3-4. LCMS: m / z=873.3, 875.3 [M+1] + .

[0411] Process 5 Compound 3-4 (6.2 g, 7.09 mmol), ethyl iodide (14.19 mmol, 1.13 mL), and cesium carbonate (4.62 g, 14.19 mmol) were added successively to 100 mL of anhydrous DMF, and the mixture was stirred at 20 °C for 10 h. The reaction solution was concentrated. The residue was diluted with 100 mL of water and 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 give compounds 3-5. LCMS: m / z = 901.4, 903.4 [M+1] + .

[0412] Process 6 Compound 3-5 (6.2 g, 6.87 mmol) in a tetrahydrofuran solution (1 M, 13.75 mL) and tetrabutylammonium fluoride were successively added to 100 mL of anhydrous tetrahydrofuran, and the mixture was stirred at 50 °C for 15 h. The reaction solution was concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to obtain compound 3-6A (TLC developing solvent: ethyl acetate, R of compound 3-6A). f =0.43, and their isomers R f =0.33). LCMS: m / z=663.2, 665.2 [M+1] + .

[0413] Process 7 Compound 3-6A (1.70 g, 2.56 mmol), bis(pinacolato)diboron (975.74 mg, 3.84 mmol), 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (187.43 mg, 256.16 μmol), and potassium acetate (754.21 mg, 7.68 mmol) were added successively to 50 mL of anhydrous dioxane. The nitrogen atmosphere was exchanged three times, and the mixture was stirred at 90 °C for 20 h. The reaction solution was concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to give compound 3-7A. LCMS: m / z = 711.1 [M+1] + .

[0414] Process 8 Compound 3-7A (0.38 g, 534.68 μmol), compound M2 (322.99 mg, 641.61 μmol), 1,1-di(tert-butylphosphino)ferrocene palladium chloride (34.85 mg, 53.47 μmol), and potassium phosphate (283.74 mg, 1.34 mmol) were added successively to 15 mL of dioxane and 5 mL of water. The nitrogen atmosphere was exchanged three times, and the mixture was stirred at 70 °C for 4 h. The reaction solution was concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to give compound 3-8A. LCMS: m / z = 1007.4 [M+1] + .

[0415] Process 9 Compound 3-8A (650 mg, 645.33 μmol) and lithium hydroxide monohydrate (54.16 mg, 1.29 mmol) were added successively 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 1N diluted hydrochloric acid was added dropwise to adjust the pH to 6-7. The solution 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 give compound 3-9A. LCMS: m / z=979.4 [M+1] + .

[0416] Step 10 Compound 3-9A (650 mg, 663.81 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.82 g, 19.91 mmol), N-diisopropylethylamine (26.55 mmol, 4.62 mL), and 1-hydroxybenzotriazole (896.94 mg, 6.64 mmol) were added sequentially to 65 mL of acetonitrile, and the mixture was stirred at 25 °C for 40 h. The reaction solution was concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to give compound 3-10A. LCMS: m / z = 961.4 [M+1] + .

[0417] Step 11 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 added successively to 10 mL of methanol, and the hydrogen was exchanged three times. The mixture was stirred under a hydrogen atmosphere (15 psi) at 20 °C for 2 h. It was filtered, and the filtrate was concentrated. The residue was purified using a flash chromatography column (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to give compound 3-11A. LCMS: m / z = 841.4 [M+1] + .

[0418] Step 12 1 mL of trifluoroacetic acid was slowly added dropwise to compound 3-11A (56 mg, 58.26 μmol) in 5 mL of anhydrous dichloromethane at 0° C., and the mixture was stirred at 0° C. for 5 hours. The reaction was concentrated to give the trifluoroacetic acid salt of compound 3-12A. LCMS: m / z=741.3 [M+1] + .

[0419] Step 13 Compound 3-12A (45 mg, trifluoroacetate salt), 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 successively to 5 mL of anhydrous DMF, and the mixture was stirred at 20 °C for 1 h. The reaction solution was concentrated, and the crude product was separated by preparative HPLC (preparation method: column model: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile %): increasing from 14% to 44% over 8 min) to obtain the trifluoroacetate salt of compound 3A. LCMS: m / z = 823.4 [M+1] + ; 1H NMR(400MHz,1H NMR CDCl3)δ=8.67(br s,1H),8.38(s,1H),7.57(br d,J=8.4Hz,1H),7.37(d,J=8.4Hz,1H),7.27(s,1H),7.20(s,1H),6.78(br d,J=7.6Hz,1H),5.91(br s,1H),4.22(br d,J=6.0Hz,1H),4.14~4.06(m,2H),3.99~3.91(m,2H),3.67(br s,4H),3.53(br dd,J=5.6.14.8Hz,4H),3.27(s,3H),3.26~2.99(m,3H),2.92(br s,3H),2.81(br d,J=14.4Hz,1H),2.52(br d,J=14.2Hz,1H),2.12~1.71(m,4H),1.47(br d,J=6.0Hz,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).

[0420] Example 4

[0421] [ka] Compound 3-12A (0.1 g, 134.96 μmol), (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (31 mg, 269.98 μmol) were dissolved in DMF (2 mL), and then N,N-diisopropylethylamine (175 mg, 1.35 mmol) and HATU (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 prepared and purified by HPLC (purification method: column model: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile %): increasing from 16% to 46% over 8 minutes) to give the trifluoroacetate salt of compound 4A. LCMS: m / z = 837.4 [M+1] + ; 1H NMR(400MHz,CD3OD)δ ppm8.53(s,1H)8.27(s,1H)7.93(s,1H)7.70(d,J=8.8Hz,1H)7.49~7.57(m,2H)6.16(t,J=6.0Hz,1 H)4.95~5.04(m,3H)4.10~4.28(m,3H)3.88~4.06(m,4H)3.45~3.70(m,3H)3.24(s,3H)3.02(s,3H)2 .82~2.90(m,1H)2.46~2.55(m,1H)2.01~2.11(m,1H)1.81~1.91(m,1H)1.68~1.74(m,1H)1.58~1.6 6(m,1H)1.42~14.7(m,3H)1.26~1.41(m,7H)1.17~1.23(m,3H)1.08~1.15(m,7H)0.75~0.85(m,6H).

[0422] Example 5

[0423] [ka] Process 1 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-di(tert-butylphosphino)ferrocene palladium chloride (22.07 mg, 33.86 μmol) were added, and the reaction solution was stirred and reacted under a nitrogen atmosphere at 70 °C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound 5-1A. LCMS: m / z = 923.5 [M+1] + .

[0424] Process 2 Compound 5-1A (205 mg, 222.07 μmol) was dissolved in a mixture 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 and reacted at 25° C. for 1 hour. The pH of the reaction solution was then adjusted to 7-8 using 1M diluted hydrochloric acid, and the solution was then extracted with ethyl acetate (10 mL*5). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 5-2A, which was used directly in the next step. LCMS: m / z=895.3 [M+1] + .

[0425] Process 3 Compound 5-2A (45 mg, 50.28 μmol) was dissolved in acetonitrile (4.5 mL), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (21.16 mg, 75.41 μmol) and N-methylimidazole (12.38 mg, 150.83 μmol) were added. The reaction solution was stirred and reacted at 25 °C for 1 hour. The reaction solution was diluted with water (20 mL) and extracted with dichloromethane (5 mL * 3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to give compound 5-3A. LCMS: m / z = 877.4 [M + 1] + .

[0426] Process 4 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 and reacted at 25° C. for 1 hour, and then concentrated under reduced pressure to give crude trifluoroacetic acid salt of compound 5-4A, which was used directly in the next step.

[0427] Process 5 The crude trifluoroacetic acid salt of compound 5-4A obtained in step 4 was dissolved in DMF (1 mL), and (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (9.70 mg, 84.95 μmol) was added. Then, N,N-diisopropylethylamine (21.96 mg, 169.90 μmol) and HATU (43.07 mg, 113.27 μmol) were added with stirring. The reaction solution was stirred and reacted at 25 ° C for 3 hours, and then purified by preparative HPLC (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: acetonitrile percentage increased from 16% to 46% in 8 minutes) to obtain compound 5A. LCMS: m / z = 873.9 [M + 1] + . 1H NMR (CD3OD, 400MHz) δ8.5~8.6(m,1H),8.2~8.3(m,1H),7.7~7.7(m,1H),7.61(br d,J=2.3Hz,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).

[0428] Example 6

[0429] [ka] Process 1 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). Potassium phosphate (129.39 mg, 609.55 μmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26.48 mg, 40.64 μmol) were added under nitrogen protection and stirred at 70 °C for 12 hours. After cooling, the reaction solution 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] + .

[0430] Process 2 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 and stirred at 25° C. for 30 minutes. The pH of the system was adjusted to 7.0 with 1 M hydrochloric acid, and then diluted with saturated brine (50 mL) and extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 6-2A, which was used directly in the next step. LCMS: m / z=735.6 [M+1] + .

[0431] Process 3 Compound M6 (21.82 mg, 95.25 μmol) and compound 6-2A (70 mg, 95.25 μmol) were dissolved in DMF (2 mL), and N,N-diisopropylethylamine (952.45 μmol, 165.90 μL) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (43.46 mg, 114.29 μmol) were added and stirred at 25 °C for 30 minutes. After the reaction was completed, saturated brine (30 mL) was added and extracted with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 6-3A, which was used directly in the next step. LCMS: m / z = 874.0 [M+1] + .

[0432] Process 4 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 and stirred at 25° C. for 30 minutes. The pH of the system was adjusted to 7.0 with 1 M hydrochloric acid, and then diluted with saturated brine (50 mL) and extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give compound 6-4A, which was used directly in the next step. LCMS: m / z=860.0 [M+1] + .

[0433] Process 5 Compound 6-4A (61 mg, 71.01 μmol) was dissolved in acetonitrile (20 mL), and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (TCFH) (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 preparative TLC (DCM / MeOH = 10:1) to obtain compound 6-5A. LCMS: m / z = 842.0 [M+1] + .

[0434] Process 6 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 and stirred for 1 hour at 25° C. The reaction solution was concentrated to give the crude trifluoroacetic acid salt of compound 6-6A, which was used directly in the next step.

[0435] Process 7 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 HATU (31.13 mg, 81.87 μmol) and N,N-diisopropylethylamine (409.37 μmol, 71.30 μL) were added and stirred for 1 hour at 25° C. The solution was diluted with saturated brine (50 mL) and extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified by preparative TLC (developing solvent: dichloromethane / methanol=10:1), and then purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.1% ammonia), gradient (B%): 50%, isobaric elution) to obtain compounds 6A and 6B.

[0436] Analysis was performed by SFC (column: Chiralcel OD-3 50*4.6 mm ID, 3 um, mobile phase: A: supercritical carbon dioxide B: ethanol (containing 0.05% diethylamine), gradient elution: mobile phase B increased from 5% to 40% in 2 minutes, then held at 40% for 1.2 minutes, then held at 5% for 0.8 minutes), compound 6A had a RT of 1.896 minutes, ee=96.98%; compound 6B had a RT of 2.201 minutes, ee=98.82%. Compound 6A: LCMS: m / z=837.5 [M+1] + ;1H NMR(400MHz,CD3OD)δ=8.33(br d,J=10.5Hz,2H),7.59(br d,J=8.3Hz,1H),7.45(s,1H),7.39(br d,J=8.5Hz,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=13.3Hz,1H),2.63(br s,4H),2.58~2.44(m,2H),2.33(br s,4H),2.10(br t,J=9.0Hz,1H),1.46(br s,1H),1.38~1.16(m,8H),1.05(br dd,J=6.0,13.3Hz,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] + ; 11H NMR (400 MHz, 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).

[0437] Example 7

[0438] [Chemical Structure] 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 HATU (53.37 mg, 140.35 μmol) and N,N-diisopropylethylamine (72.56 mg, 561.42 μmol) were added and stirred for 1 hour at 25° C. The solution was diluted with saturated brine (50 mL) and extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was purified using a flash silica gel column (mobile phase: dichloromethane / methanol = 100:1), and then separated and purified by SFC (column: DAICEL CHIRALCEL OD (250 mm * 30 mm, 10 μm); mobile phase: phase A was supercritical carbon dioxide, phase B was ethanol (0.1% ammonia), gradient (B%): 50%) to obtain compounds 7A and 7B. Analysis was performed by SFC (method: column: chiral OD-3 100 * 4.6 mm ID, 3 μm, mobile phase: A: supercritical carbon dioxide, B: ethanol (containing 0.05% diethylamine), gradient (B%): 40%). The RT of compound 7A was 1.365 min, ee = 100%; the RT of compound 7B was 2.325 min, ee = 88.2%. Compound 7A LCMS: m / z=823.7[M+1] + ; 11H NMR (400 MHz, 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). Compound 7B LCMS: m / z = 823.7 [M+1] + ; 1H NMR(400MHz,CD3OD)δ=8.38(s,1H),8.33(d,J=2.8Hz,1H),7.60~7.54(m,1H),7.39~7.34(m,2H),7.31(d,J=3.0Hz,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=14.3Hz,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=9.5Hz,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=6.0Hz,2H)0.91(td,J=4.3.8.5Hz,1H),0.69(s,3H),0.63~0.57(m,3H),0.50~0.41(m,1H).

[0439] Example 8

[0440] [ka] Using compound 8-1 and compound 6-6A as raw materials, referring to the synthesis method of Example 7, the resulting reaction solution was directly purified by HPLC (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 16% to 46% in 8 minutes) to obtain the trifluoroacetate salt of compound 8A. LCMS: m / z = 859.5 [M+1] + . 11H 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), 0.94~0.83 (m, 10H), 0.39~0.28 (m, 3H).

[0441] Example 9

[0442] [Chemical formula] Step 1 Compound M5-7 (6.83 g, 13.12 mmol) was dissolved in tetrahydrofuran (50 mL) and tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 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, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-55%) to give compound 9-1A. LCMS: m / z = 281.9 [M+1] + .

[0443] Process 2 Compound 9-1A (3.31 g, 11.73 mmol) was dissolved in dichloromethane (30 mL), and then triethylamine (3.56 g, 35.19 mmol) and 4-dimethylaminopyridine (72 mg, 596.51 μmol) were added. The solution was cooled to 0 °C, and acetic anhydride (1.16 g, 11.38 mmol) was added dropwise. The reaction solution was stirred at 0 °C for 10 minutes. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with dichloromethane (50 mL * 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to give compound 9-2A. LCMS: m / z=323.9[M+1] + .

[0444] Process 3 Compound 9-2A (3.4 g, 10.49 mmol), bis(pinacolato)diboron (6.66 g, 26.22 mmol), potassium acetate (2.57 g, 26.22 mmol), and 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.768 g, 1.05 mmol) were dissolved in toluene (40 mL). The nitrogen atmosphere was exchanged three times, and the reaction solution was stirred at 90 °C for 3 h. After completion of the reaction, the reaction solution was directly concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, 0-30% ethyl acetate) to give compound 9-3A. LCMS: m / z = 372.1 [M+1] + .

[0445] Process 4 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(diphenylphosphino)ferrocene]palladium(II) dichloride (750 mg, 1.12 mmol) were dissolved in toluene (30 mL), dioxane (10 mL), and water (10 mL). The nitrogen atmosphere was exchanged three times, and the reaction solution was stirred at 70 °C for 12 h. After completion of the reaction, the reaction solution was directly concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to give compound 9-4A. LCMS: m / z = 530.2 [M+1] + .

[0446] Process 5 Compound 9-4A (5.4 g, 10.20 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0 ° C. Then, sodium bicarbonate (1.03 g, 12.28 mmol) and silver trifluoromethanesulfonate (3.15 g, 12.25 mmol) were added, followed by dropwise addition of iodine (2.33 g, 9.18 mmol) in tetrahydrofuran solution (5 mL). The reaction solution was stirred at 0 ° C. for 15 minutes. After the reaction was completed, the reaction solution was quenched by adding saturated sodium sulfite solution (100 mL) at 0 ° C., and the resulting solution was extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The resulting crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio 0-40%) to give compound 9-5A. LCMS: m / z = 656.1 [M+1] + .

[0447] Process 6 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 h. After the reaction was completed, the pH of the reaction solution was adjusted to approximately 6 by adding saturated citric acid solution, and the resulting solution was extracted with ethyl acetate (100 mL * 3). The organic phases were combined, washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the crude product was directly concentrated and purified by HPLC (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 30% to 60% over 8 min). The target separation solution was concentrated under reduced pressure, adjusted to pH 7-8 with diluted ammonia solution, and extracted with ethyl acetate (30 mL * 3). The organic phases were combined and concentrated to give compound 9-6A. LCMS: m / z=600.1 [M+1] + .

[0448] Process 7 Compound 9-6A (0.32 g, 1.18 mmol) was dissolved in DMF (7 mL), and then N,N-diisopropylethylamine (1.44 g, 11.18 mmol), compound M9 (0.67 g, 1.12 mmol), and HATU (510 mg, 1.44 mmol) were added. The reaction solution was stirred at 25 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The resulting crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-60%) to give compound 9-7A. LCMS: m / z = 738.2 [M+1] + .

[0449] Process 8 9-7A (0.63 g, 854.07 μmol) was dissolved in tetrahydrofuran (6 mL) and methanol (6 mL), and 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 h. After the reaction was completed, the pH of the reaction solution was adjusted to approximately 6 by adding saturated citric acid solution, and the solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The resulting crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to give compound 9-8A. LCMS: m / z = 724.1 [M+1] + .

[0450] Process 9 Compound 9-8A (0.2 g, 276.39 μmol) was dissolved in acetonitrile (20 mL) and DMF (2 mL), and then N-methylimidazole (1.13 g, 13.82 mmol) and TCFH (388 mg, 1.48 mmol) were added. The reaction solution was stirred at 80 °C for 2 h. After the reaction was completed, the reaction solution was directly concentrated to remove acetonitrile, diluted with water (30 mL), and extracted with ethyl acetate (30 mL * 3). The organic phases were combined, washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The resulting crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-40%) to give compound 9-9A. LCMS: m / z = 706.1 [M+1] + .

[0451] Step 10 Compound 9-9A (0.1 g, 141.72 μmol), potassium acetate (48.68 mg, 496.03 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (30 mg, 71.86 μmol), and tris(dibenzylideneacetone)dipalladium(0) (26 mg, 28.54 μmol) were dissolved in toluene (5 mL), and pinacolborane (145.10 mg, 1.13 mmol) was added dropwise at 0 °C under nitrogen protection. The reaction solution was stirred at 60 °C under nitrogen protection for 3 hours. After the reaction was completed, saturated ammonium chloride (10 mL) was added dropwise to the reaction solution to quench it, 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. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-40%) to give compounds 9-10A. LCMS: m / z = 706.4 [M+1] + .

[0452] Step 11 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(diphenylphosphino)ferrocene]palladium(II) dichloride (21 mg, 28.54 μmol) were dissolved in toluene (3 mL), dioxane (1 mL), and water (1 mL). The nitrogen atmosphere was exchanged 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 crude 9-11A was used directly in the next step. LCMS: m / z=855.6 [M+1] + .

[0453] Step 12 Compound 9-11A (0.1 g, 116.95 μmol) and cesium carbonate (115 mg, 351.85 μmol) were dissolved in DMF (3 mL), and ethyl iodide (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 HPLC (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 22% to 52% in 8 minutes) to obtain the trifluoroacetate salt of compound 9-12A. LCMS: m / z=883.4 [M+1] + .

[0454] Step 13 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 crude 9-13A was used directly in the next step. LCMS: m / z=783.3 [M+1] + .

[0455] Step 14 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 DMF (2 mL), and then N,N-diisopropylethylamine (50 mg, 386.87 μmol) and HATU (30 mg, 78.90 μmol) were added. 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 separated and purified by HPLC (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: acetonitrile increased from 17% to 47% in 8 minutes) to obtain the trifluoroacetate salt of compound 9A. LCMS: m / z = 865.3 [M+1] + . 1 H NMR(400MHz,CD3OD)δ ppm8.88(s,1H)8.57(s,1H)8.20(s,1H)7.74(s,1H)7.54(s,2H)6.8~6. 41(m,2H)4.54~4.45(m,1H)4.29~4.11(m,9H)4.03~3.89(s,3H)3.77~3. 57(m,6H)3.06~2.97(m,1H)2.44~2.35(m,1H),2.27~2.15(m,5H),2.09~ 1.95(m, 10H), 1.66~1.57(m, 5H), 1.13~1.06(m, 3H), 0.92~0.96(m, 6H).

[0456] Example 10

[0457] [ka] Process 1 Compound 3-4 (1 g, 1.14 mmol) and cesium carbonate (2.61 g, 8.01 mmol) were dissolved in 1-methyl-2-pyrrolidinone (10 mL) and cooled to 0 °C. Then, 2,2,2-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 completed, water (100 mL) was added to the reaction, and the solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to give compound 10-1A. LCMS: m / z = 955.3 [M+1] + .

[0458] Process 2 Tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 5 mL) was added to compound 10-1A (0.5 g, 523.01 μmol) at 0°C. The reaction solution was stirred at 40°C for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (50 mL * 3). The organic phases were combined, washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified using a flash chromatography column (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to give compound 10-2A (LC-MS analysis method: 5-95AB_1.5 min, retention time of compound 10-2A was 1.009 min, and retention time of its isomer was 0.981 min). LCMS: m / z = 717.1 [M+1] + .

[0459] Steps 3~11 The reaction solution of compound 10A was obtained by referring to the synthesis methods of Examples 6 to 9. The reaction solution was filtered, and the filtrate was separated and purified by HPLC (column: C18 100 x 40 mm; mobile phase: [water (trifluoroacetic acid) - acetonitrile]; gradient: acetonitrile increased from 20% to 50% over 8 minutes) to obtain the trifluoroacetate salt of Example 10A. LCMS: m / z = 891.5 [M+1] + . 1 H NMR(400MHz,CD3OD)δ ppm8.57~8.43(m,2H)7.80~7.71(m,1H)7.64(s,1H)7.59~7.48(m,2H)5.54~5.49( m,1H)5.38~5.34(m,2H)4.12~4.00(m,1H)3.70~3.68(m,1H)3.62(s,1H)3.37~3.3 5(m,3H)3.05~2.99(m,4H),2.25~2.18(m,4H),2.11~2.01(m,4H),1.71~1.56(m,5 H),1.49~1.42(m,5H),1.41~1.36(m,10H),1.22~1.13(m,5H),1.12~1.04(m,3H).

[0460] Example 11

[0461] [ka] The reaction solution of compound 11A was obtained by referring to the synthesis methods of Examples 6 to 9. Water was added to the reaction solution until no more solids precipitated, and the reaction solution was vacuum filtered to collect the solids. The solids were then purified by HPLC (column: C18 100 x 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 15% to 45% over 8 minutes) to obtain the trifluoroacetate salt of compound 11A. LCMS: m / z = 825.4 [M+1] +. 1H NMR(400MHz,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=11.8,12.8Hz,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=5.5Hz,3H)1.44~1.36(m,1H),1.31~1.19(m,3H),1.13(br d,J=5.8Hz,3H),1.02~0.93(m,6H),0.73~0.64(m,1H),0.49~0.34(m,3H).

[0462] Example 12

[0463] [ka] The reaction solution of compound 12A was obtained by referring to the synthesis methods of Examples 6 to 9. Water was added to the reaction solution until no more solids precipitated. The solids were collected by vacuum filtration and then purified by HPLC (column: C18 100 x 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increased from 17% to 47% within 8 minutes) to obtain the trifluoroacetate salt of target compound 12A. LCMS: m / z = 862.2 [M+23] + . 11H 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).

[0464] Example 13

[0465] [Chemical formula] Step 1 Compound M11 (1.36 g, 4.90 mmol) was dissolved in tetrahydrofuran (40 mL) and water (10 mL), and sodium bicarbonate (1.44 g, 17.14 mmol) and BocO (1.17 g, 5.34 mmol) were added and stirred for 12 hours at 25° C. After the reaction was completed, water (50 mL) and ethyl acetate (50 mL*3) were added for extraction. After the organic phase was dried and concentrated, it was purified by SFC (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [phase A: supercritical carbon dioxide fluid, phase B: isopropanol containing 0.1% ammonia]; phase B was purified by 30% isocratic elution) to give compound 13-1A (Rt=3.625; SFC analytical method: column: DAICEL CHIRALPAK IG (100*4.6 mm ID, 3 um); mobile phase: [phase A: supercritical carbon dioxide fluid, phase B: isopropanol containing 0.05% ammonia solution]; phase B was increased from 5% to 40% in 4.5 minutes, then held at 5% for 1.5 minutes, flow rate 2.5 mL / min, column temperature: 40° C.) and 13-1B (Rt=4.200; SFC analytical method: column: DAICEL CHIRALPAK IG (100*4.6 mm ID, 3 μm); Mobile phase: [Phase A: supercritical carbon dioxide fluid, Phase B: isopropanol containing 0.05% ammonia solution], Phase B was increased from 5% to 40% in 4.5 minutes, then held at 5% for 1.5 minutes, flow rate 2.5 mL / min, column temperature: 40 °C). LCMS: m / z = 321.1, 323.1 [M+1-56]+.

[0466] Process 2 Compound 3-6A (1.2 g, 1.81 mmol) and bis(pinacolato)diboron (688.76 mg, 2.71 mmol) were added to toluene (10 mL), followed by the addition of potassium acetate (354.91 mg, 3.62 mmol), followed by the addition of nitrogen. 1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (1,32.31 mg, 180.82 μmol) was added. The reaction solution was stirred under nitrogen at 70°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to give compound 13-2A. LCMS: m / z = 711.4 [M+1] + .

[0467] Process 3 Compound 13-1A (0.05 g, 132.54 μmol) was dissolved in dichloromethane (2 mL), and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (30.49 mg, 159.04 μmol), 1-hydroxybenzotriazole (21.49 mg, 159.04 μmol), and N-methylmorpholine (26.81 mg, 265.07 μmol) were added and stirred at 0 °C for 0.5 hours. Then, trifluoroacetic acid salt of compound M9 (35.81 mg, 132.54 μmol) was added at 0 °C and stirred at 25 °C for 1 hour. After the reaction, the solution 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] + .

[0468] Process 4 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). Potassium phosphate (64.25 mg, 302.67 μmol) and 1,1-di(tert-butylphosphino)ferrocene palladium chloride (13.15 mg, 20.18 μmol) were then added and stirred at 70 °C for 12 hours under nitrogen protection. Water (10 mL) was added after the reaction was completed, and the solution was extracted with ethyl acetate (10 mL * 3). After drying and concentrating the organic phase, the crude product was separated using a thin-layer chromatography preparative plate (petroleum ester: ethyl acetate = 1:1) to obtain compound 13-4A. LCMS: m / z = 510.0 [M / 2+1] + .

[0469] Process 5 The reaction solution of compound 13A was obtained by referring to the synthesis methods of Examples 6 to 9. Water (10 mL) was added to the reaction solution, and the solution was extracted with ethyl acetate (10 mL x 3). After the organic phase was dried and concentrated, the crude product was separated using a thin layer chromatography preparative plate (dichloromethane:methanol = 10:1) to obtain compound 13A. LCMS: m / z = 850.0 [M+1] + . 1 H NMR(400MHz,CD3OD)δ ppm0.59(s,3H)0.67(s,3H)0.99(s,3H)1.06(br t,J=7.15Hz,6H)1.50(br s,2H)1.59(br d,J=9.29Hz,1H)1.94(s,2H)2.10(t,J=7.53Hz,1H)2.19~2.28(m,1H)2.40(br d,J=5.02Hz,2H)2.59~2.64(m,1H),2.73~2.77(m,3H)2.80(s,1H)2.95(d,J=7.28Hz,1H),3.03(s,3H),3.09~3.17(m,8H)3.43(br d,J=9.03Hz,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=8.78Hz,1H)8.34~8.38(m,2H).

[0470] Example 14

[0471] [ka] Using compound 13-1B as raw material, compound 14A was prepared with reference to the synthesis method of Example 13.

[0472] LCMS: m / z=850.0[M+1] + . 1 H NMR(400MHz,CD3OD)δ ppm0.56(br s,3H)0.66(br s,1H)0.90(s,3H)1.04(br s,3H)1.13(br d,J=5.77Hz,4H)1.24~1.29(m,1H)1.31(br s,2H)1.33~1.38(m,2H)1.44(br d,J=6.02Hz,3H)1.61(br s,1H)1.73~1.79(m,1H)2.23(s,1H)2.38(s,3H)2.47(br d,J=10.04Hz,1H)2.60(br s,1H)2.67(br s,4H)2.74(br s,1H)2.97(s,1H)3.27(s,3H)3.37(br s,4H)3.60(br d,J=10.79Hz,1H)3.74(br d,J=12.55Hz,1H)4.24(br d,J=6.53Hz,1H)4.58(br s,5H)4.68(br s,1H)7.37(s,1H)7.46~7.50(m,2H)7.66(br d,J=8.53Hz,1H)8.43(s,2H).

[0473] Example 15

[0474] [ka] Process 1 Compound M10-2 (728.03 mg, 2.13 mmol) and compound 15-1A (570 mg, 2.55 mmol) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). Potassium carbonate (735.57 mg, 5.32 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) (155.77 mg, 212.89 μmol) were then added, and the reaction solution was stirred under nitrogen at 50° C. for 2 hours. The reaction solution was then filtered to remove insoluble impurities, and the filtrate was concentrated and dried 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] + .

[0475] Process 2 Compound 15-2A (580 mg, 1.86 mmol) and bis(neopentylglycolate)diboron (505.16 mg, 2.24 mmol) were dissolved in toluene (10 mL). Potassium acetate (457.26 mg, 4.66 mmol) and 1,1-bis(diphenylphosphino)ferrocene-palladium(II) (136.37 mg, 186.37 μmol) were then added, and the reaction solution was stirred under nitrogen at 80° C. for 2 hours. The reaction solution was then filtered to remove insoluble impurities, and the filtrate was concentrated and dried to give compound 15-3A. LCMS: m / z=345.1 [M+1] + .

[0476] Process 3 Compound 15-3A (640 mg, 1.86 mmol, 1 equiv.) and compound M5 (1.20 g, 1.86 mmol, 1 equiv.) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). Potassium carbonate (770.83 mg, 5.58 mmol) was added, and the nitrogen was exchanged three times. 1,1-bis(diphenylphosphino)ferrocene-palladium(II) (136.03 mg, 185.91 μmol) was added, and the reaction solution was stirred under nitrogen at 70 °C for 3 h. After the reaction, the reaction solution was filtered to remove insoluble impurities, and the organic solvent was removed by vacuum distillation to obtain the crude product, which was purified by column chromatography (0-10% methanol / dichloromethane) to obtain compound 15-4A. LCMS: m / z = 750.2 [M+1] + .

[0477] Process 4 Compound 15A was obtained by referring to the synthesis methods of Examples 6 to 9. LCMS: m / z=834.5 [M+H] + .

[0478] Example 16

[0479] [ka] Compound 16A (LCMS: m / z=820.5[M+H] + ), Compound 17A (LCMS: m / z=836.0[M+H] + ), Compound 18A (LCMS: m / z=848.5[M+H] + ), and compound 19A (LCMS: m / z=834.5[M+H] + ) was prepared with reference to the synthesis methods of Examples 6 to 9.

[0480] Biological Test Data Experimental Example 1: In vitro AsPC-1 cell proliferation experiment Test materials: RPMI1640 medium, penicillin / streptomycin antibiotics were purchased from Gibco, fetal bovine serum was purchased from Hyclone, 3D CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega, AsPC-1 cell line was purchased from ATCC, Envision multilabel plate reader (PerkinElmer).

[0481] Experimental Method: AsPC-1 cells were seeded into 96-well ultra-low-attachment U-shaped plates using 80 μL of cell suspension per well containing 1,000 AsPC-1 cells. The plates were incubated overnight in a carbon dioxide incubator.

[0482] The test compounds were diluted 5-fold to 8-fold using a pipette, i.e., from 2 mM to 25.6 nM, and duplicate wells were set up for the experiment. 78 μL of culture medium was added to the middle plate, and then 2 μL of the gradient-diluted compounds were transferred into each well of the middle plate according to the corresponding position. After thorough mixing, 20 μL of each well was transferred to the cell plate. The compound concentrations transferred to the cell plate ranged from 10 μM to 0.128 nM. The cell plate was cultured in a carbon dioxide incubator for 10 days. Another cell plate was prepared, and the signal value was read as the maximum value (maximum value in the following formula) on the day of dosing for data analysis.

[0483] 100 μL of cell viability chemiluminescence detection reagent was added to the cell plate and incubated at room temperature for 30 minutes to stabilize the luminescence signal. A multi-label plate reader was used for reading.

[0484] Data Analysis: The raw data were converted to percentage inhibition using the equation (sample-min / max-min)*100% to give IC 50Values ​​could be obtained by four-parameter curve fitting ("log(inhibitor) vs. response--variable slope" mode in GraphPad Prism). Table 1 provides the inhibitory activity of compounds of the present disclosure against AsPC-1 cell proliferation.

[0485] [Table 1]

[0486] Experimental Example 2: In vitro cell proliferation experiment Test materials: RPMI 1640 medium, DMEM, Ham's F12 medium, F12K medium, IMDM, and penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone, Envision multilabel plate reader (PerkinElmer).

[0487] 3D CellTiter-Glo (cell viability chemiluminescence detection reagent) 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), and Capan-1 cells (IMDM + 20% FBS + 1% penicillin / streptomycin) were purchased from Nanjing Cobioer Biosciences. 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), SW620 cells (RPMI1640 + 10% FBS + 1% Cells were purchased from ATCC. HCT116 cells (RPMI1640 + 10% FBS + 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 line (Ham's F12 + 10% FBS + 1% penicillin / streptomycin) and LU99 cell line (RPMI1640 + 10% FBS + 1% penicillin / streptomycin) were purchased from JCRB.

[0488] Experimental Method: Cells were seeded into ultra-low binding 96-well U-shaped plates using 80 μL of cell suspension per well containing 1,000 cells. The plates were incubated overnight in a carbon dioxide incubator.

[0489] The test compounds were diluted 5-fold to 8-fold using a pipette, i.e., from 2 mM to 25.6 nM, and duplicate wells were set up for the experiment. 78 μL of culture medium was added to the middle plate, and then 2 μL of the gradient-diluted compounds were transferred into each well of the middle plate according to the corresponding position. After thorough mixing, 20 μL of each well was transferred to the cell plate. The compound concentrations transferred to the cell plate ranged from 10 μM to 0.128 nM. The cell plate was cultured in a carbon dioxide incubator for 5 days. Another cell plate was prepared, and the signal value was read as the maximum value (maximum in the following formula) on the day of dosing for data analysis.

[0490] 50 μL of cell viability chemiluminescence detection reagent was added to the cell plate and incubated at room temperature for 30 minutes to stabilize the luminescence signal. A multi-label plate reader was used for reading.

[0491] Data Analysis: The raw data were converted to percentage inhibition using the equation (sample-min / max-min)*100% to give IC 50 Values ​​could be obtained by four-parameter curve fitting (derived from the "log(inhibitor) vs. response--variable slope" mode in GraphPad Prism). Table 2 provides experimental results of the inhibitory activity of compounds of the present disclosure on cell proliferation.

[0492] [Table 2]

[0493] Experimental Example 3: Detection of p-ERK levels in AsPC-1 cells Test materials: 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; ERK1 / 2 (THR202 / TYR204) KIT components were: Advanced PhosphoERK1 / 2 Eu Cryptate antibody, Advanced PhosphoERK1 / 2 d2 antibody, blocking reagent (100X stock solution), lysis buffer #1 (4X stock solution), and detection buffer (ready to use), all with a storage temperature of ≤-16°C.

[0494] Experimental Method: (1) The cells were seeded into a white-bottom 384-well cell culture plate with 8 μL of cell suspension per well, with each well containing 7,500 cells. The cell plate was placed in a carbon dioxide incubator and incubated at 37°C overnight; (2) The test compound was diluted to 3 mM with 100% DMSO as the first concentration, and then diluted to 10 concentrations using a pipette: 3,000, 1,000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 μM. 2 μL of the compound was removed and added to 198 μL of cell starvation medium and mixed well. 15 μL of the compound solution was removed and added to 35 μL of cell starvation medium and mixed well. The compound solution from the last step was then added to the corresponding cell plate wells using 4 μL per well. The cell plate was then placed back into the carbon dioxide incubator and incubated for 3 hours, at which time the compound concentrations were 3,000, 1,000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 nM; (3) After incubation, 3 μL of 5× cell lysate was added to each well and shaken at room temperature for 30 minutes. (4) The phospho-ERK1 / 2 Eu cryptate antibody and the phospho-ERK1 / 2 d2 antibody were diluted 20-fold using the detection buffer, mixed at a 1:1 ratio, and added to the cell culture plate at 5 μL per well and incubated at room temperature for 2 hours; (5) After incubation, HTRF excitation: 320 nm, emission: 615 nm and 665 nm were read using a multi-label plate reader.

[0495] Data Analysis: The raw data was converted to percent inhibition using the equation (sample-min / max-min)*100%, and IC50 values ​​could be obtained by four-parameter curve fitting (log(inhibitor) vs. response--variable slope mode in GraphPad Prism). Table 4 provides the inhibitory effects of compounds of the present disclosure on p-ERK. Maximum well: Positive control well reading was 1X lysate; Minimum well: Negative control well reading was 0.5% DMSO cell well cell lysate. See Table 3 for experimental results.

[0496] [Table 3]

[0497] Experimental Example 4: Detection of p-ERK levels in GP2D cells Test materials: 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; and Advanced Phospho-ERK1 / 2 (THR202 / TYR204) KIT was purchased from Bioauxilium-Advanced Phospho; the ERK1 / 2 (THR202 / TYR204) KIT consisted of: Advanced PhosphoERK1 / 2 Eu Cryptate antibody, Advanced PhosphoERK1 / 2 d2 antibody, blocking reagent (100X stock solution), lysis buffer #1 (4X stock solution), and detection buffer (ready to use), all with a storage temperature of ≤-16°C.

[0498] Experimental Method: (1) The cells were seeded into a white-bottom 384-well cell culture plate with 8 μL of cell suspension per well, with each well containing 7,500 cells. The cell plate was placed in a carbon dioxide incubator and incubated at 37°C overnight; (2) The test compound was diluted to 3 mM with 100% DMSO as the first concentration, and then diluted to 10 concentrations using a pipette: 3,000, 1,000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 μM. 2 μL of the compound was removed and added to 198 μL of cell starvation medium and mixed well. 15 μL of the compound solution was removed and added to 35 μL of cell starvation medium and mixed well. The compound solution from the last step was then added to the corresponding cell plate wells using 4 μL per well. The cell plate was then placed back into the carbon dioxide incubator and incubated for 3 hours, at which time the compound concentrations were 3,000, 1,000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 nM; (3) After incubation, 3 μL of 5× cell lysate was added to each well and shaken at room temperature for 30 minutes. (4) The phospho-ERK1 / 2 Eu cryptate antibody and the phospho-ERK1 / 2 d2 antibody were diluted 20-fold using the detection buffer, mixed at a 1:1 ratio, and added to the cell culture plate at 5 μL per well and incubated at room temperature for 2 hours; (5) After incubation, HTRF excitation: 320 nm, emission: 615 nm and 665 nm were read using a multi-label plate reader.

[0499] Data Analysis: The raw data was converted to percent inhibition using the equation (sample-min / max-min)*100%, and IC50 values ​​could be obtained by four-parameter curve fitting (log(inhibitor) vs. response--variable slope mode in GraphPad Prism). Table 4 provides the inhibitory effects of the compounds of the present disclosure on p-ERK. Maximum well: Positive control well reading was 1X lysate; Minimum well: Negative control well reading was 0.5% DMSO cell well cell lysate. See Table 4 for experimental results.

[0500] [Table 4]

[0501] Experimental Example 5: In vivo pharmacodynamics study Objective of the experiment: To test the in vivo efficacy of compounds of the present disclosure against human lung bronchial benign NCI-H727 cells in a subcutaneous xenograft tumor model in BALB / c nude mice.

[0502] Experimental methods and procedures: Experimental animals: female BALB / c nude mice, 6–8 weeks old, weighing 18–22 g; supplied by Beijing Vital River Laboratory Animal Technology Co., Ltd. (1) Cell culture: Human pulmonary bronchial benign tumor cells were cultured in vitro in monolayers in Gibco RMPI1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Routine passage was performed twice weekly using trypsin-EDTA for digestion. When cell saturation reached 80%-90% and the required number was reached, cells were harvested, counted, and inoculated. (2) Tumor cell inoculation and grouping: 0.2 mL (2 × 10 6 ) NCI-H727 cells (added with Matrigel at a volume ratio of 1:1) were inoculated subcutaneously into the right back of each mouse, and the dose was administered until the average tumor volume reached approximately 134 mm 3 The study started when the animals reached 100 mg / kg and involved 6 animals in each group. The solvent was 5% DMSO / 10% solutol / 85% water. Control group: The solvent was administered twice a day by gavage at a dose of 10 μL / g; Treatment group: The test compound was dissolved in the solvent and then administered once a day by gavage. See Table 4 for dosage. (3) Tumor diameters were measured twice a week using Vernier calipers, and tumor volume (V) was calculated using the formula: V = 0.5a × b 2 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 tumor growth inhibition rate (TGI). The calculation formula is as follows: TGI% = [1 - (mean tumor volume at the end of dosing in a treatment group - mean tumor volume at the beginning of dosing in this treatment group) / (mean tumor volume at the end of treatment in the vehicle control group - mean tumor volume at the beginning of treatment in the vehicle control group) × 100%.

[0503] Test Results: The body weight of the mice in each treatment group was well maintained after administration, and the TGI was calculated based on the average tumor volume on day 21 after administration. See Table 5 for specific experimental results.

[0504] [Table 5]

[0505] Experimental Example 6: In vivo pharmacodynamics study Objective of the experiment: To test the in vivo efficacy of compounds of the present disclosure in a BALB / c nude mouse subcutaneous xenograft tumor model of human pancreatic cancer PK59 cells.

[0506] Experimental methods and procedures: Experimental animals: female BALB / c nude mice, 6–8 weeks old, weighing 18–22 g; supplied by Beijing Vital River Laboratory Animal Technology Co., Ltd. (1) Cell culture: Human pancreatic cancer PK59 cells were cultured in vitro in monolayers in Gibco RMPI1640 medium supplemented with 10% fetal bovine serum and incubated at 37°C in a 5% CO2 incubator. Routine passage was performed twice a week using trypsin-EDTA for digestion. When cell saturation reached 80%-90% and the required number was reached, cells were harvested, counted, and inoculated. (2) Tumor cell inoculation and grouping: 0.2 mL (2 × 10 6 ) PK59 cells (added with Matrigel at a volume ratio of 1:1) were inoculated subcutaneously into the right back of each mouse, and the dose was adjusted until the average tumor volume reached approximately 104.4 mm. 3 The study started when the animals reached 100 mg / kg and involved 6 animals in each group. The solvent was 5% DMSO / 10% solutol / 85% water. Control group: The solvent was administered via gavage once a day at a dose of 10 μL / g; Treatment group: The test compound was dissolved in the solvent and then administered via gavage once a day. See Table 5 for dosage. (3) Tumor diameters were measured twice a week using Vernier calipers, and tumor volume (V) was calculated using the formula: V = 0.5a × b 2where a and b are the long and short diameters of the tumor, respectively. The tumor-inhibiting efficacy of the test compound was evaluated by tumor growth inhibition rate (TGI). The calculation formula is as follows: TGI% = [1 - (mean tumor volume at the end of dosing in a treatment group - mean tumor volume at the beginning of dosing in this treatment group) / (mean tumor volume at the end of treatment in the vehicle control group - mean tumor volume at the beginning of treatment in the vehicle control group) × 100%.

[0507] Test Results: The body weight of the mice in each treatment group was well maintained after administration, and the TGI was calculated based on the average tumor volume on day 22 after administration. See Table 6 for specific experimental results.

[0508] [Table 6]

[0509] Experimental Example 7: In vitro determination of whole blood to plasma concentration ratios. Experimental procedure: (1) Fresh mouse and human whole blood (n ≥ 3 for individual animals and n ≥ 2 for individual humans) was collected in blood collection tubes containing EDTAK2 anticoagulant. Whole blood samples should be mixed well before use and stored at 2-8°C or on wet ice. They were used within 36 hours of collection. Blank whole blood was centrifuged at 2,000 × g for 15 minutes at room temperature to obtain blank plasma. Plasma quality was checked; hemolyzed plasma samples could not be used. (2) Hematocrit (the percentage content of red blood cells in whole blood) was determined by centrifugation of whole blood samples in microhematocrit centrifuge tubes. (3) Diclofenac (all species), chlorthalidone (mice), or chloroquine (humans) were used as control compounds. (4) A 2% DMSO solution in ACN containing the test compound at a final concentration of 1 μM was added to the blank whole blood sample for three parallel treatments. The final content of the organic phase in the system should not exceed 0.5% (the DMSO content should not exceed 0.1%). A fixed volume of the drug-containing whole blood sample was pipetted into a sample receiving plate (three times), and an equal volume of blank plasma was added and mixed well to obtain the TO sample. (5) Whole blood samples containing test compounds were incubated with shaking at 37° C. for 60 minutes. (6) After the incubation, a fixed volume of the whole blood sample containing the drug was added to the T 60 -Whole blood samples were pipetted into a sample receiving plate (three replicates). (7) The remaining whole blood sample was centrifuged at 2,000 × g for 15 minutes in a 37°C centrifuge to obtain a plasma sample. A fixed volume of plasma was collected and analyzed by T 60 Plasma samples were pipetted into a sample receiving plate (triplicates). (8) During sample processing, all samples were equilibrated with matrix (i.e., the same volume of blank whole blood or blank plasma was added) and mixed well. (9) One volume of pure water was added to the equilibrated sample, followed by the addition of a fixed volume of stop solution containing an internal standard compound to terminate the reaction. (10) Analytes and control compounds in the samples were determined by liquid chromatography tandem mass spectrometry (LC-MS / MS). The ratio of the analyte peak area to the internal standard peak area was used to express the concentration in the sample.

[0510] Test Results: See Table 7 for experimental results. B / P represents the concentration ratio of the compound in whole blood and plasma, and K E / P represents the concentration ratio of the compound in red blood cells and plasma, and recovery (%) represents the recovery of the compound in whole blood.

[0511] [Table 7]

[0512] Experimental Example 8: Pharmacokinetic testing in mice. Objective of the experiment: The pharmacokinetic behavior of compounds of the present disclosure was evaluated in male CD-1 (ICR) mice.

[0513] Experimental Method: The compounds to be tested were dissolved in a solvent (5% DMSO / 10% solutol / 85% water). Four male CD-1 mice were divided into two groups of two mice each. The first group of mice received a single intravenous bolus injection of the compound at a dose of 1 mg / kg. The second group of mice received a single dose of the compound by gavage at a dose of 10 mg / kg. Whole blood samples were collected at 0.083 hours (intravenous bolus group only), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. The concentrations of the test compounds in the whole blood samples were determined using an LC-MS / MS method.

[0514] Test Results: The test was well tolerated by all animals, and no abnormalities were observed. After intravenous bolus injection of compound 7A, the total blood clearance (Cl) was 6.29 mL / min / kg, the apparent volume of distribution at steady state (Vd) was 2.18 L / kg, and the elimination half-life (T 1 / 2 ) was 4.29 hours, and the value of the area under the whole blood concentration-time curve from time 0 to the last quantifiable time point (AUC 0-last After administration of compound 7A by gavage, the time to maximum concentration (T max ) occurred 3.0 hours after administration, and the maximum concentration (C max ) is 2,000 nmol / mL, and AUC 0-last The ATP content was 17,119 h nmol / mL, and the bioavailability (F) was 54.3%.

[0515] Conclusion: The compounds of the present disclosure have high exposure, long half-life, and good pharmacokinetic properties.

[0516] Experimental Example 9: Pharmacokinetic study in rats Objective of the experiment: To evaluate the pharmacokinetic behavior of compounds of the present disclosure in male SD rats.

[0517] Experimental Method: The compound to be tested was dissolved in a solvent (5% DMSO / 10% solutol / 85% water). Four male SD rats were divided into two groups, with two rats in each group. The first group of rats received a single intravenous bolus injection (iv) of the compound at a dose of 1 mg / kg. The second group of rats received a single dose of the compound by gavage (po) at a dose of 10 mg / kg. Whole blood samples were collected at 0.083 hours (intravenous bolus group only), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after administration. The concentration of the test compound in the whole blood samples was determined using an LC-MS / MS method.

[0518] Test Results: The test was well tolerated by all animals and no abnormalities were observed. See Table 8 for specific experimental results.

[0519] [Table 8]

[0520] Experimental Example 10: Pharmacokinetic study in beagle dogs. Objective of the experiment: To evaluate the pharmacokinetic behavior of compounds of the present disclosure in male beagle dogs.

[0521] Experimental Method: The compound to be tested was dissolved in a solvent (5% DMSO / 10% solutol / 85% water). Four male beagle dogs were divided into two groups of two. Animals in Group 1 received a single intravenous bolus injection (iv) of the compound at a dose of 1 mg / kg. Animals in Group 2 received a single dose of the compound by gavage (po) at a dose of 5 mg / kg. Whole blood samples were collected at 0.083 hours (intravenous bolus group only), 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, and 24 hours after dosing. The concentration of the test compound in the whole blood samples was determined using an LC-MS / MS method.

[0522] Test Results: The compound was well tolerated in all animals and no abnormalities were observed during testing. See Table 9 for specific experimental results.

[0523] [Table 9]

Claims

1. A compound represented by formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, 【Chemical 1】 L is R ６ or 【Chemistry 2】 and L １ But -N(R ９ )C(═O)—; L ２ is 1, 2, or 3 R ａ C optionally substituted with １－６ alkyl; L ３ But -CH ２ - and C ３－６ cycloalkyl; L ４ is 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]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 a 5-membered heteroaryl and a 5-membered heteroaryl, indolyl, and 【Chemistry 3】 Selected from: T １ , T ２ , T ３ , and T ２ are each independently selected from CH and N; R １ H, F, Cl, Br, I, OH, C １－４ Alkyl, and C １－４ alkoxy, wherein C １－４ Alkyl and C １－４ Alkoxy is each independently 1, 2, or 3 R ｈ optionally substituted with; R ２ is selected from —O— and —NH—; R ３ are selected from phenyl and 5- to 6-membered heteroaryl, each independently selected from 1, 2, or 3 R ｂ optionally substituted with; R ４ and R ５ are each independently H, C １－４ Alkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl, １－４ Alkyl, C ３－６ cycloalkyl, and 3- to 6-membered heterocycloalkyl each independently have 1, 2, or 3 R ｃ optionally substituted with; R ６ But C ３－６ cycloalkyl and 3- to 6-membered heterocycloalkyl, each of which is independently selected from 1, 2, or 3 R ｄ optionally substituted with; Each R ７ are independently H, halogen, C １－４ Alkyl, and C １－４ alkoxy, wherein C １－４ Alkyl and C １－４ Alkoxy is each independently 1, 2, or 3 R ｅ optionally substituted with; Each R ８ However, independently, H, C １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl, and 3- to 10-membered heterocycloalkyl, １－４ Alkyl, C １－４ Alkoxy, C ３－６ cycloalkyl, and 3- to 10-membered heterocycloalkyl each independently have 1, 2, or 3 R ｆ optionally substituted with; R ９ and R １０ However, H and C １－４ alkyl, wherein C １－４ alkyl is 1, 2, or 3 R ｇ optionally substituted with; Each R ａ , each R ｂ , each R ｃ , each R ｅ , each R ｆ , each R ｇ , and each R ｈ are independently H, D, F, Cl, Br, I, OH, C １－３ Alkyl, and C １－３ alkoxy, wherein C １－３ Alkyl and C １－３ each alkoxy is optionally substituted independently with 1, 2, or 3 R; Each R ｄ But independently, C １－４ Alkyl, C ３－６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C ２－４ alkenyl, wherein C １－４ Alkyl, C ３－６ Cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl, and —C(═O)—C ２－４ each alkenyl is optionally substituted independently with 1, 2, or 3 R; Each R is independently D, F, Cl, Br, I, OH, CH ３ , C.F. ３ , OCH ３ , and OCF ３ Selected from: n, p, and q are each independently selected from 0, 1, 2, and 3; A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the "3- to 6-membered heterocycloalkyl", "3- to 10-membered heterocycloalkyl", and "5- to 6-membered heteroaryl" each independently contain one or two heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N.

2. Each R ｄ But independently, CH ３ , C.H. ２ CH ３ , phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and 【Chemistry 4】 each independently optionally substituted with 1, 2, or 3 R; or each R ｄ But independently, CH ３ and CH ２ CH ３ wherein said CH ３ and CH ２ CH ３ is independently optionally substituted with 1, 2, or 3 F; or each R ｄ But independently, CH ３ , 【Chemistry 5】 Alternatively, each R ｄ But independently, CH ３ 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

3. Each R １ are independently H, F, OH, and CH ３ 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

4. The structural unit 【Chemistry 6】 but, 【Chemistry 7】 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

5. Ring A is selected from 3,4-diazabicyclo[4.1.0]heptyl and 2,3-diazabicyclo[3.1.1]heptyl, or Ring A is 【Chemistry 8】 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

6. R ２ The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein is selected from -O-.

7. R ３ is selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, pyrazolyl, and imidazolyl, each independently selected from 1, 2, or 3 R ｂ optionally substituted with; or R ３ but, 【Chemistry 9】 Alternatively, R ３ but, 【Chemistry 10】 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

8. R ６ is 1, 2, or 3 R ｄ C optionally substituted with ３－６ cycloalkyl; or R ６ is 1, 2, or 3 R ｄ cyclopropyl optionally substituted with R ６ but, 【Chemistry 11】 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

9. Each R ７ are independently H, F, Cl, and C １－３ alkyl, wherein C １－３ alkyl is 1, 2, or 3 R ｅ optionally substituted with; or R ７ H, F, Cl, CH ３ , and C.H. ２ CH ３ wherein said CH ３ and CH ２ CH ３ are independently 1, 2, or 3 R ｅ optionally substituted with; or R ７ H, F, Cl, CH ３ , C.H. ２ CH ３ , C.H. ２ F, CHF ２ , C.F. ３ , C.H. ２ CF ３ , and CD ３ 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

10. R ８ But H, CH ３ , C.H. ２ CH ３ , piperazinyl, homopiperazinyl, piperidinyl, piperidinyl, piperidenyl, homopiperidinyl, morpholinyl, 【Chemistry 12】 wherein said CH ３ , C.H. ２ CH ３ , piperazinyl, homopiperazinyl, piperidinyl, piperidenyl, homopiperidinyl, morpholinyl, 【Chemistry 13】 each independently represents 1, 2, or 3 R ｆ optionally substituted with; or R ８ But, H, 【Chemistry 14】 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

11. The structural unit 【Chemistry 15】 but, 【Chemistry 16】 or the structural unit 【Chemistry 17】 but, 【Chemistry 18】 or the structural unit 【Chemistry 19】 but, 【Chemistry 20】 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

12. L ３ But -CH ２ -, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; or L ３ But -CH ２ -, 【Chemical 21】 2. The compound of claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from:

13.

22. is selected from The structural unit 【Chemical 23】 but, 【Chemistry 24】 Selected from: The structural unit 【Chemistry 25】 but, 【Chemical 26】 Selected from: R ６ is 1, 2, or 3 R ｄ C optionally substituted with ３－６ cycloalkyl; each Ｒｄ is optionally substituted with 1, 2, or 3 R １－４ alkyl; L ３ , R ３ , R ７ , each R ８ and each R is as defined in any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

14.

27. is selected from T １ and T ３ are each independently selected from CH and N; Each R １ are independently H, F, OH, and CH ３ Selected from: R ３ are selected from phenyl and 5- to 6-membered heteroaryl, each independently selected from 1, 2, or 3 R ｂ optionally substituted with; R ６ is 1, 2, or 3 R ｄ C optionally substituted with ３－６ cycloalkyl; R ７ However, H and C １－３ alkyl, wherein C １－３ alkyl is 1, 2, or 3 R ｅ optionally substituted with; Each R ８ However, independently, H, C １－３ alkyl, and 5- to 10-membered heterocycloalkyl; １－３ alkyl and 5- to 10-membered heterocycloalkyl each independently have 1, 2, or 3 R ｆ each optionally substituted with; L ３ But -CH ２ -, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; Each R ｄ is optionally substituted with 1, 2, or 3 R １－３ alkyl; Each R ｂ are independently H, D, F, Cl, OH, and CH ３ Selected from: Each R ｅ is independently selected from H, D, F, and Cl; Each R ｆ are independently H, D, F, Cl, CH ３ , and OCH ３ wherein said CH ３ and OCH ３ are each independently optionally substituted with 1, 2, or 3 R; 14. The compound of formula (VI-1) according to claim 13, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R is independently selected from D and F.

15. R ３ The compound of claim 14, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein is a 5- to 6-membered heteroaryl.

16. Each R ８ However, independently, H, C １－３ alkyl, and 5- to 6-membered heterocycloalkyl, １－３ alkyl and 5- to 6-membered heterocycloalkyl each independently have 1, 2, or 3 R ｆ 15. The compound of claim 14, its stereoisomer, or a pharmaceutically acceptable salt thereof, each optionally substituted with:

17. The following compound, its stereoisomer, or a pharmaceutically acceptable salt thereof: 【Chemistry 28-1】 【Chemistry 28-2】 【Chemistry 28-3】 【Chemistry 28-4】 【Chemistry 28-5】

18. 18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, selected from: 【Chemistry 29-1】 【Chemistry 29-2】 【Chemistry 29-3】 【Chemistry 29-4】 【Chemistry 29-5】 【Chemistry 29-6】 【Chemistry 29-7】 【Chemistry 29-8】 【Chemistry 29-9】 【Chemistry 29-10】 【Chemistry 29-11】 【Chemistry 29-12】 【Chemistry 29-13】 【Chemistry 29-14】 【Chemistry 29-15】 【Chemistry 29-16】

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