Macrocyclic derivative and application thereof

Abstract

The invention discloses a macrocyclic derivative, and particularly discloses a compound as shown in a formula (VI), and a stereoisomer and a pharmaceutically acceptable salt thereof. # imgabs0 #

Description

Macrocyclic derivatives and their applications

[0001] The present invention claims the following priority:

[0002] CN202211213222.2, application date: September 29, 2022;

[0003] CN2023101326996, application date: February 17, 2023;

[0004] CN2023103711659, application date: April 7, 2023;

[0005] CN2023106857489, application date: June 9, 2023;

[0006] CN2023109116322, application date: July 24, 2023. Technical Field

[0007] The present invention relates to a class of macrocyclic derivatives and applications thereof, and in particular to a compound represented by formula (VI), its stereoisomers and pharmaceutically acceptable salts thereof. Background Art

[0008] RAS (including KRAS, NRAS and HRAS) is downstream of growth factor receptors such as EGFR. It is a small GTPase that is a type of molecular switch. It is a key node in the RAS-RAF-MEK-ERK signaling pathway and the PI3K-AKT-mTOR signaling pathway, and can regulate events such as cell proliferation and survival. RAS mutations can lead to functional activation of proteins by disrupting the GTP hydrolysis process. Under normal physiological conditions, RAS usually exists in the form of inactive RAS (OFF) bound to GDP; while in RAS-mutated tumor cells, RAS mainly exists in the form of activated RAS (ON) bound to GTP. RAS-mutated cancer patients account for 30% of all cancer patients (US data), of which KRAS, NRAS, and HRAS mutations account for 85%, 11%, and 4% respectively. Each type of RAS has nearly 20 mutations. For example, KRAS has KRAS G12C , KRAS G12D , KRAS G12V , KRAS G12R , KRAS G13C Since RAS mutation is an important factor in the occurrence and development of cancer, mutant RAS has become an important target for cancer treatment. G12C The covalent inhibitors Sotorasib and Adagrasib in KRAS G12C Mutation-resistant non-small cell lung cancer, but KRASG12D , KRAS G12V , KRAS G13 There are still no effective targeted therapeutics for cancers with other KRAS mutations, such as NRAS, and other RAS mutations. Therefore, the development of broad-spectrum RAS inhibitors is of great clinical significance.

[0009] Revolution Medicines, Inc. has announced a class of macrocyclic compounds (WO2020132597, WO2021091982, WO2021091967, WO2021091956). This type of compound can form a ternary complex with the chaperone proteins 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 an anti-tumor effect. This type of RAS inhibitor has a good inhibitory effect on different RAS mutations and RAS-dependent tumors. The design and synthesis of broad-spectrum RAS inhibitors with excellent drug-forming properties based on this type of macrocyclic compound has great clinical application value.

[0010] Summary of the Invention

[0011] The present invention provides a compound represented by formula (VI), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0012] L is R6 or

[0013] L1 is selected from -N(R9)C(=O)-;

[0014] L2 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0015] L3 is selected from -CH2- and C 3-6 Cycloalkyl;

[0016] L4 is selected from a single bond and -C 1-4 Alkyl-N(R 10 )C(=O)-;

[0017] Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexanyl, 5,6-diazaspiro[2.5]octanyl, 3,4-diazabicyclo[4.2.0]octanyl and 2,3-diazabicyclo[3.1.1]heptanyl;

[0018] Ring B is selected from 5-membered heteroaryl, 5-membered heteroaryl, indolyl and

[0019] T1, T2, T3 and T2 are each independently selected from CH and N;

[0020] R1 is selected from H, F, Cl, Br, I, OH, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R h replace;

[0021] R2 is selected from -O- and -NH-;

[0022] R3 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R b replace;

[0023] R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R c replace;

[0024] R6 is selected from C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R d replace;

[0025] Each R7 is independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R e replace;

[0026] Each R8 is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R f replace;

[0027] R9, R 10 Selected from H and C1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R g replace;

[0028] Each R a , each R b , each R c , each R e , each R f , each R g and each R h are independently selected from H, D, F, Cl, Br, I, OH, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R;

[0029] Each R d are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 Alkenyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 The alkenyl groups are each independently optionally substituted with 1, 2 or 3 R;

[0030] Each R is independently selected from D, F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3;

[0031] n, p and q are independently selected from 0, 1, 2 and 3;

[0032] The "3-6 membered heterocycloalkyl", "3-10 membered heterocycloalkyl" and "5-6 membered heteroaryl" each independently contain 1 or 2 groups independently selected from -NH-, -

[0033] O-, -S- and N heteroatom or heteroatom group.

[0034] The present invention also provides a compound represented by formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0035] L is R6 or

[0036] L1 is selected from -N(R9)C(=O)-;

[0037] L2 is selected from C 1-6 Alkyl, the C 1-6The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0038] L3 is selected from -CH2- and C 3-6 Cycloalkyl;

[0039] L4 is selected from a single bond and -C 1-4 Alkyl-N(R 10 )C(=O)-;

[0040] Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexanyl, 5,6-diazaspiro[2.5]octanyl, 3,4-diazabicyclo[4.2.0]octanyl and 2,3-diazabicyclo[3.1.1]heptanyl;

[0041] Ring B is selected from 5-membered heteroaryl, 5-membered heteroaryl, indolyl and

[0042] R1 is selected from H, F, Cl, Br, I, OH, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R h replace;

[0043] R2 is selected from -O- and -NH-;

[0044] R3 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R b replace;

[0045] R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R c replace;

[0046] R6 is selected from C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R d replace;

[0047] Each R7 is independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R e replace;

[0048] Each R8 is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-7 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-7 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R f replace;

[0049] R9, R 10 Selected from H and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R g replace;

[0050] Each R a , each R b , each R c , each R e , each R f , each R g and each R h Each independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3;

[0051] Each R d are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 Alkenyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 The alkenyl groups are each independently optionally substituted with 1, 2 or 3 R;

[0052] Each R is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3;

[0053] n, p and q are independently selected from 0, 1, 2 and 3;

[0054] The “3-6 membered heterocycloalkyl”, “3-7 membered heterocycloalkyl” and “5-6 membered heteroaryl” each independently contain 1 or 2 heteroatoms or heteroatom groups independently selected from —NH—, —O—, —S— and N.

[0055] The present invention also provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0056] L1 is selected from -N(R9)C(=O)-;

[0057] L2 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a replace;

[0058] L3 is selected from -CH2-;

[0059] L4 is selected from a single bond and -C 1-4 Alkyl-N(R 10 )C(=O)-;

[0060] Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptane, 2,3-diazabicyclo[3.1.0]hexane and 5,6-diazaspiro[2.5]octane;

[0061] R1 is selected from H, F, Cl, Br, I, OH, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R h replace;

[0062] R2 is selected from -O- and -NH-;

[0063] R3 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R b replace;

[0064] R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R c replace;

[0065] R6 is selected from C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R d replace;

[0066] R7 is selected from H, C 1-4 Alkyl and C 1-4 Alkoxy, the C1-4 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R e replace;

[0067] R8 is selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-7 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-7 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R f replace;

[0068] R9, R 10 Selected from H and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R g replace;

[0069] Each R a 、R b 、R c 、R e 、R f 、R g and R h Each independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3;

[0070] Each R d are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 Alkenyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 The alkenyl groups are each independently optionally substituted with 1, 2 or 3 R;

[0071] Each R is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3;

[0072] n, p and q are independently selected from 0, 1, 2 and 3;

[0073] The “3-6 membered heterocycloalkyl”, “3-7 membered heterocycloalkyl” and “5-6 membered heteroaryl” each independently contain 1 or 2 heteroatoms or heteroatom groups independently selected from —NH—, —O—, —S— and N.

[0074] In some embodiments of the present invention, each R is independently selected from D and F, and other variables are as defined in the present invention.

[0075] In some embodiments of the present invention, each R is independently selected from F, and other variables are as defined in the present invention.

[0076] In some embodiments of the present invention, the above R a are independently selected from H, D, F, Cl and CH3, and other variables are as defined in the present invention.

[0077] In some embodiments of the present invention, the above R b are independently selected from H, D, F, Cl, OH and CH3, and other variables are as defined in the present invention.

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

[0079] In some embodiments of the present invention, the above R d are independently selected from CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and The CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and are each independently optionally substituted with 1, 2 or 3 R, and the other variables are as defined herein.

[0080] In some embodiments of the present invention, the above R d are independently selected from CH3, Other variables are as defined in the present invention.

[0081] In some embodiments of the present invention, the above R d are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups, and the other variables are as defined herein.

[0082] In some embodiments of the present invention, the above R d are independently selected from CH3 and CH2CH3, said CH3 and CH2CH3 are each independently optionally substituted with 1, 2 or 3 F, and other variables are as defined herein.

[0083] In some embodiments of the present invention, the above R d are independently selected from CH3, wherein CH3 is optionally substituted with 1, 2 or 3 F, and other variables are as defined herein.

[0084] In some embodiments of the present invention, the above Rd are independently selected from CH3, and other variables are as defined in the present invention.

[0085] In some embodiments of the present invention, the above R d are independently selected from CH3, and other variables are as defined in the present invention.

[0086] In some embodiments of the present invention, the above R e are independently selected from H, D, F and Cl, and other variables are as defined in the present invention.

[0087] In some embodiments of the present invention, the above R e are independently selected from D and F, and other variables are as defined in the present invention.

[0088] In some embodiments of the present invention, the above R f are independently selected from H, D, F, Cl, CH3 and OCH3, said CH3 and OCH3 are each independently optionally substituted by 1, 2 or 3 R, and other variables are as defined herein.

[0089] In some embodiments of the present invention, the above R f are independently selected from H, D, F, Cl, CH3, CD3, CF3 and OCH3, and other variables are as defined in the present invention.

[0090] In some embodiments of the present invention, the above R g are independently selected from H, D, F and Cl, and other variables are as defined in the present invention.

[0091] In some embodiments of the present invention, the above R h are independently selected from H, D, F and Cl, and other variables are as defined in the present invention.

[0092] In some embodiments of the present invention, each of the above R1 is independently selected from H, F, OH and CH3, and other variables are as defined in the present invention.

[0093] In some embodiments of the present invention, each of the above R1 is independently selected from H, F and CH3, and other variables are as defined in the present invention.

[0094] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0095] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0096] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0097] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0098] In some embodiments of the present invention, the ring A is selected from 3,4-diazabicyclo[4.1.0]heptanyl and 2,3-diazabicyclo[3.1.1]heptanyl, and other variables are as defined herein.

[0099] In some embodiments of the present invention, the ring A is selected from Other variables are as defined in the present invention.

[0100] In some embodiments of the present invention, the ring A is Other variables are as defined in the present invention.

[0101] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0102] In some embodiments of the present invention, the above R2 is selected from -O-, and other variables are as defined in the present invention.

[0103] In some embodiments of the present invention, the above R3 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally replaced by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0104] In some embodiments of the present invention, the above R3 is selected from a 5-membered heteroaryl group, wherein the 5-membered heteroaryl group is optionally replaced by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0105] In some embodiments of the present invention, the above R3 is selected from thiazolyl, thienyl, oxazolyl, pyrazolyl and imidazolyl, and the thiazolyl, thienyl, oxazolyl, pyrazolyl and imidazolyl are independently optionally substituted by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0106] In some embodiments of the present invention, the above R3 is selected from thiazolyl and thienyl, and other variables are as defined in the present invention.

[0107] In some embodiments of the present invention, the above R3 is selected from Other variables are as defined in the present invention.

[0108] In some embodiments of the present invention, the above R3 is selected from Other variables are as defined in the present invention.

[0109] In some embodiments of the present invention, the above R3 is selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, pyrazolyl and imidazolyl, and the phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, pyrazolyl and imidazolyl are independently optionally substituted by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0110] In some embodiments of the present invention, the above R3 is selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl and imidazolyl, and the phenyl, pyridyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazolyl and imidazolyl are independently optionally substituted by 1, 2 or 3 R b Substitution, other variables are as defined in the present invention.

[0111] In some embodiments of the present invention, the above R3 is selected from Other variables are as defined in the present invention.

[0112] In some embodiments of the present invention, the above R3 is selected from Other variables are as defined in the present invention.

[0113] In some embodiments of the present invention, the above R3 is selected from Other variables are as defined in the present invention.

[0114] In some embodiments of the present invention, the above R4 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl and cyclopentyl, and the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl and cyclopentyl are independently optionally replaced by 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0115] In some embodiments of the present invention, the above R5 is selected from H, CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl and cyclopentyl, and the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclopropyl, cyclobutyl and cyclopentyl are independently optionally replaced by 1, 2 or 3 R c Substitution, other variables are as defined in the present invention.

[0116] In some embodiments of the present invention, R4 is selected from H, R5 is selected from H, CH(CH3)2 and Other variables are as defined in the present invention.

[0117] In some embodiments of the present invention, the above R6 is selected from cyclopentyl, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl and oxhexyl, and the cyclopentyl, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl and oxhexyl are independently optionally replaced by 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0118] In some embodiments of the present invention, the above R6 is selected from cyclopropyl, cyclobutyl, cyclopentyl, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl and oxhexyl, and the cyclopropyl, cyclobutyl, cyclopentyl, aziridine, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl and oxhexyl are independently optionally replaced by 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0119] In some embodiments of the present invention, the above R6 is selected from Other variables are as defined in the present invention.

[0120] In some embodiments of the present invention, the above R6 is selected from Other variables are as defined in the present invention.

[0121] In some embodiments of the present invention, the above R6 is selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0122] In some embodiments of the present invention, the above R6 is selected from cyclopropyl, which is optionally substituted by 1, 2 or 3 R d Substitution, other variables are as defined in the present invention.

[0123] In some embodiments of the present invention, the above R6 is selected from Other variables are as defined in the present invention.

[0124] In some embodiments of the present invention, the above R6 is selected from Other variables are as defined in the present invention.

[0125] In some embodiments of the present invention, each R7 is independently selected from H, F, Cl and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R e Substitution, other variables are as defined in the present invention.

[0126] In some embodiments of the present invention, the above R7 is selected from H, F, Cl, CH3 and CH2CH3, and the CH3 and CH2CH3 are each independently optionally replaced by 1, 2 or 3 R e Substitution, other variables are as defined in the present invention.

[0127] In some embodiments of the present invention, the above-mentioned R7 is selected from H, F, Cl, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3 and CD3, and other variables are as defined in the present invention.

[0128] In some embodiments of the present invention, the above R7 is selected from H, F, Cl, CH3 and CH2CH3, and other variables are as defined in the present invention.

[0129] In some embodiments of the present invention, the above R7 is selected from H, CH3 and CH2CH3, and other variables are as defined in the present invention.

[0130] In some embodiments of the present invention, each of the above R8 is independently selected from H, C 1-3 Alkyl and 3-10 membered heterocycloalkyl, the C 1-3 The alkyl and 3-10 membered heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3 R f Substitution, other variables are as defined in the present invention.

[0131] In some embodiments of the present invention, each of the above R8 is independently selected from H, C 1-3 Alkyl and 5-10 membered heterocycloalkyl, the C 1-3 The alkyl and 5-10 membered heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3 R f Substitution, other variables are as defined in the present invention.

[0132] In some embodiments of the present invention, each of the above R8 is independently selected from H, C 1-3 Alkyl and 5-6 membered heterocycloalkyl, the C 1-3 Alkyl and 5-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R f Substitution, other variables are as defined in the present invention.

[0133] In some embodiments of the present invention, the above R8 is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropyridinyl, homopiperidinyl, morpholinyl, The CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, tetrahydropyridinyl, homopiperidinyl, morpholinyl, Each independently optionally substituted by 1, 2 or 3 R f Substitution, other variables are as defined in the present invention.

[0134] In some embodiments of the present invention, the above R8 is selected from H, Other variables are as defined in the present invention.

[0135] In some embodiments of the present invention, the above R8 is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, morpholinyl and The CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl, morpholinyl and Each independently optionally substituted by 1, 2 or 3 R f Substitution, other variables are as defined in the present invention.

[0136] In some embodiments of the present invention, the above R8 is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl and morpholinyl, and the CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, homopiperidinyl and morpholinyl are independently optionally replaced by 1, 2 or 3 R f Substitution, other variables are as defined in the present invention.

[0137] In some embodiments of the present invention, the above R8 is selected from H, Other variables are as defined in the present invention.

[0138] In some embodiments of the present invention, the above R8 is selected from H, Other variables are as defined in the present invention.

[0139] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0140] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0141] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0142] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0143] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0144] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0145] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0146] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0147] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0148] In some embodiments of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.

[0149] In some embodiments of the present invention, the ring B is selected from Other variables are as defined in the present invention.

[0150] In some embodiments of the present invention, the ring B is selected from indolyl, and other variables are as defined in the present invention.

[0151] In some embodiments of the present invention, the ring B is selected from Other variables are as defined in the present invention.

[0152] In some embodiments of the present invention, the above L1 is selected from -N(CH3)C(=O)-, and other variables are as defined in the present invention.

[0153] In some embodiments of the present invention, the above L2 is selected from Other variables are as defined in the present invention.

[0154] In some embodiments of the present invention, the above-mentioned L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and other variables are as defined in the present invention.

[0155] In some embodiments of the present invention, the above L3 is selected from -CH2-, Other variables are as defined in the present invention.

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

[0157] In some embodiments of the present invention, the above L3 is selected from Other variables are as defined in the present invention. In some embodiments of the present invention, the above L4 is selected from a single bond and -CH 2- N(CH3)C(=O)-, and other variables are as defined in the present invention.

[0158] In some embodiments of the present invention, the above L is selected from Other variables are as defined in the present invention.

[0159] In some embodiments of the present invention, the above L is selected from Other variables are as defined in the present invention.

[0160] In some embodiments of the present invention, the above-mentioned L is R6, and other variables are as defined in the present invention.

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

[0162] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from:

[0163] wherein, ring A, T1, T3, R1, R3, R6, R7, R8, L3 and n are as defined in the present invention.

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

[0165] in,

[0166] Structural unit Selected from

[0167] Structural unit Selected from

[0168] R6 is selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R d replace;

[0169] Each R d are independently selected from C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R groups;

[0170] L3, R3, R7, each R8 and each R are as defined in the present invention.

[0171] In some embodiments of the present invention, the compound of formula (VI-1), formula (VI-2) or formula (VI-3), its stereoisomers or pharmaceutically acceptable salts, wherein the structural unit Selected from Other variables are as defined in the present invention.

[0172] In some embodiments of the present invention, the compound of formula (VI-1), its stereoisomers or pharmaceutically acceptable salts thereof are selected from:

[0173] in,

[0174] T1 and T3 are independently selected from CH and N;

[0175] Each R1 is independently selected from H, F, OH and CH3;

[0176] R3 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R b replace;

[0177] R6 is selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R d replace;

[0178] R7 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R e replace;

[0179] Each R8 is independently selected from H, C 1-3 Alkyl and 5-10 membered heterocycloalkyl, the C 1-3 The alkyl and 5-10 membered heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3 R f replace;

[0180] L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

[0181] Each R d are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups;

[0182] Each R b Each independently selected from H, D, F, Cl, OH and CH3;

[0183] Each R e are independently selected from H, D, F and Cl;

[0184] Each R f Each 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;

[0185] Each R is independently selected from D and F.

[0186] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R1, R3, R6, R7, each R8, T1, T3 and L3 are as defined in formula (VI), formula (III) or formula (I) of the present invention.

[0187] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R3 is a 5-6 membered heteroaryl group, and the other variables are as defined in the present invention.

[0188] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomers or pharmaceutically acceptable salts thereof, wherein R3 is thienyl and thiazolyl, and other variables are as defined in the present invention.

[0189] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomers or pharmaceutically acceptable salts thereof, wherein each R8 is independently selected from H, C 1-3 Alkyl and 5-6 membered heterocycloalkyl, the C 1-3 Alkyl and 5-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R f Substitution, other variables are as defined in the present invention.

[0190] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomers or pharmaceutically acceptable salts thereof, wherein T1 is CH, T3 is CH, and other variables are as defined in the present invention.

[0191] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomer or pharmaceutically acceptable salt, wherein L3 is selected from -CH2-, Other variables are as defined in the present invention.

[0192] In some embodiments of the present invention, the compound of formula (P-1) or (P-2), its stereoisomers or pharmaceutically acceptable salts thereof are selected from:

[0193] wherein each R1, R3, R6, R7, each R8, T1, T3 and L3 are as defined in formula (P-1) or (P-2) of the present invention.

[0194] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from:

[0195] wherein R1, R3, R4, R5, R6, R7, R8, L1, L3, L4 and n are as defined in the present invention.

[0196] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from:

[0197] wherein R1, R3, R6, R7 and R8 are as defined in the present invention.

[0198] In some embodiments of the present invention, the compound of formula (IV), its stereoisomers or pharmaceutically acceptable salts thereof are selected from:

[0199] wherein R1, R3, R6, R7 and R8 are as defined in the present invention.

[0200] In some embodiments of the present invention, the compound of formula (IV-1a), formula (IV-1b), its stereoisomers or pharmaceutically acceptable salts thereof are selected from:

[0201] wherein R1, R3, R6, R7 and R8 are as defined in the present invention.

[0202] In some embodiments of the present invention, the compounds of formula (IV), (IV-1a), (IV-1b), (IV-1a-1), (IV-1a-2), (IV-1b-1), (IV-1b-2), their stereoisomers or pharmaceutically acceptable salts thereof, wherein R1 is selected from H, F, OH and CH3; R3 is selected from phenyl and thiazolyl, and the phenyl and thiazolyl groups are each independently optionally substituted by 1, 2 or 3 R b Substituted; R6 is selected from cyclopropyl, the cyclopropyl optionally substituted by 1, 2 or 3 R d Substituted; R7 is selected from H, F, Cl, CH3 and CH2CH3; R8 is selected from H, Each R b Each R is independently selected from F, Cl, Br, I, OH, CH3, CF3, OCH3 and OCF3; d are independently selected from CH3,

[0203] Some other solutions of the present invention are obtained by any combination of the above variables.

[0204] The present invention also provides the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof:

[0205] In some embodiments of the present invention, the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt thereof is selected from:

[0206] The present invention also provides the use of the above compound, its stereoisomer or its pharmaceutically acceptable salt in the preparation of RAS inhibitor drugs.

[0207] The RAS inhibitor drug of the present invention is used to treat RAS mutations and RAS-dependent tumors, such as solid tumors; further, the solid tumor is pancreatic cancer, lung cancer or colorectal cancer.

[0208] The present invention also provides the following synthesis method:

[0209] Method 1 - Intermediate:

[0210] Method 2 - Intermediate:

[0211] Method 3 - Intermediate:

[0212] Method 4 - Intermediate:

[0213] Method 5 - Intermediate:

[0214] Method 6 - Intermediate:

[0215] Method 7-Intermediate

[0216] Method 8-Intermediate

[0217] Method 9-Intermediate

[0218] Method 10-Intermediate

[0219] Method 11:

[0220] Method 12:

[0221] Method 13:

[0222] Method 14:

[0223] Method 15:

[0224] Method 16:

[0225] Method 17:

[0226] Method 18:

[0227] Technical Effects

[0228] The compounds of the present invention have a good binding effect with the chaperone protein CypA. The binding with CypA will block the binding of RAS downstream RAF to RAS, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway to achieve anti-tumor effects; the compounds of the present invention have significant inhibitory activity on the proliferation of RAS mutant cell lines (such as GP2D, PK-59, AsPC-1, PSN-1, RKN, Capan-1, SW620, HCT116, LOVO, A549, H441, H727, LU99 and A427), but It showed no obvious inhibitory effect in wild-type independent cell lines (such as A375) and had good selectivity; it also had significant inhibitory activity on the pERK levels of AsPC-1 and GP2D cells; in various pharmacokinetic experiments, the compounds of the present invention showed good pharmacokinetic properties (such as high exposure and long half-life), and had a higher distribution in whole blood and red blood cells compared with human and mouse plasma; in in vivo efficacy experiments, the compounds of the present invention showed excellent tumor inhibition effects, with small dosage and high safety, and have broad application prospects.

[0229] Definition and Description

[0230] Unless otherwise indicated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be construed as indefinite or unclear unless specifically defined, but rather should be understood in accordance with its ordinary meaning. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0231] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0232] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared by reacting the compounds of the present invention with relatively nontoxic acids or bases, having specific substituents. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the compounds with a sufficient amount of base in neat solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the compounds with a sufficient amount of acid in neat solution or a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and can be converted into either base or acid addition salts.

[0233] Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture of the two.

[0234] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, 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 diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed within the scope of the present invention.

[0235] Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.

[0236] Unless otherwise indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability to rotate freely about double bonds or single bonds forming ring carbon atoms.

[0237] Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.

[0238] Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.

[0239] Unless otherwise specified, use a solid wedge key. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond and straight dashed bond Indicate the relative configuration of stereocenters with a wavy line Indicates a wedge-shaped solid key and / or dotted wedge key Or use a wavy line Indicates a straight solid bond and / or straight dashed key

[0240] Certain compounds of the present invention may exist as atropisomers, which are conformational isomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, either pure individual atropisomers, or enriched in one atropisomer, or as nonspecific mixtures of each. If the potential for rotation about a single bond is sufficiently high and the interconversion between conformations is sufficiently slow, separation of the isomers may be permitted.

[0241] Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or enantiomer is less than 100%, and the content of that isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0242] Unless otherwise indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.

[0243] Optically active (R)- and (S)-isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are split by conventional methods known in the art and then recovered to obtain the pure enantiomer. In addition, the separation of enantiomers and diastereoisomers is typically accomplished by using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate generated from an amine). The compounds of the present invention may contain non-natural ratios of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14C). For example, deuterated drugs can be formed by replacing hydrogen with heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of this invention.

[0244] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be any on a chemically feasible basis.

[0245] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0246] When the number of a linking group is 0, such as -(CRR)0-, it means that the linking group is a single bond.

[0247] When the number of a substituent is 0, it means that the substituent does not exist, for example, -A-(R)0 means that the structure is actually -A.

[0248] When a substituent is vacant, it means that the substituent does not exist. For example, when X in AX is vacant, it means that the structure is actually A.

[0249] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0250] When the listed linking groups do not specify their linking direction, their linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of reading from left to right to form Combinations of linkers, substituents, and / or variations thereof are permissible only if such combinations result in stable compounds.

[0251] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds, and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy lines For example, the straight solid bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if an H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.

[0252] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of members of the ring, for example, a "5-7 membered ring" refers to a "ring" having 5-7 atoms arranged around it.

[0253] Unless otherwise specified, the term “C 1-6 "Alkyl" itself or in combination with other terms is used to refer to a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms. 1-6 Alkyl groups include C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2-4 , C6 and C5 alkyl, etc.; which can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-6 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, and the like. Unless otherwise specified, the term “C 1-4"Alkyl" by itself or in combination with other terms refers to a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1-4 Alkyl groups include C 1-2 、C 1-3 and C 2-3 Alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). 1-4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl and t-butyl), and the like.

[0254] Unless otherwise specified, the term “C 1-4 "Alkoxy" by itself or in combination with other terms refers to an alkyl group containing 1 to 4 carbon atoms, which is attached to the rest of the molecule through an oxygen atom. 1-4 Alkoxy groups include C 1-3 、C 1-2 、C 2-4 , C4 and C3 alkoxy, etc. It can be monovalent, divalent or polyvalent. 1-4 Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), and the like.

[0255] Unless otherwise specified, “C 3-6 "Cycloalkyl" by itself or in combination with other terms refers to a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms. 3-6 The cycloalkyl group includes a monocyclic ring and a polycyclic ring, wherein the polycyclic ring includes a spirocyclic ring, a fused ring and a bridged ring. 3-6 Cycloalkyl groups include C 3-5 、C 4-5 and C 5-6 Cycloalkyl, etc.; it may 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.

[0256] Unless otherwise specified, the term "3-10 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated or partially unsaturated cyclic group consisting of 3 to 10 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). The 3-10 membered heterocycloalkyl group includes monocyclic and polycyclic rings, wherein the polycyclic ring includes spirocyclic, fused, and bridged rings. In addition, with respect to the "3-10 membered heterocycloalkyl group", a heteroatom may occupy the position at which the heterocycloalkyl group is connected to the rest of the molecule. The 3-10 membered heterocycloalkyl group includes 3-6 membered, 4-6 membered, 5-6 membered, 4-7 membered, 5-7 membered, 5-8 membered, 6-8 membered, 6-9 membered, 6-10 membered, 4 membered, 5 membered, 6 membered, 7 membered, 8 membered, 9 membered, and 10 membered heterocycloalkyl groups. It can be monovalent, divalent, or polyvalent. Examples of 3-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, tetrahydropyridinyl, wait.

[0257] Unless otherwise specified, the term "3-7 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, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). The 3-7 membered heterocycloalkyl group includes monocyclic and polycyclic rings, wherein the polycyclic ring includes spirocyclic, fused, and bridged rings. Furthermore, with respect to the term "3-7 membered heterocycloalkyl group," a heteroatom may occupy the position at which the heterocycloalkyl group is attached to the rest of the molecule. The 3-7 membered heterocycloalkyl group includes 3-6 membered, 4-6 membered, 5-6 membered, 4-7 membered, 5-7 membered, 4 membered, 5 membered, 6 membered, and 7 membered heterocycloalkyl groups. These groups may be monovalent, divalent, or polyvalent. Examples of 3-7 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, tetrahydropyridinyl, etc.

[0258] Unless otherwise specified, the term "3-6 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, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the carbon atoms are optionally oxoed (i.e., forming C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p , p is 1 or 2). The 3-6 membered heterocycloalkyl group includes monocyclic and polycyclic rings, wherein the polycyclic ring includes spirocyclic, fused, and bridged rings. Furthermore, with respect to the term "3-6 membered heterocycloalkyl group," a heteroatom may occupy the position at which the heterocycloalkyl group is connected to the rest of the molecule. The 3-6 membered heterocycloalkyl group includes 4-6 membered, 5-6 membered, 4 membered, 5 membered, and 6 membered heterocycloalkyl groups. It may be monovalent, divalent, or polyvalent. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl or piperidinyl, etc.

[0259] Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π electron system consisting of 5 to 6 ring atoms, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The carbon atoms are optionally oxidized (i.e., to form C=O), the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2). 5-6 membered heteroaryl can be connected to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. It can be monovalent, divalent or polyvalent. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0260] Unless otherwise specified, the term "5-membered heteroaryl and 5-membered heteroaryl" herein refers to a 5-membered heteroaryl fused to another 5-membered heteroaryl through two adjacent atoms. Examples of "5-membered heteroaryl and 5-membered heteroaryl" include but are not limited to

[0261] Unless otherwise specified, C n-n+m or C n -C n+m Any specific case including n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 、C 11 , and C 12 , also includes any range from n to n+m, such as C 1-12 Including C 1- 3. C 1-6 、C 1-9 、C 3-6 、C 3-9 、C 3-12 、C 6-9 、C 6-12 , and C 9-12Similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, a 3-12-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, and also includes any range from n to n+m, for example, a 3-12-membered ring includes a 3-6-membered ring, a 3-9-membered ring, a 5-6-membered ring, a 5-7-membered ring, a 6-7-membered ring, a 6-8-membered ring, and a 6-10-membered ring, etc.

[0262] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy groups such as acetoxy and trifluoroacetoxy, etc.

[0263] The term "protecting group" includes, but is not limited to, an "amino protecting group," a "hydroxy protecting group," or a "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (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 preventing side reactions at the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.

[0264] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0265] The structures of the compounds of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction (SXRD) is used to collect diffraction intensity data on the cultured single crystal using a Bruker D8 venture diffractometer, using CuKα radiation as the light source and scanning mode: After scanning and collecting relevant data, the crystal structure is further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0266] The solvents used in the present invention can be obtained commercially. Software naming, commercially available compounds use supplier catalog names. BRIEF DESCRIPTION OF THE DRAWINGS

[0267] Figure 1 shows the binding pattern of compound A and CypA protein.

[0268] Figure 2 shows the binding pattern of compound B and CypA protein.

[0269] Figure 3 shows the binding pattern of compound C and CypA protein.

[0270] Figure 4 shows the binding pattern of compound D and CypA protein.

[0271] Figure 5 shows the binding pattern of compound E and CypA protein.

[0272] Figure 6 shows the binding pattern of compound F and CypA protein.

[0273] Figure 7 shows the binding pattern of compound G and CypA protein.

[0274] Figure 8 shows the binding pattern of compound H to CypA protein.

[0275] Figure 9 shows the binding pattern of compound I and CypA protein.

[0276] FIG10 is a diagram showing the binding pattern of compound J to CypA protein. DETAILED DESCRIPTION

[0277] The present invention is described in detail below by way of examples, but is not intended to limit the present invention in any way. While the present invention has been described in detail herein, and specific embodiments thereof have been disclosed, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0278] Calculation Example 1

[0279] The binding mode prediction used the co-crystal complex of human CypA protein and natural product Sanglifehrin A (PDB ID code: 1YND) as the docking template. To prepare the protein, Maestro [1] The protein preparation wizard module was used to add hydrogen atoms and the OPLS4 force field was used to optimize the hydrogen bonds of the cocrystal structure and remove the ligand Sanglifehrin A in the cocrystal complex. For ligand preparation: generate a 3D structure of the molecule to be docked and perform energy minimization using LigPrep. [2] Using Maestro( Induced Fit Docking in version 2021-2 [3] Using the Protocol: Extended Sampling option, Compound A was docked into the prepared 1YND protein structure. The optimal binding model was selected, as shown in Figure 1. The selected model retained the primary hydrogen bonding between the ligand Sanglifehrin A and the protein in the original co-crystal complex. The center of mass of Compound A in this binding model was used to generate Docking the mesh with Glide [4] The Receptor Grid Generation module generates a docking model. Based on this docking model, compounds B to J were docked using Glide [3] The SP docking mode in the figure was used for docking, and the binding modes of compounds B to J are shown in Figures 2 to 10.

[0280] [1]Maestro, LLC, New York, NY, 2021.

[0281] [2]LigPrep, LLC, New York, NY, 2021.

[0282] [3]Induced Fit Docking protocol; Glide, LLC,New York,NY,2021;Prime, LLC, New York, NY, 2021.

[0283] [4]Glide, LLC, New York, NY, 2021.

[0284] Conclusion: The compounds of this invention bind well to the human Cyp A protein. They form hydrogen bonds with Arg55, Gln63, Asn102, and His126. Furthermore, Arg55 forms a cationic π bond with the indole ring. Because the compounds of this invention act on the protein surface, the enumerated hydrogen bonds acting as anchor points not only replicate the binding pattern of the natural product Sanglifehrin A in the cocrystal complex but also firmly anchor the compounds of this invention to the protein surface. Binding of the compounds of this invention to Cyp A blocks the binding of RAF downstream of RAS to RAS, thereby inhibiting the RAS-RAF-MEK-ERK signaling pathway and achieving anti-tumor effects.

[0285] Reference Example 1: Compound M1

[0286] Compound M1-1 (39 g, 106.78 mmol) was dissolved in water (100 mL) and tetrahydrofuran (200 mL). Lithium hydroxide monohydrate (13.44 g, 320.33 mmol) was added, and the reaction mixture was stirred at 25°C for 1.5 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to 5-6 with 2M dilute hydrochloric acid. The reaction mixture was then extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the organic solvent was removed by distillation under reduced pressure to obtain compound M1. LCMS: m / z = 372.8, 374.8 [M+23] + .

[0287] Reference Example 2: Compound M2

[0288] Step 1

[0289] Compound M2-1 (150 g, 1.14 mol) was dissolved in pyridine (200 mL), followed by the addition of 4-dimethylaminopyridine (7.4 g, 60.57 mmol) and acrolein (38.58 g, 688.11 mmol). The reaction mixture was stirred at 50°C for 48 hours. The reaction mixture was cooled to room temperature and poured into 2000 mL of water. Extraction was performed with ethyl acetate (300 mL x 3). The combined organic phases were washed with dilute hydrochloric acid (2M, 300 mL x 3), then washed once with water (500 mL), and once with saturated brine (200 mL). The mixture was 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.

[0290] Step 2

[0291] 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 mixture was stirred at 80°C for 16 hours. The reaction mixture was concentrated, and the crude product was purified by flash chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-15%) to obtain compound M2-3. 1 H NMR (400MHz, CDCl3) δppm 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).

[0292] Step 3

[0293] Compound M2-3 was chiral separated by SFC (column: DAICEL CHIRALPAK IC (250 mm x 50 mm, 10 μm); mobile phase: supercritical carbon dioxide phase A, 0.1% ammonia in isopropanol phase B; B%: 20%-20%) to obtain compound M2-3A. SFC analysis (column: Cellulose 2 (150 mm x 4.6 mm, ID, 5 μm); mobile phase: supercritical carbon dioxide phase A, 0.05% diethylamine in isopropanol phase B; isocratic elution B%: 5%-5%, column temperature: 35°C, column pressure: 1500 psi) yielded 100% ee. The peak time of compound M2-3A was 2.798 min, and the peak time of its enantiomer was 2.133 min. LCMS: m / z = 379.0 [M+23]+.

[0294] Step 4

[0295] Under nitrogen, trimethylsulfoxide iodide (3.09 g, 14.03 mmol) was dissolved in dimethylsulfoxide (10 mL), followed by the addition of potassium tert-butoxide (1.26 g, 11.22 mmol). The mixture was stirred at 50°C for 2 hours. Compound M2-3A (1 g, 2.81 mmol) was then added, and the reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-15%) to yield compound M2-5. LCMS: m / z = 371.2 [M+1] + ; 1H NMR (400MHz, CDCl3) δppm 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).

[0296] Step 5

[0297] Compound M2-5 (630.00 mg, 1.70 mmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (3.07 g, 26.93 mmol, 2 mL) was added. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated to obtain the crude trifluoroacetate salt of M2-6, which was used directly in the next step.

[0298] Step 6

[0299] The crude trifluoroacetate salt of compound M2-6 obtained in step 5 was dissolved in dichloromethane (10 mL). N-methylmorpholine (959.97 mg, 9.49 mmol), compound M1 (0.4 g, 1.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (364 mg, 1.90 mmol), and 1-hydroxybenzotriazole (39 mg, 284.8 μmol) were then added. The reaction mixture was stirred at 25°C for 12 hours. Water (50 mL) was added to dilute the reaction mixture, and the solution was extracted with dichloromethane (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The crude product was purified by flash chromatography (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] + .

[0300] Reference Example 3: Compound M3

[0301] Step 1

[0302] To a solution of compound M2-3A (4.28 g, 12.01 mmol) in toluene (24 mL) were added tetrabutylammonium bromide (116.14 mg, 360.26 μmol) and difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol). The mixture was stirred at 110°C for 4 hours. Additional difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added, and the mixture was stirred at 110°C for 16 hours. Additional difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added, and the mixture was stirred at 110°C for 4 hours. Additional difluorobromomethyltrimethylsilane (3.66 g, 18.01 mmol) was added, and the mixture was stirred at 110°C for 16 hours. The toluene was removed by concentration under reduced pressure. 20 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (20 mL * 3). The organic phases were combined and 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 obtain 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).

[0303] Step 2

[0304] Compound M3-1 (1 g, 2.46 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (7.68 g, 67.31 mmol, 5 mL) was added. The reaction mixture was stirred at 25°C for 3 hours. After the reaction, the organic solvent was removed by distillation under reduced pressure to obtain the crude trifluoroacetate salt of compound M3-2, which was used in the next step. LCMS: m / z = 206.8 [M+1] + .

[0305] Step 3

[0306] At 0°C, compound M1 (1.04 g, 2.95 mmol) and compound M3-2 (507 mg, crude trifluoroacetate) were dissolved in dichloromethane (10 mL). N-methylmorpholine (2.49 g, 24.59 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (1.41 g, 7.38 mmol), and 1-hydroxybenzotriazole (66.45 mg, 491.78 μmol) were added sequentially. The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture 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] + .

[0307] Reference Example 4: Compound M4

[0308] Step 1

[0309] At 0°C, under nitrogen, a tetrahydrofuran solution of compound M4-1 (25 g, 136.61 mmol) was added to a tetrahydrofuran solution of methylmagnesium bromide (3 M, 91.07 mL). The mixture was stirred at 0°C for two hours. The reaction solution was slowly poured into ice water and concentrated hydrochloric acid was added to adjust the pH to 6-7. Ethyl acetate was added for extraction (500 mL*2). The organic phases were combined and then dried over 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 obtain M4-2. LCMS: m / z = 200.0, 202.0 [M+1] + ; 1 H NMR (400MHz, CDCl3) δ 8.58 (d, J = 3.2 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.29 (dd, J = 8.4, 4.8 Hz, 1H), 2.69 (s, 3H).

[0310] Step 2

[0311] At 0°C under nitrogen, (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (700.83 mg, 1.10 mmol) was added to a mixed solvent of formic acid (12.68 g, 263.96 mmol) and triethylamine (133.55 g, 1.32 mol, 183.70 mL). The mixture was stirred at 40°C for 15 minutes, cooled to 25°C, and M4-2 (22 g, 109.98 mmol) was added. The mixture was then stirred at 40°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with 100 mL and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash silica gel column chromatography (ethyl acetate / petroleum ether 0-40%) to obtain 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).

[0312] Step 3

[0313] Under nitrogen at 0°C, sodium hydroxide (5.23 g, 130.66 mmol, 60% purity) was added portionwise to a solution of compound M4-3 (22 g, 108.88 mmol) in tetrahydrofuran (200 mL) at 0°C. The mixture was stirred at 0°C for 1 hour, and iodomethane (217.77 mmol, 13.56 mL) was added. After complete addition, the mixture was slowly warmed from 0°C to 25°C and stirred at this temperature for 2 hours. The mixture was quenched by addition of saturated aqueous ammonium chloride (100 mL) at 0°C, followed by addition of water (200 mL) and extraction with ethyl acetate (100 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-20%) to yield 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).

[0314] Step 4

[0315] To a solution of compound M4-4 (5 g, 23.14 mmol) in toluene (50 mL) were added bis-pinacol borate (7.05 g, 27.77 mmol), Pd(dppf)Cl2 (1.69 g, 2.31 mmol), and potassium acetate (4.54 g, 46.28 mmol). After complete addition, the atmosphere was replaced with nitrogen three times. The mixture was stirred at 100°C for 3 hours. After cooling to room temperature, water (100 mL) was added, followed by extraction with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate:petroleum ether 0-25%) to yield compound M4. LCMS: m / z = 182.0 [boric acid M+1] + ; 1 H 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).

[0316] Reference Example 5: Compound M5

[0317] Step 1

[0318] Compound M5-1 (18.3 g, 138.47 mmol), tert-butyldiphenylsilyl chloride (40 g, 145.53 mmol), and imidazole (12.3 g, 180.68 mmol) were dissolved in 300 mL of anhydrous water, and the mixture was stirred at 15°C for 20 hours. After concentration, the crude product 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 concentrated under reduced pressure. The residue was purified by flash chromatography (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).

[0319] Step 2

[0320] 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, diluted with 500 ml of ethyl acetate, and the pH was adjusted to 3-4 with concentrated hydrochloric acid. The layers were separated, and the aqueous phase was extracted with ethyl acetate (2 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 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).

[0321] Step 3

[0322] Oxalyl chloride (233.64 mmol, 20.45 mL) was slowly added dropwise to a solution of 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. The mixture was stirred at 20°C for 15 hours. The reaction mixture was concentrated, 300 mL of anhydrous toluene was added, and the mixture was concentrated under reduced pressure to provide compound M5-4.

[0323] Step 4

[0324] To a solution of compound M5-4 (51.00 g, 136.00 mmol) in 200 mL of anhydrous dichloromethane at 0°C, tin tetrachloride (136.00 mmol, 15.92 mL) was slowly added. The mixture was stirred under a nitrogen atmosphere for half an hour. Compound M5-5 (26.66 g, 136 mmol) in 200 mL of anhydrous dichloromethane was slowly added dropwise to the reaction mixture at 0°C. The reaction system was stirred at 0°C under a nitrogen atmosphere for 1 hour. The mixture was quenched by adding 500 mL of water, filtered, and the filtrate was allowed to stand for separation. The aqueous phase was extracted with dichloromethane (3 x 500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to yield compound M5-6. LCMS: m / z = 534.1, 536.1 [M+1] + ; 1H 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).

[0325] Step 5

[0326] At 0°C under a nitrogen atmosphere, slowly add a 1M solution of lithium borohydride in tetrahydrofuran (123.47 mL) to a solution of compound M5-6 (22 g, 41.16 mmol) in 220 mL of anhydrous tetrahydrofuran. After complete addition, raise the temperature to 60°C and stir for 15 hours. Cool to room temperature, then slowly add 10 mL of saturated aqueous ammonium chloride solution, 100 mL of ethyl acetate, and wash with 50 mL of saturated brine. The organic phase is collected, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated. The residue is purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-20%) to yield compound M5-7. LCMS: m / z = 520.1, 522.1 [M+1] + .

[0327] Step 6

[0328] Compound M5-7 (18.5 g, 35.54 mmol), elemental iodine (9.02 g, 35.54 mmol), and silver trifluoromethanesulfonate (10.04 g, 39.09 mmol) were added sequentially to 185 ml of anhydrous tetrahydrofuran, and the mixture was stirred at 20°C for 2 hours. The mixture was quenched by the addition of 50 ml of saturated aqueous sodium sulfite solution, diluted with 200 ml of ethyl acetate, and filtered. The filtrate was allowed to stand for separation, and the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 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).

[0329] Reference Example 6: Compound M6

[0330] Step 1

[0331] Compound M6-1 (10 g, 78.05 mmol) was dissolved in DCM (100 mL) and MeOH (20 mL). Trimethylsilyldiazomethane (2M, 78.05 mL) in n-hexane was added dropwise at 0°C. Stirring was continued at 0°C for 10 minutes. Concentration afforded compound M6-2, which was used directly in the next step.

[0332] Step 2

[0333] 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 when the system cooled to room temperature, water (100 mL) and ethyl acetate (100 mL) were added. The separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound M6-3, which was used directly in the next step. LCMS: m / z = 201 [M+1-56] + .

[0334] Step 3

[0335] At 0°C, under nitrogen, 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). After stirring at 0°C for half an hour, the mixture was warmed to room temperature and stirred for another hour. Methanol (250 mL) was slowly added dropwise at 0°C to quench the reaction. The quenched reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-4. LCMS: m / z = 203 [M+1-56]. + .

[0336] Step 4

[0337] Compound M6-4 (1.7 g, 6.58 mmol) was dissolved in tetrahydrofuran (30 mL). Di-tert-butyl dicarbonate (2.15 g, 9.87 mmol), triethylamine (2.00 g, 19.74 mmol), and 4-dimethylaminopyridine (80.40 mg, 658.12 μmol) were added sequentially at 25°C and stirred at 25°C for 1 hour. Water (50 mL) and ethyl acetate (30 mL) were added to the reaction system. The organic phase obtained by extraction was dried over anhydrous sodium sulfate, and the filtrate was concentrated. The crude product was purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-5. LCMS: m / z = 359 [M+1] + .

[0338] Step 5

[0339] Compound M6-5 (585 mg, 1.63 mmol) was dissolved in tetrahydrofuran (20 mL). Under nitrogen, lithium bis(trimethylsilyl)amide (1 M, 4.90 mL) was added dropwise at -70°C. After stirring at -70°C for half an hour, trimethylsilyl chloride (531.94 mg, 4.90 mmol) was added dropwise. After stirring at -70°C for one hour, N-bromosuccinimide (1.16 g, 6.53 mmol) was added. The temperature was slowly raised to 25°C and stirring was continued for one hour. Saturated brine (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound M6-6, which was used directly in the next step. LCMS: m / z = 353, 355 [M+1-100-56] + .

[0340] Step 6

[0341] A solution of citric acid (618.66 mg, 2.94 mmol) in water (5 mL) was added to a solution of compound M6-6 (500 mg, 981.34 μmol) in tetrahydrofuran (20 mL) and stirred at 25°C for 1 hour. After completion of the reaction, saturated brine (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-7. LCMS: m / z = 281,283 [M+1-100-56] + .

[0342] Step 7

[0343] Compound M6-7 (150 mg, 342.99 μmol) was dissolved in acetonitrile (20 mL), and cesium carbonate (447.02 mg, 1.37 mmol) was added. The mixture was heated to 60°C and stirred for 12 hours. The mixture was filtered, and the filtrate was concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound M6-8. LCMS: m / z = 201 [M+1-100-56] + . 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).

[0344] Step 8

[0345] Compound M6-8 (50 mg, 140.29 μmol) was dissolved in methanol (5 mL) and ethyl acetate (5 mL). A 4M solution of hydrogen chloride in ethyl acetate (5 mL) was added and stirred at 40°C for 1 hour. The reaction mixture was concentrated to obtain the hydrochloride salt of compound M6. LCMS: m / z = 157 [M+1] + .

[0346] Reference Example 7: Compound M8

[0347] Step 1

[0348] To a solution of M8-1 (22.5 g, 111.94 mmol) in tetrahydrofuran (250 mL) were added triethylamine (111.94 mmol, 15.58 mL) and 1-methylpiperazine (16.82 g, 167.91 mmol, 18.63 mL), and the mixture was stirred at 60°C for 16 hours. The reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was added with petroleum ether (100 mL), filtered, and the filter cake dried to obtain compound M8-2. 1 H NMR (400MHz, DMSO-d6) δppm 8.40 (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).

[0349] Step 2

[0350] Compound M8-2 (10 g, 35.57 mmol) was dissolved in tetrahydrofuran (150 mL). Methylmagnesium chloride (3 M solution in tetrahydrofuran, 23.7 mL) was added at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 2 hours. Saturated ammonium chloride (100 mL) was poured into the reaction mixture to quench the mixture. The solution was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to obtain compound M8-3. LCMS: m / z = 298.1, 300.1 [M+1] + . 1H NMR (400MHz, DMSO-d6) δppm 8.38 (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).

[0351] Step 3

[0352] Under nitrogen at 0°C, triethylamine (57.1 g, 563.9 mmol) was added dropwise to formic acid (5.27 g, 109.67 mmol), followed by (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (140 mg, 220 μmol). The mixture was stirred at 40°C for 15 minutes. The mixture was then cooled to room temperature, and compound M8-3 (6.54 g, 21.93 mmol) was added portionwise. The reaction mixture was heated to 50°C and stirred for 12 hours. The reaction mixture was directly concentrated, and the crude product was purified by flash chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to obtain compound M8-4. LCMS: m / z = 300.0, 302.0 [M+1] + .

[0353] Step 4

[0354] Under nitrogen, compound M8-4 (1 g, 3.33 mmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0°C, and sodium hydroxide (160 mg, 4.00 mmol, 60% purity) was added portionwise. The solution was stirred at 0°C for 1 hour, followed by the dropwise addition of iodomethane (520 mg, 3.68 mmol). The reaction mixture was allowed to react at 0°C for another 2 hours. Saturated ammonium chloride (50 mL) was added dropwise to quench the reaction mixture, and the solution was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by flash chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to afford compound M8-5. LCMS: m / z = 313.9, 316.0 [M+1] + .

[0355] Step 5

[0356] Compound M8-5 (0.72 g, 2.29 mmol) and neopentyl glycol diboronate (777 mg, 3.5 mmol) were dissolved in toluene (20 mL). Potassium acetate (563 mg, 5.75 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (168 mg, 230 μmol) were added sequentially. The atmosphere was purged with nitrogen three times and heated to 70°C for 12 hours. The reaction mixture was filtered and the filtrate was concentrated. The crude product M8-6 was used directly in the next step. LCMS: m / z = 348.1 [M+1] + .

[0357] Step 6

[0358] 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 atmosphere was purged with nitrogen three times. 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (22.07 mg, 33.86 μmol) was added, and the reaction mixture was stirred at 70°C under nitrogen for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound M8-7. LCMS: m / z = 753.2, 755.2 [M+1] + .

[0359] Step 7

[0360] Compound M8-7 (15 g, 19.90 mmol) was dissolved in tetrahydrofuran (150 mL). Sodium hydroxide (4 g, 100.00 mmol, 60% purity) was added portionwise at 0°C. The mixture was stirred under nitrogen for 30 min, followed by the dropwise addition of iodoethane (30.01 mmol, 2.4 mL). The reaction mixture was stirred at 0°C for 1 hour. Additional iodoethane (25.01 mmol, 2 mL) was added, and the reaction mixture was stirred at 20°C for 30 min. The reaction mixture was quenched with ice water (100 mL) in portions and extracted with dichloromethane (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, and the filtrate was concentrated to yield crude compound M8-8. LCMS: m / z = 781.3, 783.3 [M+1] + .

[0361] Step 8

[0362] Compound M8-8 (13.7 g, 17.52 mmol) was dissolved in tetrahydrofuran (150 mL), and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 175.21 mL) was added. The reaction mixture was stirred at 50°C under nitrogen for 12 hours. The reaction mixture 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 over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (0-15% methanol / dichloromethane) to obtain a crude product. Acetonitrile (10 mL) was added to the crude product and stirred for 10 min, filtered, and the filter cake was purified by prep-HPLC (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: the proportion of acetonitrile in the mobile phase increased from 13% to 43% over 8 min) to obtain the trifluoroacetate salt of compound M8-9A (HPLC analysis method: column ChromCore 120C18 3 μm 3.0*30 mm; Phase A: 4 L of water containing 1.5 mL of trifluoroacetic acid, Phase B: 4 L of acetonitrile containing 0.75 mL of trifluoroacetic acid; Elution gradient: Phase B from 10% to 80% over 6 minutes, then held at 80% for 0.5 minutes, then held at 10% for 0.5 minutes; Retention time of compound M8-9A: 3.205 minutes, retention time of its isomer: 3.146 minutes). LCMS: m / z = 543.5, 545.5 [M+1] + .

[0363] Step 9

[0364] Compound M8-9A (0.6 g, 1.10 mmol) and bis(chloroquinoline) boronate (420.47 mg, 1.66 mmol) were dissolved in toluene (6 mL) and dioxane (2 mL). Potassium acetate (216.67 mg, 2.21 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (80.77 mg, 110.39 μmol) were added. The reaction mixture was stirred under nitrogen at 90°C for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound M8. LCMS: m / z = 591.4 [M+1] + .

[0365] Reference Example 8: Compound M9

[0366] Step 1

[0367] Compound M6-1 (78.5 g, 612.68 mmol), compound M9-2 (119.42 g, 673.95 mmol), 4-dimethylaminopyridine (7.49 g, 61.27 mmol), and triethylamine (185.99 g, 1.84 mol) were added sequentially to 1.5 liters of anhydrous dichloromethane. 2-Chloro-1-methylpyridinium (salt) iodide (266.10 g, 1.04 mol) was then added portionwise. The mixture was stirred at 25°C for 1 hour. After the reaction was complete, the organic phase was washed with water (2 x 1 L). The organic phase was dried over 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).

[0368] Step 2

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

[0370] Step 3

[0371] At 0°C, 4-dimethylaminopyridine (74.32 g, 608.31 mmol), compound M9-4 (220 g, 760.39 mmol), and N,N-diisopropylethylamine (147.41 g, 1.14 mol) were added sequentially to 2 liters of anhydrous dichloromethane. p-Toluenesulfonyl chloride (159.46 g, 836.43 mmol) was then added portionwise to the above solution. After the addition was complete, the mixture was stirred at 25°C for 3 hours. After the reaction was complete, the mixture was washed with water (1.5 L), and the aqueous phase was extracted with dichloromethane (2*500 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (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).

[0372] Step 4

[0373] Compound M9-5 (90 g, 202.93 mmol) and lithium bromide (35.25 g, 405.85 mmol) were added sequentially to 900 ml of 1-methyl-2-pyrrolidone, and the mixture was stirred at 90°C for 13 hours. After completion of the reaction, the mixture was diluted with 2 liters of saturated brine and extracted with ethyl acetate (3 x 1 L). The organic phase was washed again with saturated brine (2 x 1 L), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-20%) to obtain compound M9-6. LCMS: m / z = 352.0, 354.0 [M+1] + .

[0374] Step 5

[0375] At -78°C, compound M9-6 (9.5 g, 23.80 mmol) was dissolved in 95 ml of anhydrous tetrahydrofuran. A 2M solution of lithium diisopropylamine in tetrahydrofuran and n-heptane (15.47 mL, 30.94 mmol) was slowly added dropwise, and the mixture was stirred under a nitrogen atmosphere for half an hour. A solution of di-tert-butyl azodicarboxylate (6.58 g, 28.56 mmol) in 20 ml of anhydrous dichloromethane was added to the above solution all at once, and stirring continued for half an hour. 1,3-Dimethyl-tetrahydro-2-pyrimidinone (91.50 g, 713.89 mmol) was slowly added to the above reaction solution, and the temperature was naturally raised to room temperature. Stirring was continued for 13 hours. After the reaction was completed, 100 ml of water was slowly added to quench the mixture, and lithium hydroxide monohydrate (3.00 g, 71.39 mmol) was added, and stirring was continued at room temperature for 1 hour. The residue was concentrated, diluted with 200 mL of saturated brine, washed with ethyl acetate (3*200 mL), and the organic phase was discarded. The aqueous phase was adjusted to pH 5 with 1N hydrochloric acid and extracted with ethyl acetate (3*200 mL). The organic phase was washed with saturated brine (2*200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to obtain compound M9-7. LCMS: m / z = 365.1 [M+23] + .

[0376] Step 6

[0377] To a solution of compound M9-7 (1.6 g, 4.67 mmol) in 32 mL of anhydrous methanol was slowly added dropwise a 2M solution of trimethylsilyldiazomethane in n-hexane (11.68 mL, 23.36 mmol) at 25°C. The mixture was stirred at 25°C for 10 minutes. After completion of the reaction, 0.1 mL of acetic acid was added to quench the reaction. The reaction solution was concentrated to yield compound M9-8. LCMS: m / z = 379.1 [M+23] + SFC analysis (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%: 5% to 40% over 4 minutes, then maintained at 40% for 0.5 minutes, then maintained at 5% for 1.5 minutes) revealed compound M9-8 with a retention time of 1.342 minutes and a chiral purity of 93.38%. The retention time of its enantiomer was 1.431 minutes, with a chiral purity of 6.62%.

[0378] Step 7

[0379] 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 at 25°C for 12 hours. After completion of the reaction, the mixture was concentrated, and the residue was added with 20 mL of methyl tert-butyl ether and stirred at room temperature for 10 minutes. The mixture was 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).

[0380] Reference Example 9: Compound M10

[0381] Step 1

[0382] Compound M4-4 (9.2 g, 42.58 mmol), bis-naphthalene borate (16.22 g, 63.87 mmol), 1,5-cyclooctadiene iridium chloride dimer (858 mg, 1.28 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (1.71 g, 6.39 mmol) were dissolved in tetrahydrofuran (200 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 70°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated and diluted with 150 mL of water and 150 mL of ethyl acetate. Alkaline water (7.5 g of sodium hydroxide and 30 g of sodium carbonate in 400 mL of water) was added to adjust the pH to 10. The mixture was separated and the organic phase was discarded. The aqueous phase was adjusted to pH 6 with concentrated hydrochloric acid and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to obtain compound M10-1.

[0383] Step 2

[0384] Compound M10-1 (5 g, 19.24 mmol) was dissolved in acetonitrile (50 mL), and cuprous iodide (733 mg, 3.85 mmol), potassium iodide (6.39 g, 38.48 mmol), potassium carbonate (5.32 g, 38.48 mmol), and 1,10-phenanthroline (694 mg, 3.85 mmol) were added in sequence. The reaction mixture was stirred at 60°C for 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was directly concentrated. The crude product was purified by flash chromatography (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] + .

[0385] Step 3

[0386] 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-binaphthyl (50 mg, 80.95 μmol), and palladium acetate (36 mg, 158.91 μmol) were then added. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 90°C for 12 hours. After completion of the reaction, the reaction mixture was directly concentrated, and the crude product was purified by flash chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to yield compound M10. LCMS: m / z = 356.0, 358.0 [M+1] + .

[0387] Reference Example 10: Compound M11

[0388] Step 1

[0389] Compound M11-1 (5 g, 20.58 mmol) and potassium carbonate (8.53 g, 61.75 mmol) were dissolved in methylpyrrolidone (25 mL), and then tert-butyl cyanoacetate (4.65 g, 32.93 mmol) was added. The reaction was stirred at 85 ° C for 12 hours. After the reaction was completed, it was cooled to room temperature and water (25 mL) was added. The pH was adjusted to 2 with 3M hydrochloric acid. The solid precipitated, filtered, and the filter cake was dried to obtain compound M11-2. 1 H NMR (400MHz, CD3OD) δppm 1.53 (s, 9H), 4.85 (s, 1H), 6.93 (s, 1H).

[0390] Step 2

[0391] 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 and stirred at 80 ° C for 15 minutes. After the reaction was completed, water (100 mL) was added and extracted with ethyl acetate (150 mL * 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound M11-3. 1 H NMR (400MHz, CD3OD) δppm 4.90 (s, 2H), 7.61 (s, 1H).

[0392] Step 3

[0393] Compound M11-3 (3 g, 14.77 mmol) was dissolved in tetrahydrofuran (30 mL). Sodium hydroxide (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. 1,2-Dibromoethane (22.16 mmol, 1.67 mL) was then added and stirred at 25°C for 12 hours under nitrogen. After completion, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (150 mL x 3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to obtain compound M11-4. 1 H NMR (400MHz, CD3OD) δppm 1.78-1.83 (m, 2H) 1.84-1.89 (m, 2H) 7.07 (s, 1H).

[0394] Step 4

[0395] Compound M11-4 (1 g, 4.36 mmol) was dissolved in tetrahydrofuran (10 mL), and then diisobutylaluminum hydride toluene solution (1 M, 10.91 mL) was added at 0°C and stirred at 0°C for 1 hour under nitrogen protection. After the reaction was completed, water (120 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL*3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product 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) δppm 1.97-2.01(m,2H)2.07-2.11(m,2H)7.79(s,1H)8.90(s,1H).

[0396] Step 5

[0397] Compound M11-5 (0.2 g, 861.71 μmol) and ammonium carbonate (248.39 mg, 2.59 mmol) were dissolved in ethanol (5 mL) and water (5 mL). Potassium cyanide (84.17 mg, 1.29 mmol) was added and stirred at 80°C for 6 hours. After completion of the reaction, water (150 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (150 mL*3). The organic phase was dried over anhydrous sodium sulfate and 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) δppm 1.20-1.32(m,2H)1.37-1.50(m,2H)4.06(s,1H)7.39(s,1H).

[0398] Step 6

[0399] Compound M11-6 (0.17 g, 562.64 μmol) was dissolved in dioxane (1 mL) and water (1 mL). Barium hydroxide (385.61 mg, 2.25 mmol) was added, and the reaction system was microwaved at 130°C for 30 minutes. Water (50 mL) was added to the reaction system, and the mixture was washed with ethyl acetate (50 mL x 3). The aqueous phase was collected to obtain an aqueous solution of compound M11. LCMS: m / z = 277.1, 279.1 [M+1] + .

[0400] Reference Example 11: Compound M12

[0401] Step 1

[0402] 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)ferrocenepalladium chloride (21 mg, 29.24 μmol) were dissolved in dioxane (5 mL) and water (1 mL), and the atmosphere was purged with nitrogen three times. The reaction mixture was stirred at 60°C for 3 hours. After completion of the reaction, the reaction mixture was directly concentrated, and the crude product was purified by flash chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-40%) to obtain compound M12-2. LCMS: m / z = 397.1, 399.0 [M+1] + .

[0403] Step 2

[0404] Trimethylsulfoxide iodide (139 mg, 629.24 μmol) and potassium tert-butoxide (71 mg, 629.24 μmol) were added to dimethylsulfoxide (3 mL) and stirred at 50°C for 2 hours. The mixture was then cooled to 25°C and a solution of compound M12-2 (0.05 g, 125.85 μmol) in dimethylsulfoxide (1 mL) was added dropwise. The reaction mixture was stirred at 80°C for 12 hours. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to yield compound M12. LCMS: m / z = 410.9, 412.9 [M+1] + .

[0405] Example 1

[0406] Step 1

[0407] 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 were added K2CO3 (3.75 g, 27.14 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (794.48 mg, 1.09 mmol). The atmosphere was purged with nitrogen three times, and the mixture was stirred at 85°C for 4 hours. 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 by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to yield compound 1-1. LCMS: m / z = 655.1, 657.1 [M+1] + .

[0408] Step 2

[0409] To a solution of compound 1-1 (4.5 g, 6.86 mmol) in DMF (50 mL) at 0°C, iodoethane (2.14 g, 13.73 mmol) and cesium carbonate (4.47 g, 13.73 mmol) were added sequentially. After the addition, the temperature was raised to 25°C and stirred at 25°C for 16 hours. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (2 x 50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-2. LCMS: m / z = 683.2, 685.2 [M+1] + .

[0410] Step 3

[0411] Compound 1-2 (3.4 g) and a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 34.81 mL) were added sequentially to 35 mL of anhydrous tetrahydrofuran, and the mixture was stirred at 50°C for 16 hours. The reaction solution was diluted with 100 mL of water and extracted with ethyl acetate (2*50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to obtain compound 1-3A (TLC developing solvent: ethyl acetate, R of compound 1-3A) f =0.38, its isomer R f =0.17). LCMS: m / z=445.1,447.1[M+1] + ; 1 H 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).

[0412] Step 4

[0413] Compound 1-3A (0.4 g, 898.09 μmol) and neopentyl glycol diboronate (406 mg, 1.80 mmol) were dissolved in toluene (10 mL). 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (131 mg, 179.62 μmol) and potassium acetate (264 mg, 2.69 mmol) were added sequentially. The atmosphere was purged with nitrogen three times, and the reaction mixture was heated to 90°C and stirred for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound 1-4A. LCMS: m / z = 411.2 [M Boric acid + 1] + .

[0414] Step 5

[0415] Compound 1-4A (300.00 mg, 627.05 μmol), compound M2 (0.36 g, 715.12 μmol), 1,1-di(tert-butylphosphino)ferrocenepalladium 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). The atmosphere was purged with nitrogen three times. The reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to obtain compound 1-5A. LCMS: m / z = 789.4 [M+1] + .

[0416] Step 6

[0417] Compound 1-5A (100.00 mg, 126.74 μmol) was dissolved in tetrahydrofuran (2 mL) and water (0.2 mL), followed by the addition of lithium hydroxide monohydrate (16 mg, 380.23 μmol). The reaction mixture was stirred at 15°C for 12 hours. 1M HCl was added to adjust the pH to 5, and the solution was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield compound 1-7A. LCMS: m / z = 761.3 [M+1] + .

[0418] Step 7

[0419] Compound 1-7A (50.00 mg, 65.71 μmol) was dissolved in dichloromethane (5 mL), followed by the addition of N,N-diisopropylethylamine (260 mg, 2.01 mmol, 0.35 mL), 1-hydroxybenzotriazole (0.044 g, 325.63 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.35 g, 1.83 mmol). The reaction mixture was stirred at 20°C for 12 hours. The mixture was diluted with water (50 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product, which was then purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to yield compound 1-8A. LCMS: m / z=743.4[M+1] + .

[0420] Step 8

[0421] 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 mixture was stirred at 15°C for 12 hours. The reaction mixture was concentrated to yield the crude trifluoroacetate salt of compound 1-9A. LCMS: m / z = 643.3 [M+1] + .

[0422] Step 9

[0423] Compound 1-9A (20.00 mg, crude trifluoroacetate) was dissolved in N,N-dimethylformamide (2 mL), followed by the addition of 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 (36 mg, 93.4 μmol). The reaction mixture was stirred at 20°C for 1.5 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to yield the crude product, which was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to yield compound 1A. LCMS: m / z=725.3[M+1] + ; 1 H NMR(400MHz,CD3OD)δppm 8.64(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,3H) ,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).

[0424] Example 2

[0425] Step 1

[0426] Compound 1-3A (295 mg, 662.34 μmol) and bis-naphthalene boronate (252.29 mg, 993.51 μmol) were dissolved in toluene (2 mL). Potassium acetate (130.01 mg, 1.32 mmol) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride (48.46 mg, 66.23 μmol) were added. The reaction mixture was stirred at 110°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-1A. LCMS: m / z = 493.3 [M+1] + .

[0427] Step 2

[0428] Compound 2-1A (300 mg, 609.19 μmol) and compound M3 (492.89 mg, 913.79 μmol) were dissolved in a mixture 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)ferrocenepalladium chloride (39.70 mg, 60.92 μmol) were added. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain a crude product, which was purified by silica gel column chromatography (20-80% ethyl acetate / petroleum ether) to obtain compound 2-2A. LCMS: m / z = 825.1 [M+1] + .

[0429] Step 3

[0430] Compound 2-2A (280 mg, 339.40 μmol) was dissolved in a mixture of tetrahydrofuran (3 mL) and water (1 mL). Lithium hydroxide monohydrate (71.21 mg, 1.70 mmol) was added and the reaction mixture was stirred at 25°C for 2 hours. The pH of the reaction mixture was then adjusted to neutral with 1M dilute hydrochloric acid and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 2-3A. LCMS: m / z = 797.2 [M+1] + .

[0431] Step 4

[0432] 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 mixture was stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (0-30% ethyl acetate / petroleum ether) and then by preparative HPLC (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 39%-69%) to obtain compound 2-4A. LCMS: m / z = 779.3 [M+1] + .

[0433] Step 5

[0434] 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 mixture was stirred at 25°C for 5 hours and concentrated under reduced pressure to obtain the crude trifluoroacetate salt of compound 2-5A. LCMS: m / z = 679.3 [M+1] + .

[0435] Step 6

[0436] Compound 2-5A (17 mg, trifluoroacetate) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (3.76 mg, 37.57 μmol) were dissolved in N,N-dimethylformamide (1 mL). N,N-diisopropylethylamine (9.71 mg, 75.13 μmol, 13.09 μL) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (19.05 mg, 50.09 μmol) were then added under stirring. The reaction mixture was stirred at 25°C for 12 hours, extracted with ethyl acetate (5 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was prepared by high performance liquid chromatography (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 27%-57%) to obtain the trifluoroacetic acid salt of compound 2A. LCMS: m / z = 761.2 [M+1] + ; 1H NMR(CDCl3,400MHz)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).

[0437] Example 3

[0438] Step 1

[0439] Compound M4-4 (30 g, 138.84 mmol), bis-naphthalene borate (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'-bipyridine (5.59 g, 20.83 mmol) were added sequentially to 600 ml of anhydrous tetrahydrofuran. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 80°C for 20 hours. The reaction solution was concentrated. The residue was diluted with 300 ml of water and 200 ml of ethyl acetate. Alkaline water (10 g of NaOH and 40 g of sodium carbonate in 400 ml of water) was added to adjust the pH to 10. The mixture was separated and the organic phase was discarded. The aqueous phase was adjusted to pH 6 with concentrated hydrochloric acid and extracted three times with 500 ml of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 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).

[0440] Step 2

[0441] At 80°C, 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. The mixture was stirred at 80°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to obtain compound 3-2. MS-ESI calculated value [M+1] + 434.1, 436.1 Measured values ​​434.3, 436.3; 1 H NMR (400MHz, CDCl3) δ = 8.23 ​​(d, J = 2.4Hz, 1H), 7.39-7.25 (m, 5H), 7.23 (d, J = 2.4Hz ,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).

[0442] Step 3

[0443] Compound 3-2 (7 g, 16.12 mmol), neopentyl glycol diboronate (5.46 g, 24.18 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (589.65 mg, 805.85 μmol), and potassium acetate (3.95 g, 40.29 mmol) were added to 140 ml of anhydrous dioxane. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 80°C for 20 hours. The reaction solution was concentrated. The residue was purified by flash chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to obtain compound 3-3. LCMS: m / z = 400.1 [M+1] + .

[0444] Step 4

[0445] Compound 3-3 (9 g, 22.54 mmol), compound M5 (14.57 g, 22.54 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (824.72 mg, 1.13 mmol), and potassium phosphate (11.96 g, 56.36 mmol) were added sequentially to 250 mL of anhydrous dioxane and 80 mL of water. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated. The residue was diluted with 200 mL of water and extracted with ethyl acetate (3 x 200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to obtain compound 3-4. LCMS: m / z = 873.3, 875.3 [M+1] + .

[0446] Step 5

[0447] Compound 3-4 (6.2 g, 7.09 mmol), iodoethane (14.19 mmol, 1.13 mL), and cesium carbonate (4.62 g, 14.19 mmol) were added sequentially to 100 mL of anhydrous DMF, and the mixture was stirred at 20°C for 10 hours. The reaction solution was concentrated. The residue was diluted with 100 mL of water and extracted with ethyl acetate (3 x 150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-5. LCMS: m / z = 901.4, 903.4 [M+1] + .

[0448] Step 6

[0449] Compound 3-5 (6.2 g, 6.87 mmol) and tetrabutylammonium fluoride in tetrahydrofuran (1 M, 13.75 mL) were added sequentially to 100 mL of anhydrous tetrahydrofuran, and the mixture was stirred at 50°C for 15 hours. The reaction solution was concentrated. The residue was purified by flash chromatography (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, its isomer R f =0.33). LCMS: m / z=663.2,665.2[M+1] + .

[0450] Step 7

[0451] Compound 3-6A (1.70 g, 2.56 mmol), bis(chloronaphthalene) boronate (975.74 mg, 3.84 mmol), 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (187.43 mg, 256.16 μmol), and potassium acetate (754.21 mg, 7.68 mmol) were added sequentially to 50 mL of anhydrous dioxane. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 90°C for 20 hours. The reaction solution was concentrated. The residue was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to obtain compound 3-7A. LCMS: m / z = 711.1 [M+1] + .

[0452] Step 8

[0453] Compound 3-7A (0.38 g, 534.68 μmol), compound M2 (322.99 mg, 641.61 μmol), 1,1-di(tert-butylphosphino)ferrocenepalladium chloride (34.85 mg, 53.47 μmol), and potassium phosphate (283.74 mg, 1.34 mmol) were added sequentially to 15 mL of dioxane and 5 mL of water. The atmosphere was purged with nitrogen three times, and the mixture was stirred at 70°C for 4 hours. The reaction solution was concentrated. The residue was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to obtain compound 3-8A. LCMS: m / z = 1007.4 [M+1] + .

[0454] Step 9

[0455] Compound 3-8A (650 mg, 645.33 μmol) and lithium hydroxide monohydrate (54.16 mg, 1.29 mmol) were added sequentially to 20 mL of tetrahydrofuran and 20 mL of water, and the mixture was stirred at 15°C for 20 hours. The reaction solution was concentrated. The residue was diluted with 5 mL of water, and 1N dilute hydrochloric acid was added dropwise to adjust the pH to 6-7. The mixture was extracted with ethyl acetate (3*30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-9A. LCMS: m / z = 979.4 [M+1] + .

[0456] Step 10

[0457] Compound 3-9A (650 mg, 663.81 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (3.82 g, 19.91 mmol), N,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 hours. The reaction solution was concentrated. The residue was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to obtain compound 3-10A. LCMS: m / z = 961.4 [M+1] + .

[0458] Step 11

[0459] 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 sequentially to 10 mL of methanol. The atmosphere was replaced with hydrogen three times, and the mixture was stirred at 20°C under a hydrogen atmosphere (15 psi) for 2 hours. Filtered. The filtrate was concentrated. The residue was purified by flash chromatography (silica gel, eluent: methanol / dichloromethane, methanol ratio: 0-10%) to obtain compound 3-11A. LCMS: m / z = 841.4 [M+1] + .

[0460] Step 12

[0461] 1 mL of trifluoroacetic acid was slowly added dropwise to a solution of 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 solution was concentrated to obtain the trifluoroacetic acid salt of compound 3-12A. LCMS: m / z = 741.3 [M+1] + .

[0462] Step 13

[0463] Compound 3-12A (45 mg, trifluoroacetic acid salt), (1S,2S)-2-methylcyclopropane-1-carboxylic acid (9.12 mg, 91.10 μmol), N,N-diisopropylethylamine (303.66 μmol, 52.89 μL), and HATU (69.28 mg, 182.20 μmol) were added sequentially to 5 mL of anhydrous DMF, and the mixture was stirred at 20°C for 1 hour. The reaction solution was concentrated, and the crude product was separated by preparative HPLC (preparative method: column model: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 14% to 44% over 8 minutes) to obtain the trifluoroacetic acid salt of compound 3A. LCMS: m / z = 823.4 [M+1] + ; 1 H NMR (400MHz, 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).

[0464] Example 4

[0465] Compound 3-12A (0.1 g, 134.96 μmol) and (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (31 mg, 269.98 μmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (175 mg, 1.35 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (154 mg, 404.9 μmol) were then added. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered, and the filtrate was directly purified by HPLC (purification method: column type: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient (acetonitrile%): 16% to 46% over 8 minutes) to obtain the trifluoroacetate salt of compound 4A. LCMS: m / z=837.4[M+1] + ; 1 H NMR(400MHz,CD3OD)δppm 8.53(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,1H), 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).

[0466] Example 5

[0467] Step 1

[0468] 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)ferrocenepalladium chloride (22.07 mg, 33.86 μmol) were added. The reaction mixture was stirred at 70°C under a nitrogen atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to obtain compound 5-1A. LCMS: m / z = 923.5 [M+1] + .

[0469] Step 2

[0470] Compound 5-1A (205 mg, 222.07 μmol) was dissolved in a mixture of tetrahydrofuran (2 mL) and water (0.5 mL). Lithium hydroxide monohydrate (46.59 mg, 1.11 mmol) was added and the reaction mixture was stirred at 25°C for 1 hour. The pH of the reaction mixture was then adjusted to 7-8 with 1M dilute hydrochloric acid and 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] + .

[0471] Step 3

[0472] Compound 5-2A (45 mg, 50.28 μmol) was dissolved in acetonitrile (4.5 mL), and tetramethyluronium chloride hexafluorophosphate (21.16 mg, 75.41 μmol) and N-methylimidazole (12.38 mg, 150.83 μmol) were added. The reaction mixture was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (5 mL*3). The organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and concentrated to obtain compound 5-3A. LCMS: m / z = 877.4 [M+1] + .

[0473] Step 4

[0474] Compound 5-3A (50 mg, 57.01 μmol) was dissolved in dichloromethane (0.5 mL), and trifluoroacetic acid (767.50 mg, 6.73 mmol, 0.5 mL) was added. The reaction solution was stirred at 25°C for 1 hour and concentrated under reduced pressure to obtain the crude trifluoroacetate salt of compound 5-4A, which was used directly in the next step.

[0475] Step 5

[0476] The crude trifluoroacetate of compound 5-4A obtained in step 4 was dissolved in N,N-dimethylformamide (1 mL), and (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (9.70 mg, 84.95 μmol) was added. Then, N,N-diisopropylethylamine (21.96 mg, 169.90 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (43.07 mg, 113.27 μmol) were added under stirring. The reaction solution was stirred at 25 ° C. for 3 hours and then purified by prep-HPLC (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: the proportion of acetonitrile increased from 16% to 46% in 8 minutes) to obtain the trifluoroacetate of 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).

[0477] Example 6

[0478] Step 1

[0479] 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(di-tert-butylphosphino)ferrocene]palladium dichloride (26.48 mg, 40.64 μmol) were added under nitrogen. The mixture was stirred at 70°C for 12 hours. After cooling, the reaction solution was directly concentrated and purified by column chromatography (eluent: ethyl acetate / petroleum ether 3% to 7%) to obtain compound 6-1A. LCMS: m / z = 749.6 [M+1]. + .

[0480] Step 2

[0481] Compound 6-1A (130 mg, 173.57 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (3 mL). Lithium hydroxide monohydrate (36.42 mg, 867.86 μmol) was added and stirred at 25°C for half an hour. The pH of the system was adjusted to 7.0 with 1M hydrochloric acid, then diluted with saturated brine (50 mL). The mixture was extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-2A, which was used directly in the next step. LCMS: m / z = 735.6 [M+1] + .

[0482] Step 3

[0483] Compound M6 (21.82 mg, 95.25 μmol) and compound 6-2A (70 mg, 95.25 μmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (952.45 μmol, 165.90 μL) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (43.46 mg, 114.29 μmol) were added, and the mixture was stirred at 25°C for half an hour. After completion of the reaction, saturated brine (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-3A, which was used directly in the next step. LCMS: m / z = 874.0 [M+1] + .

[0484] Step 4

[0485] Compound 6-3A (130 mg, 173.57 μmol) was dissolved in tetrahydrofuran (3 mL), methanol (1 mL), and water (3 mL). Lithium hydroxide monohydrate (36.42 mg, 867.86 μmol) was added and stirred at 25°C for half an hour. The pH of the system was adjusted to 7.0 with 1M hydrochloric acid, then diluted with saturated brine (50 mL). The mixture was extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 6-4A, which was used directly in the next step. LCMS: m / z = 860.0 [M+1] + .

[0486] Step 5

[0487] Compound 6-4A (61 mg, 71.01 μmol) was dissolved in acetonitrile (20 mL), and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (597.68 mg, 2.13 mmol) and N-methylimidazole (174.89 mg, 2.13 mmol, 169.80 μL) were added. The mixture was stirred at 25°C under nitrogen for 1 hour. The reaction solution was concentrated and separated by pre-TLC (DCM / MeOH = 10:1) to obtain compound 6-5A. LCMS: m / z = 842.0 [M+1] + .

[0488] Step 6

[0489] Compound 6-5A (52 mg, 61.83 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (798.20 mg, 7.00 mmol, 520.00 μL) was added. The mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain the crude trifluoroacetate salt of compound 6-6A, which was used directly in the next step.

[0490] Step 7

[0491] Compound 6-6A (35 mg, 40.9 μmol) and (1r,2R,3S)-2,3-dimethylcyclopropyl-1-carboxylic acid (9.35 mg, 81.8 μmol)) were dissolved in DMF (2 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31.13 mg, 81.87 μmol) and N,N-diisopropylethylamine (409.37 μmol, 71.30 μL) were added and stirred at 25 ° C for 1 hour. The product was diluted with saturated brine (50 mL), extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by pre-TLC (developing solvent: dichloromethane / methanol = 10:1) and then separated and purified by SFC (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [phase A: supercritical carbon dioxide, phase B: ethanol (0.1% ammonia water)]; gradient (B%): 50%, isobaric elution) to obtain compounds 6A and 6B.

[0492] SFC analysis (column: Chiralcel OD-3 50*4.6mm ID, 3um, mobile phase: A: supercritical carbon dioxide, B: ethanol (containing 0.05% diethylamine), gradient elution: mobile phase B increased from 5% to 40% over 2 minutes, then maintained at 40% for 1.2 minutes, and then maintained at 5% for 0.8 minutes) showed that compound 6A had a RT of 1.896 min and an ee of 96.98%; compound 6B had a RT of 2.201 min and an ee of 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).

[0493] 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).

[0494] Example 7

[0495] Compound 6-6A (60 mg, 70.18 μmol) and (1S,2S)-2-methylcyclopropyl-1-carboxylic acid (14.05 mg, 81.8 μmol) were dissolved in DMF (10 mL), and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (53.37 mg, 140.35 μmol) and N,N-diisopropylethylamine (72.56 mg, 561.42 μmol) were added, and the mixture was stirred at 25 ° C for 1 hour. The product was diluted with saturated brine (50 mL), extracted twice with ethyl acetate (30 mL) and tetrahydrofuran (30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product which was purified by flash silica gel column (mobile phase: dichloromethane / methanol = 100:1), followed by SFC separation and purification (column: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: [phase A: supercritical carbon dioxide, phase B: ethanol (0.1% ammonia water)]; gradient (B%): 50%) to obtain compounds 7A and 7B. SFC analysis (column: chiral OD-3 100*4.6mm ID, 3μm, mobile phase: A: supercritical carbon dioxide, B: ethanol (containing 0.05% diethylamine), gradient (B%): 40%) revealed a RT of 1.365 min for compound 7A, with an ee of 100%; a RT of 2.325 min for compound 7B, with an ee of 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).

[0496] 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).

[0497] Example 8

[0498] Compound 8-1 and compound 6-6A were used as starting materials, and the resulting reaction solution was directly purified by HPLC (column: C18 100×40 mm; mobile phase: [water(trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increasing from 16% to 46% over 8 minutes) to obtain the trifluoroacetate salt of compound 8A. LCMS: m / z = 859.5 [M+1] + . 1H NMR(400MHz,DMSO-d6)δ=8.88(br d,J=9.0Hz,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=11.3Hz,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=1.5Hz,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=6.3Hz,4H),1.05(br t,J=6.9Hz,3H),0.94-0.83(m,10H),0.39-0.28(m,3H).

[0499] Example 9

[0500] Step 1

[0501] Compound M5-7 (6.83 g, 13.12 mmol) was dissolved in tetrahydrofuran (50 mL), followed by the addition of tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 65.60 mL). The reaction mixture was stirred at 50°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated. The crude product was diluted with water (100 mL), and the solution was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-55%) to obtain compound 9-1A. LCMS: m / z = 281.9 [M+1] + .

[0502] Step 2

[0503] Compound 9-1A (3.31 g, 11.73 mmol) was dissolved in dichloromethane (30 mL), followed by the addition of triethylamine (3.56 g, 35.19 mmol) and 4-dimethylaminopyridine (72 mg, 596.51 μmol). The temperature was lowered to 0°C, and acetic anhydride (1.16 g, 11.38 mmol) was added dropwise. The reaction mixture was stirred at 0°C for 10 minutes. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to yield compound 9-2A. LCMS: m / z = 323.9 [M+1] + .

[0504] Step 3

[0505] Compound 9-2A (3.4 g, 10.49 mmol), bis-naphthalene boronate (6.66 g, 26.22 mmol), potassium acetate (2.57 g, 26.22 mmol), and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (0.768 g, 1.05 mmol) were dissolved in 40 mL of toluene. The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 90°C for 3 hours. After the reaction was complete, the reaction mixture was directly concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-30%) to obtain compound 9-3A. LCMS: m / z = 372.1 [M+1] + .

[0506] Step 4

[0507] 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)ferrocenepalladium chloride (750 mg, 1.12 mmol) were dissolved in toluene (30 mL), dioxane (10 mL), and water (10 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 70°C for 12 hours. After completion of the reaction, the reaction mixture was directly concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to obtain compound 9-4A. LCMS: m / z = 530.2 [M+1] + .

[0508] Step 5

[0509] Compound 9-4A (5.4 g, 10.20 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0°C. Sodium bicarbonate (1.03 g, 12.28 mmol) and silver trifluoromethanesulfonate (3.15 g, 12.25 mmol) were then added dropwise. A solution of iodine (2.33 g, 9.18 mmol) in tetrahydrofuran (5 mL) was then added dropwise. The reaction mixture was stirred at 0°C for 15 minutes. After completion, the reaction mixture was quenched with saturated sodium sulfite solution (100 mL) at 0°C. The resulting solution was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-40%) to yield compound 9-5A. LCMS: m / z = 656.1 [M+1] + .

[0510] Step 6

[0511] Compound 9-5A (3.2 g, 4.88 mmol) was dissolved in tetrahydrofuran (3 mL) and water (1 mL). Lithium hydroxide monohydrate (615 mg, 15.64 mmol) was added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the pH of the reaction mixture was adjusted to approximately 6 with saturated citric acid solution. The resulting solution was extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed once with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated to obtain the crude product, which was purified by preparative HPLC (column: C18 100 × 40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile from 30% to 60% over 8 minutes). The target fraction was concentrated under reduced pressure, the pH was adjusted to 7-8 with dilute aqueous ammonia, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were concentrated to yield compound 9-6A. LCMS: m / z = 600.1 [M+1] + .

[0512] Step 7

[0513] Compound 9-6A (0.32 g, 1.18 mmol) was dissolved in N,N-dimethylformamide (7 mL), followed by the addition of N,N-diisopropylethylamine (1.44 g, 11.18 mmol), compound M9 (0.67 g, 1.12 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (510 mg, 1.44 mmol). The reaction mixture was stirred at 25°C for 2 hours. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-60%) to yield compound 9-7A. LCMS: m / z = 738.2 [M+1] + .

[0514] Step 8

[0515] 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 mixture was stirred at 0°C for 1 hour. After completion of the reaction, the pH was adjusted to approximately 6 by adding saturated citric acid solution. The solution was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-100%) to obtain compound 9-8A. LCMS: m / z = 724.1 [M+1] + .

[0516] Step 9

[0517] Compound 9-8A (0.2 g, 276.39 μmol) was dissolved in acetonitrile (20 mL) and N,N-dimethylformamide (2 mL). N-methylimidazole (1.13 g, 13.82 mmol) and N,N,N,N-tetramethylchloroformamidine hexafluorophosphate (388 mg, 1.48 mmol) were then added. The reaction mixture was stirred at 80°C for 2 hours. After completion, the reaction mixture was concentrated to remove the acetonitrile and diluted with water (30 mL). The solution was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed once with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-40%) to yield compound 9-9A. LCMS: m / z = 706.1 [M+1]+ .

[0518] Step 10

[0519] Compound 9-9A (0.1 g, 141.72 μmol), potassium acetate (48.68 mg, 496.03 μmol), 2-dicyclohexylphosphino-2,6-dimethoxybiphenyl (30 mg, 71.86 μmol), and tris(dibenzylideneacetone)dipalladium (26 mg, 28.54 μmol) were dissolved in toluene (5 mL). Pinacolborane (145.10 mg, 1.13 mmol) was added dropwise at 0°C under nitrogen. The reaction mixture was stirred at 60°C under nitrogen for 3 hours. After the reaction was complete, the reaction solution was quenched by the dropwise addition of saturated ammonium chloride (10 mL). The solution was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was directly concentrated. The resulting crude product was purified by flash chromatography (silica gel, eluent ethyl acetate / petroleum ether, ethyl acetate ratio: 0-40%) to obtain compound 9-10A. LCMS: m / z = 706.4 [M+1] + .

[0520] Step 11

[0521] 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)ferrocenepalladium chloride (21 mg, 28.54 μmol) were dissolved in toluene (3 mL), dioxane (1 mL), and water (1 mL). The atmosphere was purged with nitrogen three times, and the reaction mixture was stirred at 65°C for 12 hours. After completion of the reaction, the reaction mixture was concentrated, and the crude product 9-11A was used directly in the next step. LCMS: m / z = 855.6 [M+1] + .

[0522] Step 12

[0523] Compound 9-11A (0.1 g, 116.95 μmol) and cesium carbonate (115 mg, 351.85 μmol) were dissolved in N,N-dimethylformamide (3 mL), and iodoethane (28 mg, 176.43 μmol) was added dropwise at 0°C. The reaction solution was stirred at 25°C for 12 hours. After completion of the reaction, the reaction solution was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile from 22% to 52% over 8 minutes) to obtain the trifluoroacetate salt of compound 9-12A. LCMS: m / z = 883.4 [M+1] + .

[0524] Step 13

[0525] Compound 9-12A (30 mg, 33.97 μmol) was dissolved in hydrochloric acid / dioxane (2 M, 2 mL) and the reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, the reaction mixture was concentrated and the crude product 9-13A was used directly in the next step. LCMS: m / z = 783.3 [M+1] + .

[0526] Step 14

[0527] Compound 9-13A (0.03 g, 38.31 μmol) and (1S,2S)-2-methylcyclopropane-1-carboxylic acid (8 mg, 79.91 μmol) were dissolved in N,N-dimethylformamide (2 mL). N,N-diisopropylethylamine (50 mg, 386.87 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphonate (30 mg, 78.90 μmol) were then added. The reaction mixture was stirred at 25°C for 12 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was purified by preparative high-performance liquid chromatography (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increasing from 17% to 47% over 8 minutes) to obtain the trifluoroacetic acid salt of compound 9A. LCMS: m / z=865.3[M+1] + . 1 H NMR(400MHz,CD3OD)δppm 8.88(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),2.0 9-1.95(m,10H),1.66-1.57(m,5H),1.13-1.06(m,3H),0.92-0.96(m,6H).

[0528] Example 10

[0529] Step 1

[0530] Compound 3-4 (1 g, 1.14 mmol) and cesium carbonate (2.61 g, 8.01 mmol) were dissolved in 1-methyl-2-pyrrolidone (10 mL), cooled to 0°C, and trifluoroethyl trifluoromethanesulfonate (2.66 g, 11.44 mmol) was added dropwise. The reaction mixture was stirred at 25°C for 48 hours. After completion, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-50%) to obtain compound 10-1A. LCMS: m / z = 955.3 [M+1] + .

[0531] Step 2

[0532] Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 5 mL) was added to compound 10-1A (0.5 g, 523.01 μmol) at 0°C. The reaction mixture was stirred at 40°C for 12 hours. After completion, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed once with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by flash chromatography (silica gel, eluent: ethyl acetate / petroleum ether, ethyl acetate ratio: 0-80%) to obtain compound 10-2A (LC-MS analysis: 5-95AB_1.5 min, retention time of compound 10-2A: 1.009 min, retention time of its isomer: 0.981 min). LCMS: m / z = 717.1 [M+1] + .

[0533] Steps 3-11

[0534] Referring to the synthetic methods of Examples 6-9, a reaction solution of Compound 10A was obtained. The reaction solution was filtered, and the filtrate was separated and purified by preparative high-performance liquid chromatography (column: C18 100×40 mm; mobile phase: [water(trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile from 20% to 50% over 8 minutes) to obtain the trifluoroacetate salt of Example 10A. LCMS: m / z = 891.5 [M+1] + . 1H NMR(400MHz,CD3OD)δppm 8.57-8.43(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- 3.35(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 ,5H),1.49-1.42(m,5H),1.41-1.36(m,10H),1.22-1.13(m,5H),1.12-1.04(m,3H).

[0535] Example 11

[0536] Referring to the synthetic methods of Examples 6-9, a reaction solution of Compound 11A was obtained. Water was added to the reaction solution until no solid precipitated. The solid was collected by filtration and then purified by preparative high-performance liquid chromatography (column: C18 100×40 mm; mobile phase: [water (trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increasing 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).

[0537] Example 12

[0538] Referring to the synthetic methods of Examples 6-9, a reaction solution of Compound 12A was obtained. Water was added to the reaction solution until no solid precipitated. The solid was collected by filtration and then purified by preparative high-performance liquid chromatography (column: C18 100×40 mm; mobile phase: [water(trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile increasing from 17% to 47% over 8 minutes) to obtain the trifluoroacetate salt of the 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).

[0539] Example 13

[0540] Step 1

[0541] 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 Boc2O (1.17 g, 5.34 mmol) were added and stirred at 25°C for 12 hours. After completion of the reaction, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL*3). The organic phase was dried and concentrated, and then purified by SFC preparation (column: DAICEL CHIRALPAK IG (250 mm*30 mm, 10 um); mobile phase: [phase A: supercritical fluid carbon dioxide, phase B: isopropanol containing 0.1% ammonia water]; phase B ratio 30% isocratic elution) to obtain compound 13-1A (Rt=3.625; SFC analysis method: column: DAICEL CHIRALPAK IG (100*4.6 mm ID, 3 μm); mobile phase: [Phase A: supercritical carbon dioxide, Phase B: isopropanol containing 0.05% ammonia]; Phase B increased from 5% to 40% over 4.5 minutes, then maintained at 5% for 1.5 minutes, flow rate 2.5 mL / min, column temperature: 40°C) and 13-1B (Rt = 4.200; SFC analysis method: column: DAICEL CHIRALPAK IG (100*4.6 mm ID, 3 μm); mobile phase: [Phase A: supercritical carbon dioxide, Phase B: isopropanol containing 0.05% ammonia]; Phase B increased from 5% to 40% over 4.5 minutes, then maintained 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]+.

[0542] Step 2

[0543] Compound 3-6A (1.2 g, 1.81 mmol) and bis(chloroquinoline) boronate (688.76 mg, 2.71 mmol) were added to toluene (10 mL), followed by potassium acetate (354.91 mg, 3.62 mmol). The atmosphere was purged with nitrogen, and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (132.31 mg, 180.82 μmol) was added. The reaction mixture was stirred at 70°C under nitrogen for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated. The crude product was purified by column chromatography (0-15% methanol / dichloromethane) to afford compound 13-2A. LCMS: m / z = 711.4 [M+1] + .

[0544] Step 3

[0545] Compound 13-1A (0.05 g, 132.54 μmol) was dissolved in dichloromethane (2 mL), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (30.49 mg, 159.04 μmol), 1-hydroxybenzotriazole (21.49 mg, 159.04 μmol), and N-methylmorpholine (26.81 mg, 265.07 μmol). The mixture was stirred at 0°C for 0.5 hour, followed by the addition of trifluoroacetate of compound M9 (35.81 mg, 132.54 μmol) at 0°C and stirring at 25°C for 1 hour. After completion of the reaction, the mixture was extracted with water (50 mL) and ethyl acetate (50 mL x 3). The organic phase was dried and concentrated to afford compound 13-3A. LCMS: m / z = 515.0, 517.0 [M+1]. + .

[0546] Step 4

[0547] 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)ferrocenepalladium chloride (13.15 mg, 20.18 μmol) were then added. The mixture was stirred at 70°C under nitrogen for 12 hours. After completion of the reaction, water (10 mL) was added and the mixture was extracted with ethyl acetate (10 mL*3). The organic phase was dried and concentrated, and the crude product was separated on a thin-layer chromatography plate (petroleum ether:ethyl acetate = 1:1) to obtain compound 13-4A. LCMS: m / z = 510.0 [M / 2+1] + .

[0548] Step 5

[0549] Referring to the synthetic methods of Examples 6 to 9, a reaction solution of Compound 13A was obtained. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was dried and concentrated, and the crude product was separated by thin-layer chromatography (dichloromethane:methanol = 10:1) to obtain Compound 13A. LCMS: m / z = 850.0 [M+1] + . 1H NMR (400MHz, CD3OD) δppm 0.59 (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).

[0550] Example 14

[0551] Compound 14A was prepared using compound 13-1B as the starting material and referring to the synthesis method of Example 13.

[0552] LCMS: m / z=850.0[M+1] + . 1H NMR (400MHz, CD3OD) δppm 0.56 (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).

[0553] Example 15

[0554] Step 1

[0555] 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)ferrocenepalladium chloride (155.77 mg, 212.89 μmol) were then added. The reaction mixture was stirred at 50°C under nitrogen for 2 hours. The reaction mixture was then filtered to remove insoluble impurities, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was purified by column chromatography (0-5% methanol / dichloromethane) to obtain compound 15-2A. LCMS: m / z = 312.9 [M+1] + .

[0556] Step 2

[0557] Compound 15-2A (580 mg, 1.86 mmol) and neopentyl glycol diboronate (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)ferrocenepalladium chloride (136.37 mg, 186.37 μmol) were then added. The reaction mixture was stirred at 80°C under nitrogen for 2 hours. The reaction mixture was then filtered to remove insoluble impurities, and the filtrate was concentrated to dryness to obtain compound 15-3A. LCMS: m / z = 345.1 [M+1] + .

[0558] Step 3

[0559] Compound 15-3A (640 mg, 1.86 mmol, 1 eq) and compound M5 (1.20 g, 1.86 mmol, 1 eq) were dissolved in 1,4-dioxane (20 mL) and water (4 mL). Potassium carbonate (770.83 mg, 5.58 mmol) was added, and the atmosphere was purged with nitrogen three times. 1,1-Bis(diphenylphosphino)ferrocenepalladium chloride (136.03 mg, 185.91 μmol) was added, and the reaction mixture was stirred at 70°C under nitrogen for 3 hours. After completion of the reaction, the reaction mixture was filtered to remove insoluble impurities, and the organic solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (0-10% methanol / dichloromethane) to obtain compound 15-4A. LCMS: m / z = 750.2 [M+1] + .

[0560] Step 4

[0561] Compound 15A was prepared by referring to the synthetic methods of Examples 6 to 9. LCMS: m / z = 834.5 [M+H] + .

[0562] Example 16

[0563] Referring to the synthetic methods of Examples 6 to 9, 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] + ).

[0564] Biological test data

[0565] Experimental Example 1: In vitro AsPC-1 cell proliferation assay

[0566] Experimental Materials:

[0567] RPMI1640 medium and penicillin / streptomycin antibiotics were purchased from Gibco, and fetal bovine serum was purchased from Hyclone. 3D CellTiter-Glo (a chemiluminescent cell viability assay) reagent was purchased from Promega. AsPC-1 cell lines were purchased from ATCC, and the Envision Multilabel Analyzer was purchased from PerkinElmer.

[0568] Experimental methods:

[0569] AsPC-1 cells were seeded in ultra-low attachment 96-well U-shaped plates, with 80 μL of cell suspension per well, containing 1000 AsPC-1 cells. The plates were incubated overnight in a CO2 incubator.

[0570] The compound to be tested was diluted 5-fold into 8 concentrations, from 2mM to 25.6nM, using a dispenser, and a double-well experiment was set up. 78μL of culture medium was added to the middle plate, and then 2μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10μM to 0.128nM. The cell plate was placed in a carbon dioxide incubator and cultured for 10 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0571] Add 100 μL of cell viability chemiluminescent detection reagent to the cell plate and incubate at room temperature for 30 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0572] Data Analysis:

[0573] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value of can be obtained by four-parameter curve fitting (obtained in the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 1 provides the inhibitory activity of the compounds of the present invention on AsPC-1 cell proliferation.

[0574] Table 1: Results of in vitro screening tests of compounds of the present invention

[0575] Conclusion: The compounds of the present invention have significant inhibitory activity on the proliferation of AsPC-1 cells.

[0576] Experimental Example 2: In vitro cell proliferation experiment

[0577] Experimental Materials:

[0578] RPMI1640 medium, DMEM medium, Ham's F12 medium, F12K medium, IMDM medium and penicillin / streptomycin antibiotics were purchased from Gibco, fetal bovine serum was purchased from Hyclone, and Envision multi-label analyzer was purchased from PerkinElmer.

[0579] 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 Kebai Biotechnology Co., Ltd. A375 cell line (DMEM + 10% FBS + 1% penicillin / streptomycin), AsPC-1 cells (RPMI1640 + 10% FBS + 1% penicillin / streptomycin), PSN-1 cell line (RPMI1640 + 10% FBS + 1% penicillin / streptomycin), SW620 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), LU99 cell line (RPMI1640+10% FBS+1% penicillin / streptomycin) were purchased from JCRB.

[0580] Experimental methods:

[0581] Cells were seeded in ultra-low attachment 96-well U-shaped plates, with 80 μL of cell suspension per well, containing 1000 cells. The plates were incubated overnight in a CO2 incubator.

[0582] The compound to be tested was diluted 5-fold into 8 concentrations using a dispenser, i.e., from 2mM to 25.6nM, and a double-well experiment was set up. 78μL of culture medium was added to the middle plate, and then 2μL of the gradient diluted compound per well was transferred to the middle plate according to the corresponding position. After mixing, 20μL of each well was transferred to the cell plate. The concentration range of the compound transferred to the cell plate was 10μM to 0.128nM. The cell plate was placed in a carbon dioxide incubator and cultured for 5 days. Prepare another cell plate and read the signal value on the day of drug addition as the maximum value (Max value in the equation below) for data analysis.

[0583] Add 50 μL of cell viability chemiluminescent detection reagent to each well of the cell plate and incubate at room temperature for 30 minutes to allow the luminescent signal to stabilize. Read the results using a multi-label analyzer.

[0584] Data Analysis:

[0585] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The value can be obtained by four-parameter curve fitting (obtained in the "log (inhibitor) vs. response--Variable slope" mode in GraphPad Prism). Table 2 provides the experimental results of the inhibitory activity of the compounds of the present invention on cell proliferation.

[0586] Table 2: In vitro cell proliferation inhibition activity test results of the compounds of the present invention

[0587] Conclusion: The compounds of the present invention have significant inhibitory activity on cell proliferation of RAS mutant cell lines (such as GP2D, PK-59, AsPC-1, PSN-1, RKN, Capan-1, SW620, HCT116, LOVO, A549, H441, H727, LU99 and A427), but do not show obvious inhibitory effect in wild-type independent cell lines (such as A375), and have good selectivity.

[0588] Experimental Example 3: Detection of p-ERK Levels in AsPC-1 Cells

[0589] Experimental Materials:

[0590] 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 include: Advanced PhosphoERK1 / 2 Eu Cryptate antibody, Advanced PhosphoERK1 / 2 d2 antibody, Blocking reagent (stock solution 100X), Lysis buffer #1 (stock solution 4X), and Detection buffer (ready-to-use). All products should be stored at ≤-16°C.

[0591] Experimental methods:

[0592] (1) Cells were seeded in a 384-well cell culture plate with a white bottom, 8 μL of cell suspension per well, and each well contained 7500 cells. The cell plate was placed in a CO2 incubator and incubated overnight at 37°C.

[0593] (2) Dilute the test compound with 100% DMSO to 3 mM as the first concentration, and then use a pipette to dilute it to ten concentrations of 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 μM. Take 2 μL of compound and add it to 198 μL of cell starvation medium. After mixing, take 15 μL of compound solution and add it to 35 μL of cell starvation medium and mix it. Then, add 4 μL of compound solution from the last step to the corresponding cell plate wells per well. Return the cell plate to the carbon dioxide incubator and continue incubation for 3 hours. At this time, the compound concentrations are 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 nM.

[0594] (3) After the incubation, add 3 μL of 5X cell lysis buffer to each well and incubate at room temperature with shaking for 30 minutes;

[0595] (4) Use detection buffer to dilute Phospho-ERK1 / 2Eu Cryptate antibody and Phospho-ERK1 / 2d2antibody 20 times, mix them at a ratio of 1:1, add 5 μL per well to the cell culture plate, and incubate at room temperature for 2 hours;

[0596] (5) After incubation, use a multi-label analyzer to read HTRF excitation: 320 nm, emission: 615 nm, 665 nm.

[0597] Data Analysis:

[0598] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The values ​​can be obtained by four-parameter curve fitting (using the variable slope mode in GraphPad Prism using log(inhibitor) vs. response). Table 4 provides the inhibitory effects of the compounds of the present invention on p-ERK. Max wells: Positive control wells with a 1X lysate reading; Min wells: Negative control wells with a 0.5% DMSO cell lysate reading. Experimental results are shown in Table 3.

[0599] Table 3: Results of in vitro pERK inhibition screening test of the compounds of the present invention

[0600] Conclusion: The compounds of the present invention have significant inhibitory activity on the pERK level in AsPC-1 cells.

[0601] Experimental Example 4: Detection of p-ERK Levels in GP2D Cells

[0602] Experimental Materials:

[0603] GP2D cell line (DMEM + 10% FBS + 1% penicillin / streptomycin) was purchased from ECACC; RPMI-1640 medium was purchased from GIbco; fetal bovine serum was purchased from Hyclone; Advanced Phospho-ERK1 / 2 (THR202 / TYR204) KIT was purchased from Bioauxilium-Advanced Phospho; ERK1 / 2 (THR202 / TYR204) KIT components include: Advanced PhosphoERK1 / 2 Eu Cryptate antibody, Advanced PhosphoERK1 / 2 d2 antibody, Blocking reagent (stock solution 100X), Lysis buffer #1 (stock solution 4X), Detection buffer (ready-to-use), and the storage temperature is ≤-16°C.

[0604] Experimental methods:

[0605] (1) Cells were seeded in a 384-well cell culture plate with a white bottom, 8 μL of cell suspension per well, and each well contained 7500 cells. The cell plate was placed in a CO2 incubator and incubated overnight at 37°C.

[0606] (2) Dilute the test compound with 100% DMSO to 3 mM as the first concentration, and then use a pipette to dilute it to ten concentrations of 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 μM. Take 2 μL of compound and add it to 198 μL of cell starvation medium. After mixing, take 15 μL of compound solution and add it to 35 μL of cell starvation medium and mix it. Then, add 4 μL of compound solution from the last step to the corresponding cell plate wells per well. Return the cell plate to the carbon dioxide incubator and continue incubation for 3 hours. At this time, the compound concentrations are 3000, 1000, 300, 100, 30, 10, 3, 1, 0.3, and 0.1 nM.

[0607] (3) After the incubation, add 3 μL of 5X cell lysis buffer to each well and incubate at room temperature with shaking for 30 minutes;

[0608] (4) Use detection buffer to dilute Phospho-ERK1 / 2Eu Cryptate antibody and Phospho-ERK1 / 2d2antibody 20 times, mix them at a ratio of 1:1, add 5 μL per well to the cell culture plate, and incubate at room temperature for 2 hours;

[0609] (5) After incubation, use a multi-label analyzer to read HTRF excitation: 320 nm, emission: 615 nm, 665 nm.

[0610] Data Analysis:

[0611] The raw data were converted into inhibition rate, IC, using the equation (Sample-Min) / (Max-Min)*100%. 50 The values ​​can be obtained by four-parameter curve fitting (using the variable slope mode in GraphPad Prism using log(inhibitor) vs. response). Table 4 provides the inhibitory effects of the compounds of the present invention on p-ERK. Max wells: Positive control wells with a 1X lysate reading; Min wells: Negative control wells with a 0.5% DMSO cell lysate reading. Experimental results are shown in Table 4.

[0612] Table 4: Results of in vitro pERK inhibition screening test of the compounds of the present invention

[0613] Conclusion: The compounds of the present invention have significant inhibitory activity on the pERK level in GP2D cells.

[0614] Experimental Example 5: In vivo pharmacodynamics study

[0615] Purpose of the experiment:

[0616] The in vivo efficacy of the compound of the present invention was studied in a BALB / c nude mouse subcutaneous xenograft tumor model of human lung bronchial benign tumor NCI-H727 cells.

[0617] Experimental methods and steps:

[0618] Experimental animals: Female BALB / c nude mice, 6-8 weeks old, weighing 18-22 g; Supplier: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0619] (1) Cell Culture: Human benign lung bronchial tumor cells were cultured as monolayers in Gibco RMPI1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Cells were routinely digested and passaged twice weekly using trypsin-EDTA. When cell saturation reached 80%-90% and the desired number of cells was reached, the cells were harvested, counted, and inoculated.

[0620] (2) Tumor cell inoculation and grouping: 0.2 mL (2 × 10 6 NCI-H727 cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached approximately 134 mm 3 The animals were divided into groups and dosed starting at 8:00 pm, with 6 animals in each group.

[0621] The solvent was 5% DMSO / 10% solutol / 85% water. The control group was given the solvent by gavage twice a day at a dose of 10 μL / g. The treatment group was given the test compound by gavage once a day after dissolving it in the solvent. The doses are shown in Table 4.

[0622] (3) The tumor diameter was measured with a vernier caliper twice a week and the 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 antitumor efficacy of the test compound was evaluated using the tumor growth inhibition rate (TGI). The calculation formula is: TGI (%) = [1 – (average tumor volume of a treatment group at the end of dosing – average tumor volume of that treatment group at the start of dosing) / (average tumor volume of the solvent control group at the end of treatment – ​​average tumor volume of the solvent control group at the start of treatment)] × 100%.

[0623] Experimental results:

[0624] The body weight of mice in each treatment group was maintained well after administration. The TGI was calculated based on the average tumor volume on day 21 after administration. The specific experimental results are shown in Table 5.

[0625] Table 5: Evaluation of the antitumor efficacy of the compounds of the present invention in the human lung bronchial benign tumor NCI-H727 model

[0626] Conclusion: The compounds of the present invention exhibited excellent tumor inhibitory effects in the NCI-H727 tumor model.

[0627] Experimental Example 6: In vivo pharmacodynamics study

[0628] Purpose of the experiment:

[0629] The in vivo efficacy of the compound of the present invention was studied in a subcutaneous xenograft tumor model of human pancreatic cancer PK59 cells in BALB / c nude mice.

[0630] Experimental methods and steps:

[0631] Experimental animals: Female BALB / c nude mice, 6-8 weeks old, weighing 18-22 g; Supplier: Beijing Weitonglihua Laboratory Animal Technology Co., Ltd.

[0632] (1) Cell Culture: Human pancreatic cancer PK59 cells were cultured as monolayers in Gibco RMPI1640 medium supplemented with 10% fetal bovine serum at 37°C in a 5% CO2 incubator. Cells were routinely digested and passaged twice a week using trypsin-EDTA. When cell saturation reached 80%-90% and the required number of cells was reached, the cells were harvested, counted, and plated.

[0633] (2) Tumor cell inoculation and grouping: 0.2 mL (2 × 10 6 PK59 cells (with Matrigel, volume ratio of 1:1) were subcutaneously inoculated on the right back of each mouse, and the average tumor volume reached approximately 104.4 mm 3 The animals were divided into groups and dosed starting at 8:00 pm, with 6 animals in each group.

[0634] The solvent was 5% DMSO / 10% solutol / 85% water. The control group was given the solvent by gavage once a day at a dose of 10 μL / g. The treatment group was given the test compound by gavage once a day after dissolving it in the solvent. The doses are shown in Table 5.

[0635] (3) The tumor diameter was measured with a vernier caliper twice a week and the 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 antitumor efficacy of the test compound was evaluated using the tumor growth inhibition rate (TGI). The calculation formula is: TGI (%) = [1 – (average tumor volume of a treatment group at the end of dosing – average tumor volume of that treatment group at the start of dosing) / (average tumor volume of the solvent control group at the end of treatment – ​​average tumor volume of the solvent control group at the start of treatment)] × 100%.

[0636] Experimental results:

[0637] The body weight of mice in each treatment group was maintained well after administration. The TGI was calculated based on the average tumor volume on day 22 after administration. The specific experimental results are shown in Table 6.

[0638] Table 6 Antitumor efficacy experimental results of the compounds of the present invention in the human pancreatic cancer PK59 model

[0639] Conclusion: The compounds of the present invention exhibited excellent tumor inhibitory effects in the PK59 tumor model.

[0640] Experimental Example 7: In vitro determination of the concentration ratio between whole blood and plasma

[0641] Experimental steps:

[0642] (1) Collect fresh whole blood from mice and humans using a blood collection tube containing EDTAK2 anticoagulant (n ≥ 3 for animals and n ≥ 2 for humans). Whole blood samples should be mixed well before use and stored at 2-8°C or on wet ice. Use within 36 hours of whole blood collection. Centrifuge blank whole blood at 2000 × g for 15 minutes at room temperature to obtain blank plasma. Check the plasma status; do not use plasma samples that show hemolysis.

[0643] (2) The whole blood sample is placed in a microhematocrit centrifuge tube and centrifuged to determine the hematocrit (the volume percentage of red blood cells in the whole blood).

[0644] (3) Diclofenac (all species), chlorthalidone (mice), or chloroquine (human) was used as a control compound.

[0645] (4) Add a 2% DMSO solution of the test compound to a final concentration of 1 μM in ACN to a blank whole blood sample, and perform three replicates. The final organic phase content in the system should not exceed 0.5% (DMSO content should not exceed 0.1%). Pipette a certain volume of drug-containing whole blood sample into a sample receiving plate (three replicates), add an equal volume of blank plasma, and mix well to obtain a T0 sample.

[0646] (5) The whole blood sample containing the test compound was incubated at 37°C with shaking for 60 minutes.

[0647] (6) After the incubation, a certain volume of drug-containing whole blood sample was transferred to the sample receiving plate (three parallel plates) as T 60 -Whole blood sample.

[0648] (7) Place the remaining whole blood sample in a 37°C centrifuge at 2000×g for 15 minutes to obtain a plasma sample. Transfer a certain volume of plasma to a sample receiving plate (three parallel plates) as T 60 - Plasma samples.

[0649] (8) During sample processing, all samples were balanced with the matrix (i.e., the same volume of blank whole blood or blank plasma was added) and mixed evenly.

[0650] (9) Add 1 volume of pure water to the balanced sample, and then add a certain volume of stop solution containing the internal standard compound to terminate the reaction.

[0651] (10) The analyte and reference compound in the sample were determined by liquid chromatography-tandem mass spectrometry (LC-MS / MS). The concentration in the sample was expressed as the ratio of the analyte peak area to the internal standard peak area.

[0652] Experimental results:

[0653] The experimental results are shown in Table 7. Among them, K B / P represents the concentration ratio of the compound in whole blood and plasma, K E / P The concentration ratio of the compound in erythrocytes and plasma is shown, and the recovery rate (%) shows the recovery rate of the compound in whole blood.

[0654] Table 7 Distribution results of the compounds of the present invention in whole blood and plasma

[0655] Conclusion: Compared with human and mouse plasma, the compounds of the present invention have a higher distribution in whole blood and erythrocytes.

[0656] Experimental Example 8: Pharmacokinetic Test in Mice

[0657] Purpose of the experiment:

[0658] The pharmacokinetic behavior of the compounds of the present invention was evaluated in male CD-1 (ICR) mice.

[0659] Experimental methods:

[0660] The test compound was dissolved in vehicle (5% DMSO / 10% solutol / 85% water). Four male CD-1 mice were divided into two groups of two mice each. Group 1 mice received a single intravenous bolus of the compound at a dose of 1 mg / kg. Group 2 mice received a single oral gavage of the compound at a dose of 10 mg / kg. Whole blood samples were collected at 0.083 (IV bolus group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose. The concentration of the test compound in the whole blood samples was determined by LC-MS / MS.

[0661] Experimental results:

[0662] In the experiment, all animals were well tolerated and no abnormal symptoms were observed. After intravenous injection of compound 7A, the blood clearance (Cl) was 6.29 mL / min / kg, the steady-state apparent distribution volume (Vd) was 2.18 L / kg, and the elimination half-life (T 1 / 2 ) is 4.29h, and the area under the whole blood concentration-time curve (AUC 0-last ) value was 3160h·nmol / mL. After oral administration of compound 7A, the peak time (T max ) appeared 3.0h after administration and reached the peak concentration (C max ) is 2000nmol / mL, AUC 0-last The bioavailability (F) was 17119 h·nmol / mL and 54.3%.

[0663] Conclusion: The compounds of the present invention have high exposure, long half-life and good pharmacokinetic properties.

[0664] Experimental Example 9: Pharmacokinetic Study in Rats

[0665] Purpose of the experiment:

[0666] The pharmacokinetic behavior of the compounds of the present invention was evaluated in male SD rats.

[0667] Experimental methods:

[0668] The test compound was dissolved in a solvent (5% DMSO / 10% solutol / 85% water). Four male Sprague-Dawley rats were divided into two groups of two. Group 1 rats received a single intravenous (iv) bolus of the compound at a dose of 1 mg / kg. Group 2 rats received a single oral (po) bolus of the compound at a dose of 10 mg / kg. Whole blood samples were collected at 0.083 (iv bolus group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentration of the test compound in the whole blood samples was determined by LC-MS / MS.

[0669] Experimental results:

[0670] All animals tolerated the test well and showed no abnormalities. Specific experimental results are shown in Table 8.

[0671] Table 8 Pharmacokinetic test results of the compounds of the present invention in rats

[0672] Conclusion: The compounds of the present invention have high exposure, long half-life and good pharmacokinetic properties.

[0673] Experimental Example 10: Pharmacokinetic Study in Beagle Dogs

[0674] Purpose of the experiment:

[0675] The pharmacokinetic behavior of the compounds of the present invention was evaluated in male beagle dogs.

[0676] Experimental methods:

[0677] The test compound was dissolved in a vehicle (5% DMSO / 10% solutol / 85% water). Four male beagle dogs were divided into two groups of two. Group 1 animals received a single intravenous (iv) bolus of the compound at a dose of 1 mg / kg. Group 2 animals received a single oral (po) bolus of the compound at a dose of 5 mg / kg. Whole blood samples were collected at 0.083 (iv bolus group only), 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration. The concentration of the test compound in the whole blood samples was determined by LC-MS / MS.

[0678] Experimental results:

[0679] During the experiment, all animals tolerated the compound well and showed no abnormal symptoms. Specific experimental results are shown in Table 9.

[0680] Table 9 Pharmacokinetic test results of the compounds of the present invention in beagle dogs

[0681] Conclusion: The compounds of the present invention have high exposure, long half-life and good pharmacokinetic properties.

Claims

1. A compound represented by formula (VI), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, L is R6 or L1 is selected from -N(R9)C(=O)-; L2 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 R a replace; L3 is selected from -CH2- and C 3-6 Cycloalkyl; L4 is selected from a single bond and -C 1-4 Alkyl-N(R 10 )C(=O)-; Ring A is selected from tetrahydropyridazinyl, 3,4-diazabicyclo[4.1.0]heptyl, 2,3-diazabicyclo[3.1.0]hexanyl, 5,6-diazaspiro[2.5]octanyl, 3,4-diazabicyclo[4.2.0]octanyl and 2,3-diazabicyclo[3.1.1]heptanyl; Ring B is selected from 5-membered heteroaryl, 5-membered heteroaryl, indolyl and T1, T2, T3 and T2 are each independently selected from CH and N; R1 is selected from H, F, Cl, Br, I, OH, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R h replace; R2 is selected from -O- and -NH-; R3 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R b replace; R4 and R5 are independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R c replace; R6 is selected from C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl, the C 3-6 Cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R d replace; Each R7 is independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, the C 1-4 Alkyl and C 1-4 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R e replace; Each R8 is independently selected from H, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl, the C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 3-10 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R f replace; R9, R 10 Selected from H and C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R g replace; Each R a , each R b , each R c , each R e , each R f , each R g and each R h are independently selected from H, D, F, Cl, Br, I, OH, C 1-3 Alkyl and C 1-3 Alkoxy, the C 1-3 Alkyl and C 1-3 The alkoxy groups are each independently optionally substituted with 1, 2 or 3 R; Each R d are independently selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 Alkenyl, the C 1-4 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C(=O)-C 2-4 The alkenyl groups are each independently optionally substituted with 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 independently selected from 0, 1, 2 and 3; The “3-6 membered heterocycloalkyl”, “3-10 membered heterocycloalkyl” and “5-6 membered heteroaryl” each independently contain 1 or 2 heteroatoms or heteroatom groups independently selected from —NH—, —O—, —S— and N.

2. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R d are independently selected from CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and The CH3, CH2CH3, phenyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl and are each independently optionally substituted with 1, 2 or 3 R; or, each R d are independently selected from CH3 and CH2CH3, wherein CH3 and CH2CH3 are independently optionally substituted with 1, 2 or 3 F; or, each R d are independently selected from CH3, Alternatively, each R d are independently selected from CH3.

3. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R1 is independently selected from H, F, OH and CH3.

4. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from 5. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from 3,4-diazabicyclo[4.1.0]heptyl and 2,3-diazabicyclo[3.1.1]heptyl; or, Ring A is selected from 6. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R2 is selected from -O-.

7. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R3 is selected from phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, pyrazolyl and imidazolyl, wherein the phenyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, oxazolyl, pyrazolyl and imidazolyl are independently optionally substituted by 1, 2 or 3 R b Substituted; or, R3 is selected from Alternatively, R3 is selected from 8. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R6 is selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R d Substituted; or, R6 is selected from cyclopropyl, the cyclopropyl optionally substituted by 1, 2 or 3 R d Substituted; or, R6 is selected from 9. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R7 is independently selected from H, F, Cl and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R e or, R7 is selected from H, F, Cl, CH3 and CH2CH3, wherein CH3 and CH2CH3 are independently optionally replaced by 1, 2 or 3 R e substituted; or, R7 is selected from H, F, Cl, CH3, CH2CH3, CH2F, CHF2, CF3, CH2CF3 and CD3.

10. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: R8 is selected from H, CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, piperidinyl, homopiperidinyl, morpholinyl, The CH3, CH2CH3, piperazinyl, homopiperazinyl, piperidinyl, piperidinyl, homopiperidinyl, morpholinyl, Each independently optionally replaced by 1, 2 or 3 R f Substituted; or, R8 is selected from H, 11. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Structural unit Selected from Alternatively, the structural unit Selected from Alternatively, the structural unit Selected from 12. The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or, L3 is selected from -CH2-, 13. The compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from: in, Structural unit Selected from Structural unit Selected from R6 is selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R d replace; Each R d are independently selected from C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with 1, 2 or 3 R groups; L3, R3, R7, each R8 and each R are as defined in any one of claims 1 to 12.

14. The compound of formula (VI-1) according to claim 13, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from, in, T1 and T3 are independently selected from CH and N; Each R1 is independently selected from H, F, OH and CH3; R3 is selected from phenyl and 5-6 membered heteroaryl, wherein the phenyl and 5-6 membered heteroaryl are independently optionally substituted by 1, 2 or 3 R b replace; R6 is selected from C 3-6 Cycloalkyl, the C 3-6 The cycloalkyl group is optionally substituted with 1, 2 or 3 R d replace; R7 is selected from H and C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R e replace; Each R8 is independently selected from H, C 1-3 Alkyl and 5-10 membered heterocycloalkyl, the C 1-3 The alkyl and 5-10 membered heterocycloalkyl groups are each independently optionally substituted with 1, 2 or 3 R f replace; L3 is selected from -CH2-, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; Each R d are independently selected from C 1-3 Alkyl, the C 1-3 The alkyl group is optionally substituted with 1, 2 or 3 R groups; Each R b Each independently selected from H, D, F, Cl, OH and CH3; Each R e are independently selected from H, D, F and Cl; Each R f Each 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.

15. The compound according to claim 14, its stereoisomer or pharmaceutically acceptable salt thereof, wherein: R3 is a 5-6 membered heteroaryl group.

16. The compound according to claim 14, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein: Each R8 is independently selected from H, C 1-3 Alkyl and 5-6 membered heterocycloalkyl, the C 1-3 Alkyl and 5-6 membered heterocycloalkyl are each independently optionally substituted by 1, 2 or 3 R f replace.

17. The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:

18. The compound according to claim 17 or a pharmaceutically acceptable salt thereof, which is selected from:

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