Indole derivative as ras inhibitor and use thereof

Abstract

A compound of formula (I) as an RAS inhibitor or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and a use thereof in the prevention or treatment of diseases mediated by RAS.

Description

Indole derivatives as ras inhibitors and uses thereof

[0001] Cross-reference to Related Applications

[0002] This application claims priority to and the benefit of the following patent applications for invention, the contents of which are hereby incorporated by reference in their entirety:

[0003] Chinese Patent Application No. 202410528786.8, filed April 29, 2024, with the

[0004] Chinese Patent Application No. 202510103215.4, filed January 22, 2025, with the

[0005] Chinese Patent Application No. 202510250686.8, filed March 04, 2025, with the TECHNICAL FIELD

[0006] The present disclosure belongs to the technical field of medicine, and specifically relates to macrocyclic compounds containing an indole ring or stereoisomers thereof or pharmaceutically acceptable salts thereof as RAS inhibitors, pharmaceutical compositions containing the same, and uses thereof as RAS inhibitors in the prevention or treatment of diseases related to RAS. BACKGROUND

[0007] The KRAS gene (Kirsten Rat Sarcoma Viral Oncogene Homolog) belongs to the RAS family of genes (RAS is the first human oncogene discovered, among the RAS family of genes, there are also NRAS (Neuroblastoma-RAS) and HRAS (Harvey-RAS)), located on chromosome 12, involved in intracellular signal transduction. The KRAS gene encodes a KRAS protein, a small GTPase belonging to the RAS superfamily of proteins, the KRAS protein has 188 amino acids, and the molecular weight is 21.6 kD. KRAS is in an activated state when bound to GTP, and in a closed state when bound to GDP. KRAS protein is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) to be in an activated and inactivated state. The activated KRAS protein mainly activates downstream signaling pathways such as the PI3K-AKT-mTOR signaling pathway that controls cell generation, and the RAS-RAF-MEK-ERK signaling pathway that controls cell proliferation. Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the activity of the protein. For example, cholesterol-lowering drugs called statins bind to the enzyme active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. In fact, the knowledge of many such drug / target pairs can mislead one into believing that small molecule modulators can be found for most, if not all, proteins, and thus provide a reasonable amount of time, effort, and resources. This is not the case, and currently, it is estimated that only about 10% of all human proteins are available as small molecule targets. The remaining 90% are currently considered to be small molecule drug discovery intractable or difficult to deal with as mentioned above. Such targets are often referred to as “undruggable”. A large portion of these undruggable targets or medically important human proteins have not yet been studied with a compound library. Therefore, there is a great interest in finding novel molecules that can modulate the function of such undruggable targets. Given the importance of the RAS signaling pathway in tumor therapy, targeted therapy against the RAS signaling pathway has become a research hotspot in the field of tumor therapy in recent years. SUMMARY

[0008] The present disclosure relates to a compound of Formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0009] wherein,

[0010] X 1 is selected from CHR 11 and NR 12 ;

[0011] X 2 is selected from CH2and NH;

[0012] L is selected from NH, NR 13 or CR 14 R 15 ;

[0013] A is selected from C3-C 12 cycloalkylene, 4-10 membered heterocyclyl ene, C6-C 10 arylene and 5-12 membered heteroarylene, said C3-C 12 cycloalkylene, 4-10 membered heterocyclyl ene, C6-C 10 arylene and 5-12 membered heteroarylene is optionally substituted with 1 or more R a ;

[0014] R 1 is selected from C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl, said C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-12 membered heteroaryl is optionally substituted with 1 or more R 1a ;

[0015] R 2 , R 3 , R 7 , R 8 and R 9 are independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 alkyl, C1-C 10 alkoxy, C1-C 10 haloalkyl and C3-C7cycloalkyl;

[0016] or, R 7 and R 8 , and the atoms to which they are attached, together form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring is optionally substituted with 1 or more R b ;

[0017] R 4 is selected from hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl, said hydroxyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 alkyl is optionally substituted with 1 or more R 4a ;

[0018] R 5 selected from C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R 5a ;

[0019] or, R 4 and R 5 , together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring is optionally substituted with 1 or more R c ;

[0020] or, R 4 and R 7 , together with the atom to which they are attached, form a 4-10 membered heterocyclic ring, said 4-10 membered heterocyclic ring is optionally substituted with 1 or more R d ;

[0021] R 6 , R 10 , R 11 and R 12 are independently selected from hydrogen, halogen, amino, hydroxyl, thiol, cyano, C1-C4alkyl, C1-C4haloalkyl and C1-C4alkoxy;

[0022] or, R 10 , together with the C to which they are attached, R 11 , together with the C to which they are attached, and the CH2between the two Cs, form a C4-C 12 saturated carbocyclic ring or 4-10 membered heterocyclic ring;

[0023] or, R 10 , together with the C to which they are attached, and R 12 , together with the N to which they are attached, and the CH2between the C and N, form a 4-10 membered heterocyclic ring;

[0024] R 13 , R 14 and R 15 are independently selected from absent, hydrogen, C1-C4alkyl, C1-C4haloalkyl and C1-C4alkoxy;

[0025] or, R 1 and R 13 , together with the atom to which they are attached, or R 1 and R 14and the atoms connecting them form a 4-10 membered heterocyclic ring or a 5-10 membered heteroaryl ring, which is optionally substituted with 1 or more R 1a substituted;

[0026] each R a is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, and C1-C4alkyl;

[0027] each R 1a is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, which amino, hydroxyl, thiol, C2-C 10 alkenyl, C2-C 10 alkynyl, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with R e substituted;

[0028] each R 4a , R b , and R d are independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7haloalkyl, C3-C6cycloalkyl, and C1-C7alkoxy;

[0029] each R 5a is independently selected from the group consisting of halogen, cyano, amino, hydroxyl, thiol, oxo, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4-15 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl, which amino, hydroxyl, thiol, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4-15 membered heterocyclyl, C6-C 10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1 or more R f substituted;

[0030] each R c is independently selected from the group consisting of hydroxyl, C1-C10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said hydroxy, C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with 1 or more R e substituents;

[0031] each R e is independently selected from the group consisting of halogen, cyano, amino, hydroxy, thiol, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with 1 or more R g substituents;

[0032] each R g is independently selected from the group consisting of halogen, amino, hydroxy, thiol, cyano, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, 4-10 membered heterocyclyl optionally substituted with halogen, amino, hydroxy, thiol, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxy and C3-C 10 cycloalkyl;

[0033] each R f is independently selected from the group consisting of halogen, amino, hydroxy, thiol, cyano, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 cycloalkyl and 4-12 membered heterocyclyl, said amino, hydroxy, thiol, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 cycloalkyl, 4-12 membered heterocyclyl optionally substituted with 1 or more R h substituents;

[0034] each R h is independently selected from the group consisting of halogen, hydroxy, thiol, amino, =O, =CR j R j, C1-C4alkyl, cyano, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl, C(O)R k , S(O)2R k and C1-C4alkoxy, said hydroxyl, thiol, amino, C1-C4alkyl, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, (C1-C4alkylene)OC1-C4alkyl and C1-C4alkoxy being optionally substituted with halogen, hydroxyl, cyano and C1-C4alkyl;

[0035] R j and R k are independently selected from H, halogen, hydroxyl, thiol, cyano, amino, C1-C4alkyl, C2-C 10 enyl, C2-C 10 alkynyl and C1-C 10 alkoxy, said hydroxyl, thiol, amino, C1-C4alkyl, C2-C 10 enyl, C2-C 10 alkynyl and C1-C 10 alkoxy being optionally substituted with halogen, hydroxyl, thiol, amino, =O, C1-C4alkyl, C1-C4alkoxy, C1-C4hydroxyalkyl, C1-C4aminoalkyl, C1-C4haloalkyl, C3-C6cycloalkyl, 3-6 membered heterocycloalkyl, N(C1-C4alkyl)2and NH(C1-C4alkyl); and

[0036] one or more hydrogen atoms of said compound are optionally deuterium.

[0037] In some embodiments, each R f and R g is independently selected from halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7haloalkyl, C1-C7alkoxy, 4-10 membered heterocyclyl optionally substituted with halogen, amino, hydroxyl, thiol, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl and C1-C4alkoxy, and C3-C 10 cycloalkyl.

[0038] In some embodiments, each R 4a , R b and R d is independently selected from halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7haloalkyl and C1-C7alkoxy.

[0039] In some embodiments, X1 Selected from CHR 11 .

[0040] In some implementation schemes, X 1 It is CH2.

[0041] In some implementation schemes, R 10 It is hydrogen.

[0042] In some implementation schemes, X 1 Selected from CHR 11 , where R 10 and its connected C, R 11 The C4-C is formed by the C atoms connected to the C atoms and the CH2 between the two C atoms. 12 Saturated carbon rings.

[0043] In some implementation schemes, X 1 Selected from CHR 11 , where R 10 and its connected C, R 11 The C atoms connected to the two C atoms, along with the CH2 atoms between them, together form a C4-C6 saturated carbon ring.

[0044] In some implementation schemes, X 1 Selected from CHR 11 , where R 10 and its connected C, R 11 The C atoms connected to the two C atoms, along with the CH2 atoms between them, together form a C4 saturated carbon ring.

[0045] In some implementation schemes, Selected from Preferably, R 10 It is hydrogen.

[0046] In some implementation schemes, X 2 It is NH.

[0047] In some implementation schemes, X 1 CH2 and X 2 It is NH.

[0048] In some implementations, A is selected from C6-C. 10 arylene and 5-12-membered heteroarylene, the C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a replace.

[0049] In some embodiments, A is selected from 5-12-membered heteroaryl groups, wherein the 5-12-membered heteroaryl group is optionally surrounded by one or more R groups. a replace.

[0050] In some embodiments, A is selected from 5-6 membered heteroarylene, said 5-6 membered heteroarylene being optionally substituted with 1 or more R a substituents.

[0051] In some embodiments, A is selected from 5-6 membered heteroarylene, said 5-6 membered heteroarylene being optionally substituted with 1 or more R a substituents. In some embodiments, A is selected from 6 membered heteroarylene or 5 membered heteroarylene, said 6 membered heteroarylene or 5 membered heteroarylene being optionally substituted with 1 or more R a substituents. In some embodiments, A is selected from 6 membered heteroarylene having 1 N atom and 1 O atom or 5 membered heteroarylene having 1 N atom and 1 S atom, said 6 membered heteroarylene or 5 membered heteroarylene being optionally substituted with 1 R a substituent.

[0052] In some embodiments, A is selected from morpholinylene and thiazolylene, said morpholinylene and thiazolylene being optionally substituted with 1 or more R a substituents. In some embodiments, A is selected from thiazolylene, said thiazolylene being optionally substituted with 1 or more R a substituents.

[0053] In some embodiments, A is selected from said being optionally substituted with R a substituents. In some embodiments, A is selected from said being optionally substituted with R a substituents.

[0054] In some embodiments, R a is independently selected from halogen, amino, hydroxyl, thiol, and cyano.

[0055] In some embodiments, A is

[0056] In some embodiments, A is

[0057] In some embodiments, L is NH.

[0058] In some embodiments, L is selected from NR 13 .

[0059] In some embodiments, L is selected from CR 14 R 15 .

[0060] In some embodiments, R 1selected from 4-10 membered heterocyclyl and 5-12 membered heteroaryl, said 4-10 membered heterocyclyl and 5-12 membered heteroaryl optionally substituted with 1 or more R 1a substituted.

[0061] In some embodiments, R 1 selected from 6-10 membered heterocyclyl and 5-6 membered heteroaryl, said 6-10 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with 1 or more R 1a substituted.

[0062] In some embodiments, R 1 selected from 5-9 membered heterocyclyl and 5-6 membered heteroaryl, said 5-9 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with 1 or more R 1a substituted. In some embodiments, R 1 selected from 5-9 membered heterocyclyl and 5-6 membered heteroaryl, said 5-9 membered heterocyclyl and 5-6 membered heteroaryl having 1 N atom and 1 or 2 heteroatoms independently selected from N, O or S, and optionally substituted with 1 or more R 1a substituted.

[0063] In some embodiments, R 1 selected from 8-9 membered heterocyclyl and 5-6 membered heteroaryl, said 8-9 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with 1 or more R 1a substituted. In some embodiments, R 1 selected from 8-9 membered heterocyclyl and 5-6 membered heteroaryl, said 8-9 membered heterocyclyl and 5-6 membered heteroaryl having 1 N atom and 1 or 2 heteroatoms independently selected from N, O or S, and optionally substituted with 1 or more R 1a substituted.

[0064] In some embodiments, R 1 selected from 9 membered heterocyclyl and 5-6 membered heteroaryl, said 9 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with 1 or more R 1a substituted.

[0065] In some embodiments, R 1 selected from isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazolyl, said isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazolyl, optionally substituted with 1 or more R 1a substituted.

[0066] In some embodiments, R 1isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, triazinyl, triazolyl, and thiadiazolyl, the isoxazolyl, oxazolyl, imidazolyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, triazinyl, triazolyl, and thiadiazolyl, optionally substituted with 1 or more R 1a substituents.

[0067] In some embodiments, R 1 is selected from oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazolyl, the oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazolyl, optionally substituted with 1 or more R 1a substituents.

[0068] In some embodiments, R 1 is selected from isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, triazinyl, the isoxazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, triazinyl, optionally substituted with 1 or more R 1a substituents.

[0069] In some embodiments, R 1 is selected from oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, triazinyl and the oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, triazinyl and optionally substituted with 1 or more R 1a substituents.

[0070] In some embodiments, R 1 is selected from oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl and triazinyl, the oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl and triazinyl optionally substituted with 1 or more R 1a substituents.

[0071] In some embodiments, R 1 is selected from oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl and triazinyl, the oxadiazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, and triazinyl are optionally substituted with 1 or more R 1a substituted.

[0072] In some embodiments, each R 1a is independently selected from C1-C5alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, and phenyl, optionally substituted with 1 or more R 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, and C6-C 10 aryl, said C1-C 10 alkyl, C3-C 12 cycloalkyl, and C6-C 10 aryl are optionally substituted with 1 or more R e substituted.

[0073] In some embodiments, each R 1a is independently selected from C1-C5alkyl, C3-C6cycloalkyl, 4-6 membered heterocyclyl, and phenyl, optionally substituted with 1 or more R e substituted. In some embodiments, each R 1a is independently selected from C1-C4alkyl, C3-C7cycloalkyl, 4-6 membered heterocyclyl, and phenyl, optionally substituted with 1 or more R e substituted.

[0074] In some embodiments, each R 1a is independently selected from methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, said methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, optionally substituted with 1 or more R e substituted. In some embodiments, each R 1a is independently selected from methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, cyclopropyl, cyclopentyl, phenyl, and said methyl, ethyl, C3alkyl, C4alkyl, C5alkyl, cyclopropyl, cyclopentyl, phenyl, and optionally substituted with 1 or more R e substituted.

[0075] In some embodiments, each R 1a is independently selected from methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, n-butyl, said methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, optionally substituted by one or more R e substituents.

[0076] In some embodiments, each R 1a is independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, the methyl, ethyl, propyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, optionally substituted by one or more R e substituents.

[0077] In some embodiments, each R 1a is independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, the methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, optionally substituted by one or more R e substituents.

[0078] In some embodiments, each R 1a is independently selected from the group consisting of methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclopentyl, phenyl, the methyl, ethyl, isopropyl, t-butyl, cyclopropyl, cyclopentyl, phenyl, optionally substituted by one or more R e substituents.

[0079] In some embodiments, each R e is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, and C6-C10 aryl, the hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, and C6-C10 aryl being optionally substituted by one or more R 10 substituents. 10 the hydroxyl, C1-C3 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, and C6-C10 aryl being optionally substituted by one or more R g substituents.

[0080] In some embodiments, each R e is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, the hydroxyl, C1-C3 alkyl, and C6 aryl being optionally substituted by one or more R g substituents.

[0081] In some embodiments, each R e is independently selected from the group consisting of halogen, cyano, C1-C 10 alkyl, and C6-C10 aryl, the C1-C3 alkyl and C6-C10 aryl being optionally substituted by one or more R 10 substituents. 10alkyl and C6-Ci2aryl, said alkyl and C6-Ci2aryl being optionally substituted with 1 or more R 10 aryl is optionally substituted with 1 or more R g substituents.

[0082] In some embodiments, each R e is independently selected from the group consisting of halogen, cyano, and C1-C4alkyl, said C1-C4alkyl being optionally substituted with 1 or more R 10 substituents. 10 aryl is optionally substituted with 1 or more R g substituents.

[0083] In some embodiments, each R e is independently selected from the group consisting of halogen, cyano, C1-C4alkyl, and phenyl, said C1-C4alkyl and phenyl being optionally substituted with 1 or more R g substituents.

[0084] In some embodiments, each R e is independently selected from the group consisting of halogen, cyano, and C1-C4alkyl, said C1-C4alkyl being optionally substituted with 1 or more R g substituents.

[0085] In some embodiments, each R e is independently selected from the group consisting of fluorine, cyano, hydroxyl, methyl, ethyl, isopropyl, phenyl, cyclopropyl, cyclopentyl, and vinyl, said hydroxyl, methyl, ethyl, isopropyl, phenyl, cyclopropyl, cyclopentyl, and vinyl being optionally substituted with 1 or more R g substituents.

[0086] In some embodiments, each R e is independently selected from the group consisting of fluorine, cyano, hydroxyl, methyl, ethyl, isopropyl, phenyl, cyclopropyl, cyclopentyl, and vinyl, said methyl and hydroxyl being optionally substituted with 1 or more R g substituents.

[0087] In some embodiments, each R e is independently selected from the group consisting of fluorine, cyano, methyl, ethyl, isopropyl, and phenyl, said methyl, ethyl, isopropyl, and phenyl being optionally substituted with 1 or more R g substituents.

[0088] In some embodiments, each R e is independently selected from the group consisting of fluorine, cyano, methyl, ethyl, and isopropyl, said methyl, ethyl, and isopropyl being optionally substituted with 1 or more R g substituents.

[0089] In some embodiments, each R g is independently selected from the group consisting of halogen, C1-C6alkyl, and C1-C6alkoxy.

[0090] In some embodiments, each Rg is independently selected from the group consisting of halogen, C1-C3alkyl, and C1-C3alkoxy.

[0091] In some embodiments, each R g is independently selected from the group consisting of halogen and C1-C7alkoxy.

[0092] In some embodiments, each R g is independently selected from the group consisting of fluorine, methyl, and methoxy.

[0093] In some embodiments, each R g is independently selected from the group consisting of fluorine and methoxy.

[0094] In some embodiments, each R e is independently selected from the group consisting of fluorine, cyano, methyl, ethyl, isopropyl, -CF3, -CH2-O-CH3, phenyl, -O-CH3, cyclopropyl, cyclopentyl, and ethenyl.

[0095] In some embodiments, R 1 is selected from the group consisting of

[0096] In some embodiments, L is NR 13 , R 1 and R 13 and the atoms to which they are attached collectively form a 5-6 membered heteroaromatic ring, which is optionally substituted with 1 or more R 1a .

[0097] In some embodiments, L is NR 13 , R 1 and R 13 and the atoms to which they are attached collectively form a triazole ring, which is optionally substituted with 1 or more R 1a .

[0098] In some embodiments, L is CR 14 R 15 , R 1 and R 14 and the atoms to which they are attached collectively form a 5-6 membered heteroaromatic ring, which is optionally substituted with 1 or more R 1a , R 15 is absent.

[0099] In some embodiments, L is CR 14 R 15 , R 1 and R 14 and the atoms to which they are attached collectively form a triazole ring, which is optionally substituted with 1 or more R 1aReplace, R 15 It does not exist.

[0100] In some implementations, L is NR 13 R 1 and R 13 Together with the atoms they are connected to, they form a 6-10 membered heterocycle, which optionally contains N, -C(=O)-, or -C(=O)NH- as heteroatoms or heterogroups, and is optionally bounded by one or more R atoms. 1a Replaced or by 1 R 1a Replace, where R 1a The heteroatoms are independently selected from C1-C6 alkyl groups, such as isopropyl. In some embodiments, the -NH- in the heteroatomic group "-C(=O)NH-" can serve as a linking site with the rest of the molecule.

[0101] In some implementations, L is NR 13 R 1 and R 13 Together with the atoms they connect, they form Optional by one or more R 1a replace.

[0102] In some implementations, L is NR 13 R 1 and R 13 Together with the atoms they connect, they form

[0103] In some implementations, L is CR 14 R 15 R 1 and R 14 Together with the atoms they connect, they form The Optional by one or more R 1a Replace, R 15 It does not exist.

[0104] In some implementations, L is CR 14 R 15 R 1 and R 14 Together with the atoms they connect, they form

[0105] In some implementation schemes, R 2 R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 alkyl.

[0106] In some embodiments, R 2 , R 3 is independently selected from C1-C4alkyl, such as methyl.

[0107] In some embodiments, R 2 , R 3 are each methyl.

[0108] In some embodiments, R 4 is selected from hydrogen, halogen, hydroxyl, cyano, and C1-C 10 alkyl, said hydroxyl, C1-C 10 alkyl optionally substituted with 1 or more R 4a , R 5 is selected from C6-C 10 aryl and 5-10 membered heteroaryl, said C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with 1 or more R 5a , or, R 4 and R 5 together with their attached atoms form a 4-6 membered heterocycle, said 4-6 membered heterocycle optionally substituted with 1 or more R c .

[0109] In some embodiments, R 4 is selected from C1-C 10 alkyl, said C1-C 10 alkyl optionally substituted with 1 or more R 4a .

[0110] In some embodiments, R 4 is selected from C1-C4alkyl, said C1-C4alkyl optionally substituted with 1 or more R 4a .

[0111] In some embodiments, R 4 is selected from methyl and ethyl, said methyl and ethyl optionally substituted with 1 or more R 4a .

[0112] In some embodiments, R 4 is ethyl, said ethyl optionally substituted with 1 or more R 4a .

[0113] In some embodiments, R 4a is independently selected from cyclopropyl, halogen, amino, hydroxyl, thiol, and cyano, or, R 4a is independently selected from halogen, amino, hydroxyl, thiol, and cyano.

[0114] In some embodiments, R 4a is independently selected from cyclopropyl and halogen, or, R4a It is independently selected from halogens.

[0115] In some implementation schemes, R 4a It is fluorine. In some implementations, R 4 Selected from ethyl, methyl substituted with one cyclopropyl group, or ethyl substituted with one or more halogens. In some embodiments, R 4 It is an ethyl group, a methyl group substituted with one cyclopropyl group, or an ethyl group substituted with one or more fluorine groups. In some embodiments, R 4 It can be ethyl, -CH2-cyclopropyl, or -CH2-CF3.

[0116] In some implementation schemes, R 4 and R 7 The atoms connected to it together form a 6-7 membered heterocycle, which is optionally bounded by one or more R atoms. d Replacement. In some implementations, R 4 and R 7 Together with the atoms they are attached to, they form a 6-7 membered heterocyclic alkyl group. In some embodiments, R 4 and R 7 Together with the atoms they are connected to, they form a 6-7 membered heterocyclic alkyl group having one N atom and optionally one O atom.

[0117] In some implementation schemes, R 5 Selected from 4-10 membered heterocyclic groups, C6-C 10 Aryl and 5-10 membered heteroaryl, the 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. 5a replace.

[0118] In some implementation schemes, R 5 Selected from C6-C 10 Aryl and 5-10 heteroaryl, the C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. 5a replace.

[0119] In some implementation schemes, R 5 Selected from 4-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 4-10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally surrounded by one or more R groups. 5a replace.

[0120] In some implementation schemes, R 5 Selected from 9-10-membered heterocyclic groups and 5-10-membered heteroaryl groups, wherein the 9-10-membered heterocyclic group and the 5-10-membered heteroaryl group are optionally surrounded by one or more R groups. 5a Replacement. In some implementations, R5 selected from 9-10 membered heterocyclyl and 6-10 membered heteroaryl, said 9-10 membered heterocyclyl and 6-10 membered heteroaryl optionally substituted with 1 or more R 5a substituents.

[0121] In some embodiments, R 5 selected from 5-10 membered heteroaryl, said 5-10 membered heteroaryl optionally substituted with 1 or more R 5a substituents.

[0122] In some embodiments, R 5 selected from 5-6 membered heteroaryl, said 5-6 membered heteroaryl optionally substituted with 1 or more R 5a substituents.

[0123] In some embodiments, R 5 selected from pyridyl, said pyridyl optionally substituted with 1 or more R 5a substituents.

[0124] In some embodiments, R 5 selected from said optionally substituted with 1 or more R 5a substituents. In some embodiments, R 5 the position ortho to the site at which the remainder of the molecule is attached is substituted with -CH(CH3)-O-CH3 or -(S)-CH(CH3)-O-CH3. In some embodiments, R 5 selected from pyridyl, the position ortho to the site at which the remainder of the molecule is attached is substituted with -CH(CH3)-O-CH3 or -(S)-CH(CH3)-O-CH3.

[0125] In some embodiments, R 5 selected from said optionally substituted with 1 or more R 5a substituents.

[0126] In some embodiments, R 5 is said optionally substituted with 1 or more R 5a substituents. In some embodiments, R 5 is

[0127] In some embodiments, each R 5a is independently selected from halogen, cyano, amino, hydroxyl, thiol, oxo, C1-C 10 alkyl, C2-C 10alkyl, C2-C 10 alkenyl, C2-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said amino, hydroxy, mercapto, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with 1 or more R f substituents.

[0128] In some embodiments, each R 5a is independently selected from halogen, cyano, amino, hydroxy, mercapto, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said amino, hydroxy, mercapto, C1-C 10 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl optionally substituted with 1 or more R f substituents.

[0129] In some embodiments, R 5a is independently selected from halogen, cyano, oxo, C1-C 10 alkyl, C2-C 10 alkynyl and 4-10 membered heterocyclyl, said C1-C 10 alkyl, C2-C 10 alkynyl and 4-10 membered heterocyclyl optionally substituted with 1 or more R f substituents.

[0130] In some embodiments, R 5a is independently selected from halogen, cyano, C1-C 10 alkyl, C2-C 10 alkynyl and 4-10 membered heterocyclyl, said C1-C 10 alkyl, C2-C 10 alkynyl and 4-10 membered heterocyclyl optionally substituted with 1 or more R f substituents.

[0131] In some embodiments, R 5aindependently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 10 independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 10 independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 10 independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 10 independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R f substituted.

[0132] independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 5a independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R f substituted.

[0133] independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 5a independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R f substituted.

[0134] independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 5a independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R f substituted.

[0135] independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 5a independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R f substituted.

[0136] independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 5a independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R f substituted.

[0137] independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R 5a independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R independently selected from C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl, said C1-C4alkyl, C2-C4alkynyl, and 4-7 membered heterocyclyl being optionally substituted with 1 or more R and ethyl, said propynyl, piperazinyl, f substituted.

[0138] In some embodiments, R 5a is independently selected from propynyl, piperazinyl, and ethyl, said propynyl, piperazinyl, and ethyl, said propynyl, piperazinyl, f substituted.

[0139] In some embodiments, R 5a is independently selected from fluorine, cyano, oxo, methyl, and ethyl, said methyl, and ethyl, said methyl, f substituted.

[0140] In some embodiments, R 5a is independently selected from fluorine, cyano, and ethyl, said and ethyl, said methyl, f substituted.

[0141] In some embodiments, R 5a is independently selected from and ethyl, said and ethyl, said methyl, f substituted.

[0142] In some embodiments, each R f is independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-12 membered heterocyclyl, said C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and 4-12 membered heterocyclyl optionally substituted with 1 or more R h ; optionally, said 4-12 membered heterocyclyl contains 1, 2, or 3 heteroatoms or heteroatom groups selected from N, O, S, -S(=O)2-, -P(=O)-, -PH(=O)-, -S(=O)(=NH)-, -C(=O)-, or -C(=O)NH-;

[0143] each R h is independently selected from halogen, hydroxyl, =O, =CR j R j , C1-C4 alkyl, cyano, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 haloalkyl, C(O)R k , S(O)2R kand C1-C4alkoxy, said hydroxyl, C1-C4alkyl, C3-C6cycloalkyl, 3-6 membered

[0144] R j is independently selected from the group consisting of H, halogen, and R k is independently selected from the group consisting of H, halogen, or C1-C4alkyl optionally substituted with hydroxyl, C1-C4alkoxy, 3-6 membered

[0145] In some embodiments, R f is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C5cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with C1-C4hydroxyalkyl, cyano, C1-C4alkyl, C1-C4haloalkyl, and halogen.

[0146] In some embodiments, R f is independently selected from the group consisting of C1-C7alkyl, C1-C7alkoxy, C3-C 10 cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with C1-C4hydroxyalkyl.

[0147] In some embodiments, R f is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C5cycloalkyl, and 5-7 membered heterocyclyl optionally substituted with hydroxymethyl.

[0148] In some embodiments, R f is independently selected from the group consisting of C1-C4alkyl, C1-C4alkoxy, C3-C5cycloalkyl, and 5-6 membered heterocyclyl optionally substituted with hydroxymethyl.

[0149] In some embodiments, R 5a is independently selected from the group consisting of fluorine, cyano, oxo, methyl, ethynyl, ethyl, or R 5a is ethynyl or or R 5a is or, when R 5 is , R 5a is independently selected from the group consisting of ethynyl, wherein said methyl, ethynyl, ethyl, each optionally substituted with 1 or more R f , R findependently selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and C1-C4alkyl. -CH3,

[0150] In some embodiments, R f is independently selected from the group consisting of methyl, methoxy, cyclopropyl, morpholinyl, oxetanyl,

[0151] In some embodiments, R f is independently selected from the group consisting of methyl, methoxy, cyclopropyl, morpholinyl, and

[0152] In some embodiments, R 5 is selected from the group consisting of

[0153] In some embodiments, R 5 is selected from the group consisting of

[0154] In some embodiments, R 5 is selected from the group consisting of

[0155] In some embodiments, R 5 is selected from the group consisting of

[0156] In some embodiments, R 6 is selected from the group consisting of hydrogen, halogen, amino, hydroxyl, thiol, cyano, and C1-C4alkyl.

[0157] In some embodiments, R 6 is hydrogen.

[0158] In some embodiments, R 7 is selected from the group consisting of hydrogen, halogen, hydroxyl, and cyano.

[0159] In some embodiments, R 7 is hydrogen.

[0160] In some embodiments, R 8 is selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, and C1-C 10 alkyl.

[0161] In some embodiments, R 8 is hydrogen.

[0162] In some embodiments, R 9It is selected from hydrogen, halogen, hydroxyl and cyano groups.

[0163] In some implementation schemes, R 9 Selected from hydrogen and halogens.

[0164] In some implementation schemes, R 9 Selected from hydrogen and fluorine.

[0165] In some implementation schemes, each R f and R g Independently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl, C1-C7 alkoxy, 4-10 membered heterocyclic groups optionally substituted with halogen, amino, hydroxy, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxy, and C3-C... 10 Cycloalkyl.

[0166] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (II) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0167] Among them, X 2 A, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 As defined by compound (I).

[0168] In some embodiments of the compound of formula (II), X 2 For NH; A is an imidazolyl group; R 1 It is a 5-membered heteroaryl group containing at least one nitrogen atom, or R 1 The 5-membered heteroaryl, oxadiazolyl, or thiadiazolyl group is formed by one R group. 1a Replace; R 1a For being 2 R e Replacement R e It is fluorine; R 2 and R 3 All are methyl; R 4 It is ethyl; R 5 for and R 6R 7 R 8 and R 9 Both are hydrogen.

[0169] In some embodiments of the compound of formula (II), X 2 For NH; A is R 1 The radical is oxadiazole or thiadiazole, wherein the oxadiazole or thiadiazole group is formed by an R group. 1a Replace; R 1a for R 2 and R 3 All are methyl; R 4 It is ethyl; R 5 for and R 6 R 7 R 8 and R 9 Both are hydrogen.

[0170] In some embodiments, the compound of formula (I) or its stereoisomer or a pharmaceutically acceptable salt thereof is selected from the compound of formula (III) or its stereoisomer or a pharmaceutically acceptable salt thereof.

[0171] Among them, X 2 A, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 As defined by compound (I).

[0172] In some embodiments of the compound of formula (III), X 2 For NH; A is an imidazolyl group; R 1 It is a 5-membered heteroaryl group containing at least one nitrogen atom, or R 1 The 5-membered heteroaryl, oxadiazolyl, or thiadiazolyl group is formed by one R group. 1a Replace; R 1a Selected from each of the 1 or 2 Rs. e Substituted methyl, C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl; R e It is independently fluorine, methyl, ethyl, or cyclopropyl; R 2 and R 3 All are methyl; R 4 It is ethyl; R 5 for R 5a Selected from each of 1 R f Substituted piperazine and propynyl groups; R f Selected from methyl, oxetyl, and R 6 R 7 R 8 and R 9 Both are hydrogen.

[0173] In some embodiments of the compound of formula (III), X 2 For NH; A is an imidazolyl group; R 1 It is a 5-membered heteroaryl group containing at least one nitrogen atom, or R 1 The 5-membered heteroaryl, oxadiazolyl, or thiadiazolyl group is formed by one R group. 1a Replace; R 1a Selected from each of the 1 or 2 Rs. e Substituted methyl, C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl; R e It is independently fluorine, methyl, ethyl, or cyclopropyl; R 2 and R 3 All are methyl; R 4 It is ethyl; R 5 for and R 6 R 7 R 8 and R 9 Both are hydrogen.

[0174] In some embodiments of the compound of formula (III), X 2 For NH; A is R 1 The radical is oxadiazole or thiadiazole, wherein the oxadiazole or thiadiazole group is formed by an R group. 1a Replace; R 1a Selected from methyl, C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, or cyclopentyl groups, each optionally substituted with two cyclopropyl groups, one fluorine group, two methyl groups, or two fluorine groups; R 2 and R 3 All are methyl; R 4 It is ethyl; R 5 for and R 6 R 7 R 8 and R 9 Both are hydrogen.

[0175] In some embodiments of the compound of formula (III), X2 NH; A is R 1 oxadiazolyl or thiadiazolyl substituted with 1 R 1a substituted; R 1a is selected from methyl, n-propyl, isopropyl, cyclopropyl or cyclopentyl; R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0176] In some embodiments of the compound of formula (III), X 2 NH; A is R 1 oxadiazolyl or thiadiazolyl substituted with 1 R 1a substituted; R 1a is selected from isopropyl, cyclopentyl, or cyclopropyl substituted with 2 methyl groups; R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0177] In some embodiments of the compound of formula (III), X 2 NH; A is thiazolylene; L is NR 13 , R 1 and R 13 and the atoms to which they are attached collectively form R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 and R 9 are each hydrogen.

[0178] In some embodiments of the compound of Formula (III), X 2 is NH; A is thiazolylene; L is NR 13 1 13 and the atoms to which they are attached collectively form 2 3 R 4 is ethyl; R 5 6 7 8 9

[0179] [Amended according to Rule 26 27.11.2025] In some embodiments, the compound of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, is selected from the following compounds, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,

[0180] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), Formula (II), or Formula (III) of the present disclosure, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0181] In another aspect, the present disclosure provides a method of treating a disease mediated by RAS in an individual (e.g., a mammal), comprising administering to an individual (e.g., a mammal, preferably a human) in need of such treatment a therapeutically effective amount of a compound of Formula (I), Formula (II), or Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0182] In another aspect, the present disclosure provides the use of a compound of Formula (I), Formula (II), or Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for preventing or treating a disease mediated by RAS.

[0183] In another aspect, the present disclosure provides the use of a compound of Formula (I), Formula (II), or Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the prevention or treatment of a disease mediated by RAS.

[0184] ​​​​​​​​​​In another aspect, the present disclosure provides a compound of formula (I), formula (II) or formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for preventing or treating a disease mediated by RAS.

[0185] In some embodiments, the disease mediated by RAS is a tumor.

[0186] The compound of formula (I), formula (II) or formula (III) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof of the present disclosure can selectively inhibit RAS protein, can prevent or treat a disease mediated by RAS, has a killing effect on tumor cells related to RAS protein, and can treat a tumor mediated by RAS protein mutation.

[0187] Definitions and explanations of terms

[0188] Unless otherwise indicated, the terms used in the present disclosure have the following meanings, and the definitions of groups and terms described in the present disclosure, including the definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, definitions of specific compounds in examples, etc., can be combined and integrated with each other arbitrarily. A specific term should not be considered indefinite or unclear without a specific definition, but should be understood according to the ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0189] Herein represents a connection site.

[0190] Certain compounds of the present disclosure can exist in atropisomer forms, 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 of the present disclosure include all atropisomers, either as pure individual atropisomers, or as atropisomers enriched in one, or as non-specific mixtures of each. If the potential energy for rotation about a single bond is sufficiently high, and the interconversion between conformations is sufficiently slow, then separation of isomers can be allowed. For example, (or ) and (or ) are a pair of atropisomers, in which the represents that the side stereotactic direction is outward, represents that the side stereotactic direction is inward.

[0191] The graphical representation of racemates or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the wedge solid bond and the wedge dashed bond Absolute configuration of a stereocenter, with straight bonds and dashed bonds Relative configuration of a stereocenter (e.g., cis-trans configuration of an alicyclic compound).

[0192] When one of the variables is selected from a bond or nothing, it means that the two groups to which it is attached are directly connected, such as L represents a bond in A-L-Z means that the structure is actually A-Z.

[0193] When a linking group referred to herein is not indicated as to its direction of attachment, its direction of attachment is arbitrary. For example, when L in the structural element 1 is selected from "C1-C3alkylene-O", then L 1 may either be attached to ring Q and R in the left-to-right direction to form "ring Q-C1-C3alkylene-O-R 1 ", or in the right-to-left direction to form "ring Q-O-C1-C3alkylene-R 1 ". 1 1

[0194] The compounds of the present disclosure can have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms, or asymmetric double bonds, and therefore the compounds of the present disclosure can exist in particular geometric or stereoisomeric forms. The particular geometric or stereoisomeric forms can be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, as well as racemic mixtures or other mixtures thereof, such as those that contain an excess of one enantiomer or diastereomer, and all such isomers and mixtures thereof are intended to be within the scope of the compounds of the present disclosure. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms, or asymmetric phosphorus atoms can be present in a substituent group, and all such isomers and mixtures thereof are intended to be within the scope of the compounds of the present disclosure. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically active form or as racemic mixtures, and prepared as single enantiomers, or stereoisomers, by chiral synthesis techniques or by resolution.

[0195] The term "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent group, provided that the valence of the particular atom is not exceeded, and that the substituted compound is stable. When the substituent is oxo (i.e., =0), it means that two hydrogen atoms are replaced by the oxo group. Oxos are not present on aromatic groups.

[0196] ​​​The term "optionally" or "optional" means that the subsequently described event or circumstance can or can not occur, and this description includes instances in which the event or circumstance occurs and instances in which it does not. For example, an ethyl group "optionally" substituted with one or more halogens means that the ethyl group can be unsubstituted (CH2CH3), mono-substituted (CH2CH2F, CH2CH2C1, etc.), poly-substituted (CHFCH2F, CH2CHF2, CHFCH2C1, CH2CHC12, etc.), or fully substituted (CF2CF3, CF2CC13, CC12CC13, etc.). One skilled in the art will understand that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is not spatially possible and / or synthetically feasible.

[0197] When any variable (e.g., R a , R b ) occurs more than one time in a compound; its definition in each occurrence is independent of its definition at every other occurrence. b For example, if a group is substituted with 2 R b groups, then each R m group is independently selected.

[0198] C n -C 10 herein means a carbon atom with an integer number of carbon atoms in the range of m to n. For example, "C1-C10" means that the group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms.

[0199] The term "alkyl" means a hydrocarbon group of formula C n H 2n+1 which can be straight chained or branched. The term "C1-C10" means that the alkyl group can have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, 8 carbon atoms, 9 carbon atoms, or 10 carbon atoms. 10"Alkyl" can be understood as representing a straight-chain or branched saturated hydrocarbon group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Specific examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1 2-Dimethylbutyl, etc.; the term "C1-C7 alkyl" can be understood as referring to alkyl groups having 1 to 7 carbon atoms, specific examples including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc. The term "C1-C5 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 5 carbon atoms. The term "C1-C4 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood as referring to straight-chain or branched saturated alkyl groups having 1 to 3 carbon atoms. The term "C5-C..." 10 "Alkyl" can be understood as referring to a straight-chain or branched saturated alkyl group having 5 to 10 carbon atoms. The "C1-C" 10 "alkyl" can include "C1-C6 alkyl", "C1-C4 alkyl", "C1-C3 alkyl" or "C5-C6 alkyl". 10 The term "alkyl" is used within the range of "C1-C6 alkyl," which may further include "C1-C4 alkyl" or "C1-C3 alkyl." The term "halogenated alkyl" is intended to include both monohalogenated and polyhalogenated alkyl groups. For example, the term "C1-C6 alkyl" may include "C1-C4 alkyl" or "C1-C3 alkyl." 10 "Haloalkyl" refers to a C1-C alkyl group as defined above that has been substituted with one or more halogens. 10 Alkyl groups, including but not limited to trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.

[0200] The term "alkoxy" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols, and can be understood as "alkyloxy" or "alkyl-O-", where alkyl is as defined above. The term "C1-C" refers to a group formed by the loss of a hydrogen atom from a hydroxyl group in straight-chain or branched alcohols. 10 "Alkoxy" can be understood as "C1-C" 10 "alkyloxy" or "C1-C" 10 Alkyl-O-"; the term "C1-C7 alkoxy" can be understood as "C1-C7 alkyloxy" or "C1-C7 alkyl-O-". The "C1-C"10 Alkoxy" can include "Ci-C7alkoxy" and "Ci-C3alkoxy" and the like ranges, which "Ci-C7alkoxy" can further include "Ci-C3alkoxy".

[0201] The term "alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one double bond. The term "C2-C 10 Alkenyl" can be understood to mean a straight-chain or branched unsaturated hydrocarbon group which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, the term "C6-C 10 Alkenyl" can be understood to mean a straight-chain or branched unsaturated hydrocarbon group which contains one or more double bonds and has 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 Alkenyl" can include "C2-C6alkenyl", "C2-C4alkenyl", "C6-C 10 Alkenyl", C2or C3alkenyl. It can be understood that in case the alkenyl group contains more than one double bond, the double bonds can be separated from each other or conjugated. Particular examples of the alkenyl group include, but are not limited to, ethenyl, allyl, (E)-2-methylethenyl, (Z)-2-methylethenyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl or (Z)-1-methylprop-1-enyl and the like.

[0202] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms and having at least one triple bond. The term "C2-C 10 Alkynyl" can be understood to mean a straight-chain or branched unsaturated hydrocarbon group which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. "C2-C 10 Examples of "alkynyl" include, but are not limited to, ethynyl (-C≡CH), propynyl (-C≡CCH 3、 -CH2C≡CH), but-1-ynyl, but-2-ynyl or but-3-ynyl. "C2-C 10 Alkynyl" can include "C2-C3alkynyl", examples of "C2-C3alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), prop-2-ynyl (-CH2C≡CH).

[0203] The term "cycloalkyl" refers to a fully saturated carbon ring group which exists in the form of a monocyclic, fused, bridged or spirocyclic ring or the like. Unless otherwise indicated, the carbon ring is typically a 3- to 20-membered ring. The term "C3-C 12"Cycloalkyl" refers to a cyclic alkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 ring carbon atoms. The term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3, 4, 5, or 6 ring carbon atoms. The term "cycloalkylene" refers to a residue derived from further removing one hydrogen from a cycloalkyl group.

[0204] The term "heterocyclyl" or "heterocycle" refers to a monocyclic, fused ring, spiro, or bridged ring radical which is completely saturated or partially saturated (i.e., not an aromatic heteroaromatic radical overall) having 1, 2, 3, 4, or 5 (e.g., 1, 2, or 3, or 1-2) heteroatoms or heteroatom groups (i.e., atom groups containing heteroatoms) in the ring members, including, but not limited to, nitrogen (N), oxygen (O), sulfur (S), phosphorus (P), boron (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -PH(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, -C(=O)N=, or -NHC(=O)NH-, and the like, in the ring members. The term "4-10 membered heterocyclyl" refers to a heterocyclyl radical having 4, 5, 6, 7, 8, 9, or 10 ring members, and having 1, 2, 3, 4, or 5 ring members independently selected from the heteroatoms or heteroatom groups described above. A "4-10 membered heterocyclyl" can comprise a "4-7 membered heterocyclyl". The term "4-7 membered heterocyclyl" refers to a heterocyclyl radical having 4, 5, 6, or 7 ring members, and having 1, 2, 3, 4, or 5 ring members independently selected from the heteroatoms or heteroatom groups described above. Specific examples of 4-membered heterocyclyl groups include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl, or 2,5-dihydro-lH-pyrrolyl; specific examples of 6-membered heterocyclyl groups include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl, or 4H-[l,3,4]thiadiazinyl; and specific examples of 7-membered heterocyclyl groups include, but are not limited to, diazepanyl. The heterocyclyl radical can also be a bicyclic radical, where specific examples of 5,5 membered bicyclic radicals include, but are not limited to, hexahydrocyclopenta[c]pyrrol-2(lH)-yl; specific examples of 5,6 membered bicyclic radicals include, but are not limited to, hexahydropyrrolo[l,2-a]pyrazin-2(lH)-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazinyl, or 5,6,7,8-tetrahydroimidazo[l,5-a]pyrazinyl. Optionally, the heterocyclyl radical can be a benzo-fused ring of the above 4-7 membered heterocyclyl radicals, specific examples include, but are not limited to, dihydroisoquinolinyl, and the like."4-10 membered heterocyclyl" can include the range of "5-10 membered heterocyclyl", "4-7 membered heterocyclyl", "5-6 membered heterocyclyl", "6-8 membered heterocyclyl", "4-10 membered heterocycloalkyl", "5-10 membered heterocycloalkyl", "4-7 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", "6-8 membered heterocycloalkyl", and the like. "4-7 membered heterocyclyl" can further include the range of "4-6 membered heterocyclyl", "5-6 membered heterocyclyl", "4-7 membered heterocycloalkyl", "4-6 membered heterocycloalkyl", "5-6 membered heterocycloalkyl", and the like. Although some bicyclic heterocyclyl moieties in the present disclosure contain a benzene ring or a heteroaromatic ring partially, the heterocyclyl is still non-aromatic as a whole. The term "heterocyclyl" is a residue derived from heterocyclyl by further removing one hydrogen.

[0205] The term "heterocycloalkyl" refers to a fully saturated cyclic group existing in the form of a monocyclic ring, a fused ring, a bridged ring, or a spiro ring, etc., having 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups (i.e., an atom group containing a heteroatom) in the ring atoms of the ring, the "heteroatoms or heteroatom groups" including, but not limited to, a nitrogen atom (N), an oxygen atom (O), a sulfur atom (S), a phosphorus atom (P), a boron atom (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH-, or -NHC(=O)NH-, etc. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl having 4, 5, 6, 7, 8, 9, or 10 ring atoms, and having 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups in the ring atoms. The term "5-10 membered heterocycloalkyl" refers to a heterocycloalkyl having 5, 6, 7, 8, 9, or 10 ring atoms, and having 1, 2, 3, 4, or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms or heteroatom groups in the ring atoms. "4-10 membered heterocycloalkyl" and "5-10 membered heterocycloalkyl" include "4-7 membered heterocycloalkyl", wherein specific examples of 4-membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, or thietanyl; specific examples of 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidinyl, imidazolidinyl, or tetrahydropyrazolyl; specific examples of 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1,4-thioxinanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, or 1,4-dithianyl; and specific examples of 7-membered heterocycloalkyl include, but are not limited to, azepanyl, oxepanyl, or thiepanyl.

[0206] The term "aryl" refers to a fully carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π-electron system. The aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C12 aryl" refers to an aryl group having 6, 7, 8, 9, 10, 11, 12, or 6-12 carbon atoms. The term "C6-C10 aryl" refers to an aryl group having 6, 7, 8, 9, 10, or 6-10 carbon atoms. The term "C6-C14 aryl" refers to an aryl group having 6, 7, 8, 9, 10, 11, 12, 13, 14, or 6-14 carbon atoms.10 Aryl" is understood to mean an aromatic group having 6 to 10 carbon atoms. The term "C6-C7 aryl" is understood to mean an aromatic group having 6 to 7 carbon atoms. For example a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "arylene" is a residue derived from aryl by further removal of one hydrogen. 10 Aryl" is understood to mean an aromatic group having 6 to 10 carbon atoms. The term "C6-C7 aryl" is understood to mean an aromatic group having 6 to 7 carbon atoms. For example a ring having 6 carbon atoms ("C6 aryl"), such as phenyl; or a ring having 9 carbon atoms ("C9 aryl"), such as indanyl or indenyl; or a ring having 10 carbon atoms ("C10 aryl"), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl. The term "arylene" is a residue derived from aryl by further removal of one hydrogen.

[0207] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system which is aromatic in its entirety, which contains at least one ring atom selected from N, O, S, and the remaining ring atoms are C. The term "5-12 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, for example 5 or 6 or 9 or 10 or 11 or 12 ring atoms, and which contain 1, 2, 3, 4 or 5, for example 1, 2 or 3, heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl or 1,2,5-thiadiazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or pyridazinyl and the like and their benzo derivatives, such as quinolinyl, quinazolinyl or isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like and their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl or phenoxazinyl and the like. The term "6-10 membered heteroaryl" is understood to include monocyclic or bicyclic aromatic ring systems having 6, 7, 8, 9 or 10 ring atoms, for example 6 or 9 or 10 ring atoms, and which contain 1, 2, 3, 4 or 5, for example 1, 2 or 3, heteroatoms independently selected from N, O and S. The term "5-6 membered heteroaryl" refers to an aromatic ring system having 5 or 6 ring atoms, and which contains 1, 2 or 3, for example 1-2, heteroatoms independently selected from N, O and S. The term "heteroarylene" is a residue derived from heteroaryl by further removal of one hydrogen.

[0208] The term "halo" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0209] The term "hydroxy" refers to an -OH group.

[0210] The term "cyano" refers to a -CN group.

[0211] The term "amino" refers to a -NH2 group.

[0212] The term "nitro" refers to a -NO2 group.

[0213] The term "treatment" means the administration of a compound or formulation of the disclosure to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0214] (i) inhibiting the disease or condition, i.e., arresting its development;

[0215] (ii) relieving the disease or condition, i.e., causing regression of the disease or condition.

[0216] The term "therapeutically effective amount" means an amount of a compound of the disclosure that (i) treats a particular disease, condition, or disorder, (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the disclosure that will constitute a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by the skilled practitioner as an initial consideration.

[0217] The term "prevention" means the administration of a compound or formulation of the disclosure to prevent a disease or one or more symptoms associated with the disease, and includes preventing the disease or condition from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is predisposed to the disease state but has not yet been diagnosed as having it.

[0218] The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-human mammals include, but are not limited to, birds and fish, and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "individual" are used interchangeably.

[0219] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0220] The term "pharmaceutically acceptable salt" means a salt of a compound of the present disclosure which is pharmaceutically acceptable, i.e., a salt which is suitable for use in pharmaceutical administration to a subject. Such salts include those of inorganic acids and organic acids.

[0221] The term "pharmaceutical composition" means a mixture of one or more compounds of the present disclosure or salts thereof with a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present disclosure to an organism.

[0222] The term "pharmaceutically acceptable excipient" means an excipient that is not biologically or otherwise undesirable, i.e., the excipient can be administered to an organism without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition in which it is contained. The presence of an excipient in a composition does not interfere with any of the biological activity or properties of the active compound.

[0223] The words "comprise" or "comprising" and variations thereof such as "comprises" or "comprising", when used in this document, can be understood to encompass the terms "consisting of" or "consisting of".

[0224] The present disclosure also includes isotopically-labeled compounds of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I, and 36 Cl.

[0225] Certain isotopically-labeled compounds of the present disclosure (for example, those 3 H and 14 C) can be used in compound and / or substrate tissue distribution analysis. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14C) Isotopes are particularly preferred for their ease of preparation and detectability. Positron emitting isotopes, such as 15 O, 13 N, 11 C and 18 F are useful for positron emission tomography (PET) studies to determine substrate occupancy. Isotopically-labeled compounds of the present disclosure can be prepared by substituting a readily available isotopically-labeled reagent for a non-isotopically labeled reagent in a

[0226] The pharmaceutical compositions of the present disclosure can be prepared by combining a compound of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres, aerosols and the like.

[0227] Typical routes of administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, include, but are not limited to, oral, rectal, topical, inhalant, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.

[0228] The pharmaceutical compositions of the present disclosure can be manufactured in a manner appropriate for the route of administration, using known techniques, such as conventional mixing, dissolving, granulating, emulsifying, dr ying, lyophilizing, encapsulating, entrapping or lyophilizing processes.

[0229] In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be formulated by mixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients can enable the active compound of the present disclosure to be formulated into tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions, and the like, for oral administration to a patient.

[0230] Solid oral compositions can be prepared by conventional mixing or compounding techniques. For instance, the active compound can be mixed with a solid excipient to form a stable and free-flowing homogeneous composition. The term "solid excipient" is intended to encompass a wide variety of substances used to formulate solid pharmaceutical compositions, such as binders, diluents, disintegrants, lubricants, glidants, or flavoring agents, among others.

[0231] The pharmaceutical composition can also be adapted for parenteral administration, such as sterile solutions, suspensions, or lyophilized products in suitable unit dosage forms.

[0232] The dosage administered will depend on such factors as the particular compound, the disease condition and its severity, the identity of the subject or host to be treated (e.g., body weight, sex), and the mode of administration, among others, as determined by the particular circumstances of the case, including, e.g., the specific formulation administered, the route of administration, the condition being treated, and the subject or host being treated.

[0233] In all methods of administering the compounds of general formula (I) described herein, the daily dosage ranges from 0.001 mg / kg to 5000 mg / kg, preferably from 0.01 mg / kg to 100 mg / kg, of body weight, in single or divided doses, in the case of oral administration. The daily and unit doses are varied according to many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0234] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, embodiments formed by a combination of the specific embodiments set forth below with other chemical synthetic methods well known to those skilled in the art, and equivalents thereof as appreciated by those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0235] The chemical reactions of the specific embodiments of the present disclosure are performed in solvents appropriate to the reagents and materials employed and suitable for the chemical changes being effected. In the synthetic schemes and examples described below, all substituents unless otherwise indicated, are as previously defined. Further, the skilled worker will appreciate that the application is not limited by the specific conditions (e.g., temperature, reaction time, reaction atmosphere, etc.) unless otherwise indicated. Also, where appropriate replacement reagents are used in the synthetic schemes and examples, the skilled worker will appreciate that the application is not limited by the specific reagents unless otherwise indicated.

[0236] Abbreviations:

[0237] EA stands for ethyl acetate; TMSCHN2 stands for trimethylsilyldiazomethane; DMAP stands for 4-dimethylaminopyridine; NMP stands for N-methylpyrrolidone; LDA stands for lithium diisopropylamide; DTBA stands for di-tert-butyl azodicarboxylate; DMPUN stands for N,N-dimethylpropynylurea; BPMPO stands for N1,N2-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxamide; TBDPSCl stands for tert-butyldiphenylsilyl chloride; DCM stands for dichloromethane; DMF stands for N,N-dimethylformamide; THF stands for tetrahydrofuran; MeOH stands for methanol; TsOH .H20 represents p-toluenesulfonic acid monohydrate; n-BuLi represents n-butyllithium; Boc20 represents di-tert-butyl dicarbonate; TFA: trifluoroacetic acid; DIEA or DIPEA represents N,N-diisopropylethylamine; Pd(dppf)Cl2 represents [l,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II); Pd(dtbpf)Cl2 represents 1,1'-bis(di-tert-butylphosphino) ferrocene dichloropalladium; HATU represents O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (2-(7-azobenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate); Et3N or TEA represents triethylamine; PPh3 represents triphenylphosphine; Pd(PPh3)2Cl2 represents bis(triphenylphosphine) dichloropalladium; Ru-L(S,S) represents (S,S)-N-(p-toluenesulfonyl)-l,2- diphenylethane diamine (p-isopropylbenzene) chloro ruthenium; [Ir(cod)Cl]2 represents 1,5-cyclooctadiene chloro iridium dimer; B2Pin2 represents bis(pinacolato)diboron or 4,4,4',4',5,5,5',5'-octamethyl-2,2'- bis(l,3,2-dioxaborolane); COMU represents (2-hydroxyl-cyanoacetic acid ethyl ester)-N,N- dimethyl-morpholino urea hexafluorophosphate; ACN / MeCN represents acetonitrile; NIS represents N-iodosuccinimide; KOAc represents potassium acetate; DME represents ethylene glycol dimethyl ether; EtI represents ethyl iodide; EDCI represents 1-ethyl-(3- dimethylaminopropyl)carbodiimide hydrochloride; HOBT represents 1-hydroxybenzotriazole; AcOH represents acetic acid; Boc represents tert-butoxycarbonyl; toluene represents toluene; TBAF represents tetrabutylammonium fluoride; DMSO represents dimethyl sulfoxide; NMM represents N-methylmorpholine; (CH20)n represents paraformaldehyde; dioxane represents 1,4-dioxane; CDI represents 1,1-carbonyldiimidazole; Oxone represents potassium peroxymonosulfate; Piperidine represents piperidine; t-BuOH represents tert-butanol; tBuXPhos Pd G3 represents methane sulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl- 1,1'-biphenyl)(2'-amino- 1,1'-biphenyl-2-yl)palladium(II); PE represents petroleum ether; TLC represents thin layer chromatography; FA represents formic acid; mCPBA represents meta-chloroperoxybenzoic acid; TMSCN represents trimethylsilyl cyanide; Pyridine represents pyridine; DCE represents 1,2-dichloroethane; NMI represents N-methylimidazole; Ac20 represents acetic anhydride; TCFH represents N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate; Pd2(dba)3 represents tris(dibenzylideneacetone)dipalladium; LC-MS represents liquid chromatography-mass spectrometry; MS represents mass spectrometry; 1HNMR stands for nuclear magnetic resonance hydrogen spectrum; ESI stands for electrospray ionization; PBS stands for phosphate buffer; IC 50 IC50 stands for half maximal inhibitory concentration, which refers to the concentration at which the effect of a substance is halved. Examples

[0238] The compounds of the present disclosure can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth herein, embodiments formed by a combination of the specific embodiments set forth herein with other chemical synthetic methods well known to those skilled in the art, and equivalents thereof well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present disclosure.

[0239] The present disclosure is described in detail below by way of examples, but is not meant to be limited by any unfavorable limitations. The present disclosure has been described in detail, and specific embodiments thereof have also been disclosed, and it will be obvious to those skilled in the art that various changes and improvements can be made to the specific embodiments of the present disclosure without departing from the spirit and scope of the present disclosure. All reagents used in the present disclosure are commercially available and can be used without further purification.

[0240] Unless otherwise specified, the ratio indicated by the mixed solvent is the volume mixing ratio.

[0241] Unless otherwise specified, % refers to weight percent wt%.

[0242] The compounds are named by hand or software, and commercially available compounds are named by the supplier's catalog name.

[0243] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The unit of NMR shift is 10 -6 (ppm). The solvent for NMR determination is deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0244] The eluent or mobile phase can be a mixed eluent or mobile phase composed of two or more solvents, and the ratio is the volume ratio of each solvent.

[0245] Preparation Example

[0246] Synthesis of intermediate compound Int-1 in Preparation Example 1

[0247] Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoic acid (compound A2) in the first step

[0248] Compound A2 (88 g, 246.82 mmol) was dissolved in dichloromethane (1000 mL) at 0 °C. N,N-dimethylformamide (1.80 g, 24.68 mmol, 1.91 mL) was added to the solution under nitrogen protection. Then oxalyl chloride (62.69 g, 493.65 mmol, 42.13 mL) was added dropwise to the reaction solution. The reaction solution was stirred at 0 °C for 2 hours. The reaction was monitored by LC-MS. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to give compound A3 (80 g, 213.35 mmol, yield: 86.44%) which was used directly in the next step without purification.

[0249] Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (Compound A3)

[0250] Compound A3 (80 g, 213.35 mmol) was dissolved in dichloromethane (1.5 L) at 0 °C. Tin tetrachloride solution (1 M, 213.35 mL) and 5-bromo-lH-indole (41.83 g, 213.35 mmol) were added to the solution under nitrogen protection. The reaction solution was reacted at 0 °C for 10 hours. LC-MS showed that the starting material was consumed and the product was detected. The reaction solution was diluted with ethyl acetate (600 mL) and washed with saturated brine (100 mL) four times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to give compound A4 (8 g, 14.97 mmol, yield: 7.01%) which was purified by silica gel chromatography (ethyl acetate / tetrahydrofuran = 5 / 1 to 3 / 1).

[0251] Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (Compound A3)

[0252] Compound A3 (80 g, 213.35 mmol) was dissolved in dichloromethane (1.5 L) at 0 °C. Tin tetrachloride solution (1 M, 213.35 mL) and 5-bromo-lH-indole (41.83 g, 213.35 mmol) were added to the solution under nitrogen protection. The reaction solution was reacted at 0 °C for 10 hours. LC-MS showed that the starting material was consumed and the product was detected. The reaction solution was diluted with ethyl acetate (600 mL) and washed with saturated brine (100 mL) four times. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was rotary evaporated to give compound A4 (8 g, 14.97 mmol, yield: 7.01%) which was purified by silica gel chromatography (ethyl acetate / tetrahydrofuran = 5 / 1 to 3 / 1).

[0253] MS (ESI + )m / z = 534.0 [M+H] + .

[0254] Step 4: Synthesis of l-(5-bromo-lH-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)- 2,2-dimethylpropan-l-ol (Compound A5)

[0255] Compound A4 (8 g, 14.97 mmol) was dissolved in tetrahydrofuran (71.30 mL) at 0 °C, and 2M lithium borohydride tetrahydrofuran solution (2M, 18.71 mL) was added dropwise into the reaction solution under nitrogen protection. Then the reaction solution was heated to 60 °C for 16 hours. LC-MS showed that the starting material was consumed completely and the desired compound was detected. The reaction solution was quenched with methanol (20 mL) and extracted with ethyl acetate (50 mL) for three times. The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give Compound A5 (8 g, 14.91 mmol, yield: 99.62%). Without further purification, it was used directly in the next step.

[0256] Step 5: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)- lH-indole (Compound A6)

[0257] Compound A5 (8 g, 14.91 mmol), dihydropyridine (4.37 g, 17.25 mmol), p-toluenesulfonic acid monohydrate (2.84 g, 14.91 mmol) were dissolved in dichloromethane (150 mL) and stirred at 0 °C for 2 hours under nitrogen protection. LC-MS showed that the reactants were consumed completely and the desired compound was detected. After the reaction was completed, water (50 mL) was added to quench the reaction, and dichloromethane (50 mL) was used to extract three times. The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give Compound A6 (7 g, 13.45 mmol, yield: 90.19%).

[0258] MS (ESI + )m / z = 520.0 [M+H] + .

[0259] Step 6: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)- 2-iodo-lH-indole (Compound Int-1)

[0260] Compound A6 (3 g, 5.76 mmol) was dissolved in tetrahydrofuran (10 mL), and I2 (1.46 g, 5.76 mmol) and silver trifluoromethanesulfonate (1.78 g, 6.92 mmol) were added. The reaction was stirred at room temperature for 2 hours. LC-MS showed that the reactants were completely consumed and the desired compound was detected. The reaction was diluted with ethyl acetate (50 mL), washed with saturated Na2S2O3 aqueous solution (50 mL), and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound Int-1 (973 mg, 1.51 mmol, yield: 26.12%).

[0261] MS (ESI + )m / z = 646.1 [M+H] + .

[0262] Synthesis of intermediate compound Int-2 in Preparation Example 2

[0263] Synthesis of the first step (4-bromothiazol-2-yl)methanol (compound B2)

[0264] Compound B1 (10 g, 52 mmol) was added with sodium borohydride (2.95 g, 78.11 mmol) in methanol (15 mL) and stirred at 0°C for 0.5 h. Thin layer chromatography showed that compound B1 was completely reacted. The reaction was quenched by adding 10 ml of dilute hydrochloric acid (1M). The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain compound B2 (9 g, 46.38 mmol, yield 89.07%).

[0265] MS (ESI + )m / z = 194.3 [M+H] + .

[0266] Synthesis of the second step 4-bromo-2-(bromomethyl)thiazole (compound B3)

[0267] Carbon tetrabromide (23.07 g, 69.57 mmol), compound B2 (9 g, 46.38 mmol), and triphenylphosphine (18.25 g, 69.57 mmol) were added in dichloromethane (120 mL) at 0°C. After stirring at 25°C for 1 hour, LC-MS showed that the reaction was complete. The mixture was filtered, and the filtrate was concentrated under vacuum, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-10%) to obtain compound B3 (9.0 g, 35.20 mmol, yield: 75.9%). MS (ESI + )m / z = 255.7 [M+H] + .

[0268] Step 3: Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5- dihydropyrazin-2-yl]methyl]thiazole (Compound B5)

[0269] (R)-2,5-dihydro-3,6-dimethoxy-2-isopropylpyrazine (Compound B4, 7.10 g, 38.53 mmol) was added into tetrahydrofuran (100 mL) and n-butyllithium (16.81 mL, 42.03 mmol, 2.5 M) was added slowly at -78 °C. After addition, it was stirred at -78 °C for 0.5 h. Compound B3 (9.0 g, 35.20 mmol) was added into above mixture and stirred at -78 °C for 1 h. LC-MS was used to monitor the completion of reaction. It was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column (0-15% petroleum ether / ethyl acetate) to give Compound B5 (10.5 g, 29.14 mmol, yield: 83%).

[0270] MS (ESI + )m / z = 360.2 [M+H] + .

[0271] Step 4: Synthesis of (S)-methyl 2-amino-3-(4-bromothiazol-2-yl)propanoate (B6)

[0272] Compound B5 (10.5 g, 29.14 mmol) was dissolved in acetonitrile (60 mL) and hydrochloric acid (195 mL, 0.3 M) was added. It was stirred at 25 °C for 2 h. LC-MS was used to monitor the completion of reaction. The mixture was basified with saturated aqueous sodium bicarbonate solution to pH = 8. It was then extracted with ethyl acetate (100 mL x 6). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under vacuum to give Compound B6 (6.8 g, 25.65 mmol, yield: 88%).

[0273] MS (ESI + )m / z = 264.9 [M+H] + .

[0274] Step 5: Synthesis of (S)-methyl 3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonyl)amino)propanoate (Compound B7)

[0275] Triethylamine (8.94 mL, 64.12 mmol) and di-tert-butyl dicarbonate (8.4 g, 38.47 mmol) were added to a solution of compound B6 (6.8 g, 25.65 mmol) in dichloromethane (80 mL) respectively. Stirring at 25 °C for 16 hours. LC-MS monitoring reaction complete. Quench with water (75 mL), extract with dichloromethane (75 mL x 2). The organic layer was dried over sodium sulfate and purified by silica gel column (petroleum ether / ethyl acetate = 0-30%) to give compound B7 (6.5 g, yield: 68%).

[0276] MS (ESI + )m / z = 364.9 [M+H] + .

[0277] Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (compound B8)

[0278] Compound B7 (6.5 g, 17.44 mmol) and lithium hydroxide monohydrate (2.93 g, 69.76 mmol) were added in a mixture solvent of tetrahydrofuran (60 mL), methanol (5 mL) and water (20 mL). Stirring at 25 °C for 1 hour. LC-MS monitoring reaction complete. The mixture was acidified to pH = 5 with 1M aqueous hydrochloric acid solution. Extracted with ethyl acetate (100 mL x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give compound B8 (6 g, 17.08 mmol, yield: 98%).

[0279] MS (ESI + )m / z = 351.2 [M+H] + .

[0280] Synthesis of (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester (compound Int-2)

[0281] (S)-hexahydropyridazine-3-carboxylic acid methyl ester (trifluoroacetate salt) (compound B9, 757.75 mg, 2.04 mmol), compound B8 (550 mg, 1.57 mmol), N-methylmorpholine (956 mg, 9.45 mmol), 1-hydroxybenzotriazole (639 mg, 4.73 mmol) and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (906 mg, 4.73 mmol) were added into a solution of dichloromethane (4 mL) at 0 °C. Stirring at 25 °C for 1 h. LC-MS monitoring reaction completion. Quench with water (15 mL) and extract with dichloromethane (15 mL x 2). The organic layer was dried, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0-50%) to give compound Int-2 (600 mg, 1.26 mmol, 80.12% yield).

[0282] MS (ESI + )m / z = 477.1 [M+H] + .

[0283] Synthesis of intermediate compound Int-3 in Preparation Example 3

[0284] First Step: Synthesis of (S)-1-(3-bromopyridin-2-yl)ethan-1-ol (compound C2)

[0285] A solution of formic acid (6.63 g, 143.98 mmol, 5.43 mL) in triethylamine (72.84 g, 719.88 mmol, 100.41 mL) was cooled to 0 °C under N2protection, then (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride (379 mg, 599.90 μmol) was added, the reaction was heated to 40 °C and stirred for 15 min, then cooled to room temperature, compound C1 (12 g, 59.99 mmol) was added, then the reaction was heated to 40 °C and stirred for 2 h. After the reaction was cooled to room temperature, the reaction was concentrated under reduced pressure, and column chromatography was used for purification to give compound C2 (12 g, 59.41 mmol, 99% yield).

[0286] MS (ESI + )m / z = 202.1 [M+H] + .

[0287] Second Step: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)pyridine (compound C3)

[0288] A solution of compound C2 (12.00 g, 59.41 mmol) in N,N-dimethylformamide (75 mL) was cooled to 0 °C under N2protection, sodium hydride (2.85 g, 71.27 mmol, 60% purity) was added, the mixture was stirred at 0 °C for 15 min, then iodomethane (16.86 g, 118.78 mmol) was added, and the mixture was allowed to naturally warm to room temperature, and the reaction was stirred for 2 h. The reaction solution was slowly added to ice water (750 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated, and the residue was purified by column chromatography to obtain compound C3 (11 g, 50.9 mmol, yield: 86%). + MS (ESI) m / z = 216.1 [M+H] +

[0289] Synthesis of 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-yl boronic acid (compound C4)

[0290] 4,4'-Di-tert-butyl-2,2'-bipyridine (931.61 mg, 3.47 mmol) and 1,5-cyclooctadiene iridium dichloride dimer (466.30 mg, 694.20 mmol) were added to a solution of compound C3 (5.0 g, 23.14 mmol) and bis(pinacolato)diboron (8.81 g, 34.71 mmol) in tetrahydrofuran (50 mL) under N2atmosphere. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 hours. LC-MS monitoring showed that the reaction was complete, and no starting material was left. The mixture was concentrated under reduced pressure. The resulting mixture was dissolved in ethyl acetate (30 mL), and the mixture was adjusted to pH = 10 with a solution of sodium carbonate (40 g) and sodium hydroxide (10 g) in water (600 mL). Extraction was performed with ethyl acetate (100 mL). The aqueous phase was acidified with hydrochloric acid (6 M) to pH = 6 to obtain compound C4 (4.5 g, 17.3 mmol, yield: 75%).

[0291] MS (ESI) m / z = 260.0 [M+H] + MS (ESI) m / z = 260.0 [M+H] +

[0292] Synthesis of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (compound C5)

[0293] ​​Compound C4 (4.5 g, 17.3 mmol) and N-iodosuccinimide (36.70 g, 163.14 mmol) were added in acetonitrile (50 mL) under N2protection. The resulting mixture was stirred at 80 °C under nitrogen atmosphere for 16 h. The reaction was monitored by LC-MS. The resulting mixture was dissolved in dichloromethane (80 mL) and washed with saturated aqueous sodium thiosulfate solution (80 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column (petroleum ether / ethyl acetate: 0-15%) to give compound C5 (4.3 g, 12.6 mmol, yield: 73%). MS (ESI + )m / z = 341.8 [M+H] + .

[0294] Step 5: Synthesis of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)piperazine-l- carboxylate (Compound C7)

[0295] Compound C5 (4.3 g, 12.6 mmol), compound C6 (2.77 g, 12.57 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1'-binaphthalene (BINAP) (156.59 mg, 251.48 μmol), palladium acetate (141.15 mg, 628.71 μmol), Cs2CO3(10.24 g, 31.44 mmol), toluene (50 mL) were mixed in a sealed tube under N2protection. The resulting solution was stirred at 100 °C under nitrogen atmosphere for 16 h. The reaction was monitored by LC-MS. After completion of the reaction, the reaction mixture was cooled to 25 °C. The mixture was extracted with ethyl acetate (80 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by silica gel column (petroleum ether / ethyl acetate: 0-45%) to give compound C7 (3.6 g, 8.29 mmol, yield: 65.92%).

[0296] MS (ESI + )m / z = 434.2 [M+H] + .

[0297] Step 6: Synthesis of (S)-4-(6-(l-methoxyethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)pyridin-3-yl)piperazine-l-carboxylate (Compound Int-3)

[0298] Compound C7 (9.6 g, 22.10 mmol), B2Pin2 (28.06 g, 110.52 mmol), potassium acetate (6.51 g, 66.31 mmol) were dissolved in 1,4-dioxane (100 mL), Pd(dppf)Cl2(1.62 g, 2.21 mmol) was added to the reaction solution under nitrogen protection and replaced with nitrogen for 5 times, stirred at 100 °C for 16 hours, and the reaction was monitored to completion. Filtration, concentration under reduced pressure, addition of ethyl acetate (100 mL) and 6N HCl (100 mL) and stirring for 16 hours, filtration, concentration under reduced pressure, and purification by reversed-phase silica gel column (water / acetonitrile = 1 / 0 ~ 1 / 1) to obtain compound Int-3 (4.6 g, 9.52 mmol, yield: 43.06%).

[0299] MS (ESI + )m / z = 482.2 [M+H] + .

[0300] Synthesis of intermediate compound Int-4 in Preparation Example 4

[0301] Synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)benzyl piperazine-1-carboxylate (compound D1)

[0302] Compound Int-1 (4 g, 6.19 mmol), compound Int-3 (4.47 g, 9.28 mmol), potassium carbonate (2.57 g, 18.56 mmol) were dissolved in a solution of ethylene glycol dimethyl ether (40 mL) and water (8 mL), Pd(dppf)Cl2(452.74 mg, 618.74 μmol) was added to the reaction solution under nitrogen protection and replaced with nitrogen for 5 times, stirred at 100 °C for 16 hours, and the reaction was monitored to completion by LC-MS. Diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 5) to obtain compound D1 (2.3 g, 2.63 mmol, yield: 42.49%).

[0303] MS (ESI + )m / z = 873.3 [M+H] + .

[0304] Step 2: Synthesis of (S)-4-(5-(5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2- dimethylpropyl)-1-ethyl-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)benzyl piperazine-1- carboxylate (Compound D2)

[0305] Compound D1 (2.3 g, 2.63 mmol) was dissolved in DMF (30 mL), Cesium carbonate (2.57 g, 7.89 mmol) was added in portions, iodoethane (820.88 mg, 5.26 mmol), stirred at 25 °C for 16 h. LC-MS monitored the reaction was complete. Diluted with water (100 mL), extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give compound D2 (2.0 g, crude). Used directly for next step.

[0306] MS (ESI + )m / z = 901.3 [M+H] + .

[0307] Step 3: Synthesis of (S)-4-(5-(5-bromo-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H- indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)benzyl piperazine-1-carboxylate (Compound D3)

[0308] Compound D2 (2.0 g, crude) was dissolved in tetrahydrofuran (30 mL), TBAF (1 M, 22.17 mL) was added, stirred at 25 °C for 16 h. LC-MS monitored the reaction was complete. The mixture was concentrated under reduced pressure, purified with normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 0 / 1) to give less polar isomer, compound D3 (0.5 g, 753.42 µmol, yield: 33.4%).

[0309] MS (ESI + )m / z = 663.3 [M+H] + .

[0310] Step 4: Synthesis of (S)-4-(5-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-2-yl)-6-(1-methoxyethyl)pyridin-3-yl)benzyl piperazine-1-carboxylate (Compound D4)

[0311] Compound D3 (0.5 g, 753.42 μmol), bis(pinacolato)diboron (573.96 mg, 2.26 mmol), potassium acetate (184.86 mg, 1.88 mmol) were dissolved in toluene (10 mL), Pd(dppf)Cl2(55.13 mg, 75.34 μmol) was added into the reaction solution under nitrogen atmosphere and replaced with nitrogen for 5 times, stirred at 100 °C for 16 hours, LC-MS was used to monitor the reaction completion. Filtration, concentrated under reduced pressure, diluted with water (50 mL), extracted with ethyl acetate (100 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by normal silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 3) to give compound D4 (0.4 g, 562.82 μmol, yield: 74.7%).

[0312] MS (ESI + )m / z = 711.4 [M+H] + .

[0313] Synthesis of (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2-((S)-1- methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol-2-yl)- 2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid methyl ester (Compound D5)

[0314] Compound D4 (260 mg, 365.83 μmol), compound Int-2 (174.64 mg, 365.83 μmol) and potassium phosphate (232.96 mg, 1.10 mmol) were dissolved in a mixed solution of dioxane (1 mL), toluene (3 mL) and water (1 mL), Pd(dtbpf)Cl2(23.84 mg, 36.58 μmol) was added into the reaction solution under nitrogen atmosphere and replaced with nitrogen for 5 times, stirred at 100 °C for 16 hours, LC-MS was used to monitor the reaction completion. Diluted with water (50 mL), extracted with ethyl acetate (10 mL x 3), washed with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, purified by normal silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 3) to give compound D5 (270 mg, 275.17 μmol, yield: 75.22%).

[0315] MS (ESI + )m / z = 981.4 [M+H] + .

[0316] Step 6. Synthesis of (S)-1-((S)-3-(4-(2-(5-(4-((benzyloxy)carbonyl)piperazin-1-yl)-2- ((S)-1-methoxyethyl)pyridin-3-yl)-1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-1H-indol-5-yl)thiazol- 2-yl)-2-((tert-butoxycarbonyl)amino)propanoyl)hexahydropyridazine-3-carboxylic acid (Compound D6)

[0317] Compound D5 (270 mg, 275.17 μmol) was dissolved in a mixture solution of tetrahydrofuran (5 mL) and water (5 mL), lithium hydroxide (32.95 mg, 1.38 mmol) was added into the reaction solution, stirred at 25 °C for 16 hours, LC-MS was used to monitor the reaction completion. Diluted with ethyl acetate (30 mL) and water (30 mL), the aqueous phase was adjusted to pH about 6 with 1M aqueous hydrochloric acid solution, extracted with ethyl acetate (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound D6 (220 mg, 227.47 μmol, yield: 82.66%) as a yellow solid.

[0318] MS (ESI + )m / z = 967.5 [M+H] + .

[0319] Step 7. Synthesis of Compound D7

[0320] Compound D6 (210 mg, 217.13 μmol), DIEA (1.12 g, 8.69 mmol, 1.51 mL), EDCI (1.25 g, 6.51 mmol) and HOBt (293.39 mg, 2.17 mmol) were dissolved in acetonitrile (5 mL), stirred at 25 °C for 16 hours, LC-MS was used to monitor the reaction completion. Diluted with water (20 mL), extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, purified by normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 4) to obtain Compound D7 (130 mg, 136.96 μmol, yield: 63.08%).

[0321] MS (ESI + )m / z = 949.3 [M+H] + .

[0322] Step 8. Synthesis of Compound D8

[0323] Compound D7 (130 mg, 136.96 μmol) was dissolved in methanol (10 mL), Pd(OH)2 / C (64.11 mg, 273.92 μmol, 60% purity) was added to the reaction solution under nitrogen protection, and then the nitrogen was replaced with hydrogen for 5 times, stirred at 25 °C for 16 hours under one atmosphere of hydrogen, and the reaction was monitored by LC-MS. Filtration and concentration of the filtrate under reduced pressure gave compound D8 (0.1 g, 122.69 μmol, yield: 89.58%).

[0324] MS (ESI + )m / z = 815.5 [M+H] + .

[0325] Synthesis of compound D9 in the ninth step

[0326] Compound D8 (100 mg, 122.69 μmol) and acetic acid (22.10 mg, 368.08 μmol) were dissolved in methanol (5 mL), stirred at 25 °C for 1 hour, then paraformaldehyde (36.85 mg, 1.23 mmol) and NaBH3CN (23.13 mg, 368.08 μmol) were added to the reaction solution, stirred at 25 °C for 16 hours, and the reaction was monitored by LC-MS. Filtration and concentration under reduced pressure gave compound D9 (80 mg, 96.49 μmol, yield: 78.65%).

[0327] MS (ESI + )m / z = 829.5 [M+H] + .

[0328] Synthesis of compound Int-4 in the tenth step

[0329] Compound D9 (80 mg, 96.49 μmol) was dissolved in methanol (10 mL), and a solution of 4N hydrogen chloride in dioxane (5 mL) was added to the reaction solution under nitrogen protection, stirred at 25 °C for 5 hours, and the reaction was monitored by LC-MS. Concentration after rotary evaporation gave white solid compound Int-4 (60 mg, 82.3 μmol, yield: 85.3%).

[0330] MS (ESI + )m / z = 729.4 [M+H] + .

[0331] Synthesis of intermediate compound Int-5 in Preparation Example 5

[0332] Synthesis of 3-(2-diazoacetyl)cyclobutan-1-one (compound E2) in the first step

[0333] Dichlorosulfoxide (89.12 mL, 1.23 mol) was added dropwise to a solution of compound E1 (70.0 g, 613.5 mmol) in ethyl acetate (700.0 mL) under ice-bath. The mixture was heated to 60 °C and stirred for 4 h. After the reaction was completed, the reaction was concentrated to dryness and azeotroped with toluene. The obtained crude was dissolved in a mixture of tetrahydrofuran (250.0 mL) and acetonitrile (250.0 mL). 2.0 M trimethylsilyldiazomethane in hexane (460.1 mL, 920.2 mmol) was added dropwise to the solution of crude at 0 °C, slowly warmed to room temperature and stirred for 12 h. After the reaction was completed, the reaction was cooled to 0 °C and quenched by the addition of acetic acid (50.0 mL) and water (200.0 mL), then concentrated to give a residue, which was diluted with saturated aqueous sodium bicarbonate solution (200.0 mL). The obtained mixture was extracted with ethyl acetate (300 mL) three times. The combined organic layers were washed with saturated aqueous sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to give compound E2 (45.0 g, 325.77 mmol, yield: 53.1%).

[0334] MS m / z (ESI): 139.0 [M+H] + .

[0335] Preparation of 2-(3-oxocyclobutyl)acetic acid (compound E3) in the second step

[0336] Silver nitrate (59.0 g, 347.5 mmol) was added portionwise to a mixture of compound E2 (40.0 g, 289.6 mmol) in water (360.0 mL) and tetrahydrofuran (720.0 mL) and stirred at room temperature for 12 h. After the reaction was completed, the reaction was concentrated to give a residue, to which was added water (1000.0 mL) and the pH was adjusted to 1-2 with dilute hydrochloric acid (1.0 M). The obtained mixture was extracted with ethyl acetate (300 mL) five times. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound E3 (36.0 g, 280.91 mmol, yield: 97.0%), which was used in the next step without further purification.

[0337] MS m / z (ESI): 127.0 [M-H] - .

[0338] Preparation of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (compound E4) in the third step

[0339] Compound E3 (36 g, 280.91 mmol), (S)-4-benzyl oxazolidin-2-one (49.8 g, 281.0 mmol), 4-dimethylaminopyridine (3.8 g, 31.2 mmol) and triethylamine (130.6 mL, 936.6 mmol) were added into dichloromethane (800.0 mL) in turn, then 2-chloro-1-methylpyridinium iodide (87.7 g, 343.4 mmol) was added portionwise. Stirring at room temperature for 1 hour. After the reaction was completed, the reaction was quenched with water, and the organic phase was washed with water (1000.0 mL) twice, and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound E4 (49.43 g, 171.64 mmol, yield: 61.1%).

[0340] MS m / z (ESI): 288.1 [M+H] + .

[0341] Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (compound E5)

[0342] Compound E4 (49.43 g, 171.64 mmol) and acetic acid (22.9 g, 381.4 mmol) were added into tetrahydrofuran (550.0 mL) in turn, and the temperature was lowered to 0℃, sodium borohydride (5.77 g, 152.6 mmol) was added portionwise, and after the addition was completed, stirring was performed for 2 hours. After the reaction was completed, saturated aqueous ammonium chloride solution (150.0 mL) was slowly added dropwise to quench the reaction, and the residue was concentrated under reduced pressure, and the residue was extracted with ethyl acetate (300.0 mL) three times, the organic phase was washed with saturated aqueous sodium bicarbonate solution, the pH was adjusted to 8, the organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound E5 (48.68 g, 167.86 mmol, yield: 97.8%), which was used directly in the next step without further purification. MS m / z (ESI): 290.2 [M+H] + .

[0343] Preparation of (S)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl-4-methylbenzenesulfonate (compound E6)

[0344] Compound E5 (48.68 g, 167.86 mmol), 4-dimethylaminopyridine (18.2 g, 149.3 mmol) and N,N-diisopropylethylamine (48.8 mL, 280.0 mmol) were added to anhydrous dichloromethane (500.0 mL), cooled to 0°C, and p-toluenesulfonyl chloride (39.1 g, 205.3 mmol) was added portionwise. After the addition was completed, the reaction solution was slowly warmed to room temperature and stirred overnight. After the reaction was completed, the mixture was washed with water (500.0 mL) and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound E6 (49.8 g, 112.14 mmol, yield: 66.8%).

[0345] MS m / z (ESI): 444.1 [M+H] + .

[0346] Preparation of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (compound E7)

[0347] Compound E6 (49.8 g, 112.14 mmol) and lithium bromide (19.0 g, 219.2 mmol) were added to N-methylpyrrolidone (500.0 mL), and the reaction solution was heated to 90°C and stirred for 12 hours. After the reaction was completed, it was diluted with saturated aqueous sodium chloride solution (1.0 L) and extracted with ethyl acetate (300.0 mL) three times. The organic phase was washed once more with saturated sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound E7 (34.74 g, 98.68 mmol, yield: 88.0%).

[0348] MS m / z (ESI): 352.2 [M+H] + .

[0349] Preparation of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid (compound E8)

[0350] Compound E7 (10.0 g, 28.4 mmol) was dissolved in tetrahydrofuran (100.0 mL) under argon atmosphere, cooled to -78 °C, then lithium diisopropylamide tetrahydrofuran n-heptane mixed solution (18.5 mL, 2.0 M) was added dropwise slowly, stirred for 0.5 h. Then di-tert-butyl azodicarboxylate (7.84 g, 34.0 mmol) in anhydrous dichloromethane (20.0 mL) was added to the above solution, continued to stir for 0.5 h. Then N,N-dimethylpropenylurea (109.2 g, 851.7 mmol) was added slowly to the above reaction solution, slowly warmed to room temperature and continued to stir for 13 h. After the reaction was completed, the reaction was quenched by adding water (100.0 mL), then lithium hydroxide monohydrate (3.58 g, 85.1 mmol) was added, stirred at room temperature for 1 h. After the reaction was completed, the reaction solution was concentrated, then saturated aqueous sodium chloride solution (200.0 mL) was added to dilute, extracted with ethyl acetate (200.0 mL) three times, the organic phase was discarded, the aqueous phase was adjusted to pH 5 with dilute hydrochloric acid (1.0 M), then extracted with ethyl acetate (200.0 mL) three times, the organic phase was washed with saturated aqueous sodium chloride solution once, the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound E8 (1.0 g, 2.91 mmol, yield: 10.2%).

[0351] MS m / z (ESI): 343.1 [M+H] + .

[0352] Eighth Step Preparation of 2,3-di-tert-butyl-4-methyl (S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tricarboxylate (Compound E9)

[0353] To a solution of compound E8 (1.0 g, 2.91 mmol) in methanol (10.0 mL) was added dropwise slowly trimethylsilyldiazomethane in n-hexane (7.3 mL, 2.0 M) at room temperature, the mixture was stirred at room temperature for 30 min. After the reaction was completed, a few drops of acetic acid were added to quench the reaction. The reaction solution was concentrated to obtain the title compound E9 (1.0 g, 2.8 mmol, yield: 96.2%).

[0354] MS m / z (ESI): 343.1 [M+H] + .

[0355] Ninth Step Preparation of (S)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid methyl ester (Compound Int-5)

[0356] To a solution of compound E9 (706.0 mg, 1.98 mmol) in dichloromethane (6.0 mL) was added trifluoroacetic acid (2.0 mL) slowly at room temperature. The mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated to obtain the title compound Int-5 (312 mg, 1.98 mmol, yield: 100.0%).

[0357] MS m / z (ESI): 157.0 [M+H] + .

[0358] Synthesis of intermediate compound Int-6 in Preparation Example 6

[0359] To a solution of compound Int-5 (309 mg, 1.98 mmol) and N,N- diisopropylethylamine (3.45 mL, 19.8 mmol) was added compound B8 (695.4 mg, 1.98 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (896.3 mg, 2.38 mmol) in N,N-dimethylformamide (7.0 mL) sequentially, and stirred at room temperature for 2 hours. Purification by a reverse phase silica gel column (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain compound Int-6 (600.0 mg, yield: 61.9%).

[0360] MS m / z (ESI): 489.2 [M+H] + .

[0361] Synthesis of intermediate compound Int-7 in Preparation Example 7

[0362] Synthesis of compound F1 in the first step

[0363] To a solution of compound D4 (117.6 mg, 165.5 µmol), compound Int-6 (89 mg, 182.05 µmol) and potassium phosphate (232.96 mg, 1.10 mmol) in a mixed solution of dioxane (1 mL), toluene (3 mL) and water (1 mL) was added Pd(dtbpf)Cl2 (23.84 mg, 36.58 µmol) under nitrogen protection, and nitrogen was replaced for 5 times. After stirring at 100 ℃ for 16 hours, the reaction was monitored by LC-MS. After dilution with water (50 mL), extraction was performed with ethyl acetate (10 mL × 3), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 3) to obtain compound F1 (142.2 mg, 143.16 µmol, yield: 86.5%).

[0364] MS (ESI+ m / z = 993.4 [M+H] +

[0365] Synthesis of compound F2 in the second step

[0366] Compound F1 (142.2 mg, 143.16 μmol) was dissolved in a mixture solution of tetrahydrofuran (5 mL) and water (5 mL), and lithium hydroxide (32.95 mg, 1.37 mmol) was added to the reaction solution. The mixture was stirred at 25 °C for 16 hours, and LC-MS was used to monitor the completion of the reaction. The reaction solution was diluted with ethyl acetate (30 mL) and water (30 mL), and the aqueous phase was adjusted to pH about 6 with 1M aqueous hydrochloric acid solution. Ethyl acetate (30 mL) was added to extract the organic phase, which was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound F2 (120 mg, 122.83 μmol, yield: 85.8%) as a yellow solid.

[0367] MS (ESI + m / z = 979.5 [M+H] +

[0368] Synthesis of compound F3 in the third step

[0369] Compound F2 (120 mg, 122.83 μmol), DIEA (1.12 g, 8.69 mmol, 1.51 mL), EDCI (1.25 g, 6.51 mmol), and HOBt (293.39 mg, 2.17 mmol) were dissolved in acetonitrile (5 mL), and the mixture was stirred at 25 °C for 16 hours. LC-MS was used to monitor the completion of the reaction. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 mL x 3), which was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The filtrate was purified by normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 ~ 1 / 4) to obtain compound F3 (35.4 mg, 36.85 μmol, yield: 30.4%).

[0370] MS (ESI + m / z = 961.1 [M+H] +

[0371] Synthesis of compound F4 in the fourth step

[0372] ​​​Compound F3 (35.4 mg, 36.85 μmol) was dissolved in methanol (10 mL), Pd(OH)2 / C (64.11 mg, 273.92 μmol, 20% purity) was added to the reaction solution under nitrogen protection, then replaced with hydrogen for 5 times, stirred at 25 °C for 16 hours under one atmosphere of hydrogen, LC-MS was used to monitor the completion of the reaction. Filtration, the filtrate was concentrated under reduced pressure to obtain compound F4 (28 mg, 33.9 μmol, yield: 92%).

[0373] MS (ESI + )m / z = 827.2 [M+H] + .

[0374] Step 5: synthesis of compound F5

[0375] Compound F4 (40.0 mg, 48.37 μmol), 3-oxetanone (7.0 mg, 97 μmol), sodium cyanoborohydride (6.0 mg, 97 μmol) and acetic acid (9.0 mg, 150 μmol) were added to isopropanol (3 mL), the mixture was reacted at room temperature for 2 hours, after the reaction was completed, the reaction solution was spin-dried, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 30:1) to obtain compound F5 (38.0 mg, 43 μmol, yield 89%).

[0376] MS (ESI + )m / z = 883.4 [M+H] + .

[0377] Step 6: synthesis of compound Int-7

[0378] Compound F5 (38.0 mg, 43 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added dropwise to the solution at 0 °C, the mixture was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, the residue was poured into saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (10 ml x 3), the combined organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to obtain compound Int-7 (32.0 mg, 40.85 μmol, yield 95%). MS: m / z (ESI) = 783.4 [M+H] + .

[0379] Synthesis of intermediate compound Int-8 in Preparation Example 8

[0380] Step 1: synthesis of compound G2

[0381] Compound G1 (1.05 g, 9.08 mmol) and tert-butyl hydrazinecarboxylate (1.00 g, 7.57 mmol) were dissolved in dichloromethane (20 mL), and then 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.74 g, 9.08 mmol), 1-hydroxybenzotriazole (1.23 g, 9.08 mmol) and N,N-diisopropylethylamine (1.96 g, 15.13 mmol, 2.64 mL) were added, and then the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to obtain compound G2 (1.30 g, 5.64 mmol, yield: 74.5%).

[0382] MS (ESI + )m / z = 231.1 [M+H] + .

[0383] Synthesis of compound Int-8 of the second step

[0384] Compound G2 (200.0 mg, 868.42 µmol) was dissolved in hydrochloric acid dioxane (4 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, and the residue was poured into an excess of saturated sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound Int-8 (108.5 mg, 833.39 µmol, yield: 96.0%).

[0385] MS (ESI + )m / z = 131.1 [M+H] + .

[0386] Synthesis of intermediate compound Int-9 in Preparation Example 9

[0387] Synthesis of compound H1 of the first step

[0388] Compound F4 (100 mg, 120.91 µmol), acetic acid (22.10 mg, 368.08 µmol) were dissolved in methanol (5 mL), and then stirred at 25°C for 1 hour. Then, paraformaldehyde (36.85 mg, 1.23 mmol) and NaBH3CN (23.13 mg, 368.08 µmol) were added to the reaction solution, and then stirred at 25°C for 16 hours. The reaction was monitored by LC-MS. Filtration and concentration under reduced pressure gave compound H1 (84 mg, 99.85 µmol, yield: 82.58%).

[0389] MS (ESI + )m / z = 841.3 [M+H] + .

[0390] Synthesis of compound Int-9 in the second step

[0391] Compound H1 (84 mg, 99.85 μmol) was dissolved in methanol (10 mL), 4N hydrochloric acid 1,4-dioxane solution (5 mL) was added to the reaction solution under the condition of nitrogen protection, stirred at 25°C for 5 hours, LC-MS monitoring reaction completion, rotary evaporation to concentrate to obtain white solid compound Int-9 (66 mg, 89.0 μmol, yield: 89.1%).

[0392] MS (ESI + )m / z = 741.3 [M+H] + .

[0393] Synthesis of intermediate compound Int-10 in Preparation Example 10

[0394] Synthesis of compound I2 in the first step

[0395] Compound I1 (1.05 g, 11.92 mmol) and tert-butyl carbazate (1.00 g, 7.57 mmol) were dissolved in dichloromethane (20 mL), then 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.28 g, 11.92 mmol), 1-hydroxybenzotriazole (1.61 g, 11.92 mmol) and N,N-diisopropyl ethylamine (1.96 g, 15.13 mmol, 2.64 mL) were added, and then the reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to obtain compound I2 (0.96 g, 4.72 mmol, yield: 62.3%).

[0396] MS (ESI + )m / z = 203.1 [M+H] + .

[0397] Synthesis of compound Int-10 in the second step

[0398] Compound I2 (203.1 mg, 1000.0 μmol) was dissolved in hydrochloric acid 1,4-dioxane solution (4 mL), and the mixture was reacted at room temperature for 1 hour. The reaction solution was concentrated, the residue was poured into excess saturated sodium bicarbonate solution, extracted with ethyl acetate (20 mL*3), the organic phase was combined, dried over anhydrous sodium sulfate, filtered and rotary evaporated to obtain compound Int-10 (93.8 mg, 918.4 μmol, yield: 91.0%).

[0399] MS (ESI +m / z = 103.1 [M+H] + .

[0400] Synthesis of intermediate compound Int-11 in Preparation Example 11

[0401] Synthesis of compound J3 in the first step

[0402] Compound J1 (40 g, 184.95 mmol) was dissolved in N,N-dimethylformamide (800 mL) and cooled to 0 °C, sodium hydride (18.49 g, 462.38 mmol, 60%) was slowly added under nitrogen protection and stirred at 0 °C for 0.5 h, then J2 (58.70 g, 462.38 mmol) was added dropwise into the reaction solution at 0 °C, then stirred at 25 °C for 16 h under nitrogen protection. The reaction was monitored by LC-MS. The reaction mixture was quenched by the addition of saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (500 mL*3). The combined organic layer was washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give compound J3 (45 g, 145.54 mmol, yield: 78.69%).

[0403] MS (ESI + m / z = 309.2 [M+H] + .

[0404] Synthesis of compound J4 in the second step

[0405] Compound J3 (45 g, 145.54 mmol) was dissolved in a solution of trifluoroacetic acid (120 mL) and dichloromethane (480 mL) and stirred at 25 °C for 16 h. The reaction was monitored by LC-MS. The mixture was filtered and concentrated under reduced pressure to give compound J4 (14.8 g, 75.09 mmol, yield: 51.59%). MS (ESI + m / z = 197.1 [M+H] + .

[0406] Synthesis of compound Int-11 in the third step

[0407] Compound J4 (14.8 g, 75.09 mmol) was dissolved in tetrahydrofuran (200 mL), 1,1-carbonyldiimidazole (13.46 g, 83.00 mmol) was added in portions, and the mixture was stirred at 25 °C for 16 hours. Then sodium hydroxide (5 M, 45.27 mL) was added, and the mixture was stirred at 25 °C for 16 hours. The reaction was monitored by LC-MS. The mixture was adjusted to acidic pH = 1 with 6N hydrochloric acid, extracted with ethyl acetate (100 mL*2) and then with dichloromethane (100 mL*2), washed with brine (100 mL*2) respectively, and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound Int-11 (10.6 g, 69.24 mmol, yield: 92.21%).

[0408] MS (ESI + )m / z = 153.1 [M+H] + .

[0409] Synthesis of intermediate compound Int-12 in Preparation Example 12

[0410] Synthesis of compound K2 in the first step

[0411] Diethyl 2-oxomalonate (23.1 g, 132.5 mmol, 20.2 mL) was added to a solution of compound K1 (50.0 g, 132.5 mmol) in tetrahydrofuran (200 mL) under nitrogen protection, and the mixture was reacted at 70 °C overnight. The reaction was monitored by TLC, and the reaction solvent was removed by reduced pressure distillation. The residue was dissolved in toluene (300 mL), then n-heptane (60 mL) was added dropwise, and a solid was precipitated. The mixture was filtered, and the filtrate was concentrated to give compound K2 (25.0 g, 91.2 mmol, yield: 68.8%).

[0412] MS (ESI + )m / z = 274.1 [M+H] + .

[0413] Synthesis of compound K3 in the second step

[0414] Compound K2 (10.0 g, 36.5 mmol) was dissolved in a mixed solvent of acetonitrile (80 mL) and water (60 mL), and a mixture of potassium monopersulfate (53.9 g, 87.82 mmol) and sodium bicarbonate (11.4 g, 135.39 mmol) was added portionwise, and the reaction was allowed to proceed at room temperature for 5 hours. The reaction was monitored by TLC, and the reaction was completed. The reaction mixture was added to water, extracted with dichloromethane (100 mL*3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-70:30) to obtain compound K3 (5.2 g, 17.9 mmol, yield: 49.0%).

[0415] MS (ESI + )m / z = 290.1 [M+H] + .

[0416] Synthesis of compound Int-12 in the third step

[0417] Compound K3 (4.0 g, 13.8 mmol) and compound B6 (3.7 g, 13.8 mmol) were dissolved in toluene (80 mL), and stirred at room temperature under nitrogen protection overnight. The reaction was monitored by LC-MS, and the reaction was completed. The reaction mixture was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to obtain compound Int-12 (3.5 g, 9.2 mmol, yield: 66.7%).

[0418] MS (ESI + )m / z = 380.2 [M+H] + .

[0419] Synthesis of intermediate compound Int-13 in Preparation Example 13

[0420] Synthesis of compound L2 in the first step

[0421] Compound L1 (128 mg, 1.0 mmol) was dissolved in dichloromethane sulfone (5.0 mL), and zinc chloride (27.3 mg, 0.2 mmol) was added. The reaction was stirred at 60°C for 12 hours. After the reaction was completed, the reaction was concentrated under reduced pressure to obtain compound L2 (183 mg, 1.0 mmol, yield: 99%), and the product was used in the next step without purification.

[0422] Synthesis of compound Int-13 in the second step

[0423] Compound Int-12 (76 mg, 0.2 mmol) was dissolved in acetone (1.0 mL) at 0 °C, potassium carbonate (138 mg, 1.0 mmol) and compound L2 (183 mg, 1.0 mmol) were added successively into the solution under nitrogen protection. The reaction was stirred at 25 °C for 16 h. The reaction was monitored by LC-MS and was heated to 60 °C and stirred for 24 h. The reaction was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to give compound Int-13 (31 mg, 0.063 mmol, 31.6% yield).

[0424] MS (ESI+) m / z = 490.3 [M+H] + .

[0425] Synthesis of intermediate compound Int-14 in Preparation Example 14

[0426] Synthesis of compound M1 in the first step

[0427] Compound Int-11 (210.0 mg, 1.4 mmol) was added into thionyl chloride (2 mL) and reacted at room temperature for 2 h. The reaction was concentrated to give compound M1 (235.0 mg, 1.4 mmol, 100% yield).

[0428] Synthesis of compound Int-14 in the second step

[0429] (Trimethylsilyl)diazomethane (2 M, 1.5 mL) was added into the reaction flask, followed by dropwise addition of a solution of compound M1 (235.0 mg, 1.4 mmol) in anhydrous tetrahydrofuran (2 mL) and anhydrous acetonitrile (2 mL) at ice bath, and reacted at room temperature for 5 h; then dropwise addition of aqueous hydrobromic acid (40%, 2 mL) at ice bath, and reacted at room temperature for 18 h. Water and ethyl acetate were added into the reaction, and after the organic layer was separated, it was washed successively with water, saturated sodium bicarbonate solution, water, dried over anhydrous sodium sulfate, filtered and rotary evaporated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-85:15) to give compound Int-14 (165.0 mg, 0.72 mmol, 51.4% yield). It was used directly in the next step.

[0430] Synthesis of intermediate compound Int-15 in Preparation Example 15

[0431] Synthesis of compound N2 in the first step

[0432] To a solution of compound N2 (307.5 mg, 2.21 mmol), bis(triphenylphosphine) palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol) and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) in acetonitrile (5 mL) was added compound C5 (600.0 mg, 1.75 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:3) to give compound Int-15 (609.2 mg, 1.72 mmol, yield: 99%).

[0433] MS (ESI + )m / z = 140.1 [M+H] + .

[0434] Synthesis of intermediate compound Int-15 in the second step

[0435] To a solution of compound N2 (307.5 mg, 2.21 mmol), bis(triphenylphosphine) palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol) and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) in acetonitrile (5 mL) was added compound C5 (600.0 mg, 1.75 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:3) to give compound Int-15 (609.2 mg, 1.72 mmol, yield: 99%).

[0436] MS (ESI + )m / z = 354.2 [M+H] + .

[0437] Synthesis of intermediate compound Int-16 in Preparation Example 16

[0438] Compound 02 (450 mg, 2.6 mmol), bis(triphenylphosphine)palladium(II) chloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol) and N,N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) were added to a solution of compound C5 (600.0 mg, 1.75 mmol) in acetonitrile (5 mL) under nitrogen protection, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to give compound Int-16 (561.4 mg, 1.45 mmol, yield: 83%).

[0439] MS (ESI + )m / z = 387.2 [M+H] + .

[0440] Synthesis of intermediate compound Int-17 in Preparation Example 17

[0441] Synthesis of compound P2 in the first step

[0442] 2-amino-5-bromobenzaldehyde (5.0 g, 25.0 mmol) and ethyl nitroacetate (6.65 g, 49.99 mmol) were added to a mixture of acetic acid (20.0 mL) and water (20.0 mL), and then piperidine (1.23 mL, 12.5 mmol) was added, and the mixture was stirred at 100°C for 16 hours. After the reaction was completed, the mixture was added dropwise to ice water, and the precipitated solid was filtered off, washed with pure water and dried to give compound P2 (6.0 g, 22.3 mmol, yield: 89.2%). MS (ESI + )m / z = 269.0 [M-H] - .

[0443] Synthesis of compound P3 in the second step

[0444] Compound P2 (2.0 g, 7.43 mmol) and benzyl piperazine-1-carboxylate (2.46 g, 11.15 mmol) were added into tert-butyl alcohol (20.0 mL), then added methane sulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) palladium(II) (2'-amino-1,1'-biphenyl-2-yl) (590.2 mg, 743.3 μmol) and potassium tert-butoxide (2.5 g, 22.3 mmol), stirred at 90 °C for 16 hours under argon protection, the reaction was monitored by LC-MS. The mixture was filtered, the filtrate was added into water (50 mL), extracted with ethyl acetate (50 mL), concentrated to get the crude product. The crude product was purified by reverse phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to get compound P3 (1.2 g, 2.94 mmol, yield: 39.5%).

[0445] MS (ESI + )m / z = 409.1 [M+H] + .

[0446] Synthesis of compound P4 in the third step

[0447] Compound P3 (1.2 g, 2.94 mmol) was added into phosphorus oxychloride (20.0 mL), stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was added dropwise into ice water to quench the reaction, then extracted with ethyl acetate, the organic phase was concentrated to get the crude product. The crude product was purified by column chromatography (PE:EA = 1:1) to get compound P4 (500.0 mg, 1.17 mmol, yield: 39.8%).

[0448] MS (ESI + )m / z = 427.1 [M+H] + .

[0449] Synthesis of compound P5 in the fourth step

[0450] Compound P4 (500.0 mg, 1.17 mmol) was added into N,N-dimethylformamide (10.0 mL), then bis(triphenylphosphine)palladium dichloride (82.1 mg, 117.1 μmol), (1-ethoxyvinyl)trimethylstannane (846.0 mg, 3.58 mmol) were added, and the mixture was stirred at 110 °C under nitrogen protection for 1 hour. After the reaction was completed, hydrochloric acid 1,4-dioxane solution (10.0 mL, 4.0 M) was added into the reaction solution, and the mixture was stirred for 30 minutes. After the reaction was completed, the pH value of the reaction solution was adjusted to 7-8 with saturated sodium bicarbonate aqueous solution, and then the mixture was extracted with ethyl acetate. The obtained crude product was concentrated, and then purified by column chromatography (PE:EA = 3:1) to obtain compound P5 (380.0 mg, 874.7 μmol, yield: 74.7%).

[0451] MS (ESI + )m / z = 435.1 [M+H] + .

[0452] Synthesis of compound P6 in the fifth step

[0453] Compound P5 (330.0 mg, 759.5 μmol) and iron powder (849.4 mg, 15.19 mmol) were added into acetic acid (10.0 mL), and the mixture was stirred at 60 °C for 1 hour. After the reaction was completed, the residue was filtered off, and the filtrate was washed with saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The obtained crude product was concentrated, and then purified by reverse phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound P6 (280.0 mg, 692.2 μmol, yield: 91.1%).

[0454] MS (ESI + )m / z = 405.1 [M+H] + .

[0455] Synthesis of compound P7 in the sixth step

[0456] In an argon atmosphere and ice bath condition, triethylamine (744.5 mg, 7.36 mmol) and (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanedi-amine (p-isopropylbenzene) chloro-ruthenium (39.0 mg, 61.3 μmol) were added to formic acid (67.7 mg, 1.47 mmol), heated to 40 °C and stirred for 15 minutes. The reaction was cooled to room temperature and compound P6 (248.0 mg, 613.1 μmol) was added, then heated to 40 °C and stirred for 2 hours. After the reaction was completed, the reaction was concentrated to obtain the crude product which was purified by reverse phase (Water / NH4OH (0.5%):MeCN = 95:5 to 5:95) to obtain compound P7 (196.0 mg, 482.1 μmol, yield: 78.6%).

[0457] MS (ESI + )m / z = 407.1 [M+H] + .

[0458] Synthesis of compound P8 in the seventh step

[0459] In an ice bath condition, p-toluenesulfonic acid (360.0 mg, 2.09 mmol) and compound P7 (170.0 mg, 418.23 μmol) were added to acetonitrile (10.0 mL), then an aqueous solution of sodium nitrite (144.3 mg, 2.09 mmol) and potassium iodide (347.1 mg, 2.09 mmol) was added dropwise to the system, after stirring for 10 minutes in an ice bath, then transferred to room temperature and continue to stir for 1 hour. After the reaction was completed, saturated aqueous sodium sulfite was added to quench the reaction, and extracted with ethyl acetate, the organic phase was concentrated to obtain the crude product which was purified by column chromatography (PE:EA = 3:1) to obtain compound P8 (132.0 mg, 255.1 μmol, yield: 61.0%).

[0460] MS (ESI + )m / z = 518.0 [M+H] + .

[0461] Synthesis of compound Int-17 in the eighth step

[0462] Compound P8 (150.0 mg, 289.9 µmol) was added to sodium hydride (23.2 mg, 579.9 µmol, 60% dispersion in paraffin liquid) in N,N-dimethylformamide (5.0 mL) under an argon atmosphere with ice-bath cooling, stirred for 10 minutes, then iodomethane (82.3 mg, 579.9 µmol) was added, then the mixture was transferred to room temperature and stirred for a further 1 hour. After the reaction was completed, the reaction solution was added dropwise to 0.5 M dilute hydrochloric acid, then extracted with ethyl acetate, and the crude product obtained after concentration of the organic phase was purified by column chromatography (PE:EA = 3:1) to obtain compound Int-17 (132.0 mg, 248.1 µmol, yield: 85.6%).

[0463] MS (ESI + )m / z = 532.0 [M+H] + .

[0464] Synthesis of intermediate compound Int-18 in Preparation Example 18

[0465] Synthesis of compound Q2 in the first step

[0466] Compound Q1 (6.00 g, 30.30 mmol) was dissolved in anhydrous ethyl acetate (80 mL), then m-chloroperoxybenzoic acid (10.46 g, 60.60 mmol) was added, and the reaction was carried out at room temperature for 30 minutes and then at 50°C for 5 hours. The reaction solution was filtered, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to obtain compound Q2 (5.60 g, 26.17 mmol, yield: 86.4%).

[0467] MS (ESI + )m / z = 213.9 [M+H] + .

[0468] Synthesis of compound Q3 in the second step

[0469] Compound Q2 (5.40 g, 25.23 mmol) was dissolved in acetonitrile (100 mL), then trimethylsilyl cyanide (5.01 g, 50.46 mmol) and triethylamine (7.66 g, 75.69 mmol, 10.55 mL) were added, and the mixture was heated to 80°C and reacted for 12 hours. The reaction solution was concentrated, the residue was slurried with ethyl acetate (20 mL), the reaction solution was filtered, the filter cake was washed with a small amount of ethyl acetate, and the filter cake was dried to obtain compound Q3 (4.10 g, 18.39 mmol, yield: 73%).

[0470] MS (ESI + )m / z = 222.9 [M+H] + .

[0471] Synthesis of compound Q4 in the third step

[0472] Methylmagnesium bromide (3 M, 18 mL) was added dropwise to a solution of compound Q3 (4.00 g, 17.93 mmol) in tetrahydrofuran (20 mL) at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into dilute hydrochloric acid (6 M, 20 mL), and tetrahydrofuran was removed by concentration under reduced pressure. Water (60 mL) was added to the residue, and dichloromethane (80 mL*3) was extracted. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to obtain compound Q4 (2.80 g, 11.66 mmol, yield: 65%).

[0473] MS (ESI + )m / z = 240.2 [M+H] + .

[0474] Synthesis of compound Q5 in the fourth step

[0475] Compound Q4 (1.4 g, 5.83 mmol) was dissolved in N,N-dimethylformamide (20 mL), and then potassium carbonate (2.4 g, 17.50 mmol) and 4-((methylsulfonyl)oxy)piperidine-1-carboxylic acid benzyl ester (2.92 g, 9.33 mmol) were added. The mixture was reacted at 100 °C for 8 hours. The reaction solution was filtered, and water (100 mL) was added to the filtrate. Ethyl acetate (80 mL*3) was extracted, and the combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-50:50) to obtain compound Q5 (640.0 mg, 1.40 mmol, yield: 24%).

[0476] MS (ESI + )m / z = 457.0 [M+H] + .

[0477] Synthesis of compound Q6 in the fifth step

[0478] To a solution of compound Q5 (540.0 mg, 1.18 mmol) in N,N- dimethylformamide (5 mL) was added sodium hydride (51.5 mg, 1.25 mmol, 60% dispersion in paraffin liquid) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then iodomethane (296.7 mg, 2.09 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (10 mL) and water (10 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound Q7 (480.0 mg, 1.01 mmol, 85% yield).

[0479] MS (ESI + m / z = 459.2 [M+H] + .

[0480] Synthesis of compound Q7 in the sixth step

[0481] To a solution of compound Q6 (480.0 mg, 1.04 mmol) in N,N- dimethylformamide (5 mL) was added sodium hydride (51.5 mg, 1.25 mmol, 60% dispersion in paraffin liquid) portionwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then iodomethane (296.7 mg, 2.09 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was poured into saturated aqueous ammonium chloride solution (10 mL) and water (10 mL) was added. The mixture was extracted with ethyl acetate (100 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound Q7 (480.0 mg, 1.01 mmol, 97% yield).

[0482] MS (ESI + m / z = 473.0 [M+H] + .

[0483] Synthesis of compound Q8 in the seventh step

[0484] Trifluoroacetic acid (72.3 mg, 633.76 umol, 48.8 uL) and N-iodosuccinimide (784.2 mg, 3.49 mmol) were added to a solution of compound Q7 (1.5 g, 3.17 mmol) in dichloromethane (5 mL) at room temperature. The mixture was stirred at 40 °C for 4 h. When the reaction was completed, the reaction mixture was added to a saturated sodium bicarbonate solution (20 mL) dropwise, and then water (20 mL) was added. The mixture was extracted with ethyl acetate (100 mL*3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:00-70:30) to give compound Q8 (1.40 g, 2.34 mmol, 74% yield).

[0485] MS (ESI + m / z = 599.0 [M+H] + .

[0486] Synthesis of compound Int-18 in the second step

[0487] Copper(I) cyanide (56.2 mg, 627.51 umol) was added to a solution of compound Q8 (300.0 mg, 500.62 umol) in pyridine (2 mL) at room temperature. The mixture was stirred at 100 °C for 8 h. When the reaction was completed, the reaction mixture was directly rotary evaporated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 80:20-50:50) to give compound Int-18 (180.0 mg, 361.18 umol, 72% yield).

[0488] MS (ESI + m / z = 498.0 [M+H] + .

[0489] Synthesis of intermediate compound Int-19 in Preparation Example 19

[0490] Synthesis of compound R2 in the first step

[0491] Compound R1 (1.1 g, 10.0 mmol) was dissolved in acetonitrile (10 mL), and then potassium carbonate (2.4 g, 17.50 mmol) and 3-bromopropyne (1.77 g, 15.0 mmol) were added. The mixture was reacted at 25 °C for 4 h. The reaction mixture was filtered, and then water (50 mL) was added to the filtrate. The mixture was extracted with ethyl acetate (50 mL*3), and the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-30:70) to give compound R2 (940.0 mg, 6.3 mmol, 63% yield).

[0492] MS (ESI + m / z = 149.2 [M+H] + .

[0493] Synthesis of compound Int-19

[0494] Compound R2 (388.0 mg, 2.6 mmol), bis(triphenylphosphine)palladium dichloride (129.6 mg, 184.07 μmol), cuprous iodide (70.1 mg, 368.13 μmol) and N, N-diisopropylethylamine (475.8 mg, 3.68 mmol, 641.20 μL) were added to a solution of compound C5 (600.0 mg, 1.75 mmol) in acetonitrile (5 mL) under nitrogen protection, and the reaction was allowed to proceed at room temperature for 2 hours. The reaction was poured into ethyl acetate (50 mL), washed with saturated brine (20 mL*3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound Int-16 (450.0 mg, 1.24 mmol, yield: 71%).

[0495] MS (ESI + m / z = 362.2 [M+H] + .

[0496] Synthesis of compound 1 of Example 1

[0497] Compound Int-4 (10 mg, 13.72 μmol), compound 1A (6.71 mg, 41.16 μmol) were dissolved in DMF (2 mL), and TEA (5.69 mg, 56.21 μmol, 7.84 μL) was added portionwise, and the reaction was allowed to proceed at 80°C for 20 hours. The reaction was monitored by LC-MS until completion. Ethyl acetate (5 mL) and water (5 mL) were added to extract, and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column (Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration 0.05%, NH4HCO3 concentration 2 mM; mobile phase B: MeCN; MeCN ratio 40%-60%) to obtain compound 1 (1 mg, 1.23 μmol, yield: 8.99%).

[0498] MS (ESI + m / z = 811.3 [M+H] + .

[0499] 1H NMR (400 MHz, DMSO-d6) d = 8.52-8.40 (m, 2H), 8.05-7.97 (m, 1H), 7.81 (s, 1H), 7.77-7.69 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.22 (d, J = 2.8 Hz, 1H), 5.29-5.14 (m, 2H), 4.40-4.10 (m, 5H), 3.66-3.52 (m, 2H), 3.22-3.16 (m, 8H), 2.98-2.88 (m, 2H), 2.84-2.77 (m, 1H), 2.43-2.41 (m, 4H), 2.31 (s, 3H), 2.24-2.20 (m, 4H), 2.10 (s, 1H), 1.81 (s, 2H), 1.57-1.48 (m, 1H), 1.33 (d, J = 6.0 Hz, 3H), 0.96-0.87 (m, 6H), 0.35 (s, 3H).

[0500] Synthesis of compound 2 of example 2

[0501] Compound Int-4 (10 mg, 13.72 μmol), 2A (2.59 mg, 13.72 μmol), potassium phosphate (8.74 mg, 41.16 μmol) were dissolved in tert-butanol (1 mL), cuprous oxide (196.30 μg, 1.37 μmol) and N1,N2-bis(5-methyl-[1,1'-biphenyl]-2-yl)oxal amide (576.86 μg, 1.37 μmol) were added to the reaction under nitrogen atmosphere, nitrogen was replaced for three times, reacted at 60 °C for 16 hours. LC-MS was used to monitor the reaction completion. Water (5 mL) was added, extracted with ethyl acetate (5 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by reversed phase column (the chromatographic column was Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), NH3H2O concentration was 0.05%, NH4HCO3 concentration was 2 mM; mobile phase B: MeCN; MeCN ratio 50%-70%, flow rate: 15 mL / min) to obtain white solid compound 2 (1 mg, 1.2 μmol, yield: 8.7%)

[0502] MS (ESI + )m / z = 837.5 [M+H] + .

[0503] 1H NMR (400 MHz, DMSO-d6) d = 8.49 (s, 1H), 8.45 (d, J = 3.2 Hz, 1H), 7.79 (s, 1H), 7.76 - 7.70 (m, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.27 - 7.17 (m, 2H), 5.20 - 5.04 (m, 2H), 4.38 - 4.07 (m, 5H), 3.63 - 3.52 (m, 2H), 3.21 (s, 6H), 2.22 (s, 3H), 2.15 - 2.05 (m, 3H), 2.04 - 1.94 (m, 2H), 1.85 - 1.72 (m, 3H), 1.60 - 1.43 (m, 2H), 1.34 (d, J = 6.0 Hz, 3H), 1.24 (br s, 4H), 1.18 - 1.13 (m, 2H), 1.03 - 0.99 (m, 2H), 0.94 - 0.84 (m, 7H), 0.36 (s, 3H)

[0504] Synthesis of compound 3 of example 3

[0505] First Step: Synthesis of compound 3-1

[0506] Compound Int-7 (150 mg, 191.57 μmol) in tetrahydrofuran (10 mL) at room temperature for 2 hours. The reaction was concentrated, the residue was poured into water (20 mL), extracted with ethyl acetate (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-80:20) to give compound 3-1 (166.0 mg, 176.90 μmol, yield: 92.3%).

[0507] MS (ESI + )m / z = 938.4 [M+H] +

[0508] Second Step: Synthesis of compound 3-2

[0509] Compound 3-1 (60.0 mg, 63.95 μmol) was dissolved in a mixed solvent of N,N- dimethylformamide (1 mL) and tetrahydrofuran (2 mL), then potassium carbonate (26.5 mg, 191.85 μmol) was added, the mixture was stirred at room temperature for 10 minutes, then iodomethane (18.2 mg, 127.90 μmol) was added, and stirring was continued at room temperature for 2 hours. The reaction solution was filtered, the filtrate was poured into water (20 mL), extracted with ethyl acetate (10 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 100:0-70:30) to obtain compound 3-2 (59.5 mg, 62.47 μmol, yield: 97.7%).

[0510] MS (ESI + )m / z = 952.4 [M+H] + .

[0511] Step 3: Synthesis of compound 3

[0512] Sodium acetate (12.9 mg, 157.52 μmol) was added to a solution of hydroxylamine hydrochloride (11.0 mg, 157.52 μmol) in methanol (2 mL), the mixture was stirred at room temperature for 30 minutes, then compound 3-2 (50.0 mg, 52.51 μmol) was added, and stirring was continued at room temperature for 2 hours. The reaction solution was poured into water (20 mL), extracted with dichloromethane (10 mL*4), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative chromatography (the chromatographic column was XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 50%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 3 (12.0 mg, 13.05 μmol, yield: 24.85%).

[0513] MS (ESI + )m / z = 919.4 [M+H] + .

[0514] 1H NMR (400 MHz, CDC13) d = 8.50 (d, J = 2.9 Hz, 1H), 8.48 (d, J = 1.6 Hz, 1H), 7.62 (dd, J = 8.6, 1.6 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.32 (s, 1H), 7.11 (s, 1H), 5.37 (d, J = 10.9 Hz, 1H), 5.32-5.27 (m, 1H), 5.18 (d, J = 11.0 Hz, 1H), 4.86 (d, J = 10.9 Hz, 1H), 4.79-4.69 (m, 4H), 4.34-4.24 (m, 2H), 4.21-4.14 (m, 1H), 3.75-3.62 (m, 3H), 3.47-3.43 (m, 2H), 3.38 (s, 3H), 3.22-3.11 (m, 3H), 2.77-2.70 (m, 2H), 2.62-2.54 (m, 2H), 2.49-2.39 (m, 2H), 2.25-2.13 (m, 2H), 2.12-1.99 (m, 3H), 1.95-1.87 (m, 2H), 1.83-1.77 (m, 2H), 1.70-1.64 (m, 4H), 1.47-1.44 (m, 3H), 1.33-1.30 (m, 2H), 0.98-0.93 (m, 6H), 0.42 (s, 3H).

[0515] Synthesis of compound 4 of Example 4

[0516] Synthesis of compound 4-2 of the first step

[0517] Compound Int-7 (100.0 mg, 127.72 µmol) was dissolved in dichloromethane (2 mL), and N,N-diisopropylethylamine (33.0 mg, 255.43 µmol, 44.49 µL) was added, followed by the slow addition of compound 4-1 (35.6 mg, 153.26 µmol) at 0°C. The mixture was reacted at 0°C for 5 minutes. The reaction solution was concentrated, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-10:1) to obtain compound 4-2 (40.0 mg, 48.46 µmol, yield: 37.94%).

[0518] MS (ESI + )m / z = 825.4 [M+H] + .

[0519] Synthesis of compound 4-3 of the second step

[0520] Compound Int-8 (8.0 mg, 61.45 µmol) and compound 4-2 (50.7 mg, 61.45 µmol) were dissolved in acetonitrile (1 mL), the mixture was reacted at 80 °C for 15 min, and the reaction solution was directly subjected to high performance liquid chromatography column preparation (the column was XBridge Prep C18; 150*19 mm*5 µm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 60%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 4-3 (15.0 mg, 15.70 µmol, 25.5% yield).

[0521] MS (ESI + )m / z = 955.4 [M+H] + .

[0522] Synthesis of compound 4 in the third step

[0523] Compound 4-3 (10.0 mg, 10.47 µmol) was dissolved in acetonitrile (0.3 mL), then triphenylphosphine (5.5 mg, 20.94 µmol), N,N-diisopropylethylamine (10.8 mg, 83.75 µmol, 14.59 µL) were added, followed by the addition of hexachloroethane (5.0 mg, 20.94 µmol), and then reacted at room temperature for 12 h. The reaction solution was concentrated, and the residue was subjected to high performance liquid chromatography column preparation (the column was XBridge Prep C18; 150*19 mm*5 µm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 45%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 4 (3.0 mg, 3.26 µmol, 31.14% yield).

[0524] MS (ESI + )m / z = 921.4 [M+H] + .

[0525] 1H NMR (400 MHz, DMSO-d6) d = 8.45 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.03 (d, J = 9.8 Hz, 1H), 7.84 (s, 1H), 7.74 (dd, J = 8.6, 1.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 2.9 Hz, 1H), 6.03 (d, J = 11.0 Hz, 1H), 5.09 (t, J = 8.7 Hz, 1H), 4.72 (d, J = 11.0 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.53 - 4.48 (m, 1H), 4.48 - 4.43 (m, 2H), 4.32 - 4.24 (m, 1H), 4.18 - 4.12 (m, 2H), 3.62 - 3.50 (m, 2H), 3.48 - 3.41 (m, 1H), 3.31 - 3.27 (m, 4H), 3.23 - 3.19 (m, 3H), 2.93 (d, J = 14.4 Hz, 1H), 2.68 - 2.64 (m, 2H), 2.47 - 2.44 (m, 2H), 2.43 - 2.39 (m, 4H), 2.34 - 2.32 (m, 1H), 2.21 - 2.16 (m, 1H), 1.69 - 1.54 (m, 6H), 1.34 (d, J = 6.1 Hz, 3H), 0.93 - 0.86 (m, 6H), 0.85 - 0.79 (m, 6H), 0.33 (s, 3H).

[0526] Synthesis of compounds 5-P1 and 5-P2 of Example 5

[0527] Synthesis of compound 5-1 of the first step

[0528] Compound 4-1 (34.5 mg, 148.46 µmol) was slowly added to a solution of compound Int-9 (100.0 mg, 134.96 µmol) and N,N-diisopropylethylamine (34.9 mg, 269.92 µmol, 47.01 µL) in dichloromethane (2 mL) at -5 °C and the mixture was reacted at -5 °C for 5 minutes. The reaction was concentrated and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-50:1) to give compound 5-1 (80.0 mg, 102.17 µmol, yield: 76%).

[0529] Synthesis of compound 5-2 of the second step

[0530] Compound 5-1 (80.0 mg, 102.17 umol) and compound Int-10 (20.8 mg, 204.34 umol) were dissolved in acetonitrile (1 mL) under nitrogen protection, and the mixture was reacted at 90 °C for 30 min. The reaction solution was directly subjected to high performance liquid chromatography column preparation (YMC TA-C18, 30*150 mm, 5 um; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 5 mmol / L; mobile phase B: MeCN; MeCN ratio 40%-75%, time: 15 min, flow rate: 25 mL / min) to obtain compound 5-2 (15.0 mg, 16.95 umol, yield: 16%).

[0531] MS (ESI + )m / z = 885.4 [M+H] + .

[0532] Synthesis of compounds 5-P1 and 5-P2 in the fifth step

[0533] Compound 5-2 (10.0 mg, 11.30 umol) was dissolved in acetonitrile (0.2 mL), and then triphenylphosphine (5.9 mg, 22.60 umol), N,N-diisopropylethylamine (11.6 mg, 90.38 umol, 15.74 uL) and hexachloroethane (5.4 mg, 22.60 umol, 2.56 uL) were added. The mixture was reacted at room temperature for 2 h. The reaction solution was directly subjected to high performance liquid chromatography column preparation (YMC TA-C18, 30*150 mm, 5 um; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 5 mmol / L; mobile phase B: MeCN; MeCN ratio 60%-90%, time: 15 min, flow rate: 25 mL / min) to obtain compound 5-P1 (2.0 mg, 2.33 umol, yield: 20.6%, retention time: 10.25 min) and 5-P2 (1.5 mg, 1.69 umol, yield: 15.0%, retention time: 11.50 min).

[0534] Compound 5-P1 MS (ESI + )m / z = 851.4 [M+H] + .

[0535] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.8 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.05 (d, J = 9.8 Hz, 1H), 7.84 (s, 1H), 7.76 - 7.71 (m, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.24 (d, J = 2.8 Hz, 1H), 6.04 (d, J = 11.0 Hz, 1H), 5.11 - 5.00 (m, 1H), 4.73 (d, J = 11.0 Hz, 1H), 4.54 - 4.46 (m, 1H), 4.34 - 4.23 (m, 1H), 4.20 - 4.08 (m, 2H), 3.62 - 3.50 (m, 2H), 3.39 - 3.36 (m, 1H), 3.32 - 3.24 (m, 4H), 3.21 (s, 3H), 3.20 - 3.15 (m, 1H), 3.06 - 2.97 (m, 1H), 2.97 - 2.90 (m, 1H), 2.71 - 2.60 (m, 2H), 2.56 - 2.52 (m, 2H), 2.48 - 2.46 (m, 2H), 2.45 - 2.40 (m, 1H), 2.38 - 2.32 (m, 2H), 2.27 (s, 2H), 2.22 - 2.17 (m, 1H), 1.69 - 1.61 (m, 1H), 1.34 (d, J = 6.0 Hz, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 0.94 - 0.83 (m, 6H), 0.33 (s, 3H).

[0536] Compound 5-P2 MS (ESI + m / z = 867.3 [M+H] + .

[0537] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.20 (d, J = 9.4 Hz, 1H), 7.83 (s, 1H), 7.77 - 7.72 (m, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.25 (s, 1H), 6.02 (d, J = 11.0 Hz, 1H), 5.32 - 5.23 (m, 1H), 4.71 (d, J = 11.0 Hz, 1H), 4.52 - 4.47 (m, 1H), 4.33 - 4.24 (m, 1H), 4.20 - 4.09 (m, 2H), 3.61 - 3.52 (m, 2H), 3.40 - 3.36 (m, 1H), 3.32 - 3.23 (m, 4H), 3.21 (s, 3H), 3.18 - 3.11 (m, 2H), 2.94 (d, J = 14.4 Hz, 1H), 2.69 - 2.62 (m, 2H), 2.55 - 2.52 (m, 2H), 2.49 - 2.47 (m, 2H), 2.46 - 2.43 (m, 1H), 2.38 - 2.31 (m, 2H), 2.28 (s, 2H), 2.21 - 2.16 (m, 1H), 1.68 - 1.61 (m, 1H), 1.34 (d, J = 6.1 Hz, 3H), 1.26 (d, J = 2.0 Hz, 3H), 1.25 (d, J = 2.0 Hz, 3H), 0.94 - 0.82 (m, 6H), 0.33 (s, 3H).

[0538] Synthesis of compounds 6-P1 and 6-P2 of Example 6

[0539] Synthesis of compound 6-2 of the first step

[0540] Compound 6-1 (70.0 mg, 613.27 umol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (349.7 mg, 919.91 umol) and N,N- diisopropylethylamine (198.1 mg, 1.53 mmol) were added to N,N-dimethylformamide (1 mL) at room temperature, the mixture was stirred at room temperature for 15 minutes, then a solution of hydrazine hydrate (1.44 g, 28.8 mmol, 85%) in N,N-dimethylformamide (1 mL) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction solution was poured into ethyl acetate (30 mL), washed with saturated brine three times, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 6-2 (70.0 mg, 546.14 umol, yield: 89%).

[0541] MS (ESI +m / z = 129.1 [M+H] + .

[0542] Synthesis of compound 6-3 in the second step

[0543] Compound 4-2 (50.0 mg, 61.65 μmol) and compound 6-2 (15.8 mg, 123.29 μmol) were added to acetonitrile (0.5 mL), and the mixture was reacted at 90°C for 30 minutes under nitrogen protection. After the reaction was completed, the reaction solution was spin-dried, and the residue was purified by column chromatography (dichloromethane:methanol = 98:2) to obtain compound 6-3 (40.0 mg, 41.96 μmol, yield: 68.06%).

[0544] MS (ESI + )m / z = 953.4 [M+H] + .

[0545] Synthesis of compounds 6-P1 and 6-P2 in the third step

[0546] Compound 6-3 (40.0 mg, 41.96 μmol) was dissolved in acetonitrile (2 mL), and then triphenylphosphine (22.0 mg, 83.93 μmol), N,N-diisopropylethylamine (43.3 mg, 335.70 μmol, 58.4 μL), and hexachloroethane (19.8 mg, 83.93 μmol, 9.6 μL) were added, and the reaction was performed at room temperature for 2 hours. Water (10 mL) was added to the reaction solution, and ethyl acetate (10 mL*3) was extracted, and the organic phase was combined and concentrated under reduced pressure, and the residue was purified by reversed-phase column (YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: H2O-(5 mmol NH4HCO3); mobile phase B: MeCN; MeCN ratio 55%-85%, time: 15 min, flow rate: 25 mL / min) to obtain 6-P1 (3.0 mg, 3.26 μmol, yield: 7.76%, retention time: 9.50 min) and 6-P2 (1.0 mg, 1.07 μmol, yield: 2.55%, retention time: 11.0 min).

[0547] Compound 6-P1 MS (ESI + )m / z = 919.4 [M+H] + .

[0548] 1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 2.9 Hz, 1H), 8.36 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 9.9 Hz, 1H), 7.77 (s, 1H), 7.68 (dd, J = 8.7, 1.6 Hz, 1H), 7.49 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 2.9 Hz, 1H), 5.96 (d, J = 10.9 Hz, 1H), 4.97 (t, J = 8.6 Hz, 1H), 4.64 (d, J = 11.0 Hz, 1H), 4.50 (t, J = 6.5 Hz, 2H), 4.46 - 4.36 (m, 3H), 4.26 - 4.20 (m, 1H), 4.13 - 4.04 (m, 2H), 3.54 - 3.45 (m, 2H), 3.41 - 3.34 (m, 2H), 3.25 - 3.21 (m, 4H), 3.19 - 3.08 (m, 4H), 2.87 (d, J = 14.4 Hz, 1H), 2.59 - 2.55 (m, 2H), 2.38 - 2.31 (m, 4H), 2.30 - 2.22 (m, 2H), 2.11 (t, J = 9.7 Hz, 1H), 1.58 (t, J = 9.4 Hz, 1H), 1.38 (t, J = 4.8 Hz, 1H), 1.30 - 1.25 (m, 4H), 1.21 - 1.14 (m, 1H), 1.10 - 0.97 (m, 6H), 0.87 - 0.75 (m, 6H), 0.26 (s, 3H).

[0549] Compound 6-P2 MS (ESI + m / z = 935.4 [M+H] + .

[0550] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 8.41 (d, J = 10.2 Hz, 1H), 8.10 (d, J = 9.4 Hz, 1H), 7.83 (d, J = 1.9 Hz, 1H), 7.73 (t, J = 8.1 Hz, 1H), 7.57 (dd, J = 8.6, 4.2 Hz, 1H), 7.25 (s, 1H), 6.00 (d, J = 10.6 Hz, 1H), 5.29 - 5.23 (m, 1H), 4.70 (d, J = 11.2 Hz, 1H), 4.59 - 4.54 (m, 2H), 4.54 - 4.43 (m, 3H), 4.38 - 4.33 (m, 1H), 4.33 - 4.26 (m, 1H), 4.20 - 4.08 (m, 3H), 3.91 - 3.81 (m, 2H), 3.58 - 3.50 (m, 2H), 3.47 - 3.42 (m, 2H), 3.32 - 3.27 (m, 4H), 3.26 - 3.17 (m, 3H), 2.99 - 2.92 (m, 1H), 2.44 - 2.38 (m, 4H), 2.20 - 2.15 (m, 1H), 1.64 - 1.59 (m, 1H), 1.53 - 1.48 (m, 1H), 1.38 - 1.31 (m, 4H), 1.28 - 1.25 (m, 1H), 1.15 - 1.10 (m, 3H), 1.08 - 1.05 (m, 2H), 0.95 - 0.92 (m, 1H), 0.92 - 0.86 (m, 3H), 0.86 - 0.78 (m, 4H), 0.32 (d, J = 4.5 Hz, 3H).

[0551] Synthesis of compounds 7-P1 and 7-P2 of Example 7

[0552] Synthesis of compound 7-1 of the first step

[0553] Compound Int-11 (121.6 mg, 800.0 μmol), 2-(7-azobenzotriazol)-N,N,N',N'- tetramethyluronium hexafluorophosphate (349.7 mg, 919.91 μmol) and N,N- diisopropylethylamine (198.1 mg, 1.53 mmol) were added to N,N-dimethylformamide (2 mL) at room temperature, the mixture was stirred at room temperature for 15 minutes, then a solution of hydrazine hydrate (1.44 g, 24.53 mmol, 85%) in N,N-dimethylformamide (1 mL) was added, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was poured into ethyl acetate (30 mL), washed with saturated brine three times, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 7-1 (113 mg, 676.24 μmol, yield: 84.53%).

[0554] MS (ESI + m / z = 167.1 [M+H] + .

[0555] Synthesis of compound 7-2 in the second step

[0556] Compound 4-2 (150.0 mg, 181.81 μmol) and compound 7-1 (60.4 mg, 363.61 μmol) were added to acetonitrile (0.5 mL), and the mixture was reacted at 90°C for 30 minutes under nitrogen protection. The reaction solution was directly subjected to high performance liquid chromatography column preparation (chromatography column YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 5 mmol / L; mobile phase B: MeCN; MeCN ratio 40%-75%, time: 15 min, flow rate: 25 mL / min) to obtain compound 7-2 (40.0 mg, 40.35 μmol, yield: 22%).

[0557] MS (ESI + m / z = 991.4 [M+H] + .

[0558] Synthesis of compounds 7-P1 and 7-P2 in the third step

[0559] Compound 7-2 (35.0 mg, 35.31 μmol) was dissolved in acetonitrile (0.5 mL), and then triphenylphosphine (18.5 mg, 70.62 μmol), N,N-diisopropylethylamine (36.5 mg, 282.48 μmol, 49.2 μL) and hexachloroethane (16.7 mg, 70.62 μmol, 8.0 μL) were added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was directly subjected to high performance liquid chromatography column preparation (chromatography column YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 5 mmol / L; mobile phase B: MeCN; MeCN ratio 70%-95%, time: 15 min, flow rate: 25 mL / min) to obtain compound 7-P1 (5.0 mg, 5.21 μmol, yield: 15%, retention time: 8.50 min) and 7-P2 (8.0 mg, 8.11 μmol, yield: 23%, retention time: 9.50 min).

[0560] Compound 7-P1 MS (ESI + m / z = 957.4 [M+H] + .

[0561] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.13 (d, J = 9.6 Hz, 1H), 7.84 (s, 1H), 7.74 (dd, J = 8.6, 1.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 2.9 Hz, 1H), 6.05 (d, J = 11.0 Hz, 1H), 5.12 - 5.06 (m, 1H), 4.71 (d, J = 11.0 Hz, 1H), 4.61 - 4.53 (m, 3H), 4.54 - 4.42 (m, 5H), 4.40 - 4.32 (m, 1H), 4.32 - 4.24 (m, 1H), 4.19 - 4.09 (m, 2H), 3.63 - 3.51 (m, 2H), 3.47 - 3.42 (m, 1H), 3.41 - 3.35 (m, 2H), 3.31 - 3.27 (m, 4H), 3.27 - 3.22 (m, 1H), 3.20 (s, 3H), 3.17 - 3.12 (m, 1H), 2.96 - 2.89 (m, 1H), 2.68 - 2.64 (m, 1H), 2.47 - 2.44 (m, 1H), 2.44 - 2.37 (m, 4H), 2.35 - 2.30 (m, 1H), 2.20 - 2.14 (m, 1H), 2.12 - 2.06 (m, 2H), 2.06 - 1.96 (m, 2H), 1.69 - 1.60 (m, 1H), 1.34 (d, J = 6.1 Hz, 3H), 0.98 - 0.84 (m, 6H), 0.33 (s, 3H).

[0562] Compound 7-P2 MS (ESI + m / z = 973.4 [M+H] + .

[0563] 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.6 Hz, 1H), 8.31 (d, J = 9.3 Hz, 1H), 7.83 (s, 1H), 7.77 - 7.71 (m, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 2.9 Hz, 1H), 6.03 (d, J = 11.0 Hz, 1H), 5.38 - 5.28 (m, 1H), 4.71 (d, J = 11.0 Hz, 1H), 4.59 - 4.53 (m, 3H), 4.53 - 4.49 (m, 1H), 4.49 - 4.40 (m, 4H), 4.37 - 4.24 (m, 2H), 4.20 - 4.09 (m, 2H), 3.63 - 3.51 (m, 2H), 3.47 - 3.41 (m, 1H), 3.41 - 3.36 (m, 1H), 3.36 - 3.34 (m, 1H), 3.32 - 3.27 (m, 4H), 3.27 - 3.23 (m, 1H), 3.20 (s, 3H), 3.19 - 3.15 (m, 1H), 2.96 - 2.88 (m, 1H), 2.69 - 2.63 (m, 1H), 2.48 - 2.44 (m, 1H), 2.45 - 2.38 (m, 4H), 2.37 - 2.31 (m, 1H), 2.22 - 2.15 (m, 1H), 2.14 - 2.08 (m, 1H), 2.09 - 2.00 (m, 2H), 2.00 - 1.91 (m, 1H), 1.68 - 1.58 (m, 1H), 1.34 (d, J = 6.1 Hz, 3H), 0.96 - 0.80 (m, 6H), 0.34 (s, 3H).

[0564] Synthesis of compound 8 of example 8

[0565] Synthesis of compound 8-1 of first step

[0566] To a solution of compound Int-7 (95.0 mg, 121.33 umol) in tetrahydrofuran (1 mL) was added a solution of 2-ethylbutyryl chloride (163.3 mg, 1.21 mmol) in tetrahydrofuran (1 mL) dropwise at 0 °C. The mixture was stirred at room temperature for 2 hours. Then the reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was prepared by high performance liquid chromatography column (YMC TA-C18, 30*150mm, 5um; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 5mmol / L; mobile phase B: MeCN; MeCN ratio 65%-95%, time: 15 min, flow rate: 25 mL / min) to give compound 8-1 (20.0 mg, 21.27 umol, 17.6% yield).

[0567] MS (ESI + )m / z = 940.4 [M+H] + .

[0568] Synthesis of compound 8-2 in the second step

[0569] To a solution of compound 8-1 (20.0 mg, 21.27 umol) in N,N-dimethylformamide (0.2 mL) and tetrahydrofuran (0.2 mL) was added potassium carbonate (11.8 mg, 85.09 umol) and iodomethane (15.1 mg, 106.36 umol) at 0 °C. The mixture was stirred at room temperature for 4 hours. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 8-2 (15.0 mg, 15.72 umol, 73.9% yield).

[0570] MS (ESI + )m / z = 954.4 [M+H] + .

[0571] Synthesis of compound 8 in the third step

[0572] Sodium acetate (5.2 mg, 62.88 μmol) was added to a solution of hydroxylamine hydrochloride (4.4 mg, 62.88 μmol) in methanol (0.5 mL), the mixture was stirred at room temperature for 30 min, then compound 8-2 (15.0 mg, 15.72 μmol) was added, and the stirring was continued at room temperature for 4 h. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was prepared by high performance liquid chromatography column (YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 5 mmol / L; mobile phase B: MeCN; MeCN ratio 60%-95%, time: 15 min, flow rate: 25 mL / min) to give compound 8 (1.5 mg, 1.57 μmol, 10% yield).

[0573] MS (ESI + )m / z = 921.4 [M+H] + .

[0574] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.9 Hz, 1H), 8.43 (d, J = 1.7 Hz, 1H), 7.82 (s, 1H), 7.74 (dd, J = 8.7, 1.6 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.35 (d, J = 10.0 Hz, 1H), 7.25 (d, J = 2.9 Hz, 1H), 5.94 (d, J = 11.1 Hz, 1H), 4.98 (t, J = 8.4 Hz, 1H), 4.73 (d, J = 11.1 Hz, 1H), 4.56 (t, J = 6.5 Hz, 2H), 4.53 - 4.42 (m, 3H), 4.33 - 4.24 (m, 1H), 4.20 - 4.09 (m, 2H), 3.62 - 3.51 (m, 2H), 3.48 - 3.41 (m, 1H), 3.28 - 3.25 (m, 2H), 3.21 (s, 3H), 2.94 (d, J = 14.3 Hz, 1H), 2.79 - 2.70 (m, 1H), 2.70 - 2.62 (m, 2H), 2.45 - 2.37 (m, 5H), 2.35 - 2.30 (m, 2H), 2.18 (t, J = 9.8 Hz, 1H), 2.03 - 1.95 (m, 1H), 1.71 - 1.60 (m, 4H), 1.37 - 1.31 (m, 3H), 1.28 - 1.19 (m, 4H), 0.94 - 0.88 (m, 4H), 0.88 - 0.78 (m, 6H), 0.33 (s, 3H).

[0575] Synthesis of compound 9 of example 9

[0576] Synthesis of compound 9-1 of first step

[0577] Oxalyl chloride (325.4 mg, 2.56 mmol, 223.6 μL) was added slowly dropwise to a solution of Int-11 (300.0 mg, 1.97 mmol) in dichloromethane (3 mL) at 0°C, followed by the addition of 1 drop of N,N-dimethylformamide, and the mixture was allowed to react at room temperature for 1 hour. The reaction solution was directly concentrated to dryness to obtain a crude of compound 9-1 (360.0 mg), which was directly used in the next step.

[0578] Synthesis of compound 9-2 of second step

[0579] Compound 9-1 (130.7 mg, 766.29 μmol) was added dropwise to a solution of ammonium thiocyanate (74.8 mg, 996.18 μmol) in tetrahydrofuran (1 mL) at 0°C, and the mixture was allowed to react at room temperature for 2 hours. Then it was added to a solution of compound Int-7 (60 mg, 76.63 μmol) in tetrahydrofuran (1 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (dichloromethane:methanol = 95:5) to obtain compound 9-2 (63.0 mg, 64.54 μmol, yield: 84%).

[0580] MS (ESI + )m / z = 976.4 [M+H] + .

[0581] Synthesis of compound 9-3 of third step

[0582] Compound 9-2 (58.0 mg, 59.41 μmol) was dissolved in N,N-dimethylformamide (1 mL) and tetrahydrofuran (1 mL), and then potassium carbonate (24.6 mg, 178.23 μmol) was added, followed by the addition of iodomethane (25.3 mg, 178.23 μmol, 11.10 μL) at 0°C, and the mixture was allowed to react at room temperature for 4 hours. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL*3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 9-3 (55.0 mg, 55.53 μmol, yield: 93.45%).

[0583] MS (ESI + )m / z = 990.4 [M+H] + .

[0584] Step 4 Synthesis of compound 9

[0585] Sodium acetate (17.9 mg, 218.13 μmol) was added to a solution of hydroxylamine hydrochloride (15.2 mg, 218.13 μmol) in methanol (0.5 mL), the mixture was stirred at room temperature for 30 min, then compound 9-3 (55.0 mg, 55.53 μmol) was added, and the mixture was stirred at room temperature for another 4 h. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was prepared by high performance liquid chromatography column (YMC TA-C18, 30*150 mm, 5 μm; mobile phase A: H2O-(NH4HCO3), NH4HCO3 concentration was 5 mmol / L; mobile phase B: MeCN; MeCN ratio 50%-80%, time: 15 min, flow rate: 25 mL / min) to give compound 9 (2.2 mg, 2.3 μmol, yield: 4.1%).

[0586] MS (ESI + )m / z = 957.4 [M+H] + .

[0587] 1 H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J = 2.8 Hz, 1H), 8.43 (s, 1H), 7.83 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 9.8 Hz, 1H), 7.28 - 7.23 (m, 1H), 5.96 (d, J = 11.1 Hz, 1H), 5.35 - 5.31 (m, 1H), 5.00 - 4.94 (m, 1H), 4.75 - 4.71 (m, 1H), 4.63 - 4.43 (m, 8H), 4.40 - 4.35 (m, 1H), 4.35 - 4.26 (m, 2H), 4.18 - 4.12 (m, 2H), 3.59 - 3.51 (m, 2H), 3.48 - 3.41 (m, 2H), 3.31 - 3.25 (m, 4H), 3.23 - 3.17 (m, 3H), 2.97 - 2.89 (m, 1H), 2.66 - 2.61 (m, 1H), 2.45 - 2.38 (m, 4H), 2.21 - 2.12 (m, 3H), 2.11 - 2.04 (m, 2H), 2.02 - 1.97 (m, 2H), 1.67 - 1.61 (m, 1H), 1.48 - 1.42 (m, 1H), 1.34 (d, 3H), 0.93 - 0.89 (m, 3H), 0.88 - 0.81 (m, 3H), 0.32 (s, 3H).

[0588] Synthesis of compound 10 of Example 10

[0589] Synthesis of compound 10-1 in the first step

[0590] Compound D4 (44.7 mg, 0.063 mmol) and Int-13 (37.2 mg, 0.076 mmol) were dissolved in a mixed solution of dioxane (0.3 mL), toluene (0.3 mL) and water (0.1 mL), Pd(dtbpf)Cl2 (9.8 mg, 0.015 mmol), potassium phosphate (48.8 mg, 0.23 mmol) were added to the reaction solution under nitrogen protection condition and replaced with nitrogen for 5 times, stirred at 70 °C for 4 hours, LC-MS monitoring reaction completion. Diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the crude product was purified by reverse phase column chromatography (Water (containing 0.5% NH4OH): MeCN = 95:5 to 5:95), to obtain compound 10-1 (40.0 mg, 0.040 mmol, yield: 63.5%).

[0591] MS (ESI + )m / z = 994.3 [M+H] + .

[0592] Synthesis of compound 10-2 in the second step

[0593] Compound 10-1 (34.8 mg, 0.035 mmol) was dissolved in DCE (0.6 mL), and trimethyltin hydroxide (63.3 mg, 0.35 mmol) was added. Then it was moved to 70 °C reaction for 24 hours. After the reaction was completed, dilute HCl (2 mL, 1M) was added to quench the reaction. The organic phase was extracted with ethyl acetate (5.0 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 10-2 (33.3 mg, 0.034 mmol, yield: 97.1%), which was used directly in the next step without purification.

[0594] MS (ESI + )m / z = 980.3 [M+H] + .

[0595] Synthesis of compound 10-3 in the third step

[0596] Compound 10-2 (33.3 mg, 0.034 mmol) was dissolved in N,N-dimethylformamide (0.5 mL), moved to 0 °C and added compound Int-5 (10.9 mg, 0.070 mmol) and N,N-diisopropyl ethylamine (13.6 mg, 0.11 mmol) in turn. The reaction was continued to stir at this temperature for 10 minutes, and then 2-(7-azobenzo triazole)-N,N,N',N'-tetramethyl urea hexafluorophosphate (26.8 mg, 0.070 mmol) was added. The reaction was moved to room temperature and continued to stir for 30 minutes. The reaction was complete, the reaction was filtered through diatomite, concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (Water (containing 0.5% NH4OH): MeCN = 95:5 to 5:95) to obtain compound 10-3 (16.8 mg, 0.015 mmol, yield: 44.1%).

[0597] MS (ESI + )m / z = 1118.4 [M+H] + .

[0598] Synthesis of compound 10-4 in the fourth step

[0599] Compound 10-3 (16.8 mg, 0.015 mmol) was dissolved in DCE (0.6 mL), and trimethyl tin hydroxide (63.3 mg, 0.35 mmol) was added. Then moved to 70 °C for 12 hours. The reaction was complete, and the reaction was quenched by adding dilute HCl (2 mL, 1M) in the reaction. The organic phase was extracted with ethyl acetate (5.0 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 10-4 (15.5 mg, 0.014 mmol, yield: 93.3%), which was used directly in the next step without purification.

[0600] MS (ESI + )m / z = 1104.3 [M+H] + .

[0601] Synthesis of compound 10-5 in the fifth step

[0602] N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (42.1 mg, 0.15 mmol) and N-methylimidazole (24.6 mg, 0.30 mmol) were dissolved in anhydrous acetonitrile (1.00 mL) and stirred at 0 °C for 10 min. Compound 10-4 (15.5 mg, 0.014 mmol) was then dissolved in anhydrous acetonitrile (0.5 mL) and added dropwise to the above reaction solution at 0 °C. After the addition was completed, the reaction was continued to stir at 0 °C for 10 min. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-50:1) to obtain compound 10-5 (10.9 mg, 0.010 mmol, yield: 71.4%). MS (ESI + )m / z = 1086.3 [M+H] + .

[0603] Synthesis of compound 10-6 in the sixth step

[0604] Compound 10-5 (10.9 mg, 0.010 mmol) was dissolved in anhydrous methanol (2.00 mL), and palladium hydroxide on carbon (2.00 mg) and paraformaldehyde (11.0 mg, 0.37 mmol) were added. The reaction was stirred under a hydrogen atmosphere for 17 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain compound 10-6 (7.7 mg, 0.008 mmol, yield: 80%) which was used directly in the next step.

[0605] MS (ESI + )m / z = 966.3 [M+H] + .

[0606] Synthesis of compound 10 in the seventh step

[0607] Compound 10-6 (7.7 mg, 0.008 mmol) was dissolved in anhydrous dichloromethane (0.2 mL), and trifluoroacetic acid (7.00 mg, 0.060 mmol) was added. The reaction was carried out at 25 °C for 4 hours, and the reaction was completed. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative chromatography (the column was XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 50%-70%, time: 10 min, flow rate: 15 mL / min) to obtain compound 10 (2.1 mg, 0.0024 mmol, yield: 30%).

[0608] MS (ESI + )m / z = 866.3 [M+H] +

[0609] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.0 Hz, 1H), 8.42 (s, 1H), 7.81 (s, 1H), 7.75-7.70 (m, 1H), 7.55 (d, J = 8.7 Hz, 1H), 7.22 (s, 1H), 5.92 (d, J = 11.0 Hz, 1H), 5.72 (d, J = 7.1 Hz, 1H), 5.35 (dd, J = 10.4, 4.8 Hz, 1H), 4.75 (d, J = 11.1 Hz, 1H), 4.50 (q, J = 4.0 Hz, 1H), 4.33-4.25 (m, 1H), 4.19-4.13 (m, 2H), 3.90 (dd, J = 15.4, 7.3 Hz, 1H), 3.58 (d, J = 10.7 Hz, 1H), 3.48 (d, J = 10.8 Hz, 1H), 3.23 (s, 3H), 3.13 (d, J = 15.2 Hz, 1H), 3.09-3.01 (m, 1H), 2.97 (d, J = 14.6 Hz, 1H), 2.70-2.60 (m, 4H), 2.34-2.30 (m, 3H), 2.27-2.19 (m, 5H), 2.15 (d, J = 9.7 Hz, 1H), 2.12-2.02 (m, 2H), 2.01-1.91 (m, 1H), 1.69-1.59 (m, 2H), 1.33 (d, J = 6.1 Hz, 3H), 1.24 (s, 2H), 0.98 (d, J = 6.9 Hz, 3H), 0.95-0.92 (m, 5H), 0.91-0.82 (m, 6H), 0.30 (s, 3H).

[0610] Synthesis of compound 11

[0611] Synthesis of compound 11-1

[0612] Compound 4-2 (5.0 mg, 6.1 μmol) was dissolved in anhydrous N,N- dimethylformamide (1 mL), then ammonia water (1 mL) was added, and the reaction was carried out at room temperature for 1 hour. Water and ethyl acetate were added, and after the organic phase was separated, it was washed with saturated brine, and concentrated to dryness to obtain compound 11-1 (5.0 mg, 5.9 μmol, yield: 96.7%).

[0613] MS (ESI + )m / z = 842.4 [M+H] + .

[0614] Synthesis of compound 11

[0615] Compound 11-1 (5.0 mg, 5.9 µmol), compound Int-14 (1.4 mg, 6.1 µmol) were dissolved in absolute ethanol (1 mL), and the reaction was refluxed for 2 hours. The reaction was concentrated to dryness, and the residue was prepared by high performance liquid chromatography column (column: YMC TA-C18, 30*150 mm, 5 µm; mobile phase A: H2O (with 5 mmol NH4HCO3); mobile phase B: MeCN; MeCN ratio 50%-80%, time: 10 min, flow rate: 25 mL / min) to give compound 11 (0.9 mg, 0.9 µmol, yield: 16%).

[0616] MS (ESI + )m / z = 972.3 [M+H] + .

[0617] 1 H NMR (400 MHz, CD3OD) δ 8.35 (s, 1H), 8.31 (d, J = 2.9 Hz, 1H), 7.58 (dd, J = 8.5, 1.6 Hz, 1H), 7.44 (s, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 2.9 Hz, 1H), 6.18 (s, 1H), 5.51-5.43 (m, 1H), 4.63 (t, J = 6.6 Hz, 2H), 4.59-4.51 (m, 3H), 4.49 (s, 2H), 4.35-4.26 (m, 1H), 4.26-4.14 (m, 4H), 4.13-4.04 (m, 2H), 3.67-3.60 (m, 1H), 3.60-3.53 (m, 1H), 3.39-3.34 (m, 1H), 3.31-3.26 (m, 4H), 3.04-2.92 (m, 1H), 2.63-2.54 (m, 2H), 2.51-2.43 (m, 4H), 2.40-2.32 (m, 1H), 2.13-2.06 (m, 1H), 1.96-1.80 (m, 4H), 1.54-1.40 (m, 2H), 1.33 (d, J = 6.1 Hz, 3H), 1.29-1.14 (m, 6H), 0.95-0.86 (m, 3H), 0.86-0.77 (m, 3H), 0.41 (s, 3H).

[0618] Synthesis of compound 12 of example 12

[0619] Synthesis of compound A6-1 of first step

[0620] Compound A6 (10.4 g, 20.0 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 50.0 mL) was added. The mixture was stirred at 60 °C for 16 hours. After the reaction was completed, the reaction solution was added dropwise to water to quench the reaction, and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain the title compound A6-1 (4.67 g, 16.6 mmol, yield: 83.0%).

[0621] MS (ESI + )m / z = 282.1 [M+H] + .

[0622] Synthesis of compound 12-1 in the second step

[0623] Acetic anhydride (1.28 mL, 13.11 mmol) was slowly added dropwise to a solution of compound A6-1 (3.7 g, 13.11 mmol), 4-dimethylaminopyridine (80.1 mg, 655.6 µmol), and triethylamine (3.98 g, 39.34 mmol) in dichloromethane (40.0 mL) under ice bath. The mixture was slowly warmed to room temperature and stirred for 6 hours. After the reaction was completed, the reaction solution was added dropwise to ice water to quench the reaction, and extracted with dichloromethane. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound 12-1 (4.0 g, 12.34 mmol, yield: 94.0%).

[0624] MS (ESI + )m / z = 324.1 [M+H] + .

[0625] Synthesis of compound 12-2 in the third step

[0626] Compound 12-1 (4.6 g, 14.19 mmol), potassium acetate (3.48 g, 35.47 mmol) and bis(pinacolato)diboron (9.0 g, 35.47 mmol) were added to 1,4-dioxane (46.0 mL), then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.04 g, 1.42 mmol) was added, and the resulting mixture was purged with argon three times. The resulting mixture was heated to 90°C under argon protection and stirred for 3 hours. After the reaction was completed, the reaction solution was filtered with diatomite, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain the title compound 12-2 (4.5 g, 12.12 mmol, yield: 85.4%).

[0627] MS (ESI + )m / z = 372.1 [M+H] + .

[0628] Synthesis of compound 12-3 in the fourth step

[0629] Compound 12-2 (2.6 g, 7.0 mmol), compound B7 (2.81 g, 7.7 mmol) and potassium phosphate (3.71 g, 17.5 mmol) were dissolved in a mixed solution of dioxane (30.0 mL) and water (3.0 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (452.2 mg, 618 µmol) was added to the reaction solution under nitrogen protection and purged with argon five times, and stirred at 90°C for 12 hours. The reaction was monitored by LC-MS. Diluted with water (50 mL), extracted with ethyl acetate (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain compound 12-3 (3.0 g, 5.66 mmol, yield: 80.9%).

[0630] MS (ESI + )m / z = 530.1 [M+H] + .

[0631] Synthesis of compound 12-4 in the fifth step

[0632] Compound 12-3 (3.7 g, 6.98 mmol) and N-iodosuccinimide (1.57 g, 6.99 mmol) were added to N,N-dimethylformamide (40.0 mL), warmed to 50 °C, and stirred for 2 hours. After the reaction was completed, the reaction solution was poured into water (400.0 mL) and extracted with ethyl acetate (50.0 mL) three times. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure, and the crude product was purified by reverse phase column chromatography (water:acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound 12-4 (2.6 g, 3.97 mmol, yield: 56.77%).

[0633] MS (ESI + )m / z = 656.5 [M+H] + .

[0634] Synthesis of compound 12-5 in the sixth step

[0635] Compound 12-4 (2.6 g, 3.97 mmol) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (5 mL), and lithium hydroxide (474.9 mg, 19.8 mmol) was added to the reaction solution. After stirring at 25 °C for 16 hours, the reaction was completed as monitored by LC-MS. The organic solvent was removed by distillation under reduced pressure, diluted with ethyl acetate and water, and the aqueous phase was adjusted to about pH 6 with 1M aqueous HC1 solution. Ethyl acetate (30.0 mL) was added to extract the organic phase, which was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12-5 (2.3 g, 3.84 mmol, yield: 96.7%).

[0636] MS (ESI + )m / z = 600.0 [M+H] + .

[0637] Synthesis of compound 12-6 in the seventh step

[0638] Compound 12-5 (393.0 mg, 655.2 μmol), compound Int-5 (265.0 mg, 1.7 mmol), N,N-diisopropylethylamine (1.69 g, 13.11 mmol), and 2-(7-azobenzo-triazol-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (370.8 mg, 975.3 μmol) were added to a solution of N,N-dimethylformamide (8.0 mL), and stirred at room temperature for 2 hours. After the reaction was completed, the crude product was purified by reverse phase column chromatography (water:acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound 12-6 (290.0 mg, 393.1 μmol, yield: 60.0%).

[0639] MS (ESI+ m / z = 738.1 [M+H] +

[0640] Synthesis of compound 12-7 in the eighth step

[0641] Compound 12-6 (290 mg, 393.1 μmol) was dissolved in a mixed solution of tetrahydrofuran (2.0 mL) and water (2.0 mL), and lithium hydroxide (94.1 mg, 3.93 mmol) was added to the reaction solution. The mixture was stirred at 25°C for 2 hours, and the reaction was monitored by LC-MS. After dilution with ethyl acetate and water, the aqueous phase was adjusted to pH 6 with 1M aqueous HC1 solution, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12-7 (200.0 mg, 276.4 μmol, yield: 70.3%).

[0642] MS (ESI + m / z = 724.1 [M+H] +

[0643] Synthesis of compound 12-8 in the ninth step

[0644] Compound 12-7 (140.0 mg, 193.4 μmol), N-methylimidazole (794.2 mg, 9.67 mmol), and N,N,N',N'-tetramethylchloroformamidium hexafluorophosphate (298.5 mg, 1.06 mmol) were added to a mixed solution of N,N-dimethylformamide (1.2 mL) and acetonitrile (12.0 mL), and stirred at room temperature for 2 hours. After the reaction was completed, the crude product was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to obtain the title compound 12-8 (44.0 mg, 62.3 μmol, yield: 32.2%).

[0645] MS (ESI + m / z = 706.2 [M+H] +

[0646] Synthesis of compound 12-9 in the tenth step

[0647] ​​​Compound 12-8 (98.0 mg, 138.0 μmol), potassium acetate (19.47 mg, 198.4 μmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-biphenyl (SPhos) (11.6 mg, 28.3 μmol) and tris(dibenzylideneacetone)dipalladium (10.3 mg, 11.3 μmol) were added to 1,4-dioxane (4.0 mL) and purged with argon three times. The mixture was cooled to 0 °C in an ice bath and a solution of pinacolborane (58.0 mg, 453.5 μmol) in 1,4-dioxane (4.0 mL) was added dropwise to the mixture under argon atmosphere. The reaction was then heated to 50 °C and stirred for 3 h. After completion of the reaction, the reaction mixture was filtered over celite and the filtrate was washed with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude obtained was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to give the title compound 12-9 (25.0 mg, 35.4 μmol, 25.6% yield).

[0648] MS (ESI + )m / z = 706.1 [M+H] + .

[0649] Synthesis of compound 12-10

[0650] Compound 12-9 (25.0 mg, 35.4 μmol), compound Int-15 (18.7 mg, 53.1 μmol) and potassium carbonate (14.7 mg, 106.2 μmol) were added to a mixture of 1,4-dioxane (3.6 mL) and water (0.9 mL) and purged with argon. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (5.2 mg, 7.1 μmol) was added under argon atmosphere and the resulting mixture was heated to 70 °C for 16 h under argon atmosphere. After completion of the reaction, the reaction mixture was filtered over celite and the filtrate was washed with saturated aqueous sodium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude obtained was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to give the title compound 12-10 (19.6 mg, 23.0 μmol, 65% yield).

[0651] MS (ESI + )m / z = 852.2 [M+H] + .

[0652] Synthesis of compound 12-11

[0653] Compound 12-10 (19.6 mg, 23.0 μmol) and cesium carbonate (24.5 mg, 75.2 μmol) were added to N,N-dimethylformamide (2.0 mL) and argon was bubbled through. To the reaction, iodoe thane (5.8 mg, 37.5 μmol) was added dropwise under argon atmosphere and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the organic phase was dried and concentrated to give the crude product which was purified by reverse phase column chromatography (water: acetonitrile, gradient: 95 / 5 to 5 / 95) to isolate the less polar isomer to give the title compound 12-11 (7.0 mg, 8.0 μmol, yield: 34.8%).

[0654] MS (ESI + )m / z = 880.2 [M+H] + .

[0655] Synthesis of compound 12-12

[0656] To a solution of compound 12-11 (15.2 mg, 17.2 μmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.7 mL) dropwise at room temperature and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction was concentrated to dryness and washed with aqueous sodium bicarbonate solution and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound 12-12 (12.7 mg, 16.3 μmol, yield: 94.8%).

[0657] MS (ESI + )m / z = 780.2 [M+H] + .

[0658] Synthesis of compound 12-13

[0659] To a solution of compound 4-1 (2.6 mg, 11.28 μmol) in dichloromethane (1 mL) was added dropwise a solution of compound 12-12 (12.7 mg, 16.3 μmol) and N,N-diisopropylethylamine (2.7 mg, 20.51 μmol, 3.57 μL) in dichloromethane (1 mL) under argon protection at an ice-salt bath. The mixture was stirred for 5 minutes. TLC showed that the starting material was completely converted. The reaction was concentrated and the residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to give compound 12-13 (9.0 mg, 10.9 μmol, yield: 66.9%).

[0660] MS (ESI + )m / z = 822.3

[0661] Synthesis of compound 12-14

[0662] Under argon protection, 4-fluoro-2-(2-fluoroethyl)butyric hydrazide (compound 7-1, 2.7 mg, 16.42 μmol) was added to a solution of compound 12-13 (9.0 mg, 10.9 μmol) in acetonitrile (0.5 mL), and the mixture was reacted at 90 °C for 30 min. LC-MS was used to monitor the completion of the reaction, and the reaction solution was distilled under reduced pressure. The residue was purified by column chromatography (dichloromethane:methanol = 100:0-90:10) to obtain compound 12-14 (10.0 mg, 10.1 μmol, yield: 92.7%). MS (ESI + )m / z = 988.4 [M+H] + .

[0663] Synthesis of compounds 12-P1 and 12-P2 in the sixteenth step

[0664] Triphenylphosphine (7.4 mg, 28.33 μmol) and N,N-diisopropylethylamine (14.7 mg, 113.34 μmol, 19.8 μL) and hexachloroethane (6.7 mg, 28.33 μmol) were sequentially added to a solution of compound 12-14 (10.0 mg, 10.1 μmol) in acetonitrile (1 mL), and the mixture was reacted at room temperature for 18 h. The reaction solution was concentrated to dryness, and the residue was subjected to high performance liquid chromatography (the column was XBridge Prep C18; 150*19 mm*5 μm; mobile phase A: H2O-(NH3H2O), NH3H2O concentration was 0.05%; mobile phase B: MeCN; MeCN ratio 55%-75%, time: 10 min, flow rate: 15 mL / min) to obtain compound 12-P1 (1.3 mg, 1.4 μmol, yield: 13.8%, retention time: 7.62 min) and 12-P2 (1.0 mg, 1.0 μmol, yield: 9.9%, retention time: 8.38 min).

[0665] Compound 12-P1 MS (ESI + )m / z = 954.4 [M+H] + .

[0666] 1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 9.7 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.86 (s, 1H), 7.76 (dd, J = 8.6, 1.6 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 6.01 (d, J = 10.9 Hz, 1H), 5.04 (t, J = 8.5 Hz, 1H), 4.77 (d, J = 11.0 Hz, 1H), 4.62 - 4.53 (m, 1H), 4.53 - 4.42 (m, 3H), 4.41 - 4.32 (m, 1H), 4.02 - 3.88 (m, 2H), 3.87 - 3.78 (m, 1H), 3.71 - 3.66 (m, 4H), 3.66 - 3.52 (m, 4H), 3.25 - 3.22 (m, 1H), 3.17 - 3.13 (m, 1H), 3.09 (s, 3H), 3.07 - 3.02 (m, 1H), 2.80 - 2.73 (m, 4H), 2.39 - 2.34 (m, 2H), 2.22 - 2.13 (m, 1H), 2.13 - 1.94 (m, 5H), 1.88 - 1.81 (m, 2H), 1.72 - 1.64 (m, 1H), 1.21 (d, J = 6.3 Hz, 3H), 1.16 - 1.07 (m, 4H), 0.93 (s, 3H), 0.49 (s, 3H).

[0667] Compound 12-P2 MS (ESI + m / z = 970.4 [M+H] + .

[0668] 1H NMR (400 MHz, DMSO-d6) δ 8.80 (d, J = 2.1 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 8.30 (d, J = 9.1 Hz, 1H), 7.86 (d, J = 2.2 Hz, 1H), 7.85 (s, 1H), 7.77 (dd, J = 8.8, 1.7 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 6.03 (d, J = 11.0 Hz, 1H), 5.33 - 5.32 (m, 1H), 4.71 (d, J = 11.0 Hz, 1H), 4.56 - 4.48 (m, 2H), 4.47 - 4.40 (m, 2H), 4.38 - 4.24 (m, 3H), 4.12 - 4.03 (m, 1H), 3.71 - 3.67 (m, 4H), 3.65 - 3.62 (m, 2H), 3.60 - 3.54 (m, 2H), 3.27 - 3.25 (m, 1H), 3.24 (s, 3H), 3.20 - 3.16 (m, 1H), 2.94 - 2.89 (m, 1H), 2.78 - 2.72 (m, 4H), 2.23 - 2.15 (m, 2H), 2.12 - 2.07 (m, 1H), 1.98 - 1.93 (m, 5H), 1.87 - 1.82 (m, 2H), 1.66 - 1.59 (m, 1H), 1.36 (d, J = 6.1 Hz, 3H), 1.32 - 1.29 (m, 4H), 0.85 (s, 3H), 0.34 (s, 3H).

[0669] The compounds in the following table were synthesized according to the methods of the above examples by changing some of the starting materials:

[0670] Biological tests

[0671] Test Example 1, Effect of compounds on the proliferation activity of tumor cells

[0672] Experimental materials and instruments:

[0673] Materials needed for this experiment include: cell culture medium RPMI-1640 (Basal Media #L240KJ); DMEM (Basal Media #L110KJ); fetal bovine serum (FBS) (Proteintech #PM00011); PBS phosphate buffer (Basal Media #B320KJ); 0.25% trypsin (Gibco #25200-072); 100% DMSO (Sigma #D2650); 96-well sterile transwell culture plates (Corning #3599); 96-well plates (Corning #3610); CellTiter-Glo® Luminescent Cell Viability Assay Kit (Vazyme #DD1101); 25 mL pipette (Corning); 5 mL pipette (Corning); P1000 pipette tips, P200 pipette tips, and P10 pipette tips (Axygen). 2.0

[0674] Instruments and equipment needed for this experiment include: Eppendorf pipette; Eppendorf pipette gun; Eppendorf centrifuge; constant temperature carbon dioxide incubator (ThermoFisher); automatic cell counter Vi-cell XR (Beckman Coulter); Envision microplate reader (Perkin Elmer).

[0675] Cells needed for this experiment include: KRAS G12D mutant cell line AsPC-1 (ATCC #CRL-1682 TM ), and the complete culture medium is RPMI-1640 medium containing 10% FBS.

[0676] Experimental methods:

[0677] AsPC-1 cells were digested from culture flasks using 0.25% trypsin and resuspended with corresponding fresh complete medium. After counting, AsPC-1 was adjusted to a cell density of 2000 cells / 90 μL / well, and 90 μL was added to a 96-well plate, which was incubated in a 37°C, 5% CO2 cell incubator overnight. Compound stock solution was 10 mM, diluted to 1 mM using DMSO 10-fold, then diluted to 10 μM using complete medium 100-fold, and then diluted 3-fold gradient using complete medium containing 1% DMSO, with 9 concentration gradients in sequence; 10 μL / well of the gradient-diluted compound was added to the cell culture well, so that the final DMSO content in each well was 1 / 1000. The positive control group was the medium well without cell planting; the negative control group was the cell planting well without compound treatment. The cell plate was incubated in a 37°C, 5% CO2 incubator for 5 days. An equal volume of Cell Counting-Lite 2.0 detection reagent was added to each well of the cell plate, and the cells were fully lysed by shaking for 2-5 min, and the luminescence signal was stabilized by placing the plate at room temperature for 10 min. The luminescence value was read using an Envision microplate reader. The inhibition rate was calculated according to the following formula: Inhibition % = (Signal negative control - Signal sample ) / (Signal negative control - Signal positive control) * 100. The IC 50 values were calculated using 4-parameter fitting of IDBS XLfit. The measured IC 50 values are shown in Table 1.

[0678] Table 1

[0679] Test Example 2: Inhibition of cytochrome P450 enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 by the compounds of the present disclosure

[0680] I. Test materials and test equipment

[0681] 1. Reagents

[0682] 2. Liver microsomes

[0683] 3. Test equipment

[0684] II. Experimental procedures

[0685] 1. Prepare the test compound as a 10 mM stock solution in DMSO. Dilute the stock solution with DMSO to obtain the following concentrations of the test compound in DMSO: 0, 4, 20, 100, 400, 2000 and 10000 μM. The final concentration of the test compound in the incubation system is 0, 0.02, 0.1, 0.5, 2, 10 and 50 μM. The volume ratio of the organic solvent introduced into the test system with the test compound is 0.5%. The final concentration of the positive inhibitor in the reaction system is shown in the following table.

[0686] Working solution concentration of the positive inhibitor

[0687] Final concentration of the positive inhibitor in the reaction system

[0688] 2. Preparation of the substrate stock solution

[0689] The preparation of the substrate stock solution is shown in the following table. The stock solution is stored at -20 °C. Before use, it is thawed at room temperature.

[0690] Information of the substrate stock solution

[0691] 3. Preparation of the phosphate buffer (100 mM, pH 7.4)

[0692] Weigh 7.098 g of disodium hydrogen phosphate and add 500 mL of purified water. Dissolve by ultrasonic and use as solution A. Weigh 3.400 g of potassium dihydrogen phosphate and add 250 mL of purified water. Dissolve by ultrasonic and use as solution B. Place solution A on a stirrer and slowly add solution B until the pH value reaches 7.4. Store the phosphate buffer at 4 °C.

[0693] 4. Preparation of 10 mM NADPH

[0694] Before the test, weigh an appropriate amount of NADPH and prepare a working solution with a concentration of 10 mM in phosphate buffer. The final concentration of NADPH in the test system is 1 mM.

[0695] 5. Preparation of the incubation system

[0696] The preparation of the incubation system is shown in the following table. Before use, preheat in a water bath at 37 °C for 15 minutes.

[0697] 6. Test method

[0698] The entire incubation was performed in a 96-well deep well plate. First, 179 μL of incubation system was added to the deep well plate, then 1 μL of compound solution or vehicle (DMSO) was added, and then 20 μL of 10 mM NADPH solution was added. Before starting the reaction, the incubation system was preheated at 37 °C for 15 minutes. After adding NADPH to start the reaction, it was incubated at 37 °C for 45 minutes. The test sample was prepared in duplicate.

[0699] After incubation for 45 min, the reaction was terminated by adding 400 μL of ice methanol (containing internal standard, 10 ng / mL gliclazide and 10 ng / mL propranolol). After vortex mixing, the deep well plate was centrifuged at 4000 rpm, 4 °C for 10 min. 100 μL of supernatant was transferred to a new 96-well plate, 100 μL of pure water was added and mixed, and then subjected to LC-MS / MS analysis.

[0700] III. Data analysis

[0701] The generated metabolites were analyzed by LC-MS / MS. The decrease in the generation of metabolites in the drug administration group compared with the blank solvent control group was compared by the ratio of the peak area of the sample to the internal standard, and the IC value was calculated based on the percentage of residual activity using GraphPad Prism 8.0. 50

[0702] The percentage of residual activity was calculated using the following formula:

[0703] Percentage of residual activity (%) = ratio of peak area of metabolite to peak area of internal standard 受试物 / ratio of peak area of metabolite to peak area of internal standard 空白溶剂 x 100%.

[0704] The test results are shown in Table 2.

[0705] Table 2 Inhibition of cytochrome P450 enzymes by compounds of the present disclosure

[0706] “-” data not read out

[0707] Test Example 3: Rat hepatocyte stability test

[0708] Purpose of the experiment: to study the metabolic stability of the compound in cryopreserved SD rat hepatocytes

[0709] Experimental materials: suspended hepatocytes of SD rats

[0710] ​Experimental operation: The cryopreserved rat hepatocytes were taken out from the liquid nitrogen tank and recovered, and the cell viability was calculated by trypan blue staining method. The hepatocyte suspension was added to the preheated incubation plate, then the test product and control compound working solution (preparation method: 1 mM test product compound was diluted to 100 μM with ACN, 3 mM control compound was diluted to 300 μM with ACN) were added, mixed and immediately placed in the shaking plate machine in the incubator, and the timer was started to start the reaction. The reaction was set at 0, 15, 30, 60 and 90 minutes incubation time points, and the incubation conditions were 37℃, saturated humidity, containing 5% CO2. In the reaction system, the final concentration of the test product was 1 μM, the final concentration of the control product was 3 μM, and the final concentration of rat hepatocytes was 0.5×10 6 cells / mL. At the corresponding time point, the incubation plate was taken out, and an appropriate amount of cell suspension was taken into a sample plate containing a certain volume of stop solution (250 nM tolbutamide and labetalol in acetonitrile solution). After all the sample plates were sealed and shaken on the shaking plate machine at 600 rpm for 10 minutes, they were centrifuged at 3220×g for 20 minutes. The supernatant of the test product and control product was diluted with ultrapure water at a ratio of 1:3. After all the samples were mixed, they were analyzed by LC / MS / MS method, and the elimination rate constant and clearance rate of the test compound in rat hepatocytes were calculated by using the following formula.

[0711] Data analysis: The in vitro elimination rate constant k of the test product and control compound was obtained by converting the ratio of the peak area of the compound to the internal standard in the following formula into the remaining percentage. e :

[0712] When

[0713] The in vitro intrinsic clearance (CL e ) was obtained by the elimination rate k int(liver) , and the formula was as follows:

[0714] CL int(hep) = k e / per million cells (million cells / mL)

[0715] CL int(liver) = CL int(hep) × liver weight / body weight ratio × liver cell number per gram of liver

[0716] The experimental results showed that the compound of the present application had excellent stability in rat hepatocytes.

[0717] The test results are shown in Table 3.

[0718] Table 3 Rat stability results of the compound of the present disclosure

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, X 1 selected from CHR 11 and NR 12 ; X 2 is selected from CH2and NH; L is selected from NH, NR 13 or CR 14 R 15 ; A is selected from C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12-membered heteroarylene, the C3-C 12 Cycloalkylene, 4-10 membered heterocyclic alkylene, C6-C 10 arylene and 5-12 heteroarylene are optionally enclosed by one or more R a replace; R 1 Selected from C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl, the C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-12 heteroaryl groups are optionally substituted with one or more R groups. 1a replace; R 2 R 3 R 7 R 8 and R 9 Independently selected from hydrogen, halogen, hydroxyl, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Halogenated alkyl groups and C3-C7 cycloalkyl groups; or R 7 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R 8 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R b substituents; R 4 selected from hydrogen, halogen, hydroxyl, cyano, C2-C 10 alkenyl, C2-C 10 alkynyl and CrC 10 alkyl, said hydroxyl, C2-C 10 alkenyl, C2-C 10 alkynyl and CrC 10 alkyl optionally substituted with 1 or more R 4a ; R 5 selected from the group consisting of C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl, said C1-C 10 alkyl, C3-C 12 cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl and 5-10 membered heteroaryl are optionally substituted with 1 or more R 5a ; or R 4 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R 5 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R c substituents; or R 4 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R 7 and the atom to which they are attached together form a 4-10 membered heterocyclyl ring, which is optionally substituted with 1 or more R d substituents; R 6 , R 10 , R 11 and R 12 are independently selected from the group consisting of hydrogen, halogen, amino, hydroxyl, thiol, cyano, C1-C4alkyl, C1-C4haloalkyl and C1-C4alkoxy; or R 10 and the C attached thereto, and CH2between the two Cs collectively form C4-C 11 and the C attached thereto, and CH2between the two Cs collectively form C4-C 12 saturated carbocyclic or 4-10 membered heterocyclic ring; or R 10 and the C and R 12 and the C and N to which they are attached, and CH2between the C and N, collectively form a 4-10 membered heterocyclic ring; R 13 , R 14 , and R 15 are independently selected from the group consisting of null, hydrogen, C1-C4alkyl, C1-C4haloalkyl, and C1-C4alkoxy; or R 1 and R 13 and the atom to which they are attached, or R 1 and R 14 and the atom to which they are attached, together form a 4-10 membered heterocyclic ring or a 5-10 membered heteroaromatic ring, which is optionally substituted with 1 or more R 1a substituents; Each R a Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, and C1-C4 alkyl groups; each R is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, wherein the amino, hydroxyl, thiol, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with R 1a 10 10 10 12 10 10 10 10 12 10 e each R is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl, wherein the amino, hydroxyl, thiol, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyl, C3-C6cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl are optionally substituted with R​​​​​​​​​​​ Each R 4a R b and R d Independently selected from halogens, amino groups, hydroxyl groups, mercapto groups, cyano groups, C1-C7 alkyl groups, C1-C7 haloalkyl groups, C3-C6 cycloalkyl groups, and C1-C7 alkoxy groups; Each R 5a Independently selected from halogen, cyano, amino, hydroxyl, mercapto, oxo, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl, 4-15 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the amino, hydroxyl, mercapto, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl, 4-15 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. f replace; Each R c Independently selected from hydroxyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl and 5-10 heteroaryl groups, wherein the hydroxyl group, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. e replace; Each R e Independently selected from halogen, cyano, amino, hydroxyl, mercapto, C1-C 10 Alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl group, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl groups are optionally bounded by one or more R groups. g replace; each R is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7haloalkyl, C1-C7alkoxy, 4-10 membered heterocyclyl optionally substituted with halogen, amino, hydroxyl, thiol, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, and C1-C4alkoxy; and g each R is independently selected from the group consisting of halogen, amino, hydroxyl, thiol, cyano, C1-C7alkyl, C1-C7haloalkyl, C1-C7alkoxy, 4-10 membered heterocyclyl optionally substituted with halogen, amino, hydroxyl, thiol, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4hydroxyalkyl, and C1-C4alkoxy; and 10 cycloalkyl; Each R f Independently selected from halogen, amino, hydroxyl, mercapto, cyano, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl and 4-12 membered heterocyclic groups, wherein the amino, hydroxyl, mercapto, C1-C7 alkyl, C1-C7 alkoxy, C3-C 10 Cycloalkyl groups and 4-12 membered heterocyclic groups are optionally surrounded by one or more R groups. h replace; each R is independently selected from the group consisting of halogen, hydroxyl, thiol, amino, =0, =CR h =CR j R j , C1-C4 alkyl, cyano, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 haloalkyl, (C1-C4 alkylene)OC1-C4 alkyl, C(O)R k , S(O)2R k and C1-C4 alkoxy, said hydroxyl, thiol, amino, C1-C4 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocycloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 haloalkyl, (C1-C4 alkylene)OC1-C4 alkyl and C1-C4 alkoxy being optionally substituted with halogen, hydroxyl, cyano and C1-C4 alkyl; R j and R k Independently selected from H, halogen, hydroxyl, mercapto, cyano, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 Alkoxy, hydroxyl, mercapto, amino, C1-C4 alkyl, C2-C 10 alkenyl, C2-C 10 alkynyl and C1-C 10 The alkoxy group may be optionally substituted with halogen, hydroxyl, mercapto, amino, =O, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, N(C1-C4 alkyl)2, and NH(C1-C4 alkyl); and one or more hydrogen atoms of the compound are optionally deuterium atoms.

2. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 1 is selected from CHR 11 ; or X 1 is CH2; and / or X 2 is NH; and / or R 10 is hydrogen.

3. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 1 is selected from CHR 11 wherein R 10 and the C to which they are attached, R 11 and the C to which they are attached, and CH2between the two Cs together form a C4-C6saturated carbocyclic ring; or, X 1 is selected from CHR 11 wherein R 10 and the C to which they are attached, R 11 and the C to which they are attached, and CH2between the two Cs together form a C4saturated carbocyclic ring.

4. The compound of claim 1 of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, selected from optionally, R 10 is hydrogen.

5. The compound of formula (I) as claimed in any one of claims 1-4, or its stereoisomer or its pharmaceutically acceptable salt, wherein, A is selected from C6-C10 arylene, 5-6 membered heterocyclylene, and 5-6 membered heteroarylene, said C6-C10 arylene, 5-6 membered heterocyclylene, and 5-6 membered heteroarylene being optionally substituted with 1 or more R 10 arylene, 5-6 membered heterocyclylene, and 5-6 membered heteroarylene being optionally substituted with 1 or more R 10 arylene, 5-6 membered heterocyclylene, and 5-6 membered heteroarylene being optionally substituted with 1 or more R a substituted; or, A is selected from 6 membered heterocyclylene or 5 membered heteroarylene, wherein said 6 membered heterocyclylene or 5 membered heteroarylene is optionally substituted with 1 or more R a substituted; or, A is selected from 6 membered heterocyclylene having 1 N atom and 1 O atom or 5 membered heteroarylene having 1 N atom and 1 S atom, wherein said 6 membered heterocyclylene or 5 membered heteroarylene is optionally substituted with 1 R a substituted; or, A is selected from morpholylene and thiazolylene, said morpholylene and thiazolylene being optionally substituted with 1 or more R a substituted; or, A is substituted; or A is substituted; or A is a substituted; or A is 6. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-5, wherein, R 1 is selected from 6-10 membered heterocyclyl and 5-6 membered heteroaryl, said 6-10 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with 1 or more R 1a ; or, R 1 is selected from 8-9 membered heterocyclyl and 5-6 membered heteroaryl, said 8-9 membered heterocyclyl and 5-6 membered heteroaryl optionally substituted with 1 or more R 1a ; or, R 1 is selected from 8-9 membered heterocyclyl and 5-6 membered heteroaryl, said 8-9 membered heterocyclyl and 5-6 membered heteroaryl having 1 N atom and 1 or 2 heteroatoms independently selected from N, O or S, and optionally substituted with 1 or more R 1a ; or, R 1 is selected from isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyrimidinyl, pyridazinyl, triazinyl, isoxazolyl, oxazolyl, imidazolyl, optionally substituted with 1 or more R 1a ; or, R 1 is selected from oxadiazolyl or thiadiazolyl, said oxadiazolyl or thiadiazolyl optionally substituted with 1 or more R 1a ; or, R 1 is selected from 7. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-6, wherein, Each R 1a Independently selected from C1-C5 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups and phenyl, wherein the C1-C5 alkyl, C3-C6 cycloalkyl, 4-6 membered heterocyclic groups and phenyl are optionally surrounded by one or more R... e Replace; or, each R 1a Independently selected from methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, The methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, Optional by one or more R e Replace; or, each R 1a Independently selected from methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, n-butyl, The methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, n-butyl, Optional by one or more R e Replace; and / or each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R g each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R e each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R g each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R e each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R g each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R e each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R g each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R e each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 aryl, said hydroxyl, C1-C3 alkyl, and C6 aryl optionally substituted with one or more R g each R is independently selected from the group consisting of halogen, cyano, hydroxyl, C1-C3 alkyl, C2 alkenyl, C3-C6 cycloalkyl, and C6 ar each R g is independently selected from the group consisting of halogen, Ci-C6alkyl, and Ci-C6alkoxy; or each R g is independently selected from the group consisting of halogen, Ci-C3alkyl, and Ci-C3alkoxy, or each R g is independently selected from the group consisting of fluorine, methyl, and methoxy; or each R g is independently selected from the group consisting of fluorine and methoxy.

8. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-7, wherein, L is NH; or, L is NR 13 , R 1 and R 13 , together with the atom to which they are attached, form a 5-6 membered heteroaromatic ring or a triazole ring, said 5-6 membered heteroaromatic ring or triazole ring being optionally substituted with one or more R 1a ; or, L is CR 14 R 15 , R 1 and R 14 , together with the atom to which they are attached, form a 5-6 membered heteroaromatic ring or a triazole ring, said 5-6 membered heteroaromatic ring or triazole ring being optionally substituted with one or more R 1a , R 15 is absent; or, L is NR 13 , R 1 and R 13 , together with the atom to which they are attached, form a 6-10 membered heterocyclic ring, said 6-10 membered heterocyclic ring optionally containing N, -C(=O)-, -C(=O)NH- as heteroatoms or heteroatom groups, and being optionally substituted with one or more R 1a or with one R 1a , wherein R 1a is independently selected from C1-C6 alkyl, such as isopropyl; or, L is NR 13 , R 1 and R 13 , together with the atom to which they are attached, form said being optionally substituted with one or more R 1a ; or, L is NR 13 , R 1 and R 13 , together with the atom to which they are attached, form or, L is CR 14 R 15 , R 1 and R 14 , together with the atom to which they are attached, form said being optionally substituted with one or more R 1a , R 15 is absent; or, L is CR 14 R 15 , R 1 and R 14 , together with the atom to which they are attached, form 9. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-8, wherein, R 2 and R 3 Independently selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 Alkyl; or R 2 and R 3 Independently selected from C1-C4 alkyl groups, such as methyl; or R 2 and R 3 All are methyl groups.

10. The compound of formula (I) as claimed in any one of claims 1-9, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein, R 4 is selected from C1-C4alkyl, said C1-C4alkyl optionally substituted with 1 or more R 4a ; or, R 4 is ethyl, said ethyl optionally substituted with 1 or more R 4a ; or, R 4 is ethyl, ethyl substituted with 1 cyclopropyl, or ethyl substituted with 1 or more fluoro; or, R 4 is ethyl, -CH2-cyclopropyl, or -CH2-CF3; and / or R 4a is independently selected from the group consisting of cyclopropyl, halo, amino, hydroxy, thiol, and cyano; or, R 4a is independently selected from the group consisting of cyclopropyl and halo; or, R 4a is halo, for example, fluoro; or, R 4 and R 7 together with the atom to which they are attached form a 6-7 membered heterocycloalkyl optionally substituted with 1 or more R d ; or, R 4 and R 7 together with the atom to which they are attached form an unsubstituted 6-7 membered heterocycloalkyl; or, R 4 and R 7 together with the atom to which they are attached form an unsubstituted 6-7 membered heterocycloalkyl having 1 N atom and optionally 1 O atom.

11. The compound of formula (I) as claimed in any one of claims 1-10, or its stereoisomer or pharmaceutically acceptable salt thereof, wherein, R 5 selected from 4-10 membered heterocyclyl and 5-10 membered heteroaryl, said 4-10 membered heterocyclyl and 5-10 membered heteroaryl optionally substituted with 1 or more R 5a ; or, R 5 selected from 9-10 membered heterocyclyl and 6-10 membered heteroaryl, said 9-10 membered heterocyclyl and 6-10 membered heteroaryl optionally substituted with 1 or more R 5a ; or, R 5 selected from said optionally substituted with 1 or more R 5a ; optionally, R 5 is substituted at the position ortho to the site of attachment of the remainder of the molecule with -CH(CH3)-O-CH3 or -(S)-CH(CH3)-O-CH3; or R 5 is ; or, R 5 selected from ; or R 5 selected from 12. The compound of formula (I) or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-11, wherein, R 5a is independently selected from the group consisting of halogen, cyano, oxo, Ci-C4alkyl, C2-C4alkynyl, and 4-10 membered heterocyclyl, said Ci-C4alkyl, C2-C4alkynyl, and 4-10 membered heterocyclyl being optionally substituted with 1 or more R 10 10 10 10 f is independently selected from the group consisting of halogen, cyano, oxo, Ci-C4alkyl, C2-C4alkynyl, and 6-10 membered heterocyclyl, said Ci-C4alkyl, C2-C4alkynyl, and 6-10 membered heterocyclyl being optionally substituted with 1 or more R 5a f 5a is independently selected from the group consisting of fluorine, cyano, oxo, methyl, piperidinyl, propynyl, piperazinyl, ethyl, ethynyl, said methyl, piperidinyl, propynyl, piperazinyl, ethyl, ethynyl, optionally substituted with 1 or more R f 5a is independently selected from the group consisting of ethyl, said ethyl, optionally substituted with 1 or more R f .​​​​​​​ 13. The compound of formula (I) as claimed in any one of claims 1-12, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R f is independently selected from C1-C4alkyl, C1-C4alkoxy, unsubstituted C3-C5cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with C1-C4hydroxyalkyl, cyano, C1-C4alkyl, C1-C4haloalkyl, and halogen; or, R f is independently selected from C1-C4alkyl, C1-C4alkoxy, unsubstituted C3-C5cycloalkyl, and 5, 6, or 7 membered heterocyclyl optionally substituted with hydroxymethyl; or, R f is independently selected from methyl, methoxy, cyclopropyl, morpholinyl, oxetanyl, or R f is independently selected from methoxy, -CH3, 14. The compound of formula (I) as claimed in any one of claims 1-13, or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein, R 6 Selected from hydrogen, halogen, amino, hydroxyl, mercapto, cyano, and C1-C4 alkyl, as well as R 7 Selected from hydrogen, halogen, hydroxyl, and cyano groups; or, R 6 and R 7 All are hydrogen; and / or, R 8 Selected from hydrogen, halogen, hydroxyl, cyano and C1-C 10 Alkyl; or R 8 For hydrogen; and / or, R 9 Selected from hydrogen, halogen, hydroxyl, and cyano groups; or, R 9 Selected from hydrogen and halogens; or, R 9 Selected from hydrogen and fluorine.

15. The compound of Formula (I) according to any one of claims 1 and 5-14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of a compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 2 , A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 as defined in any one of claims 1 and 5-14.

16. The compound of formula (I) as claimed in claim 15, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein X 2 For NH; A is an imidazolyl group; R 1 It is a 5-membered heteroaryl group containing at least one nitrogen atom, or R 1 The 5-membered heteroaryl, oxadiazolyl, or thiadiazolyl group is formed by one R group. 1a Replace; R 1a For being 2 R e Replacement R e It is fluorine; R 2 and R 3 All are methyl; R 4 It is ethyl; R 5 for and R 6 R 7 R 8 and R 9 All are hydrogen, or, X 2 NH; A is R 1 is oxadiazolyl or thiadiazolyl, said oxadiazolyl or thiadiazolyl being substituted by 1 R 1a substituted; R 1a is R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 , and R 9 are each hydrogen.

17. The compound of Formula (I) according to any one of claims 1 and 5-14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, selected from a compound of Formula (III), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 2 , A, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 as defined in any one of claims 1 and 5-14.

18. The compound of claim 17 of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein X is NH; A is thiazolylene; R is a 5-membered heteroaryl containing at least one N atom, or R is oxadiazolyl or thiadiazolyl, said 5-membered heteroaryl, oxadiazolyl or thiadiazolyl being substituted with 1 R ; R is selected from C3alkyl, C4alkyl, C5alkyl, cyclopropyl, cyclobutyl or cyclopentyl, each optionally substituted with 1 or 2 R ; R is independently fluoro, methyl or ethyl; R and R are each methyl; R is ethyl; R is 2 1 1 1a 1a e e 2 3 4 5 1a f f 6 7 8 9 each R is hydrogen; or,​​​​​​​​​​​​​​​​​​​ X 2 is NH; A is thiazolylene; R 1 is a 5-membered heteroaryl containing at least one N atom, or R 1 is oxadiazolyl or thiadiazolyl, said 5-membered heteroaryl, oxadiazolyl or thiadiazolyl being substituted with 1 R 1a ; R 1a is selected from C3alkyl, C4alkyl, C5alkyl, cyclopropyl, cyclobutyl or cyclopentyl, each optionally substituted with 1 or 2 R e ; R e is independently fluoro, methyl or ethyl; R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 and R 9 are each hydrogen; or, X 2 is NH; A is R 1 is oxadiazolyl or thiadiazolyl, said oxadiazolyl or thiadiazolyl being substituted with 1 R 1a ; R 1a is selected from C3alkyl, C4alkyl, C5alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, each optionally substituted with 2 methyl or 2 fluoro; R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 , and R 9 are each hydrogen; or, X 2 is NH; A is R 1 is oxadiazolyl or thiadiazolyl, said oxadiazolyl or thiadiazolyl being substituted with 1 R 1a substituted; R 1a is selected from isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, each optionally substituted with 2 methyl or 2 fluoro, cyclopropyl or cyclopentyl; R 2 and R 3 are both methyl; R 4 is unsubstituted ethyl; R 5 is and R 6 , R 7 , R 8 and R 9 are each hydrogen; or, X 2 is NH; A is R 1 is oxadiazolyl or thiadiazolyl, said oxadiazolyl or thiadiazolyl being substituted by 1 R 1a substituted; R 1a is selected from isopropyl, cyclopentyl, or cyclopropyl substituted with 2 methyl groups; R 2 and R 3 are both methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 and R 9 are each hydrogen; or, X 2 is NH; A is thiazolylene; L is NR 13 , R 1 and R 13 and the atoms to which they are attached collectively form R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 , and R 9 are each hydrogen; or, X 2 is NH; A is thiazolylene; L is NR 13 , R 1 and R 13 and the atoms to which they are attached collectively form R 2 and R 3 are each methyl; R 4 is ethyl; R 5 is and R 6 , R 7 , R 8 and R 9 are each hydrogen.

19. [Amended according to Rule 26 27.11.2025] A compound or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, selected from the following compounds or a pharmaceutically acceptable salt thereof, 20. A pharmaceutical composition comprising a compound of any one of claims 1-19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

21. A method for preventing or treating a disease mediated by RAS in an individual in need thereof, comprising administering to the individual a compound of any one of claims 1-20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 21.

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