Indole derivative as ras inhibitor, and use thereof

Abstract

The present disclosure relates to an RAS inhibitor compound represented by formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising same, and a use of the compound in the prevention or treatment of RAS-mediated diseases.

Description

Indole derivatives as RAS inhibitors and their applications

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

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

[0003] Patent application No. 202410143837.5 submitted to the State Intellectual Property Office on February 1, 2024. Technical Field

[0004] The present disclosure belongs to the field of medical technology, and specifically relates to macrocyclic compounds of RAS inhibitors or stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and their use as RAS inhibitors in preventing or treating related diseases. Background Art

[0005] The KRAS gene (Kirsten Rat Sarcoma Viral Oncogene Homolog) belongs to the RAS gene family (RAS was the first human oncogene discovered; the RAS family also includes NRAS (Neuroblastoma-RAS) and HRAS (Harvey-RAS)). It is located on chromosome 12 and is involved in intracellular signaling. The KRAS protein encoded by the KRAS gene is a small GTPase, part of the RAS superprotein family. The KRAS protein consists of 188 amino acids and has a molecular weight of 21.6 kDa. KRAS is active when bound to GTP and inactive when bound to GDP. The KRAS protein is regulated by guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs), maintaining its activation and inactivation states. Activated KRAS primarily activates downstream signaling pathways such as the PI3K-AKT-mTOR pathway, which controls cell growth, and the RAS-RAF-MEK-ERK pathway, which controls cell proliferation. Most small molecule drugs work by binding to functionally important pockets on target proteins, thereby modulating the protein's activity. For example, cholesterol-lowering drugs called statins bind to the active site of HMG-CoA reductase, preventing the enzyme from binding to its substrate. The fact that so many such drug / target interaction pairs are known might mislead one into believing that small molecule modulators for most, if not all, proteins could be discovered with a reasonable amount of time, effort, and resources. However, this is not the case. Currently, it is estimated that only approximately 10% of all human proteins are targets for small molecules. The remaining 90% are currently considered refractory or difficult to treat with the aforementioned small molecule drug discovery. Such targets are often referred to as "undruggable." Compound libraries for most of these undruggable targets, or medically important human proteins, are not yet available. Consequently, there is significant interest in discovering novel molecules that can modulate the function of these undruggable targets. Given the importance of the RAS signaling pathway in cancer treatment, targeted therapies targeting the RAS signaling pathway have become a research hotspot in the field of cancer treatment in recent years. The present disclosure discloses a class of heterocyclic compounds that can selectively inhibit RAS protein, have a killing effect on related tumor cells, and can treat tumors mediated by RAS protein mutations. Summary of the Invention

[0006] The present disclosure relates to a compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof,

[0007] in,

[0008] X1 and X 2 are each independently selected from CH2 and NH;

[0009] A is selected from C3-C 12 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene and 5-12 membered heteroarylene, the C3-C 12 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene and 5-12 membered heteroarylene are optionally substituted by one or more R a replace;

[0010] R 1 Selected from amino, hydroxyl, thiol, cyano, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the amino, hydroxyl, thiol, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 1a replace;

[0011] R 2 、R 3 、R 7 and R 8 independently selected from hydrogen, halogen, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl and C3-C7 cycloalkyl;

[0012] Or, R 7 and R 8 and the atoms to which they are attached together form a 4-10 membered heterocyclic ring, wherein the 4-10 membered heterocyclic ring is optionally substituted by one or more R b replace;

[0013] R 4 Selected from hydrogen, halogen, hydroxy, cyano, C2-C 10 Alkenyl, C2-C 10 Alkynyl and C1-C 10 Alkyl, the hydroxyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl and C1-C10 The alkyl group is optionally substituted with one or more R 4a replace;

[0014] R 5 Selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 5a replace;

[0015] Or, R 4 and R 5 and the atoms to which they are attached together form a 4-10 membered heterocyclic ring, wherein the 4-10 membered heterocyclic ring is optionally substituted by one or more R c replace;

[0016] Or, R 4 and R 7 and the atoms to which they are attached together form a 4-10 membered heterocyclic ring, wherein the 4-10 membered heterocyclic ring is optionally substituted by one or more R d replace;

[0017] R 6 is selected from hydrogen, halogen, amino, hydroxy, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy;

[0018] Every R a Independently selected from halogen, amino, hydroxy, mercapto, cyano and C1-C4 alkyl;

[0019] Every R 1a independently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the amino, hydroxyl, thiol, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 1aa replace;

[0020] Every R 4a 、R 1aa 、R b and R dIndependently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy;

[0021] Every R c Independently selected from hydroxyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the hydroxyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R e replace;

[0022] Every R 5a and R e Independently selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R f replace;

[0023] Every R f Independently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy;

[0024] One or more hydrogen atoms of the compound are optionally deuterium atoms.

[0025] In some embodiments, X 1 For CH2.

[0026] In some embodiments, X 2 For NH.

[0027] In some embodiments, X 1 is CH2 and X 2 For NH.

[0028] In some embodiments, A is selected from C6-C 10 Arylene and 5-12 membered heteroarylene, the C6-C 10 Arylene and 5-12 membered heteroarylene are optionally substituted by one or more R a replace.

[0029] In some embodiments, A is selected from 5-12 membered heteroarylene, wherein the 5-12 membered heteroarylene is optionally substituted with one or more R a replace.

[0030] In some embodiments, A is selected from 5-6 membered heteroarylene, wherein the 5-6 membered heteroarylene is optionally substituted with one or more R a replace.

[0031] In some embodiments, A is selected from a thiazole ring, an imidazopyridine ring, and a pyrazolopyridine ring, wherein the thiazole ring, the imidazopyridine ring, and the pyrazolopyridine ring are optionally substituted by one or more R a replace.

[0032] In some embodiments, A is selected from described Optional one or more R a replace.

[0033] In some embodiments, R a are independently selected from halogen, amino, hydroxy, mercapto and cyano.

[0034] In some embodiments, A is selected from

[0035] In some embodiments, A is

[0036] In some embodiments, R 1 Selected from amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, the amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are optionally substituted by one or more R 1a replace.

[0037] In some embodiments, R 1 is selected from amino, C1-C5 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic groups, wherein the amino, C1-C5 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic groups are optionally substituted by one or more R 1a replace.

[0038] In some embodiments, R 1 Selected from amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, The amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, Optionally, one or more R 1a replace.

[0039] In some embodiments, R 1 Selected from amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, The amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, Optionally, one or more R 1a replace.

[0040] In some embodiments, R 1a Independently selected from halogen, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 1aa replace;

[0041] In some embodiments, R 1a independently selected from halogen, C1-C4 alkyl, C3-C4 cycloalkyl, 4-7 membered heterocyclyl, C6-C7 aryl and 5-6 membered heteroaryl, wherein the C1-C4 alkyl, C3-C4 cycloalkyl, 4-7 membered heterocyclyl, C6-C7 aryl and 5-6 membered heteroaryl are optionally substituted by one or more R 1aa replace.

[0042] In some embodiments, R 1a independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropyl, pyridyl, phenyl and The methyl, ethyl, isopropyl, cyclopropyl, pyridyl, phenyl and Optionally, one or more R 1aa replace.

[0043] In some embodiments, R 1a independently selected from fluoro, methyl, ethyl, cyclopropyl, pyridyl, phenyl and The methyl, ethyl, cyclopropyl, pyridyl, phenyl and Optionally, one or more R 1aa replace.

[0044] In some embodiments, R 1aaindependently selected from halogen, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy.

[0045] In some embodiments, R 1aa independently selected from halogen, C1-C4 alkyl and C1-C4 alkoxy.

[0046] In some embodiments, R 1aa Independently selected from halogen and C1-C4 alkyl.

[0047] In some embodiments, R 1aa independently selected from methyl, chloro, fluoro and methoxy.

[0048] In some embodiments, R 1aa independently selected from methyl, chloro and fluoro.

[0049] In some embodiments, R 2 、R 3 independently selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 alkyl.

[0050] In some embodiments, R 2 、R 3 Independently selected from C1-C4 alkyl, such as methyl.

[0051] In some embodiments, R 2 、R 3 All are methyl.

[0052] In some embodiments, R 4 Selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 Alkyl, the hydroxyl, C1-C 10 The alkyl group is optionally substituted with one or more R 4a Replacement, R 5 Selected from C6-C 10 Aryl and 5-10 membered heteroaryl, the C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 5a Replace, or, R 4 and R 5 and the atoms to which they are attached together form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by one or more R c replace.

[0053] In some embodiments, R 4 Selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 Alkyl, the hydroxyl, C1-C 10 The alkyl group is optionally substituted with one or more R 4a Replacement, R7 is selected from hydrogen, halogen, hydroxyl and cyano, or, R 4 and R 7 and the atoms to which they are attached together form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted by one or more R d replace.

[0054] In some embodiments, R 4 Selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 Alkyl, the hydroxyl, C1-C 10 The alkyl group is optionally substituted with one or more R 4a replace.

[0055] In some embodiments, R 4 is selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted by one or more R 4a replace.

[0056] In some embodiments, R 4 is an ethyl group, the ethyl group is optionally replaced by one or more R 4a replace.

[0057] In some embodiments, R 4a are independently selected from halogen, amino, hydroxy, mercapto and cyano.

[0058] In some embodiments, R 4a are independently selected from halogen.

[0059] In some embodiments, R 4a For fluorine.

[0060] In some embodiments, R 4 Selected from ethyl and trifluoroethyl, trifluoroethyl is preferably CH2CF3.

[0061] In some embodiments, R 5 Selected from C6-C 10 Aryl and 5-10 membered heteroaryl, the C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 5a replace.

[0062] In some embodiments, R 5 is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by one or more R 5a replace.

[0063] In some embodiments, R 5 is selected from pyridyl, said pyridyl being optionally substituted by one or more R 5a replace.

[0064] In some embodiments, R 5 for described Optionally, one or more R 5a replace.

[0065] In some embodiments, R 5a Independently selected from C1-C 10 Alkyl and 4-10 membered heterocyclic group, the C1-C 10 The alkyl group and the 4-10 membered heterocyclic group are optionally substituted by one or more R f replace.

[0066] In some embodiments, R 5a independently selected from C1-C4 alkyl and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl and 4-7 membered heterocyclic groups are optionally substituted by one or more R f replace.

[0067] In some embodiments, R 5a independently selected from piperazinyl and ethyl, said piperazinyl and ethyl being optionally substituted with one or more R f replace.

[0068] In some embodiments, R 5a Independently selected and ethyl, the and ethyl optionally replaced by one or more R f replace.

[0069] In some embodiments, R f Independently selected from C1-C7 alkyl and C1-C7 alkoxy.

[0070] In some embodiments, R f Independently selected from C1-C4 alkyl and C1-C4 alkoxy.

[0071] In some embodiments, R f are independently selected from methyl and methoxy.

[0072] In some embodiments, R 5 Selected from

[0073] In some embodiments, R 4 and R 5 and the atoms to which they are attached together form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by one or more R c replace.

[0074] In some embodiments, Selected from The n is selected from 0, 1, 2 and 3.

[0075] In some embodiments, R c Independently selected from hydroxyl, C6-C 10 Aryl and 5-10 membered heteroaryl, the hydroxyl, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R e replace.

[0076] In some embodiments, R c independently selected from hydroxy, pyridyl and phenyl, said hydroxy, pyridyl and phenyl being optionally substituted by one or more R e replace.

[0077] In some embodiments, R c Independently selected from hydroxyl, phenyl and The hydroxyl group, phenyl group and Optionally, one or more R e replace.

[0078] In some embodiments, R e Independently selected from C1-C 10 Alkyl and 4-10 membered heterocyclic group, the C1-C 10 The alkyl group and the 4-10 membered heterocyclic group are optionally substituted by one or more R f replace.

[0079] In some embodiments, R e independently selected from C1-C4 alkyl and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl and 4-7 membered heterocyclic groups are optionally substituted by one or more R f replace.

[0080] In some embodiments, R e Independently selected from methyl, piperazinyl, said methyl, piperazinyl optionally substituted by one or more R f replace.

[0081] In some embodiments, R 6 Selected from hydrogen, halogen, amino, hydroxy, mercapto, cyano and C1-C4 alkyl.

[0082] In some embodiments, R 6 For hydrogen.

[0083] In some embodiments, R 7 is selected from hydrogen, halogen, hydroxy and cyano.

[0084] In some embodiments, R 7 For hydrogen.

[0085] In some embodiments, R4 and R 7 and the atoms to which they are attached together form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted by one or more R d replace.

[0086] In some embodiments, R 4 and R 7 and the atoms to which they are attached together form a 6-7 membered heterocyclic ring, wherein the 6-7 membered heterocyclic ring is optionally substituted by one or more R d replace.

[0087] In some embodiments, Selected from The t is selected from 1 and 2.

[0088] In some embodiments, R d are independently selected from halogen, amino, hydroxy, mercapto and cyano.

[0089] In some embodiments, R 8 Selected from hydrogen, halogen, hydroxy, cyano, C1-C 10 Alkyl and C3-C7 cycloalkyl.

[0090] In some embodiments, R 8 is selected from hydrogen, cyano and C3-C7 cycloalkyl.

[0091] In some embodiments, R 8 is selected from hydrogen, cyano and cyclopropyl.

[0092] In some embodiments, R 7 and R 8 and the atoms to which they are attached together form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted by one or more R b replace.

[0093] In some embodiments, R 7 and R 8 and its connected atoms together form wherein a bond represents a bond shared with the connected ring, Optionally, one or more R b replace.

[0094] In some embodiments, R b are independently selected from halogen, amino, hydroxy, mercapto and cyano.

[0095] In some embodiments, the compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt of the present disclosure is selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt,

[0096] Among them, R 1 、R 4 、R 5 、R 7 、R 8 As defined above.

[0097] In some embodiments, the compound of formula (I) 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,

[0098] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0099] In another aspect, the present disclosure provides a method for treating a disease mediated by RAS in a subject (e.g., a mammal), comprising administering to a subject (e.g., a mammal, preferably a human) in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0100] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for preventing or treating RAS-mediated diseases.

[0101] In another aspect, the present disclosure provides use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in preventing or treating RAS-mediated diseases.

[0102] In another aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in preventing or treating RAS-mediated diseases.

[0103] In some embodiments, the RAS-mediated disease is a tumor.

[0104] Definitions and Explanations of Terms

[0105] Unless otherwise indicated, the terms used in this disclosure have the following meanings. The definitions of groups and terms described in this disclosure, including their definitions as examples, exemplary definitions, preferred definitions, definitions described in tables, and definitions of specific compounds in the examples, may be combined and coupled with each other in any manner. A particular term should not be considered as undefined or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears in this document, it is intended to refer to the corresponding commercial product or its active ingredient.

[0106] In this article Indicates the attachment site.

[0107] Certain compounds of the present application may exist as atropisomers, which are conformational isomers that occur when rotation about a single bond in a molecule is prevented or greatly slowed due to steric interactions with other parts of the molecule. The compounds disclosed herein include all atropisomers, either pure individual atropisomers, or atropisomers enriched in one of them, or nonspecific mixtures of each. If the rotational potential about the single bond is high enough and the interconversion between conformations is slow enough, separation of the isomers may be permitted. For example, (or )and (or ) are a pair of atropisomers, in which the pyridyl Indicates that the side is facing outward. Indicates that the three-dimensional orientation of this side is inward.

[0108] The diagrammatic representations of racemates or enantiomerically pure compounds herein are from Maehr, J. Chem. Ed. 1985, 62: 114-120. Unless otherwise indicated, the solid and imaginary bonds are wedge-shaped. To express the absolute configuration of a stereocenter, use direct real bonds and direct virtual bonds. Indicates the relative configuration of a stereocenter (such as the cis-trans configuration of an alicyclic compound).

[0109] When one of the variables is selected from a chemical bond or does not exist, it means that the two groups it connects are directly connected. For example, when L in ALZ represents a bond, it means that the structure is actually AZ.

[0110] When the linking group mentioned in this article does not specify its connection direction, its connection direction is arbitrary. L in 1 When selected from "C1-C3 alkylene-O", L 1 You can connect rings Q and R from left to right. 1 Constitute "ring Q-C1-C3 alkylene-OR 1 ", you can also connect rings Q and R from right to left 1 Constitute the "ring QO-C1-C3 alkylene-R 1 ”.

[0111] When a substituent's bond crosses two atoms in a ring, the substituent may be bonded to any atom in the ring. Represents R c Substitution can occur at any position on the ring.

[0112] The compounds of the present invention may have asymmetric atoms such as carbon atoms, sulfur atoms, nitrogen atoms, phosphorus atoms or asymmetric double bonds, so that the compounds of the present invention may exist in specific geometric or stereoisomeric forms. Specific geometric or stereoisomeric forms may be cis and trans isomers, E and Z geometric isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures or other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which are within the definition of the compounds of the present invention and mixtures thereof. Additional asymmetric carbon atoms, asymmetric sulfur atoms, asymmetric nitrogen atoms or asymmetric phosphorus atoms may be present in substituents such as alkyl groups, and all of which are within the definition of the compounds of the present invention and mixtures thereof. Compounds of the present disclosure containing an asymmetric atom can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.

[0113] The term "substituted" refers to the replacement of any one or more hydrogen atoms on a particular atom by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo (i.e., =O), it means that two hydrogen atoms are replaced. Oxo does not occur on aromatic groups.

[0114] The term "optionally" or "optionally" refers to that the event or situation described subsequently may or may not occur, and the description includes that the event or situation occurs and that the event or situation does not occur. For example, ethyl is "optionally" substituted by one or more halogens, meaning that ethyl can be unsubstituted (CH2CH3), monosubstituted (CH2CH2F, CH2CH2Cl etc.), polysubstituted (CHFCH2F, CH2CHF2, CHFCH2Cl, CH2CHCl2 etc.) or fully substituted (CF2CF3, CF2CCl3, CCl2CCl3 etc.). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, any sterically impossible existence and / or incomposable replacement or substitution pattern will not be introduced.

[0115] When any variable (such as R a 、R b ) appears more than once in the composition or structure of a compound, its definition is independent in each case. For example, if a group is represented by two R b is replaced, then each R b There are independent options.

[0116] In this article, C m -Cn It means having an integer number of carbon atoms in the range mn. For example, "C1-C 10 ” 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.

[0117] The term "alkyl" refers to a group of the formula C n H 2n+1 The term "C1-C 10 The term "alkyl" is understood to mean a straight-chain or branched saturated hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of such alkyl radicals 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 to mean an alkyl group having 1 to 7 carbon atoms, specific examples of which include but are 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 to mean a straight-chain or branched saturated alkyl group having 1 to 5 carbon atoms. The term "C1-C4 alkyl" can be understood to mean a straight-chain or branched saturated alkyl group having 1 to 4 carbon atoms. The term "C1-C3 alkyl" can be understood to mean a straight-chain or branched saturated alkyl group having 1 to 3 carbon atoms. The "C1-C 10 The term "alkyl" may include "C1-C6 alkyl", "C1-C4 alkyl" or "C1-C3 alkyl", and the "C1-C6 alkyl" may further include "C1-C4 alkyl" or "C1-C3 alkyl". The term "haloalkyl" is intended to include monohaloalkyl and polyhaloalkyl. For example, the term "C1-C 10 "Haloalkyl" means a C1-C12 group as defined above substituted by one or more halogens. 10 Alkyl groups include, but are not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, and the like.

[0118] The term "alkoxy" refers to a group generated by the loss of a hydrogen atom from a hydroxyl group of a straight-chain or branched alcohol, and can be understood as "alkyloxy" or "alkyl-O-". The term "C1-C 10 "Alkoxy" can be understood as "C1-C 10 Alkyloxy" or "C1-C 10 The term "C1-C7 alkoxy" can be understood as "C1-C7 alkyloxy" or "C1-C7 alkyl-O-". The "C1-C 10 The term "alkoxy" may include "C1-C7 alkoxy" and "C1-C3 alkoxy", and the "C1-C7 alkoxy" may further include "C1-C3 alkoxy".

[0119] The term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. 10 "Alkenyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, "C2-C 10 The term "alkenyl" may include "C2-C6 alkenyl", "C2-C4 alkenyl", C2 or C3 alkenyl. It will be understood that when the alkenyl contains more than one double bond, the double bonds may be separated or conjugated with each other. Specific examples of the alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (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, etc.

[0120] The term "alkynyl" refers to a straight or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. 10 "Alkynyl" is understood to mean a linear or branched unsaturated hydrocarbon radical containing one or more triple bonds and having 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 The term "alkynyl" may include "C2-C3 alkynyl". Examples of "C2-C3 alkynyl" include ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH3), and prop-2-ynyl (-CH2C≡CH).

[0121] The term "cycloalkyl" refers to a fully saturated carbocyclic group that exists in the form of a monocyclic, fused, bridged, or spirocyclic ring. Unless otherwise indicated, the carbocyclic ring is typically a 3- to 20-membered ring. The term "C3-C 12 The term "cycloalkyl" refers to a cycloalkyl 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" is a residue derived from a cycloalkyl group by further removing a hydrogen.

[0122] The term "heterocyclyl" or "heterocycle" refers to a fully saturated or partially saturated (heteroaromatic as a whole that is not aromatic) monocyclic, fused, spiro or bridged ring group, which contains 1-5 (e.g., 1-3 or 1-2) heteroatoms or heteroatomic groups (i.e., heteroatom-containing groups) in its ring atoms, wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -P(=O)2-, -P(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "4-10 membered heterocyclyl" refers to a heterocyclyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups in its ring atoms. “4-10 membered heterocyclyl” may include “4-7 membered heterocyclyl”. The term “4-7 membered heterocyclyl” refers to a heterocyclyl having 4, 5, 6 or 7 ring atoms, and containing 1, 2, 3, 4 or 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. Specific examples of 4-membered heterocyclyl include, but are not limited to, azetidinyl or oxetanyl; specific examples of 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, 4,5-dihydrooxazolyl or 2,5-dihydro-1H-pyrrolyl; specific examples of 6-membered heterocyclyl include, but are not limited to, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, tetrahydropyridinyl or 4H-[1,3,4]thiadiazinyl; specific examples of 7-membered heterocyclyl include, but are not limited to, diazepanyl. The heterocyclic group may also be a bicyclic group, wherein specific examples of 5,5-membered bicyclic groups include but are not limited to hexahydrocyclopenta[c]pyrrol-2(1H)-yl; specific examples of 5,6-membered bicyclic groups include but are not limited to hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazinyl or 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinyl. Optionally, the heterocyclic group may be a benzo-fused ring group of the above-mentioned 4-7-membered heterocyclic groups, specific examples of which include but are not limited to dihydroisoquinolinyl and the like. The “4-10 membered heterocyclyl” may include the ranges 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, and the “4-7 membered heterocyclyl” may further include the ranges 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 heterocyclic groups in the present disclosure partially contain a benzene ring or a heteroaromatic ring, the heterocyclic group as a whole is still non-aromatic. The term "heterocyclylene" is a residue derived from a heterocyclic group by further removing a hydrogen atom.

[0123] The term "heterocycloalkyl" refers to a fully saturated cyclic group in the form of a monocyclic, fused, bridged or spirocyclic ring, wherein the ring atoms of the ring contain 1-5 heteroatoms or heteroatomic groups (i.e., heteroatomic groups containing heteroatoms), wherein the "heteroatoms or heteroatomic groups" include, but are not limited to, nitrogen atom (N), oxygen atom (O), sulfur atom (S), phosphorus atom (P), boron atom (B), -S(=O)2-, -S(=O)-, -NH-, -S(=O)(=NH)-, -C(=O)NH- or -NHC(=O)NH-. The term "4-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 4, 5, 6, 7, 8, 9 or 10 ring atoms, wherein the ring atoms of the heterocycloalkyl group contain 1-5 heteroatoms or heteroatomic groups independently selected from the above-mentioned heteroatoms or heteroatomic groups. The term "5-10 membered heterocycloalkyl" refers to a heterocycloalkyl group having 5, 6, 7, 8, 9 or 10 ring atoms, and containing 1 to 5 heteroatoms or heteroatom groups independently selected from the above-mentioned heteroatoms. “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-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl or 1,4-dithianyl; specific examples of 7 membered heterocycloalkyl include but are not limited to azepanyl, oxetanyl or thiepanyl.

[0124] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. The aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. The term "C6-C 10 The term "aryl" is understood to mean an aryl group having 6 to 10 carbon atoms. The term "C6-C7 aryl" is understood to mean an aryl 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 ("C 10 The term "arylene" is a residue derived from an aryl group by further removing a hydrogen.

[0125] The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system with aromatic character, 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, such as 5 or 6 or 9 or 10 or 11 or 12 ring atoms, and which contain 1 to 5, for example 1 to 3 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl or thiadiazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl or isoindolyl, and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl or isoquinolyl, and the like; or acinyl, indolizinyl, purinyl, and the like, and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, 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 containing 1 to 5, for example 1 to 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 containing 1 to 3, for example 1 to 2, heteroatoms independently selected from N, O and S. The term "heteroarylene" is a residue derived from a heteroaryl group by further removing one hydrogen.

[0126] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0127] The term "hydroxy" refers to an -OH group.

[0128] The term "cyano" refers to a -CN group.

[0129] The term "amino" refers to a -NH2 group.

[0130] The term "nitro" refers to a -NO2 group.

[0131] The term "treatment" means administering the compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:

[0132] (i) inhibiting a disease or disease state, i.e., arresting its development;

[0133] (ii) ameliorating the disease or condition, i.e., causing regression of the disease or condition.

[0134] The term "therapeutically effective amount" means an amount of a compound of the present disclosure that (i) treats a particular disease, condition, or disorder, and (ii) alleviates, ameliorates, or eliminates one or more symptoms of a particular disease, condition, or disorder. The amount of a compound of the present disclosure that constitutes a "therapeutically effective amount" varies depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art based on their knowledge and this disclosure.

[0135] The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes preventing the disease or disease state from occurring in an individual (e.g., a mammal), particularly when such individual (e.g., a mammal) is susceptible to the disease state but has not yet been diagnosed as having the disease state.

[0136] The term "subject" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (e.g., chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, and pigs; domestic animals, such as rabbits, dogs, and cats; and laboratory animals, including rodents, such as rats, mice, and guinea pigs. Examples of non-human mammals include, but are not limited to, birds and fish. In one embodiment of the methods and compositions provided herein, the mammal is a human. The terms "patient" and "subject" are used interchangeably.

[0137] 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 human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0138] The term "pharmaceutically acceptable salt" refers to a salt of a pharmaceutically acceptable acid or base, including a salt formed between a compound and an inorganic acid or organic acid, and a salt formed between a compound and an inorganic base or an organic base.

[0139] The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present disclosure or their salts and a pharmaceutically acceptable excipient. The purpose of a pharmaceutical composition is to facilitate administration of the compounds of the present disclosure to an organism.

[0140] The term "pharmaceutically acceptable excipient" refers to an excipient that is non-irritating to organisms and does not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art and include, for example, carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

[0141] The word "comprise" or "comprises" and its English variations such as comprises or comprising are to be understood as having an open and non-exclusive meaning, ie, "including but not limited to".

[0142] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where 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 incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, 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 et al.

[0143] Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) can be used in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Positron emitting isotopes, such as 15 O. 13 N. 11 C and 18 F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the disclosure can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0144] The pharmaceutical compositions of the present disclosure can be prepared by combining the compounds of the present disclosure with suitable pharmaceutically acceptable excipients, and can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols.

[0145] Typical routes of administration of the disclosed compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.

[0146] The pharmaceutical composition of the present disclosure can be manufactured by methods well known in the art, such as conventional mixing methods, dissolution methods, granulation methods, emulsification methods, freeze-drying methods, and the like.

[0147] 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 enable the compounds of the present disclosure to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, and the like for oral administration to a patient.

[0148] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be prepared by mixing the active compound with a solid excipient, optionally grinding the resulting mixture, adding other suitable excipients as needed, and then granulating the mixture to obtain a tablet or dragee core. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, or flavoring agents.

[0149] The pharmaceutical composition may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in appropriate unit dosage forms.

[0150] The dosage administered will depend on factors such as the specific compound, the disease state and its severity, the identity of the subject or host to be treated (e.g., weight, sex), and will be determined by the particular circumstances of the case, including, for example, the specific formulation being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0151] In all methods of administration of the compounds of formula (I) described herein, oral administration is administered at a daily dose of 0.001 mg / kg to 5000 mg / kg body weight, preferably 0.01 mg / kg to 100 mg / kg body weight, in single or divided doses. The daily dose and unit dose vary depending on 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 to be treated, and the judgment of the practitioner.

[0152] The compounds disclosed herein can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples disclosed herein.

[0153] The chemical reactions of the embodiments of the present disclosure are carried out in a suitable solvent that is compatible with the chemical transformations of the present disclosure and the reagents and materials required. In order to obtain the compounds of the present disclosure, it is sometimes necessary for those skilled in the art to modify or select synthetic steps or reaction schemes based on existing embodiments.

[0154] Abbreviations: 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·H2O stands for p-toluenesulfonic acid monohydrate; n-BuLi stands for n-butyllithium; Boc2O stands for di-tert-butyl dicarbonate; TFA stands for trifluoroacetic acid; DIEA or DIPEA stands for N,N-diisopropylethylamine; Pd(dppf)Cl2 stands for [1,1'-bis(diphenyl [Ir] represents (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride; [Ir] represents (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene) ruthenium chloride. (cod)Cl]2 represents 1,5-cyclooctadiene iridium chloride dimer; B2Pin2 represents bispinacol boronate or 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane); COMU represents (ethyl 2-oximinocyanoacetate)-N,N-dimethylmorpholinourea hexafluorophosphate; ACN represents acetonitrile; NIS represents N-iodosuccinimide; KOAc represents potassium acetate; and DME represents ethylene glycol. dimethyl ether; EtI stands for ethyl iodide; EDCI stands for 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride; HOBT stands for 1-hydroxybenzotriazole; AcOH stands for acetic acid; Boc stands for tert-butyloxycarbonyl; toluene stands for toluene; TBAF stands for tetrabutylammonium fluoride; DMSO stands for dimethyl sulfoxide; NMM stands for N-methylmorpholine; (CHO)n stands for paraformaldehyde; LC-MS stands for liquid chromatography-mass spectrometry; MS stands for mass spectrometry; 1 H NMR stands for proton nuclear magnetic resonance; ESI stands for electrospray ionization; DTT stands for dithiothreitol; HEPES stands for 4-hydroxyethylpiperazineethanesulfonic acid; PBS stands for phosphate-buffered saline; BSA stands for bovine serum albumin; IC 50 It stands for half-maximal inhibitory concentration, which refers to the concentration at which half of the maximum inhibitory effect is achieved. DETAILED DESCRIPTION

[0155] 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 listed herein, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present disclosure.

[0156] The present disclosure is described in detail below by way of examples, but this is not intended to limit the present disclosure in any way. While the present disclosure has been described in detail herein, including specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments 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.

[0157] Unless otherwise specified, the ratios expressed for mixed solvents are volume ratios.

[0158] Unless otherwise specified, % refers to weight %.

[0159] Compounds are manually or Software naming, commercially available compounds use supplier catalog names.

[0160] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The units of NMR shifts are 10 -6 (ppm). The solvents for NMR measurements are deuterated dimethyl sulfoxide, deuterated chloroform, deuterated methanol, etc., and the internal standard is tetramethylsilane (TMS);

[0161] The eluent or mobile phase may be a mixed eluent or mobile phase consisting of two or more solvents, the ratio of which is the volume ratio of each solvent.

[0162] Preparation Example

[0163] Preparation Example 1 Synthesis of Intermediate Compound Int-1

[0164] Step 1: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropionic acid (Compound A2)

[0165] Tert-butyldiphenylsilyl chloride (76.82 g, 279.35 mmol), imidazole (19.02 g, 279.35 mmol), and compound A1 (30 g, 253.96 mmol) were added to dichloromethane (1000 mL). The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the reaction mixture was acidified to pH 5 with 2N HCl. The solution was extracted three times with dichloromethane (100 mL). The resulting organic phases were combined, washed twice with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and dried to dryness to obtain compound A2 (88 g, 246.82 mmol, yield: 97.19%), which was used directly in the next step without purification.

[0166] Step 2: Synthesis of 3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropanoyl chloride (Compound A3)

[0167] 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. Oxalyl chloride (62.69 g, 493.65 mmol, 42.13 mL) was then added dropwise to the reaction mixture. The mixture was stirred at 0°C for 2 hours. LC-MS confirmed the reaction was complete. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford compound A3 (80 g, 213.35 mmol, 86.44% yield). This product was used directly in the next step without purification.

[0168] Step 3 Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-one (Compound A4)

[0169] Compound A3 (80 g, 213.35 mmol) was dissolved in dichloromethane (1.5 L) at 0°C. Under nitrogen, tin tetrachloride solution (1 M, 213.35 mL) and 5-bromo-1H-indole (41.83 g, 213.35 mmol) were added. The reaction mixture was allowed to react at 0°C for 10 hours. LC-MS showed that the starting material was consumed and the product was detected. The reaction mixture was diluted with ethyl acetate (600 mL) and washed four times with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was then purified by silica gel chromatography (ethyl acetate / tetrahydrofuran = 5 / 1 to 3 / 1) to afford compound A4 (8 g, 14.97 mmol, 7.01% yield).

[0170] MS (ESI + )m / z=534.0[M+H] + .

[0171] Step 4: Synthesis of 1-(5-bromo-1H-indol-3-yl)-3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropane-1-ol (Compound A5)

[0172] Compound A4 (8 g, 14.97 mmol) was dissolved in tetrahydrofuran (71.30 mL) at 0°C. 2M lithium borohydride solution in tetrahydrofuran (2M, 18.71 mL) was slowly added dropwise to the reaction mixture under nitrogen. The reaction mixture was then heated to 60°C and allowed to react for 16 hours. LC-MS showed complete consumption of the starting material and the desired compound was detected. The reaction mixture was quenched with methanol (20 mL) and extracted three times with ethyl acetate (50 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and filtered to dryness to afford compound A5 (8 g, 14.91 mmol, 99.62% yield). This product was used directly in the next step without further purification.

[0173] Step 5: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1H-indole (Compound A6)

[0174] Compound A5 (8 g, 14.91 mmol), dihydropyridine (4.37 g, 17.25 mmol), and p-toluenesulfonic acid monohydrate (2.84 g, 14.91 mmol) were dissolved in dichloromethane (150 mL) and stirred at 0°C under nitrogen for 2 hours. LC-MS showed complete consumption of the reactants and the desired compound was detected. After the reaction, the mixture was quenched with water (50 mL) and washed three times with dichloromethane (50 mL). The organic phases were combined and washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and dried. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford compound A6 (7 g, 13.45 mmol, yield: 90.19%).

[0175] MS (ESI + )m / z=520.0[M+H] + .

[0176] Step 6: Synthesis of 5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-iodo-1H-indole (Compound Int-1)

[0177] 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 complete consumption of the reactants and the desired compound was detected. The reaction solution was diluted with ethyl acetate (50 mL) and washed with saturated aqueous Na2S2O3 solution (50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound Int-1 (973 mg, 1.51 mmol, yield: 26.12%).

[0178] MS (ESI + )m / z=646.1[M+H] + .

[0179] Preparation Example 2 Synthesis of Intermediate Compound Int-2

[0180] Step 1 Synthesis of (4-bromothiazol-2-yl)methanol (Compound B2)

[0181] Compound B1 (10 g, 52 mmol) was dissolved in methanol (15 mL) and sodium borohydride (2.95 g, 78.11 mmol) was added. The mixture was stirred at 0°C for 0.5 hours. Thin-layer chromatography indicated that the reaction of Compound B1 was complete. The reaction was quenched by the addition of 10 mL of dilute hydrochloric acid. The reaction mixture was concentrated under reduced pressure and the solvent removed to afford Compound B2 (9 g, 46.38 mmol, 89.07% yield).

[0182] MS (ESI + )m / z=194.3[M+H] + .

[0183] Step 2 Synthesis of 4-bromo-2-(bromoethyl)thiazole (Compound B3)

[0184] 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 to dichloromethane (120 mL) at 0°C. Stirring was continued at 25°C for 1 hour. LC-MS monitored the reaction for completion. The mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 0-10%) to afford compound B3 (9.0 g, 35.20 mmol, 75.9% yield).

[0185] MS (ESI + )m / z=255.7[M+H]+ .

[0186] Step 3 Synthesis of 4-bromo-2-[[(2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl]methyl]thiazole (Compound B5)

[0187] (R)-2,5-Dihydro-3,6-dimethoxy-2-isopropylpyrazine (Compound B4, 7.10 g, 38.53 mmol) was added to tetrahydrofuran (100 mL), and n-butyllithium (16.81 mL, 42.03 mmol, 2.5 M) was slowly added at -78°C. After addition, the mixture was stirred at -78°C for 0.5 hour. Compound B3 (9.0 g, 35.20 mmol) was added to the above mixture, and stirred at -78°C for 1 hour. LC-MS monitored the reaction completion. The mixture was quenched with saturated aqueous ammonium chloride (30 mL) and extracted with ethyl acetate (100 mL x 2). The organic layer was dried and purified by silica gel column chromatography (0-15% petroleum ether / ethyl acetate) to obtain Compound B5 (10.5 g, 29.14 mmol, 83% yield).

[0188] MS (ESI + )m / z=360.2[M+H] + .

[0189] Step 4: Synthesis of methyl (S)-2-amino-3-(4-bromothiazol-2-yl)propionate (B6)

[0190] To a solution of compound B5 (10.5 g, 29.14 mmol) in acetonitrile (60 mL) was added hydrochloric acid (195 mL, 0.3 M). The mixture was stirred at 25°C for 2 hours. LC-MS monitored the reaction for completion. The mixture was basified to pH 8 with saturated aqueous sodium bicarbonate. The mixture 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 in vacuo to afford compound B6 (6.8 g, 25.65 mmol, 88% yield).

[0191] MS (ESI + )m / z=264.9[M+H] + .

[0192] Step 5: Synthesis of methyl (S)-3-(4-bromothiazol-2-yl)-2-(tert-butoxycarbonyl)amino)propanoate (Compound B7)

[0193] Triethylamine (8.94 mL, 64.12 mmol) and di-tert-butyl dicarbonate (8.4 g, 38.47 mmol) were added separately to a solution of compound B6 (6.8 g, 25.65 mmol) in dichloromethane (80 mL). Stir at 25°C for 16 hours. LC-MS monitored the reaction for completion. The mixture was quenched with water (75 mL) and extracted with dichloromethane (75 mL x 2). The organic layer was dried and purified on a silica gel column (petroleum ether / ethyl acetate = 0-30%) to afford compound B7 (6.5 g, 68% yield).

[0194] MS (ESI + )m / z=364.9[M+H] + .

[0195] Step 6: Synthesis of (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionic acid (Compound B8)

[0196] Compound B7 (6.5 g, 17.44 mmol) and lithium hydroxide monohydrate (2.93 g, 69.76 mmol) were added to a mixed solvent of tetrahydrofuran (60 mL), methanol (5 mL), and water (20 mL). The mixture was stirred at 25°C for 1 hour. LC-MS monitored the reaction for completion. The mixture was acidified to pH 5 with 1 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford compound B8 (6 g, 17.08 mmol, 98% yield).

[0197] MS (ESI + )m / z=351.2[M+H] + .

[0198] Step 7: Synthesis of (S)-1-((S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (Compound Int-2)

[0199] To a dichloromethane (4 mL) solution at 0°C was added (S)-hexahydropyridazine-3-carboxylic acid methyl ester (trifluoroacetate) (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). The mixture was stirred at 25°C for 1 hour. LC-MS monitored the reaction for completion. The mixture was quenched with water (15 mL) and extracted with dichloromethane (15 mL x 2). The organic layer was dried and filtered, and the filtrate was purified by silica gel chromatography (petroleum ether / ethyl acetate = 0-50%) to afford Compound Int-2 (600 mg, 1.26 mmol, 80.12% yield).

[0200] MS (ESI + )m / z=477.1[M+H] + .

[0201] Preparation Example 3 Synthesis of Intermediate Compound Int-3

[0202] Step 1: Synthesis of (S)-1-(3-bromopyridin-2-yl)ethan-1-ol (Compound C2)

[0203] Under N2 protection, 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. (S,S)-N-(p-toluenesulfonyl)-1,2-diphenylethanediamine (p-isopropylbenzene)ruthenium chloride (379 mg, 599.90 μmol) was then added. The reaction solution was heated to 40°C and stirred for 15 minutes. The mixture was then cooled to room temperature and compound C1 (12 g, 59.99 mmol) was added. The reaction solution was then heated to 40°C and stirred for 2 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by column chromatography to obtain compound C2 (12 g, 59.41 mmol, 99% yield).

[0204] MS (ESI + )m / z=202.1[M+H] + .

[0205] Step 2: Synthesis of (S)-3-bromo-2-(1-methoxyethyl)pyridine (Compound C3)

[0206] Under N2 protection, a solution of compound C2 (12.00 g, 59.41 mmol) in N,N-dimethylformamide (75 mL) was cooled to 0°C and sodium hydride (2.85 g, 71.27 mmol, 60% purity) was added. The mixture was stirred at 0°C for 15 minutes, followed by the addition of iodomethane (16.86 g, 118.78 mmol). The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction solution was slowly added to ice water (750 mL) and extracted with ethyl acetate (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography to obtain compound C3 (11 g, 50.9 mmol, 86% yield).

[0207] MS (ESI + )m / z=216.1[M+H] + .

[0208] Step 3 Synthesis of 5-bromo-6-[(1S)-1-methoxyethyl]pyridin-3-ylboronic acid (Compound C4)

[0209] 4,4'-di-tert-butyl-2,2'-bipyridine (931.61 mg, 3.47 mmol) and 1,5-cyclooctadiene iridium chloride dimer (466.30 mg, 694.20 mmol) were added to a tetrahydrofuran (50 mL) solution of compound C3 (5.0 g, 23.14 mmol) and bis-naphthalene borate (8.81 g, 34.71 mmol) under N2 atmosphere. The resulting mixture was stirred at 80 ° C under a nitrogen atmosphere for 16 hours. LC-MS monitoring showed that the reaction was complete and no starting material remained. 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) (mass: 4:1) in water (600 mL). Extracted with ethyl acetate (100 mL). The aqueous phase was acidified with hydrochloric acid (6 M) to pH = 6 to give compound C4 (4.5 g, 17.3 mmol, yield: 75%).

[0210] MS (ESI + )m / z=260.0[M+H] + .

[0211] Step 4: Synthesis of (S)-3-bromo-5-iodo-2-(1-methoxyethyl)pyridine (Compound C5)

[0212] Compound C4 (4.5 g, 17.3 mmol) and N-iodosuccinimide (36.70 g, 163.14 mmol) were added to acetonitrile (50 mL) under N2 protection. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours. LC-MS monitored the reaction for completion. The resulting mixture was dissolved in dichloromethane (80 mL) and washed with a 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 on a silica gel column (petroleum ether / ethyl acetate: 0-15%) to afford compound C5 (4.3 g, 12.6 mmol, yield: 73%).

[0213] MS (ESI + )m / z=341.8[M+H] + .

[0214] Step 5: Synthesis of (S)-4-(5-bromo-6-(1-methoxyethyl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (Compound C7)

[0215] Under nitrogen protection, compound C5 (4.3 g, 12.6 mmol), compound C6 (2.77 g, 12.57 mmol), (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (156.59 mg, 251.48 μmol), palladium acetate (141.15 mg, 628.71 μmol), Cs2CO3 (10.24 g, 31.44 mmol), and toluene (50 mL) were combined and placed in a sealed tube. The resulting solution was stirred at 100°C under nitrogen for 16 hours. LC-MS monitored the reaction for completion. After completion, 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%).

[0216] MS (ESI + )m / z=434.2[M+H] + .

[0217] Step 6: Synthesis of (S)-4-(6-(1-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)piperazine-1-carboxylic acid benzyl ester (Compound Int-3)

[0218] Compound C7 (9.6 g, 22.10 mmol), B2Pin2 (28.06 g, 110.52 mmol), and potassium acetate (6.51 g, 66.31 mmol) were dissolved in dioxane (100 mL). Pd(dppf)Cl2 (1.62 g, 2.21 mmol) was added to the reaction mixture under nitrogen protection, and the nitrogen atmosphere was replaced five times. The reaction mixture was stirred at 100°C for 16 hours and monitored for completion. The mixture was filtered and concentrated under reduced pressure. Ethyl acetate (100 mL) and 6N HCl (100 mL) were added and stirred for 16 hours. The mixture was filtered and concentrated under reduced pressure. The mixture was purified on a reverse-phase silica gel column (water / acetonitrile = 1 / 0 to 1 / 1) to obtain compound Int-3 (4.6 g, 9.52 mmol, yield: 43.06%).

[0219] MS (ESI + )m / z=482.2[M+H] + .

[0220] Preparation Example 4 Synthesis of Intermediate Compound Int-4

[0221] Step 1 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)piperazine-1-carboxylic acid benzyl ester (Compound D1)

[0222] Compound Int-1 (4 g, 6.19 mmol), compound Int-3 (4.47 g, 9.28 mmol), and potassium carbonate (2.57 g, 18.56 mmol) were dissolved in 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 the nitrogen atmosphere was replaced five times. The reaction was stirred at 100°C for 16 hours. LC-MS monitored the reaction completion. The solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified on a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 1 / 5) to obtain compound D1 (2.3 g, 2.63 mmol, yield: 42.49%).

[0223] MS (ESI + )m / z=873.3[M+H] + .

[0224] 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)piperazine-1-carboxylic acid benzyl ester (Compound D2)

[0225] Compound D1 (2.3 g, 2.63 mmol) was dissolved in DMF (30 mL). Cesium carbonate (2.57 g, 7.89 mmol) and iodoethane (820.88 mg, 5.26 mmol) were added portionwise and stirred at 25°C for 16 hours. LC-MS monitored the reaction for completion. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound D2 (2.0 g, crude product). This was used directly in the next step.

[0226] MS (ESI + )m / z=901.3[M+H] + .

[0227] 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)piperazine-1-carboxylic acid benzyl ester (Compound D3)

[0228] Compound D2 (2.0 g, crude product) was dissolved in tetrahydrofuran (30 mL), and TBAF (1 M, 22.17 mL) was added. The mixture was stirred at 25°C for 16 hours. LC-MS monitored the reaction for completion. The mixture was concentrated under reduced pressure and purified using a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain the less polar isomer, yielding compound D3 (0.5 g, 753.42 μmol, yield: 33.4%).

[0229] MS (ESI + )m / z=663.3[M+H] + .

[0230] 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)piperazine-1-carboxylic acid benzyl ester (Compound D4)

[0231] Compound D3 (0.5 g, 753.42 μmol), bis-naphthalene boronate (573.96 mg, 2.26 mmol), and 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 to the reaction mixture under nitrogen, and the nitrogen atmosphere was replaced five times. The reaction mixture was stirred at 100°C for 16 hours. LC-MS monitored the reaction for completion. The mixture was filtered and concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (100 mL x 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified on a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 1 / 3) to obtain compound D4 (0.4 g, 562.82 μmol, yield: 74.7%).

[0232] MS (ESI + )m / z=711.4[M+H] + .

[0233] Step 5: 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)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (Compound D5)

[0234] 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 mixture of dioxane (1 mL), toluene (3 mL), and water (1 mL). Pd(dtbpf)Cl2 (23.84 mg, 36.58 μmol) was added to the reaction mixture under nitrogen, and the nitrogen atmosphere was replaced five times. The reaction mixture was stirred at 100°C for 16 hours. LC-MS monitored the reaction for completion. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (10 mL × 3). The mixture was washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified on a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 1 / 3) to obtain compound D5 (270 mg, 275.17 μmol, yield: 75.22%).

[0235] MS (ESI + )m / z=981.4[M+H] + .

[0236] 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)propionyl)hexahydropyridazine-3-carboxylic acid (Compound D6)

[0237] Compound D5 (270 mg, 275.17 μmol) was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL). Lithium hydroxide (32.95 mg, 1.38 mmol) was added to the reaction solution and stirred at 25°C for 16 hours. The reaction was completed after LC-MS monitoring. Ethyl acetate (30 mL) and water (30 mL) were added to dilute the solution. The aqueous phase was adjusted to pH 6 with 1M HCl aqueous solution and extracted with ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide Compound D6 (220 mg, 227.47 μmol, 82.66% yield) as a yellow solid.

[0238] MS (ESI + )m / z=967.5[M+H] + .

[0239] Step 7: Synthesis of Compound D7

[0240] 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) and stirred at 25°C for 16 hours. The reaction was complete after LC-MS monitoring. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (50 mL × 3). The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was purified on a normal phase silica gel column (petroleum ether / ethyl acetate = 1 / 0 to 1 / 4) to obtain compound D7 (130 mg, 136.96 μmol, yield: 63.08%).

[0241] MS (ESI + )m / z=949.3[M+H] + .

[0242] Step 8 Synthesis of Compound D8

[0243] 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 mixture under nitrogen. The nitrogen atmosphere was then replaced with hydrogen five times. The mixture was stirred at 25°C under atmospheric pressure for 16 hours. The reaction was monitored for completion by LC-MS. The filtrate was filtered and concentrated under reduced pressure to afford compound D8 (0.1 g, 122.69 μmol, 89.58% yield).

[0244] MS (ESI + )m / z=815.5[M+H] + .

[0245] Step 9: Synthesis of compound D9

[0246] Compound D8 (100 mg, 122.69 μmol) and acetic acid (22.10 mg, 368.08 μmol) were dissolved in methanol (5 mL) and stirred at 25°C for 1 hour. Paraformaldehyde (36.85 mg, 1.23 mmol) and NaBH3CN (23.13 mg, 368.08 μmol) were then added to the reaction mixture. The mixture was stirred at 25°C for 16 hours. LC-MS monitored the reaction for completion. The mixture was filtered and concentrated under reduced pressure to afford compound D9 (80 mg, 96.49 μmol, 78.65% yield).

[0247] MS (ESI + )m / z=829.5[M+H] + .

[0248] Step 10: Synthesis of compound Int-4

[0249] Compound D9 (80 mg, 96.49 μmol) was dissolved in methanol (10 mL). 4N dioxane hydrochloride (5 mL) was added to the reaction solution under nitrogen protection. The mixture was stirred at 25°C for 5 hours. The reaction was monitored for completion and concentrated to dryness to obtain compound Int-4 (60 mg, 82.3 μmol, yield: 85.3%) as a white solid.

[0250] MS (ESI + )m / z=729.4[M+H] + .

[0251] Example 1 Synthesis of Compound 1

[0252] Step 1: Synthesis of ethyl 2-(((1S,2S)-2-methylcyclopropyl)amino)-2-oxoacetate (Compound 1-2)

[0253] Compound 1-1 (80 mg, 743.62 μmol) and TEA (225.74 mg, 2.23 mmol, 311.15 μL) were dissolved in dichloromethane (2 mL) and stirred. Compound 1A (101.53 mg, 743.62 μmol) was added dropwise to the reaction solution at 0°C, followed by stirring at 25°C for 2 hours. LC-MS monitored the reaction for completion. Ethyl acetate (10 mL) and water (10 mL) were added for extraction. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 1-2 (50 mg, 292.07 μmol, 39.28% yield).

[0254] MS (ESI + )m / z=172.1[M+H]+.

[0255] Step 2: Synthesis of 2-(((1S,2S)-2-methylcyclopropyl)amino)-2-oxoacetic acid (Compound 1-3)

[0256] Compound 1-2 (10 mg, 58.41 μmol) was dissolved in tetrahydrofuran (0.5 mL). LiOH (6.99 mg, 292.07 μmol) dissolved in water (0.5 mL) was added to the reaction mixture and stirred at 25°C for 1 hour. The reaction was monitored for completion. Ethyl acetate (5 mL) and water (5 mL) were added for extraction. The aqueous phase was adjusted to a pH of approximately 5 with 1N hydrochloric acid and extracted with ethyl acetate (5 mL). The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 1-3 (5 mg, 34.93 μmol, yield: 59.80%) as a yellow oil.

[0257] MS (ESI + )m / z=144.1[M+H] + .

[0258] Step 3 Synthesis of Compound 1

[0259] Compound 1-3 (3.93 mg, 27.44 μmol) and compound Int-4 (20 mg, 27.44 μmol) were dissolved in DMF (2 mL). DIEA (17.73 mg, 137.18 μmol, 23.90 μL) and (ethyl 2-hydroxyiminocyanoacetate)-N,N-dimethylmorpholinourea hexafluorophosphate (23.50 mg, 54.87 μmol) were added portionwise. The mixture was stirred at 25° C. for 2 hours. LCMS showed that the desired MS was detected. Ethyl acetate (5 mL) and water (5 mL) were added for extraction. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase column purification (Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), mobile phase B: MeCN; MeCN ratio 43%-73%) to obtain compound 1 (2 mg, 2.30 μmol, yield: 8.37%).

[0260] MS (ESI + )m / z=854.5[M+H] + .

[0261] 1 H NMR (400MHz, DMSO-d6) δ = 8.93 (d, J = 9.2Hz, 1H), 8.75 (d, J = 5.2Hz, 1H), 8.48 (s, 1H), 8.44 (d, J = 2.4Hz, 1 H),7.79(s,1H),7.72(d,J=8.8Hz,1H),7.55(d,J=8.4Hz,1H),7.22(d,J=2.4Hz,1H),5.55-5.45(m,1H), 5.22-5.15(m,1H),4.35-4.08(m,5H),3.67-3.50(m,3H),3.40-3.35(m,2H),3.30-3.25(m,4H),3.20(s ,3H),2.95-2.88(m,1H),2.83-2.71(m,1H),2.47-2.43(m,4H),2.21(s,3H),2.15-2.05(m,1H),1.80(br s,2H),1.60-1.43(m,1H),1.33(d,J=6.4Hz,3H),1.26-1.20(m,1H),1.08-0.95 (m,4H),0.94-0.86(m,6H),0.85-0.80(m,1H),0.50-0.44(m,1H),0.36(s,3H).

[0262] Example 2 Synthesis of Compound 2

[0263] The first step is the synthesis of ethyl 2-carbonyl-2-(pyrrolidin-1-yl)acetate (compound 2-2)

[0264] Compound 2-1 (1 g, 14.06 mmol) and triethylamine (1.42 g, 14.06 mmol, 1.96 mL) were dissolved in dichloromethane (20 mL) and stirred. Compound 1A (1.91 g, 14.06 mmol) was added dropwise to the reaction solution at 0°C, followed by stirring at 25°C for 2 hours. LC-MS monitored the reaction for completion. Ethyl acetate (100 mL) and water (100 mL) were added for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-2 as a yellow solid (0.9 g, 5.26 mmol, yield: 37.39%).

[0265] MS (ESI + )m / z=172.1[M+H] + .

[0266] Step 2 Synthesis of 2-carbonyl-2-(pyrrolidin-1-yl)acetic acid (Compound 2-3)

[0267] Compound 2-2 (0.9 g, 5.26 mmol) was dissolved in tetrahydrofuran (5 mL), and LiOH (629.51 mg, 26.29 mmol) dissolved in water (5 mL) was added to the reaction mixture. The mixture was stirred at 25°C for 1 hour, and the reaction was complete after LC-MS monitoring. Ethyl acetate (30 mL) and water (30 mL) were added for extraction. The aqueous phase was adjusted to a pH of approximately 2 with 6M hydrochloric acid, and then extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 2-3 (0.4 g, 2.79 mmol, yield: 53.15%) as a yellow oil.

[0268] MS (ESI + )m / z=144.0[M+H] + .

[0269] Step 3 Synthesis of Compound 2

[0270] Compound 2-3 (4.71 mg, 32.92 μmol) and compound Int-4 (24 mg, 32.92 μmol) were dissolved in DMF (2 mL). DIEA (21.28 mg, 164.62 μmol, 28.67 μL) and COMU (28.20 mg, 65.85 μmol) were added portionwise and stirred at 25°C for 2 hours. The reaction was monitored for completion. Ethyl acetate (5 mL) and water (5 mL) were added for extraction, and the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase column (Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), mobile phase B: MeCN; MeCN ratio 40%-70%) to give compound 2 (3 mg, 3.51 μmol, yield: 10.67%).

[0271] MS (ESI + )m / z=854.5[M+H] + .

[0272] 1 H NMR (400MHz, DMSO-d6) δ=9.04(d,J=8.8Hz,1H),8.48(s,1H),8.45(d,J=2.8Hz,1H),7.82(s,1H),7.74(d,J=8.8Hz,1H ),7.56(d,J=8.4Hz,1H),7.22(d,J=2.4Hz,1H),5.61-5.52(m,1H),5.23-5.15(m,1H),4.36-4.06(m,5H),3.68-3.42(m ,5H),3.41-3.36(m,4H),3.29-3.25(m,4H),3.21(s,3H),2.96-2.89(m,1H),2.84-2.72(m,1H),2.47-2.43(m,4H),2.2 2(s,3H),2.13-2.05(m,1H),1.89-1.78(m,6H),1.57-1.49(m,1H),1.37-1.31(m,3H),0.97-0.87(m,6H),0.36(s,3H).

[0273] Example 3 Synthesis of Compound 3

[0274] Compound Int-4 (10 mg, 13.06 μmol), 2-((5-chloropyridin-2-yl)amino)-2-oxoacetic acid (Compound 3A, 3 mg, 15.68 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (7 mg, 19.60 μmol) and N,N-diisopropylethylamine (14 mg, 104.52 μmol, 18 μL) were added sequentially to a solution of N,N-dimethylformamide (0.5 mL). The mixture was reacted at room temperature for 1 hour, filtered, and extracted with ethyl acetate (5 mL) and water (5 mL). 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 (Chromatographic column: Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), mobile phase B: MeCN; MeCN ratio 40%-70%) to obtain compound 3 (3 mg, 3.29 μmol, yield: 25%).

[0275] MS (ESI + )m / z:911.30[M+H] + .

[0276] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.50(d,J=8.7Hz,1H),8.49(s,1H),8.47(d,J=2.6Hz,1H),8.45(d,J=2.8Hz,1H),8.12(d,J=8.9Hz,1H) ,8.06(dd,J=8.8,2.6Hz,1H),7.80(s,1H),7.76–7.70(m,1H),7.55(d,J=8.7Hz,1H),7.22(d,J=2.9Hz,1H),5.63(t,J=8.9Hz,1H),5.25(d,J=1 2.1Hz,1H),4.33–4.09(m,5H),3.75–3.66(m,1H),3.64–3.51(m,2H),3 .37–3.35(m,1H),3.29–3.24(m,4H),3.19(s,3H),2.95–2.87(m,1H),2. 47–2.43(m,4H),2.22(s,3H),2.14–2.04(m,1H),1.87–1.73(m,2H),1. 59–1.44(m,1H),1.34(d,J=6.1Hz,3H),0.95–0.88(m,6H),0.38(s,3H).

[0277] Example 4 Synthesis of Compound 4

[0278] The first step is the synthesis of ethyl 2-((5-fluoropyridin-2-yl)amino)-2-carbonyl acetate (compound 4-2)

[0279] Compound 4-1 (3 g, 26.76 mmol) and triethylamine (8.12 g, 80.28 mmol, 11.20 mL) were dissolved in tetrahydrofuran (20 mL) and stirred. Ethyl oxalyl chloride (Compound 1A, 3.64 g, 26.76 mmol) was added dropwise to the reaction solution at 0°C, followed by stirring at 25°C for 5 hours. LC-MS monitored the reaction for completion. Ethyl acetate (100 mL) and water (100 mL) were added for extraction. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was rotary evaporated and purified on a normal silica gel column (petroleum ether:ethyl acetate = 89:11) to afford compound 4-2 (2.4 g, 11.27 mmol, 42% yield).

[0280] MS (ESI + )m / z=213.1[M+H]+.

[0281] Step 2 Synthesis of 2-((5-fluoropyridin-2-yl)amino)-2-carbonylacetic acid (Compound 4-3)

[0282] Compound 4-2 (200 mg, 942.61 μmol) and lithium hydroxide monohydrate (198 mg, 4.71 mmol) were added to a mixed solution of water (2 mL) and tetrahydrofuran (2 mL), and the mixture was reacted at room temperature overnight. Water (10 mL) was added to the system, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. Compound 4-3 (80 mg, 433.6 μmol, yield: 46%) was obtained by passing through a forward silica gel column (petroleum ether: ethyl acetate = 50:50).

[0283] MS (ESI + )m / z=185.2[M+H]+.

[0284] Step 3 Synthesis of Compound 4

[0285] Compound 4-3 (3.3 mg, 17.83 μmol), compound Int-4 (10 mg, 13.72 μmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (16 mg, 41.16 μmol) and N,N-diisopropylethylamine (18 mg, 137.18 μmol, 24 μL) were added to N,N-dimethylformamide (1 mL), and the mixture was reacted at 40 ° C for 2 hours. Ethyl acetate (5 mL) and water (5 mL) were added for extraction. 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 (chromatographic column was Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), mobile phase B: MeCN; MeCN ratio 45%-70%) to obtain compound 4 (3.83 mg, 4.28 μmol, yield: 24%).

[0286] 1 H NMR (400MHz, DMSO-d6) δ10.28(s,1H),9.49(d,J=8.8Hz,1H),8.49(s,1H),8.45(d,J=2.8Hz,1H),8.43(d,J=3.0Hz,1H),8.13(dd,J=9.1,4.0Hz,1 H),7.93–7.86(m,1H),7.81(s,1H),7.73(d,J=8.5Hz,1H),7.56(d,J=8.6 Hz,1H),7.23(d,J=2.9Hz,1H),5.62(t,J=8.9Hz,1H),5.25(d,J=12.2Hz, 1H),4.33–4.09(m,5H),3.76–3.68(m,1H),3.62–3.53(m,2H),3.39–3.3 7(m,1H),3.31–3.23(m,4H),3.20(s,3H),2.95–2.88(m,1H),2.84–2.76( m,1H),2.46–2.42(m,4H),2.23(s,3H),2.14–2.05(m,1H),1.82(s,2H),1 .57–1.49(m,1H),1.34(d,J=6.0Hz,3H),0.96–0.79(m,6H),0.38(s,3H).

[0287] MS (ESI + )m / z:895.3[M+H] + .

[0288] Example 5 Synthesis of Compound 5

[0289] The first step is the synthesis of (S)-2-(1-methoxyethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Compound 5-1)

[0290] Under nitrogen, potassium acetate (9.08 g, 92.56 mmol) and Pd(dppf)Cl2 (1.69 g, 2.31 mmol) were added to a 100 mL toluene mixture of compound C3 (10 g, 46.28 mmol) and bis(pinacol boronate) (14.10 g, 55.54 mmol). The mixture was stirred at 100°C under nitrogen for 4 hours. LC-MS monitored the reaction for completion. The reaction solution was concentrated under reduced pressure and purified on a silica gel column (dichloromethane / methanol: 0-20%) to afford compound 5-1 (5.05 g, 19.15 mmol, yield: 41.39%).

[0291] MS (ESI + )m / z=264.2[M+H] + .

[0292] Step 2: Synthesis of (S)-5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Compound 5-2)

[0293] Under a nitrogen atmosphere, Pd(dppf)Cl2 (278.07 mg, 380.03 μmol) was added to a mixture of compound 5-1 (1.0 g, 3.80 mmol), compound Int-1 (2.46 g, 3.80 mmol), potassium carbonate (1.31 g, 9.50 mmol), 1,4-dioxane (2.5 mL), and water (0.5 mL). The mixture was stirred at 100°C under a nitrogen atmosphere for 2 hours. LC-MS monitored the reaction for completion. The mixture was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified on a silica gel column (petroleum ether / ethyl acetate: 0-28%) to afford compound 5-2 (539 mg, 823.50 μmol, yield: 21.67%).

[0294] MS (ESI + )m / z=655.4[M+H] + .

[0295] Step 3: Synthesis of (S)-5-bromo-3-(3-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylpropyl)-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indole (Compound 5-3)

[0296] To a mixed solution of compound 5-2 (1.28 g, 1.96 mmol) and cesium carbonate (1.28 g, 3.92 mmol) in DMF (8 mL) was added iodoethane (611.13 mg, 3.92 mmol) under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for 16 hours. LC-MS monitored the reaction for completion. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a silica gel column (petroleum ether / ethyl acetate: 0-30%) to afford compound 5-3 (490 mg, 718.05 μmol, yield: 36.65%).

[0297] MS (ESI + )m / z=683.2[M+H] + .

[0298] Step 4: Synthesis of (S)-3-(5-bromo-1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-1H-indol-3-yl)-2,2-dimethylpropane-1-ol (Compound 5-4)

[0299] To a solution of compound 5-3 (500 mg, 731.22 μmol) in tetrahydrofuran (2.5 mL) was added tetrabutylammonium fluoride (1 M, 2.5 mL) with stirring. The resulting mixture was stirred at 60°C for 16 hours. The reaction was monitored for completion. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified on a silica gel column (petroleum ether / ethyl acetate: 0-60%) to afford compound 5-4 (85 mg, 190.84 μmol, yield: 26.10%).

[0300] MS (ESI + )m / z=445.2[M+H] + .

[0301] Step 5: Synthesis of (S)-3-(1-ethyl-2-(2-(1-methoxyethyl)pyridin-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-3-yl)-2,2-dimethylpropane-1-ol (Compound 5-5)

[0302] To a mixed solvent of compound 5-4 (100 mg, 224.52 μmol) and potassium acetate (44.07 mg, 449.04 μmol) under a nitrogen atmosphere were added bis(pinacol) borate (68.42 mg, 269.43 μmol) and Pd(dppf)Cl2 (8.21 mg, 11.23 μmol). The resulting mixture was stirred at 100°C under a nitrogen atmosphere for 4 hours. LC-MS monitored the reaction for completion. The mixture was quenched with water (15 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford compound 5-5 (100 mg, 203.06 μmol, 90.6% yield), which was used directly in the next step.

[0303] MS (ESI + )m / z=493.3[M+H] + .

[0304] Step 6: Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylic acid methyl ester (Compound 5-6)

[0305] Under a nitrogen atmosphere, Pd(dppf)Cl2 (14.86 mg, 20.31 μmol) was added to a mixed solution of compound 5-5 (100 mg, 203.06 μmol), compound Int-2 (96.94 mg, 203.06 μmol), potassium phosphate (129.31 mg, 609.19 μmol), 1,4-dioxane (1.5 mL), water (0.5 mL), and toluene (0.5 mL). The resulting mixture was stirred at 70°C under a nitrogen atmosphere for 16 hours. LC-MS monitored the reaction for completion. After completion, the reaction mixture was cooled to room temperature. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (25 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified using a silica gel column (petroleum ether / ethyl acetate: 0-70%) to afford compound 5-6 (30 mg, 39.32 μmol, yield: 19.4%).

[0306] MS (ESI + )m / z=763.4[M+H] + .

[0307] Step 7: Synthesis of (S)-1-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(1-ethyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-(2-((S)-1-methoxyethyl)pyridin-3-yl)-1H-indol-5-yl)thiazol-2-yl)propionyl)hexahydropyridazine-3-carboxylic acid (Compound 5-7)

[0308] Compound 5-6 (30 mg, 39.32 μmol) was added to a mixture of tetrahydrofuran (1 mL) and water (0.25 mL), followed by the addition of lithium hydroxide monohydrate (6.60 mg, 157.28 μmol). The mixture was stirred at 25°C for 1 hour. LC-MS monitored the reaction for completion. The mixture was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to afford compound 5-7 (25.5 mg, 34.05 μmol, yield: 86.59%), which was used directly in the next step.

[0309] MS (ESI + )m / z=749.4[M+H] + .

[0310] Step 8 Synthesis of Compound 5-8

[0311] Compound 5-7 (25.5 mg, 34.05 μmol), N,N-diisopropylethylamine (155.31 mg, 1.20 mmol, 209.32 μL), 1-hydroxybenzotriazole (27.06 mg, 200.29 μmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (215.01 mg, 1.12 mmol) were added to dichloromethane (2 mL) at 0°C. The mixture was stirred at 25°C for 16 hours. LC-MS monitored the reaction completion. The mixture was extracted with dichloromethane (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified on a silica gel column (petroleum ether / ethyl acetate: 0-40%) to afford compound 5-8 (10 mg, 13.68 μmol, 40.17% yield).

[0312] MS (ESI + )m / z=731.4[M+H] + .

[0313] Step 9 Synthesis of Compound 5-9

[0314] Compound 5-8 (10 mg, 13.68 μmol) was added to a mixture of trifluoroacetic acid (15.60 mg, 136.82 μmol, 0.25 mL) and dichloromethane (0.5 mL). The mixture was stirred at 25°C for 1 hour. LC-MS monitored the reaction for completion. The mixture was concentrated in vacuo to afford compound 5-9 (10 mg, crude product).

[0315] MS (ESI + )m / z=631.3[M+H] + .

[0316] Step 10 Synthesis of compound 5

[0317] Compound 5-9 (8.62 mg, 13.68 μmol) was added to a solution of N,N-dimethylformamide (1 mL). Compound 3A (6.36 mg, 31.71 μmol), O-(7-azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphonate (11.96 mg, 31.71 μmol), and N,N-diisopropylethylamine (10.24 mg, 79.26 μmol, 13.81 μL) were added at 0°C. The reaction was stirred at 25°C for 2 hours. LC-MS monitored the reaction for completion. The resulting residue was purified by reverse phase column (Boston Prime C18; 150*30 mm*5 μm; mobile phase A: H2O-(NH3H2O-NH4HCO3), mobile phase B: MeCN; MeCN ratio 55%-95%) to give white solid compound 5 (7.1 mg, 8.71 μmol, yield: 63.67%).

[0318] MS (ESI + )m / z=813.2[M+H] + .

[0319] 1H NMR (400MHz, DMSO-d6)δ=10.34-10.24(m,1H),9.54-9.47(m,1H),8.79-8.72(m,1H),8.53-8.49(m,1H),8.48-8.45(m,1H),8.15-8.08(m, 1H),8.07-8.02(m,1H),7.84-7.82(m,2H),7.81-7.76(m,1H),7.61-7 .57(m,1H),7.57-7.54(m,1H),5.66-5.58(m,1H),5.29-5.20(m,1H), 4.34-4.19(m,4H),4.16-4.05(m,1H),3.77-3.67(m,1H),3.64-3.54( m,2H),3.40-3.38(m,1H),3.24(s,3H),2.98-2.87(m,1H),2.85-2.73 (m,1H),2.46-2.40(m,1H),2.15-2.04(m,1H),1.87-1.75(m,2H),1.60-1.46(m,1H),1.37(d,J=6.0Hz,3H),0.93-0.83(m,6H),0.35(s,3H)

[0320] Examples 6-7

[0321] Using a synthetic route and steps similar to Example 4, the following compound 6-7 was synthesized by replacing raw material 4-3 with raw material A in the table below.

[0322] Examples 8-26

[0323] Using a synthetic route and steps similar to Example 2, the following compound 8-26 was synthesized by replacing raw material 2-1 with raw material A in the table below.

[0324] Biological tests

[0325] Test Example 1: Compounds for KRAS and B-Raf Ras-binding Domain (BRAF RBD ) The effect of the binding

[0326] Experimental materials and instruments:

[0327] The materials required for this experiment include: His6-KRAS G12D[1-169], GST-BRAF[155-229], and human CYPA protein were purified by Shanghai Panchao Biotechnology Co., Ltd.; GMPPNP (Sigma#G0635); alkaline phosphatase AP (Roche#10108138001); LANCE Eu-W1024 anti-6xHis antibody (PerkinElmer#AD0402); Allophycocyanin-anti-GST antibody (PerkinElmer#AD0059G); 384-well LDV shallow well plate (Beckman Coulter#LP-0200); 384-well PP shallow well plate (Beckman Coulter#PP-0200); 384-well test plate (PerkinElmer#6007299); ClipTip TM 384-gauge pipette tips (Thermo Scientific #94410150). Nucleotide exchange buffer: 40 mM Tris-HCl (pH 7.4) (Sigma #T2663), 5 mM DTT (Thermo #P2325), 150 mM (NH4)2SO4 (Sigma #A4418), 4 μM ZnCl2 (Sigma #Z0152); reaction buffer: 25 mM HEPES (Gibco #15630-080), 0.002% Tween-20 (Sigma #P1379), 0.10% BSA (Sigma #V900933), 100 mM NaCl (Beyotime #ST347), 5 mM MgCl2 (Merck #M1028).

[0328] The instruments and equipment required for this experiment include: Eppendorf pipette, Eppendorf centrifuge, nanoliter pipetting system ECHO650, and Envision microplate reader (Perkin Elmer).

[0329] Experimental methods:

[0330] Recombinantly expressed His6-KRAS G12D [1-169] was co-incubated with GMPPNP (GMPPNP:KRAS molar ratio was 10:1), 20 U alkaline phosphatase AP was added, and incubated at 30 ° C for 4 hours for nucleotide exchange to prepare the KRAS-ON active protein form. The test was carried out in a 384-well plate, and the above KRAS-ON active protein (final concentration 100 nM GMPPNP bound-His6-KRAS G12D) in 10 μL of reaction buffer, and a final concentration of 20 μM CYPA and 50 nM GST-BRAF[155-229] protein were added. Compounds were serially diluted three-fold using Echo650 over 10 concentration points (compound stock concentration was 10 mM in DMSO). The dilutions were added according to the dilution schedule and added to the assay plate containing the previously prepared test protein. The volume of compound dilution added was 100 nL, and the final compound concentration tested was 30 μM. After incubation at 25°C for 3 hours, 10 μL of a detection solution containing 10 nM LANCE Eu-W1024 anti-6xHis antibody and 50 nM Allophycocyanin-anti-GST antibody was added to the reaction mixture, mixed thoroughly, and incubated for an additional 1.5 hours. Control (no compound) and Blank (no compound or KRAS-ON active protein) were designated as the control group and the background group, respectively. The TR-FRET Ratio (665 / 615) was read on an Envision microplate reader. The inhibition rate was calculated according to the following formula: Inhibition % = (FRET Ratio control –FRET Ratio sample ) / (FRET Ratio control –FRET Ratio blank )*100. IC was calculated using IDBS XLfit with 4-parameter fitting. 50 Value. Measured IC 50 See Table 1 for values.

[0331] Table 1

[0332] Test Example 2: Effect of Compounds on Tumor Cell Proliferation Activity

[0333] Experimental materials and instruments:

[0334] The materials required for this experiment include: cell culture medium RPMI-1640 (BasalMedia#L240KJ); DMEM (BasalMedia#L110KJ); fetal bovine serum (FBS) (Proteintech#PM00011); PBS phosphate buffer (BasalMedia#B320KJ); 0.25% trypsin (Gibco#25200-072); 100% DMSO (Sigma#D2650); 96-well sterile culture plates (Corning#3599); 96-well plates (Corning#3610); CellTiter- 2.0 Luminescent Cell Viability Assay Kit (Vazyme #DD1101); 25 mL pipettes (Corning); 5 mL pipettes (Corning); P1000 pipette tips, P200 pipette tips, and P10 pipette tips (Axygen).

[0335] The instruments and equipment required for this experiment include: Eppendorf pipette; Eppendorf pipette gun; Eppendorf centrifuge; constant temperature carbon dioxide incubator (ThermoFisher); fully automatic cell counter Vi-cell XR (Beckman Coulter); Envision microplate reader (Perkin Elmer).

[0336] The cells required for this experiment include: KRAS G12D Mutant cell line AsPC-1 (ATCC#CRL-1682 TM ), the complete culture medium was RPMI-1640 medium containing 10% FBS. G12C The cell line was NCI-H358 (Cell Bank of the Chinese Academy of Sciences #SCSP-583), and the complete culture medium was RPMI-1640 medium containing 10% FBS.

[0337] Experimental methods:

[0338] AsPC-1 and NCI-H358 cells were dissociated from culture flasks using 0.25% trypsin and resuspended in fresh complete medium. After counting, the cell density was adjusted to 2000 cells / 90 μL / well for AsPC-1 and 1500 cells / 90 μL / well for NCI-H358. 90 μL of each was added to a 96-well plate and incubated overnight at 37°C in a cell culture incubator with 5% CO2. A 10 mM stock solution of the compound was diluted 10-fold with DMSO to 1 mM, then 100-fold with complete medium to 10 μM. From this starting concentration, a three-fold serial dilution was performed in complete medium containing 1% DMSO, and nine serial dilutions were performed. 10 μL / well of the serially diluted compound was then added to the cell culture wells, resulting in a final DMSO content of 1 / 1000 in each well. Positive controls consisted of wells seeded with culture medium without cells; negative controls consisted of wells seeded with cells but not treated with compound. Incubate the cell plate at 37°C and 5% CO2 for 5 days. Remove the cell plate and add an equal volume of CellCounting-Lite 2.0 detection reagent to each well. Vortex and mix for 2-5 minutes to fully lyse the cells. Incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the luminescence value using an Envision microplate reader. Calculate the inhibition rate according to the following formula: Inhibition % = (Signal negative control – Signal negative control) sample ) / (Signal negative control IC was calculated using IDBS XLfit with 4-parameter fitting. 50 Value. Measured IC 50 See Table 2 for values.

[0339] Table 2 Note: “-” means not determined

[0340] Test Example 3: Effects of Compounds on ERK Phosphorylation in Tumor Cells

[0341] Experimental materials and instruments:

[0342] The experimental materials required for this experiment include: cell culture medium RPMI-1640 (BasalMedia#L240KJ); DMEM (BasalMedia#L110KJ); fetal bovine serum (FBS) (Proteintech#PM00011); PBS phosphate buffered saline (BasalMedia#B320KJ); 0.25% trypsin (Gibco#25200-072); 100% DMSO (Sigma#D2650); 96-well sterile culture plates (Corning#3599); 96-well sterile culture plates (Corning#3799); 384-well plates (PerkinElmer#6007299); Advanced PHOSPHO-ERK1 / 2 (THR202 / TYR204) KITS (Perkin Elmer #64AERPEG); 25 mL pipettes (Corning); 5 mL serological pipette tips (Corning); P1000 pipette tips and P200 pipette tips (Axygen).

[0343] The instruments and equipment required for this experiment include: Eppendorf pipette; Eppendorf pipette gun; Eppendorf centrifuge; constant temperature carbon dioxide incubator (ThermoFisher); fully automatic cell counter Vi-cell XR (Beckman Coulter); Envision microplate reader (Perkin Elmer).

[0344] The cells required for this experiment include: KRAS G12D Mutant cell line AsPC-1 (ATCC#CRL-1682 TM ), the complete culture medium was RPMI-1640 medium containing 10% FBS; KRAS G12C The cell line was NCI-H358 (Cell Bank of the Chinese Academy of Sciences #SCSP-583), and the complete culture medium was RPMI-1640 medium containing 10% FBS.

[0345] Experimental methods:

[0346] AsPC-1 and NCI-H358 cells were dissociated from culture flasks using 0.25% trypsin, harvested by centrifugation at 1000 rpm for 3 minutes, and resuspended in fresh complete culture medium. After counting, the cells were seeded into cell culture plates at a density of 70,000 cells / 100 μL / well for AsPC-1 and 50,000 cells / 100 μL / well for NCI-H358. The cells were cultured in a 37°C, 5% CO2 incubator for 6 hours, followed by overnight starvation with 90 μL of serum-free RPMI-1640 medium (RPMI-1640 cell culture medium). A 10 mM stock solution of the compound was diluted to 3 mM with DMSO and then diluted 100-fold to 30 μM in serum-free medium. From this starting concentration, three-fold serial dilutions were performed in serum-free medium containing 1% DMSO. A total of nine serial dilutions were added, and 10 μL / well of the compound was added to each well. After 1 hour, the supernatant was aspirated and each well was washed once with PBS. Lysis buffer was prepared according to the instructions of the pERK detection kit (ADVANCED PHOSPHO-ERK1 / 2 (THR202 / TYR204) KITS), 50 μL of lysis buffer was added to each well, and the cells were shaken at 450 rpm for 1 hour at room temperature. After the cells were completely lysed, 16 μL of supernatant was transferred to a 384-well assay plate, and the mixed detection antibody (d2 / Eu=1:1) was added. The cells were incubated at room temperature for 4 hours, and the HTRF Ratio (665 / 615) was read on an Envision microplate reader. The Cell control group was a group in which cells were lysed without compound treatment, and the lysis blank group was a group in which only lysis buffer was added for detection. Inhibition%=(HTRF Ratiocell control–HTRF Ratio sample ) / (HTRF Ratiocell control–HTRF Ratiolysis blank)*100. IC was calculated using IDBS XLfit with a 4-parameter fit. 50 Data. Measured IC 50 See Table 3 for values.

[0347] Table 3 Note: “-” means not determined

[0348] Test Example 4 Pharmacokinetic Study in Mice

[0349] Purpose of the experiment:

[0350] Mice were used as test animals, and the LC-MS / MS method was used to determine the drug concentration in plasma at different times after injection or oral administration of the test compound to study the pharmacokinetic behavior of the compound in mice and evaluate its pharmacokinetic characteristics.

[0351] Experimental methods:

[0352] Six healthy Balbc female mice were selected, of which three were injected (IV) at a dose of 2 mg / kg, and the other three were orally administered (PO) at a dose of 10 mg / kg. The mice were free to eat and drink water throughout the experiment. A complete solvent 5% NMP + 15% PEG400 + 80% (20% HP-β-CD) (reagent purchased from Sigma) was used as the solvent. On the day of the experiment, the corresponding compound (0.5 mg / mL) was prepared and the corresponding dose of the compound was administered by intravenous injection and gavage. The animals were weighed before administration and the administration volume was calculated based on the animal weight. The collection time was: 0 (before administration), 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. Approximately 100 microliters of whole blood was collected from the jugular vein at each sampling time point for the preparation of plasma, and the plasma samples were stored in a -80°C refrigerator.

[0353] A 10 μL mouse plasma sample was prepared and protein precipitated with 150 μL of acetonitrile (containing the internal standard verapamil, purchased from Sigma). After vortexing for 5 minutes, the sample was centrifuged for 5 minutes (14,000 rpm, 4°C). The supernatant was diluted 2-fold with water containing 0.1% formic acid (v / v) and quantified using an LC-MS / MS system (AB Sciex Triple Quad 6500+). A standard curve and quality control samples using female Balbc mouse plasma were also used for sample concentration determination. For the 20× diluted sample, 2 μL of the sample was added to 38 μL of blank mouse plasma. After vortexing for 1 minute, protein precipitation was performed with 600 μL of acetonitrile (containing the internal standard verapamil, purchased from Sigma). The remaining processing steps were the same as for the undiluted sample.

[0354] Drug concentrations in plasma samples were determined using LC-MS / MS, with a detection limit of 1 ng / mL. All animals were euthanized by CO2 anesthesia after the final plasma sample was collected. Plasma concentrations and corresponding pharmacokinetic parameters were calculated using a non-compartmental model using Phoenix WinNonlin (version 8.3.4) pharmacokinetic software.

[0355] The in vivo pharmacokinetic results are shown in the following table:

Claims

1. A compound of formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, in: X 1 and X 2 are each independently selected from CH2 and NH; A is selected from C3-C 12 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene and 5-12 membered heteroarylene, the C3-C 12 Cycloalkylene, 4-10 membered heterocyclylene, C6-C 10 Arylene and 5-12 membered heteroarylene are optionally substituted by one or more R a replace; R 1 Selected from amino, hydroxyl, thiol, cyano, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the amino, hydroxyl, thiol, C2-C 10 Alkenyl, C2-C 10 Alkynyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 1a replace; R 2 、R 3 、R 7 and R 8 independently selected from hydrogen, halogen, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkyl and C3-C7 cycloalkyl; Or, R 7 and R 8 and the atoms to which they are attached together form a 4-10 membered heterocyclic ring, wherein the 4-10 membered heterocyclic ring is optionally substituted by one or more R b replace; R 4 Selected from hydrogen, halogen, hydroxy, cyano, C2-C 10 Alkenyl, C2-C 10 Alkynyl and C1-C 10 Alkyl, the hydroxyl, C2-C 10 Alkenyl, C2-C 10 Alkynyl and C1-C 10 The alkyl group is optionally substituted with one or more R 4a replace; R 5 Selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 5a replace; Or, R 4 and R 5 and the atoms to which they are attached together form a 4-10 membered heterocyclic ring, wherein the 4-10 membered heterocyclic ring is optionally substituted by one or more R c replace; Or, R 4 and R 7 and the atoms to which they are attached together form a 4-10 membered heterocyclic ring, wherein the 4-10 membered heterocyclic ring is optionally substituted by one or more R d Replacement; R 6 is selected from hydrogen, halogen, amino, hydroxy, mercapto, cyano, C1-C4 alkyl, C1-C4 haloalkyl and C1-C4 alkoxy; Every R a Independently selected from halogen, amino, hydroxy, mercapto, cyano and C1-C4 alkyl; Every R 1a independently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the amino, hydroxyl, thiol, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 1aa replace; Every R 4a 、R 1aa 、R b and R d Independently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy; Every R c Independently selected from hydroxyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the hydroxyl, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R e replace; Every R 5a and R e Independently selected from C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R f replace; Every R f Independently selected from halogen, amino, hydroxy, mercapto, cyano, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy; One or more hydrogen atoms of the compound are optionally deuterium atoms.

2. The compound of formula (I) according to claim 1, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X 1 For CH2.

3. The compound of formula (I) according to claim 1 or 2, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X 2 For NH.

4. The compound of formula (I) according to any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: X 1 is CH2 and X 2 For NH.

5. The compound of formula (I) according to any one of claims 1 to 4, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: A is selected from C6-C 10 Arylene and 5-12 membered heteroarylene, the C6-C 10 Arylene and 5-12 membered heteroarylene are optionally substituted by one or more R a or A is selected from 5-12 membered heteroaryl groups, wherein the 5-12 membered heteroaryl groups are optionally substituted by one or more R a or A is selected from 5-6 membered heteroaryl groups, wherein the 5-6 membered heteroaryl groups are optionally substituted by one or more R a or A is selected from a thiazole ring, an imidazopyridine ring and a pyrazolopyridine ring, wherein the thiazole ring, the imidazopyridine ring and the pyrazolopyridine ring are optionally substituted with one or more R a Substituted; or A is selected from described Optional one or more R a Substituted; or A is selected from Or A is 6. The compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R a are independently selected from halogen, amino, hydroxy, mercapto and cyano.

7. The compound of formula (I) according to any one of claims 1 to 6, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups, the amino, C1-C 10 Alkyl, C3-C 12 Cycloalkyl and 4-10 membered heterocyclic groups are optionally substituted by one or more R 1a Replacement; or R 1 is selected from amino, C1-C5 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic groups, wherein the amino, C1-C5 alkyl, C3-C6 cycloalkyl and 4-7 membered heterocyclic groups are optionally substituted by one or more R 1a Replacement; or R 1 Selected from amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, The amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, morpholinyl, Optionally, one or more R 1a Replacement; or R 1 Selected from amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, The amino, ethyl, tetrahydropyrrolyl, azetidinyl, piperidinyl, cyclopropyl, cyclobutyl, cyclopentyl, Optionally, one or more R 1a replace.

8. The compound of formula (I) according to any one of claims 1 to 7, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1a Independently selected from halogen, C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl, the C1-C 10 Alkyl, C3-C 12 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 1aa Replacement; or R 1a independently selected from halogen, C1-C4 alkyl, C3-C4 cycloalkyl, 4-7 membered heterocyclyl, C6-C7 aryl and 5-6 membered heteroaryl, wherein the C1-C4 alkyl, C3-C4 cycloalkyl, 4-7 membered heterocyclyl, C6-C7 aryl and 5-6 membered heteroaryl are optionally substituted by one or more R 1aa Replacement; or R 1a independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropyl, pyridyl, phenyl and The methyl, ethyl, isopropyl, cyclopropyl, pyridyl, phenyl and Optionally, one or more R 1aa Replacement; or R 1a independently selected from fluoro, methyl, ethyl, cyclopropyl, pyridyl, phenyl and The methyl, ethyl, cyclopropyl, pyridyl, phenyl and Optionally, one or more R 1aa replace.

9. The compound of formula (I) according to any one of claims 1 to 8, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 1aa R is independently selected from halogen, C1-C7 alkyl, C1-C7 haloalkyl and C1-C7 alkoxy; or 1aa are independently selected from halogen, C1-C4 alkyl and C1-C4 alkoxy; or R 1aa are independently selected from halogen and C1-C4 alkyl; or R 1aa are independently selected from methyl, chloro, fluoro and methoxy; or R 1aa independently selected from methyl, chloro and fluoro.

10. The compound of formula (I) according to any one of claims 1 to 9, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 2 、R 3 independently selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 Alkyl; or R 2 、R 3 independently selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 alkyl; or R 2 、R 3 Independently selected from C1-C4 alkyl, such as methyl; or R 2 、R 3 All are methyl.

11. The compound of formula (I) according to any one of claims 1 to 10, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 Alkyl, the hydroxyl, C1-C 10 The alkyl group is optionally substituted with one or more R 4a Replacement, R 5 Selected from C6-C 10 Aryl and 5-10 membered heteroaryl, the C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 5a Replace, or, R 4 and R 5 and the atoms to which they are attached together form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by one or more R c Replacement; or R 4 Selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 Alkyl, the hydroxyl, C1-C 10 The alkyl group is optionally substituted with one or more R 4a Replacement, R 7 is selected from hydrogen, halogen, hydroxyl and cyano, or, R 4 and R 7 and the atoms to which they are attached together form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted by one or more R d replace.

12. The compound of formula (I) according to any one of claims 1 to 11, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4 Selected from hydrogen, halogen, hydroxy, cyano and C1-C 10 Alkyl, the hydroxyl, C1-C 10 The alkyl group is optionally substituted with one or more R 4a Replacement; or R 4 is selected from C1-C4 alkyl, wherein the C1-C4 alkyl is optionally substituted by one or more R 4a Replacement; or R 4 is an ethyl group, the ethyl group is optionally replaced by one or more R 4a Replacement; or R 4 Selected from ethyl and trifluoroethyl, trifluoroethyl is preferably CH2CF3.

13. The compound of formula (I) according to any one of claims 1 to 12, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4a are independently selected from halogen, amino, hydroxy, mercapto and cyano; or R 4a are independently selected from halogen; or R 4a For fluorine.

14. The compound of formula (I) according to any one of claims 1 to 13, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 5 Selected from C6-C 10 Aryl and 5-10 membered heteroaryl, the C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R 5a Replacement; or R 5 is selected from 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by one or more R 5a Replacement; or R 5 is selected from pyridyl, said pyridyl being optionally substituted with one or more R 5a Replacement; or R 5 for described Optionally, one or more R 5a Replacement; or R 5 Selected from 15. The compound of formula (I) according to any one of claims 1 to 14, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 5a Independently selected from C1-C 10 Alkyl and 4-10 membered heterocyclic group, the C1-C 10 The alkyl group and the 4-10 membered heterocyclic group are optionally substituted by one or more R f Replacement; or R 5a independently selected from C1-C4 alkyl and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl and 4-7 membered heterocyclic groups are optionally substituted by one or more R f Replacement; or R 5a independently selected from piperazinyl and ethyl, said piperazinyl and ethyl being optionally substituted by one or more R f Replacement; or R 5a Independently selected and ethyl, the and ethyl optionally replaced by one or more R f replace.

16. The compound of formula (I) according to any one of claims 1 to 15, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R f independently selected from C1-C7 alkyl and C1-C7 alkoxy; or R f independently selected from C1-C4 alkyl and C1-C4 alkoxy; or R f are independently selected from methyl and methoxy.

17. The compound of formula (I) according to any one of claims 1 to 16, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4 and R 5 and the atoms to which they are attached together form a 4-6 membered heterocyclic ring, wherein the 4-6 membered heterocyclic ring is optionally substituted by one or more R c Replace; or Selected from The n is selected from 0, 1, 2 and 3.

18. The compound of formula (I) according to any one of claims 1 to 17, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R c Independently selected from hydroxyl, C6-C 10 Aryl and 5-10 membered heteroaryl, the hydroxyl, C6-C 10 Aryl and 5-10 membered heteroaryl are optionally substituted by one or more R e Replacement; or R c independently selected from hydroxy, pyridyl and phenyl, said hydroxy, pyridyl and phenyl being optionally substituted by one or more R e Replacement; or R c Independently selected from hydroxyl, phenyl and The hydroxyl group, phenyl group and Optionally, one or more R e replace.

19. The compound of formula (I) according to any one of claims 1 to 18, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R e Independently selected from C1-C 10 Alkyl and 4-10 membered heterocyclic group, the C1-C 10 The alkyl group and the 4-10 membered heterocyclic group are optionally substituted by one or more R f Replacement; or R e independently selected from C1-C4 alkyl and 4-7 membered heterocyclic groups, wherein the C1-C4 alkyl and 4-7 membered heterocyclic groups are optionally substituted by one or more R f Replacement; or R e Independently selected from methyl, piperazinyl, said methyl, piperazinyl optionally substituted by one or more R f replace.

20. The compound of formula (I) according to any one of claims 1 to 19, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 6 is selected from hydrogen, halogen, amino, hydroxy, mercapto, cyano and C1-C4 alkyl; or R 6 For hydrogen.

21. The compound of formula (I) according to any one of claims 1 to 20, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 7 is selected from hydrogen, halogen, hydroxy and cyano; or R 7 For hydrogen.

22. The compound of formula (I) according to any one of claims 1 to 21, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 4 and R 7 and the atoms to which they are attached together form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted by one or more R d Replacement; or R 4 and R 7 and the atoms to which they are attached together form a 6-7 membered heterocyclic ring, wherein the 6-7 membered heterocyclic ring is optionally substituted by one or more R d Replace; or Selected from The t is selected from 1 and 2.

23. The compound of formula (I) according to any one of claims 1 to 22, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R d are independently selected from halogen, amino, hydroxy, mercapto and cyano.

24. The compound of formula (I) according to any one of claims 1 to 23, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 8 Selected from hydrogen, halogen, hydroxy, cyano, C1-C 10 Alkyl and C3-C7 cycloalkyl; or R 8 is selected from hydrogen, cyano and C3-C7 cycloalkyl; or R 8 is selected from hydrogen, cyano and cyclopropyl.

25. The compound of formula (I) according to any one of claims 1 to 24, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: R 7 and R 8 and the atoms to which they are attached together form a 4-7 membered heterocyclic ring, wherein the 4-7 membered heterocyclic ring is optionally substituted by one or more R b Replacement; or R 7 and R 8 and its connected atoms together form wherein a bond represents a bond shared with the connected ring, Optionally, one or more R b replace.

26. The compound of formula (I) or its stereoisomer or its pharmaceutically acceptable salt according to claim 1, selected from the compound of formula (II) or its stereoisomer or its pharmaceutically acceptable salt, in, R 1 、R 4 、R 5 、R 7 、R 8 As defined in any one of claims 1 to 25.

27. The compound of formula (I) according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, is selected from the following compounds, or their stereoisomers, or their pharmaceutically acceptable salts, 28. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 27, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. Use of the compound of formula (I) according to any one of claims 1 to 27, or its stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 28 in the preparation of a medicament for preventing or treating RAS-mediated diseases.

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